Development of a New in vivo Model for Labeling Secretory Insulin Granule Pools
Sequential in vivo labeling of insulin secretory granule pools in INS-SNAP transgenic pigs.
PNAS September 14, 2021 118 (37) e2107665118; doi.org/10.1073/pnas.2107665118
Dysfunction of pancreatic beta cells is a key contributor to type 2 diabetes (T2D). Each beta cell stores insulin in several thousand organelles termed insulin secretory granules (SG), which release insulin extracellularly when blood glucose is elevated. So far, our understanding of the principles governing insulin SG turnover remains very rudimental and derives almost exclusively from ex vivo experiments using isolated pancreatic islets. To overcome the existing translational gap to humans, researchers of the German Center for Diabetes Research (DZD) have developed a new in vivo model (a transgenic pig model) that allows studying secretory insulin granule turnover in vivo.
Pancreatic beta cells produce, store and secrete insulin upon elevated blood glucose levels. However, the highly regulated process of insulin secretion, especially its molecular features and the stimuli behind this process have not yet been fully understood. Furthermore, the current understanding of beta cell function is mostly derived from studies of ex vivo isolated islets in rodent models. To overcome this translational gap and to study insulin secretory granule turnover in vivo, a national research team under the lead of scientists from the DZD-partner Paul Langerhans Institute of the Helmholtz Zentrum München at the University Hospital Carl Gustav Carus and Faculty of Medicine of TU Dresden (PLID) and the LMU Munich has generated a transgenic pig model allowing for the first time the in vivo fluorescent labeling of age-distinct insulin secretory granule pools, hence providing a close-to-life readout of insulin turnover in normoglycemic conditions.
The results of this highly collaborative project have been published in the renowned journal `Proceedings of the National Academy of Sciences of the United States of America (PNAS)`, given the likelihood that this novel large animal model close to humans will provide insight into the turnover of insulin pools in physiological and pathological conditions resembling human type 2 diabetes.
Kemter E., Müller, A., … Wolf, E., Solimena, M.: Sequential in vivo labeling of insulin secretory granule pools in INS-SNAP transgenic pigs. PNAS (2021)
In COVID-19 Patients the Virus Also Infects Pancreatic Islet Cells
Viral Infiltration of Pancreatic Islets in Patients with COVID-19.
Nature Communications 2021
In people with COVID-19, the SARS-CoV-2 virus can also infect the pancreatic islet cells and replicate there. This is the result of a recent study in which DZD researchers also participated. The study has now been published in Nature Communications.
Metabolic disorders increase the risk of severe courses of COVID-19 disease. On the other hand, new-onset hyperglycemia (elevated blood glucose levels), metabolic derailments (ketoacidosis), diabetes, and severe metabolic complications of pre-existing diabetes, among others, are also observed in COVID-19 patients. But what is the cause of this? Does the virus also infect the insulin-producing beta cells? Initial studies on stem cells indicated that the SARS-CoV-2 virus can infiltrate and infect human alpha cells and the insulin-producing beta cells of the pancreas and can replicate there. Now, a team of researchers has analyzed pancreatic autopsy tissue from COVID-19 patients. Here, too, they found viral SARS-CoV-2 inﬁltration of beta cells. Using SARS-CoV-2 pseudoviruses, the team also demonstrated that isolated human islet cells are susceptible (permissive) to infection.
In eleven COVID-19 patients, the team of scientists examined the expression of various receptors and factors that can facilitate viral entry, including ACE2. They found that while 70% of COVID-19 patients expressed ACE2 in the circulatory system, only 30% displayed ACE2 expression in beta cells.
"In summary, using human islet cells and autopsy tissue from patients who died of COVID-19, we have provided unequivocal evidence that beta cells are permissive for infection with SARS-CoV-2," said last author Stefan Bornstein of the DZD-Paul Langerhans Institute Dresden of Helmholtz Zentrum München at the University Hospital and Medical Faculty Carl Gustav Carus of TU Dresden. "However, the exact mechanisms of viral entry are not fully understood at this point, as ACE2 is expressed in beta cells only in a subset of patients."
Steenblock et al.: Viral infiltration of pancreatic islets in patients with COVID-19. Nature Communications (2021) 12:3534, DOI: doi.org/10.1038/s41467-021-23886-3
Development of Novel Blood Glucose-Lowering Dextromethorphan Derivatives That Do Not Affect the Brain
Peripherally Active Dextromethorphan Derivatives Lower Blood Glucose Levels by Targeting Pancreatic Islets.
Cell Chemical Biology 2021
Researchers have chemically modified the active ingredient dextromethorphan (DXM) so that it acts on the pancreatic islet cells and lowers blood glucose levels without affecting the central nervous system. The current results have now been published in Cell Chemical Biology.
The active ingredient dextromethorphan (DXM) is mainly known as a cough suppressant. Studies show that DXM also protects the islet cells of the pancreas and can lower blood glucose levels. However, the drug also affects the brain and can cause dizziness and fatigue. Researchers at the DZD partner German Diabetes Center (DDZ) have now succeeded in chemically modifying DXM in such a way that it no longer passes the blood-brain barrier, but nevertheless fully unfolds its positive effects.
The research team showed that the new DXM derivatives protect murine and human pancreatic islets from cell death. The derivatives also lower blood glucose levels without affecting the behavior of mice. The observation that the new compounds have significantly fewer side effects makes them interesting candidates for future diabetes therapy.
However, the findings may also be interesting for other applications: The active ingredient dextromethorphan is chemically related to morphine. These results show how DXM and possibly other morphinans can be chemically modified so that they have no side effects on the brain and still reach the peripheral tissue.
Scholz, O., Otter, S., Welters, A., Wörmeyer, L., Dolenšek, J., Klemen, S.M., Pohorec, V., Eberhard, D., Mrugala, J., Hamacher, A., Koch, A., Sanz, M., Hoffmann, T., Hogeback, J., Herebian, D., Klöcker, N., Piechot, A., Mayatepek, E., Lammert, E.: Peripherally active dextromethorphan derivatives lower blood glucose levels by targeting pancreatic islets. Cell Chemical Biology. 2021, 11 June, DOI: https://doi.org/10.1016/j.chembiol.2021.05.011
New Mechanism Discovered: How Higher Leptin Levels Can Lead to Hypertension
Obesity-Associated Hyperleptinemia Alters the Gliovascular Interface of the Hypothalamus to Promote Hypertension.
Nature Metabolism 2021
Researchers have shown for the first time the role of astrocytes in the hypothalamus in obesity-related hypertension and how the hormone leptin is involved in the increase of blood vessels in the hypothalamus of obese mice. The study was published in Nature Metabolism.
Pathologies of the micro- and macrovascular systems are a hallmark of the metabolic syndrome, which can lead to chronically elevated blood pressure. However, the underlying pathomechanisms involved still need to be clarified. Researchers have now shown for the first time that an obesity-associated increases in serum leptin triggers the select expansion of the micro-angioarchitecture in pre-autonomic brain centers that regulate hemodynamic homeostasis.
Once the researchers increased the hormone leptin in these mice, certain brain cells, the astrocytes, boosted the production of a specific growth factor. This growth factor, in turn, promoted vessel growth. The result was an increased number of vessels in the hypothalamus (and no other brain region).
When the researchers increased leptin levels, certain brain cells, astrocytes, boosted the production of a specific growth factor. This growth factor, in turn, promoted vessel growth. The result was an increased number of vessels in the hypothalamus (and no other brain region). The scientists thus demonstrated that leptin is mainly responsible for the increased concentration of vessels in the hypothalamus and that this process is mediated via astrocytes.
The study was led by Helmholtz Zentrum München, and researchers from Ludwig-Maximilians-Universität, Technische Universität München and the German Diabetes Center were also involved.
Gruber et al., 2021: Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension. Nature Metabolism, DOI: 10.1016/j.cmet.2021.04.007
Highlight-Artikel in Nature Reviews Endocrinology: https://www.nature.com/articles/s41574-021-00511-3
A High BMI Has a Negative Effect on Socioeconomic Status
The Effect of BMI and Type 2 Diabetes on Socioeconomic Status: A Two-Sample Multivariable Mendelian Randomization Study.
Diabetes Care 2021
People with a high body mass index (BMI) often have a low income and live in areas with higher regional deprivation*. Researchers at Helmholtz Zentrum München and the German Center for Diabetes Research (DZD) have shown in a study that there is a causal relationship between high BMI and low socioeconomic status. The study was published in Diabetes Care and was conducted in cooperation with researchers from LMU (Munich School of Management and Munich Center of Health Sciences) and TUM (Public Health and Prevention).
Previous evidence indicates that people with severe overweight and type 2 diabetes (T2D) also have poorer labor market prospects and a lower income. In the present study, researchers have now investigated the causal effect of a high BMI and T2D on socioeconomic status using a special study design (Mendelian randomization). The genetic influence – that is, independent of environmental influences – of BMI and diabetes were taken into account.
People with a higher BMI were found to be more likely to have low incomes and to live in areas of higher deprivation. Reasons for this may include lower ability to work, higher absenteeism, higher likelihood of musculoskeletal disorders or higher social discrimination. These factors may in turn lead to poorer career prospects, decreasing labor market participation and lower income, the authors conclude. Lower income could in turn lead to people moving to disadvantaged areas with more affordable housing and food options.
However, the studies did not show any negative influence of type 2 diabetes on socioeconomic status. The authors encourage further research to investigate in more detail the effects of T2D on socio-economic status using new genome-wide association studies. In addition, the mechanisms that lead to a disadvantage for people with an increased BMI should be further investigated.
Sara Pedron et al: The Effect of BMI and Type 2 Diabetes on Socioeconomic Status: A Two-Sample Multivariable Mendelian Randomization Study. Diabetes Care 2021 Mar; 44(3): 850-852. DOI: https://doi.org/10.2337/dc20-1721
* Regional deprivation
Regional deprivation is a measure of social inequality and describes material differences between regions or areas based on variables such as the unemployment rate, ownership of a house or car, and living space per household member.
Risk of Type 1 Diabetes Declines With Age
An Age-Related Exponential Decline in the Risk of Multiple Islet Autoantibody Seroconversion During Childhood.
Diabetes Care, 2021
The risk of developing islet autoimmunity and type 1 diabetes declines exponentially with age. This is the result of a recent analysis of the TEDDY study, which has now been published in Diabetes Care. The new findings may also improve screening for pre-symptomatic type 1 diabetes.
Islet autoimmunity develops before clinical type 1 (T1D) diabetes and includes multiple and single autoantibody phenotypes. The objective was to determine age-related risks of islet autoantibodies that reflect etiology and improve screening for pre-symptomatic T1D. For this purpose, the researchers prospectively monitored 8,556 genetically at-risk children at 3- to 6-month intervals from birth for the development of islet autoantibodies and T1D.
The results showed that the 5-year risk of developing multiple islet autoantibodies was 4.3 per cent at 7.5 months of age. At an age of just over six years, it declined to 1.1 percent. The authors of the study therefore suspect that the risk of developing islet autoimmunity declines exponentially with age and the influence of major genetic factors on this risk is limited to the first few years of life.
The new findings may also help to improve screening for pre-symptomatic T1D. The study showed that testing twice for islet autoantibodies, first at two years of age and then again at 5-7 years of age, had the highest sensitivity and positive predictive value of multiple islet autoantibody phenotypes for T1D.
According to the authors, one strength of the current evaluation is the large number of robust data collected in the TEDDY study. One limitation is that all TEDDY children have a certain genetic constellation, which was determined as an inclusion criterion for the TEDDY study. Thus, the study population does not quite correspond to the general population.
Bonifacio, E. et al.: An age-related exponential decline in the risk of multiple islet autoantibody seroconversion during childhood. DOI: https://doi.org/10.2337/dc20-2122
*About the TEDDY study
The TEDDY study (The Environmental Determinants of Diabetes in the Young), is an international research project (USA, Finland, Germany and Sweden) that investigates the possible risk factors for the development of type 1 diabetes. More than 8,600 newborns with an increased genetic risk for T1D were included in the study and closely monitored until their teenage years. The vast majority of the participating children (89 percent) had no close relatives with type 1 diabetes.
The Longevity Gene mINDY (I’m Not Dead, Yet) not only Prevents Metabolic Disease, but also Lowers Arterial Blood Pressure and Heart Rate
The Longevity Gene mINDY (I’m Not Dead, Yet) Affects Blood Pressure Through Sympathoadrenal Mechanisms.
JCI Insight, 2021
Authors from the German Center for Diabetes Research (DZD) presented data showing that the longevity gene mammalian Indy (mINDY) is involved in blood pressure regulation in the Journal of Clinical Investigation (JCI) insight. Reduced expression of mINDY, which is known to extend life span in lower organisms and to prevent from diet induced obesity, fatty liver and insulin resistance in mice, has now been shown to lower blood pressure and heart rate in rodents. The authors provided mechanistic insights for the underlying physiological mechanism based on in vivo data in a genetic knock out model as well as microarray and in vitro studies. Furthermore, the hypothesis is supported by confirming critical effects in vitro using a small molecule inhibitor of mINDY. The authors conclude that deletion of mIndy recapitulates beneficial cardiovascular and metabolic responses to caloric restriction, making it an attractive therapeutic target.
Andreas Birkenfeld and colleagues provide a comprehensive study showing that mIndy deletion attenuates sympathoadrenal support of blood pressure and reduced arterial blood pressure and heart rate in a muine knockout model. Blood pressure was assessed invasively using intra-arterial pressure probes over several days. Urinary analysis for catecholamines and metanephrines as well as unbiased transcriptomic analysis of adrenal glands identified the affected biosynthetic pathways. Indeed, catecholamine biosynthesis was attenuated in mINDY-KO adrenals, whereas plasma steroids and steroid hormone synthesis were unaffected.
In vitro studies on an adrenal cell line supported this hypothesis. mIndy codes for a is a carboxylic acid transporter protein expressed in plasma membrane. Citrate, the main substrate of the mINDY transporter, increased catecholamine content, while pharmacological inhibition of mINDY by a small molecule inhibitor blunted the effect.
The study provided further insights into the physiological mechanisms of the beneficial effects of reducing mINDY activity which is known to protect from diet and aging induced metabolic diseases by mechanisms akin to caloric restriction. Therefore, the data showed a novel mechanism contributing to a cardiometabolic cross talk and further supporting mINDY as a promising target for the whole spectrum of metabolic syndrome components, including increased blood pressure.
The study was published from the Institute of Diabetes Research and Metabolic Disorders (IDM) of the Helmholtz Center Munich at the University Tübingen and the Clinic of Diabetes, Endocrinology and Nephrology of the University Hospital Tübingen.
Willmes DM et al.: The longevity gene mIndy (I’m Not Dead, Yet) affects blood pressure through sympathoadrenal mechanisms. JCI Insight. 2021, https://doi.org/10.1172/jci.insight.136083.
Use of Diabetes Technologies also Depends on Socio-Economic Status
A Decade of Disparities in Diabetes Technology Use and HbA 1c in Pediatric Type 1 Diabetes: A Transatlantic Comparison.
Diabetes Care, 2020
Insulin pumps, continuous glucose monitors (CGMs) - over the past decade, the use of diabetes technologies to manage type 1 diabetes in children and adolescents has increased worldwide. Researchers at the DZD in Düsseldorf, Munich and Ulm, together with colleagues from the USA, have investigated whether inequality in access to these technologies based on socioeconomic status (SES) also leads to different levels of blood glucose (HbA1c). Their study, now published in Diabetes Care, shows " A decade of disparities in diabetes technology use and HbA1c in pediatric type 1 diabetes: A transatlantic Comparison".
For the study, researchers examined the use of diabetes technology and HbA1c levels in children and adolescents under 18 years of age from the Type 1 Diabetes Exchange (T1DX, USA, n = 16,457) and Diabetes Prospective Follow-up (DPV, Germany, n = 39,836) registries by socioeconomic status (SES) between two time periods 2010-2012 and 2016-2018. For this purpose, the registers were divided into quintiles. For categorisation into Q1 (lowest SES) to Q5 (highest SES), insurance type, education level and annual income, among others, were used.
The study showed that participants with lower SES had higher HbA1c (in 2010-2012 and 2016-2018, respectively: 8.0% and 7.8% in Q1 and 7.6% and 7.5% in Q5 for DPV; 9.0% and 9.3% in Q1 and 7.8% and 8.0% in Q5 for T1DX). For DPV, the association between SES and HbA1c did not change between the two time periods, whereas for T1DX, disparities in HbA1c by SES increased significantly (P < 0.001). After adjusting for technology use, results for DPV did not change, whereas the increase in T1DX was no longer significant.
Although no causal conclusions can be drawn, diabetes technology use is lowest and HbA1c is highest in those of the lowest SES quintile in the T1DX, and this difference for HbA1c broadened in the past decade. Associations of SES with technology use and HbA1c were weaker in the DPV registry.
Addala et al.: A Decade of Disparities in Diabetes Technology Use and HbA 1c in Pediatric Type 1 Diabetes: A Transatlantic Comparison. Diabetes Care (2020); DOI: 10.2337/dc20-0257
High Resolution 3D Microscopy Enables to Reconstruct the Highways of Insulin Transport
Three-Dimensional Fib-Sem Reconstruction of Microtubule-Organelle Interaction in Whole Primary Mouse Beta Cells.
Journal of Cell Biology, 2020
Microtubules are a part of cytoskeleton and act as highways for the transport of vesicles within the cell. However, their role in insulin transport and secretion is currently under debate. Now, an international team led by scientists of the Paul-Langerhans-Institute Dresden, a partner of the German Center of Diabetes Research (DZD), together with the CSBD, MPI-CBG, Janelia Research Campus, CMCB, Fondazione Human Technopole as well as the EPFL used high resolution 3D electron microscopy to image insulin secreting pancreatic islet beta cells in their entirety at an unprecedented resolution and reconstructed all insulin secretory granules, microtubules, mitochondria, Golgi apparati, and centrioles to generate a comprehensive spatial map of microtubule-organelle interactions. The outcome of this highly collaborative project was now published in the renowned journal “Journal of Cell Biology”.
Müller A, Schmidt D, Shan Xu C, Pang S, Verner D’Costa J, Kretschmar S, Münster C, Kurth T, Jug F, Weigert M, Hess HF, Solimena M., Three-dimensional Fib-Sem reconstruction of microtubule-organelle interaction in whole primary mouse beta cells. Journal of Cell Biology (2020), DOI: https://doi.org/10.1083/jcb.202010039
Pancreatic Steatosis Associates With Impaired Insulin Secretion
Pancreatic Steatosis Associates With Impaired Insulin Secretion in Genetically Predisposed Individuals.
The Journal of Clinical Endocrinology & Metabolism, 2020
In people with a high genetic risk for diabetes, a pancreatic steatosis can lead to a decrease in insulin secretion. This is indicated by studies of the DZD, which have now been published in The Journal of Clinical Endocrinology & Metabolism.
So far, there are conflicting evidence on whether and how pancreatic steatosis affects insulin secretion. Accumulating evidence implicates that fat compartment as a modulator of islet function. Specifically, pancreatic steatosis was inversely associated with insulin secretion in subjects with prediabetes. However, subjects with normal glucose tolerance do not exhibit the negative association between pancreatic steatosis and insulin secretion. Researchers at the DZD in Tübingen therefore suspect that pancreatic steatosis only has a negative effect on the function of beta cells if there is a genetic predisposition for diabetes.
To test this hypothesis, they investigated the interaction between genotype and fat in the pancreas on insulin secretion. To this end, they evaluated the data of 360 nondiabetic individuals with elevated risk for T2D from the Tuebingen Family Study (TUEF), and 64 patients undergoing pancreatectomy. The fat content of the pancreas was measured by magnetic resonance imaging (MRI) and the genetic risk score for type 2 diabetes was determined. Insulin secretion was determined by oral glucose tolerance testing and fasting blood sampling prior to surgery.
There was a negative association between pancreatic fat and insulin secretion in participants with high genetic risk. However, individuals with low genetic risk showed a positive correlation between pancreatic fat and insulin secretion. The researchers suspect that only genetic insulin resistance leads to pancreatic fat becoming harmful to insulin secretion.
Róbert Wagner et al: Pancreatic Steatosis Associates With Impaired Insulin Secretion in Genetically Predisposed Individuals. The Journal of Clinical Endocrinology & Metabolism, Volume 105, Issue 11, November 2020, dgaa435, https://doi.org/10.1210/clinem/dgaa435
Different Response of Mitochondrial Respiration in Skeletal Muscle and Adipose Tissue to Endurance Exercise
Response of mitochondrial respiration in adipose tissue and muscle to 8 weeks of endurance exercise in obese subjects.
The Journal of Clinical Endocrinology & Metabolism, 2020
In obese individuals, endurance exercise improves fitness and increases the number of mitochondria * and cellular respiration in skeletal muscles. However, the intervention has no effect on cellular respiration in adipose tissue. This is the result of a study by DZD researchers that has now been published in The Journal of Clinical Endocrinology & Metabolism.
Studies in rodents suggest that exercise not only increases the number of mitochondria and the respiratory capacity of skeletal muscles, but also in adipose tissue. In a study, researchers at the DZD in Tübingen investigated the effects of endurance training on cellular respiration in the human skeletal muscles and abdominal adipose tissue and whether there is a direct connection between increased cellular respiration and improved insulin sensitivity. For this purpose, the researchers carried out an 8-week aerobic endurance training intervention with 25 untrained test subjects (16 women, 9 men aged 29.8 ± 8.4 years) who were overweight or obese. The researchers then analyzed mitochondrial respiration in skeletal muscle fibers and in the subcutaneous adipose tissue of the abdomen.
Based on the change in insulin sensitivity after the intervention, the subjects were grouped into responders (subjects whose insulin sensitivity increased) and low responders (subjects whose insulin sensitivity did not increase significantly). In both groups, fitness, cellular respiration and the amount of mitochondrial enzymes in the skeletal muscles improved equally. The endurance training had no effect on the mitochondria in the abdominal subcutaneous adipose tissue. Another interesting finding of the study is that women exhibited higher cellular respiration in adipose tissue than men.
“Our data show that the increase in the mitochondrial respiratory capacity of the skeletal muscles after endurance training has no predictive power for the improvement of the peripheral insulin sensitivity. Furthermore, the endurance training does not increase cellular respiration in the subcutaneous adipose tissue, with a simultaneous decrease in this fat compartment,“ said Cora Weigert of the DZD partner Institute for Diabetes Research and Metabolic Diseases of Helmholtz Zentrum München at the University of Tübingen, summarizing the findings.
* Mitochondria are the "power plants" of the cells and play a central role in cellular energy production. In a process known as cellular respiration, glucose and fatty acids are converted with oxygen into carbon dioxide and water, creating adenosine triphosphate (ATP), the energy carrier of the cells.
Hoffmann, C. et al.: Response of mitochondrial respiration in adipose tissue and muscle to 8 weeks of endurance exercise in obese subjects. The Journal of Clinical Endocrinology & Metabolism (2020) DOI: 10.1210/clinem/dgaa571
High Protein Diet Reduces Liver Fat
High-protein diet more effectively reduces hepaticfat than low-protein diet despite lower autophagy and FGF21 levels.
Liver International, 2020
Non-alcoholic fatty liver diseases (NAFLD) are particularly widespread in industrialized countries. Lifestyle changes with a balanced diet and increased exercise are still the treatment of choice for fatty liver disease. DZD researchers were able to show that a calorie-reduced diet with a high protein content reduced liver fat more effectively than a calorie-reduced low-protein diet. The results were published in the journal Liver International.
The researchers investigated how the protein content of the diet affects the amount of liver fat in severely overweight people with a non-alcoholic fatty liver. For this purpose, 19 participants with morbid obesity undergoing bariatric surgery were randomized into two hypocaloric (1500‐1600 kcal/day) diet groups, a low protein (LP) and a high protein (HP), for three weeks prior to surgery. Intrahepatic lipid levels (IHL) and serum fibroblast growth factor 21 (FGF21) were measured before and after the dietary intervention. Autophagy flux, histology, mitochondrial activity and gene expression analyses were performed in liver samples collected during surgery.
The group that received a high-protein diet lost about five kilograms and IHL levels decreased by 42.6 %. In the LP group, IHL values did not change significantly despite similar weight loss. Hepatic autophagy flux and serum FGF21 increased by 66.7% and 42.2%, respectively, after 3 weeks in the LP group only. Expression levels of fat uptake and lipid biosynthesis genes were lower in the HP group compared with those in the LP group. RNA‐seq analysis revealed lower activity of inflammatory pathways upon HP diet. Hepatic mitochondrial activity and expression of β‐oxidation genes did not increase in the HP group.
The HP diet reduces liver fat more effectively than the LP diet despite less autophagy. The data suggest that the liver fat reduction in HP diet results primarily from the suppression of fat absorption and lipid biosynthesis.
Xu, C., Markova, M., Seebeck, N., Loft, A., Hornemann, S., Gantert, T., Kabisch, S., Herz, K., Loske, J., Ost, M., Coleman, V., Klauschen, F., Rosenthal, A., Lange, V., Machann, J., Klaus, S., Grune, T., Herzig, S., Pivovarova-Ramich, O., Pfeiffer, A. F. H.: High-protein diet more effectively reduces hepaticfat than low-protein diet despite lower autophagy and FGF21 levels. Liver Inter. in press (E-pub ahead of print) (2020). [Open Access] [https://doi.org/10.1111/liv.14596]
How Insulin in the Brain Controls Metabolism and Food Intake
Central nervous pathways of insulin action in the control of metabolism and food intake.
The Lancet Diabetes & Endocrinology, 2020
The brain is an insulin-sensitive organ. A number of areas of the brain react to insulin, such as areas that are important for food intake, metabolism and memory. In a review article in The Lancet Diabetes & Endocrinology, DZD researchers provide an overview of recent studies investigating how insulin acts on the CNS to modulate behaviour and systemic metabolism. Disturbances in brain insulin action represent a possible link between metabolic and cognitive health.
Current findings from human research suggest that boosting central insulin action in the brain modulates peripheral metabolism, enhancing whole-body insulin sensitivity and suppressing endogenous glucose production. Moreover, central insulin action curbs food intake by reducing the salience of highly palatable food cues and increasing cognitive control.
Research in rodents and humans shows that the mesocorticolimbic circuitry is finely tuned in response to insulin, driven mainly by the dopamine system. These mechanisms are impaired in people with obesity, which might increase their risk of developing type 2 diabetes and associated diseases. Overall, current findings highlight the role of insulin action in the brain and its consequences on peripheral metabolism and cognition.
Kullmann et al: Central nervous pathways of insulin action in the control of metabolism and food intake. The Lancet Diabetes & Endocrinology (2020), DOI: https://doi.org/10.1016/S2213-8587(20)30113-3
Additional Genetic Cause for NAFLD Discovered
Immunity-related GTPase induces lipophagy to prevent excess hepatic lipid accumulation.
Journal of Hepatology, 2020
The cause of non-alcoholic fatty liver disease (NAFLD) is multifactorial, including genetic and environmental factors. Currently, only a few genetic variants explain the heritability of the disease. DZD researchers have now discovered new genes that play a role in the development of fatty liver. The results have been published in the Journal of Hepatology.
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in Europe and the United States. In addition to an unhealthy lifestyle with a high-fat, high-sugar diet and lack of exercise, a genetic predisposition is also responsible for the development of this liver disease.
Using molecular markers and statistical methods – quantitative trait locus (QTL) analysis – genes that cause complex human diseases can be identified in mouse strains. Researchers have now discovered a new family of genes that play an important role in preventing fatty liver development. In humans and mice, the genes IRGM, Ifgga2 and Ifgga4 produce regulatory proteins from the family of immunity-related GTPases that counteract fat accumulation in the liver. However, if there is a genetic modification, fewer proteins are formed. Studies show that the liver of patients with NAFLD and mice with fatty liver have significantly lower amounts of these proteins.
Functional studies have shown that an overproduction of immunity-related GTPases in liver cells or in the liver of mice, significantly reduced their fat content. The reason for this is the induction of a particular form of autophagy that is specific for the degradation of fats and is therefore called lipophagy.
“Our work has identified further important genes that cause fatty liver disease. The study results also deepen our understanding of which cellular processes have to be stimulated to counteract fatty liver development,” said Professor Annette Schürmann, head of the Department of Experimental Diabetology at the German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE) and spokesperson for the German Center for Diabetes Research (DZD).
Schwerbel, K. et al: Immunity-related GTPase induces lipophagy to prevent excess hepatic lipid accumulation. Journal of Hepatology (2020); DOI: https://doi.org/10.1016/j.jhep.2020.04.031
Beta Cell Dysfunction Is a Hallmark of Early Type 2 Diabetes Pathogenesis
Dysfunction of Persisting β-Cells is a Key Feature of Early Type 2 Diabetes Pathogenesis.
Cell Reports, 2020
Already at an early stage of type 2 diabetes pathogenesis, the function of the insulin-producing beta cells deteriorates. The number of beta cells is unchanged at this stage. This is the result of a study recently published in Cell Reports by scientists of the German Center for Diabetes Research.
Type 2 diabetes is not only characterized by insulin resistance, but also by the fact that the pancreas produces less insulin. However, it has so far been unclear whether the insufficient insulin level during the development of the disease can be attributed to a dysfunction of the beta cells or to the loss of the beta cell mass. In order to gain new insights here, researchers led by Professor Stephan Speier have used a novel in situ platform for investigating the human pancreas in diabetes pathogenesis. Researchers from the DZD, the Paul Langerhans Institute in Dresden of Helmholtz Zentrum München and the Faculty of Medicine Carl Gustav Carus of TU Dresden, University Hospital Dresden and King's College London were involved in the study.
The group used freshly resected living pancreatic tissue to analyze the function of the beta cells in their original organ environment and to determine the beta cell volume. The tissues examined in this study came from donors from a larger patient cohort who had been metabolically phenotyped prior to pancreatectomy. The group included people without diabetes (ND), people with restricted glucose tolerance (IGT) and people with type 2 diabetes and thus represented the entire development spectrum of T2D pathogenesis. "After the production of 120 µm thick tissue sections, we were able to quantify glucose-induced insulin secretion in the tissue of test subjects under almost physiological conditions and, in parallel, examine the 3D cell morphology on adjacent sections," said the first author, Dr. Christian Cohrs from PLID and the DZD. This novel in situ approach for human pancreatic tissue sections made it possible for the first time to simultaneously investigate beta cell mass and function and to correlate these with the patients' diabetes status.
"Our data demonstrate that beta cells exhibit significant functional deterioration and exhaustion in early stages of T2D pathogenesis, when subjects have impaired glucose tolerance but are not yet diabetic. In contrast, beta cell numbers in the investigated tissues are maintained at this stage of the disease process," said Professor Speier, research group leader at the Paul Langerhans Institute Dresden (PLID) and professor at the Institute of Physiology of TU Dresden. "Thus, our results identify beta cell dysfunction as an initial feature of diabetes development.”
Cohrs CM, Panzer JK, Drotar DM, Enos SJ, Kipke N, Chen C, Bozsak R, Schöniger E, Ehehalt F, Distler M, Brennand A, Bornstein SR, Weitz J, Solimena M, and Speier S. Dysfunction of Persisting β-Cells is a Key Feature of Early Type 2 Diabetes Pathogenesis. DOI:https://doi.org/10.1016/j.celrep.2020.03.033
New drug combination restores beta cell function in animal model
Targeted pharmacological therapy restores β-cell function for diabetes remission.
Nature Metabolism, 2020
One of the causes of diabetes could be the dedifferentiation of insulin-producing beta cells in the Langerhans' islets of the pancreas, i.e. the loss of cell identity. If and how dedifferentiated beta cells can be targeted by pharmacological intervention for beta cell regeneration is unknown. DZD-Researchers at Helmholtz Zentrum München demonstrated in collaboration with Novo Nordisk for the first time that a targeted combinatorial drug treatment is able to restore beta cell function, achieve beta cell redifferentiation and therefore potentially open new ways for diabetes remission.
To investigate whether dedifferentiated beta cells can be targeted pharmacologically to restore beta cell function, the researchers used streptozotocin-induced diabetes in mice. Using single cell RNA sequencing the researchers could show that after streptozotocin treatment, the surviving beta cells dedifferentiate into a dysfunctional state. The team then tested treatments for their potential to restore beta cell function. The researchers showed that a stable Glucagon-like peptide-1 (GLP-1)/estrogen conjugate (provided by Novo Nordisk) enables targeted and selective delivery of the nuclear hormone cargo to beta cells. The combination of GLP-1/estrogen and a long acting insulin was superior to mono-treatments to both normalize glycemia, glucose tolerance, to increase pancreatic insulin content and to increase the number of beta cells.
This study not only describes the mechanisms of beta cell dedifferentiation and regeneration, , but also reveals pharmacological entry points to target dedifferentiated dedifferentiated beta cells for diabetes remission.
This study brought together scientists from Helmholtz Zentrum München (Helmholtz Diabetes Center and Institute for Computational Biology), the German Center for Diabetes Research (DZD), Technical University Munich (TUM) as well as InSphero AG and Novo Nordisk with the aim to explore the potential therapeutic benefits of GLP1/estrogen treatment in an animal models and in human cells in vitro.
* Streptozotocin is a chemical compound that has a specific toxic effect on insulin-producing beta cells.
Sachs, S. et al, 2020: Targeted pharmacological therapy restores β-cell function for diabetes remission. Nature Metabolism, DOI: 10.1038/s42255-020-0171-3.
Cilia and diabetes: Small cell extension with large effect
Glucose homeostasis is regulated by pancreatic β-cell cilia via endosomal EphA-processing.
Nature Communications, 2019
If the cilia on beta cells of the pancreas do not function properly, glucose intolerance and type 2 diabetes develop. In Nature Communications, a research team from Helmholtz Zentrum München and the German Center for Diabetes Research (DZD) describes the underlying mechanism.
The insulin producing beta cells have primary cilia which are implicated in the regulation of glucose metabolism, insulin signaling and secretion. In order to understand better how these cilia influence the handling of glucose, the researchers removed the cilia from mature beta cells. They found that glucose tolerance and insulin release deteriorated significantly over twelve weeks.
These phenomena were conveyed by special binding sites on beta cells, the ephrin receptors. In this process, EphA/ephrin signals are upregulated, which suppress insulin secretion. Researchers observed similar reactions with islet cells from organ donors. The research group also evaluated data from a small cohort of 19 patients and found a correlation between ciliopathy* genes and blood sugar levels.
"We were able to show in a mouse model that cilia in the pancreas regulate direct pathways of cell-cell communication and thus control blood glucose levels," said Dr. Jantje M. Gerdes. The results of the investigations could provide a basis for future therapies - both for ciliopathies and diabetes.
* Ciliopathies are genetic disorders of the ciliated cell.
F. Volta et al., 2019: Glucose homeostasis is regulated by pancreatic β-cell cilia via endosomal EphA-processing. Nature Communications, doi: 10.1038/s41467-019-12953-5
Type 1 diabetes: defective protection against attack on the body's own cells
miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes.
Nature Communications, 2019
Regulatory T cells (Tregs) prevent excessive immune reactions in healthy people. In the development of autoimmune type 1 diabetes, this protection is not sufficiently effective. Researchers at the DZD have now deciphered a mechanism that impairs Treg differentiation and stability. The results have now been published in 'Nature Communications'.
Prof. Dr. Carolin Daniel's team was able to decipher a mechanism that leads to the formation of less functional Tregs at an early stage of type 1 diabetes. The microRNA miRNA142-3p plays a decisive role in this process. MicroRNAs can suppress the expression of individual genes. "During the development of autoimmunity in type 1 diabetes, we were able to detect an increased abundance of miRNA142-3p. This leads to a reduced expression of the protein Tet2 in T-helper cells," said Carolin Daniel. As a consequence, faulty epigenetic changes occur in the Foxp3 gene of the regulatory T cells. A decreased number of these important immune cells are formed, and the Tregs are no longer as stable.
New target for future intervention strategies
In order to investigate whether the findings could also open up new therapeutic approaches in the future, the scientists specifically blocked the miRNA142-3p molecule. This improved the formation and stability of the regulatory T cells. In the animal model, the autoimmune response to the insulin-producing beta cells also decreased.
Researchers at the Institute of Diabetes Research (IDF) of Helmholtz Zentrum München, the German Center for Diabetes Research (DZD) and Ludwig-Maximilians-Universität Munich were involved in the studies.
Scherm, M. G. et al. (2019): miRNA142-3p targets Tet2 and impairs Treg differentiation and stability in models of type 1 diabetes. Nature Communications, DOI: 10.1038/s41467-019-13587-3
First Time: Orally Available GLP-1 Agonist More Effective than DPP-IV Inhibitor
With the participation of researchers from the Paul Langerhans Institute Dresden (PLID), a GLP-1 receptor agonist in the form of tablets was compared for the first time with the most common second-line therapy of T2D, a DPP-IV inhibitor. The investigations were carried out in parallel in Japan, France, England, Mexico, Denmark, the USA and Germany as part of the international, randomised double-blind study PIONEER-3. The results are considered to point the way for future therapy of type 2 diabetes.
Patients with diabetes still die 2-3 times more frequently from cardiovascular diseases than people without diabetes. Against this background, so-called incretin analogues have been developed in recent years, i.e. drugs that, like the intestinal hormone GLP-1, lead to the release of insulin in the beta cells of the pancreas and at the same time reduce the feeling of hunger in the brain. "Unfortunately, these drugs, like all peptide-based drugs due to their chemical structure, have to be administered by subcutaneous injection and cannot be taken orally as tablets," said Prof. Dr. Andreas Birkenfeld, PLID, co-author of the study. "Fortunately, the GLP-1 receptor agonist (GLP-1RA) semaglutide is now available as a tablet in combination with an absorption enhancer for the first time."
The 78-week PIONEER-3 study compared 1864 adults with diagnosed type 2 diabetes who took either metformin (with or without sulfonylurea), oral semaglutide in three different doses or sitagliptin (100 mg/d). Oral semaglutide was found to be superior to sitagliptin (at the highest dose) in terms of blood glucose lowering and body weight reduction. The most frequent side effects of GLP-1RA were gastrointestinal effects such as nausea. Although these were more common with semaglutide than with sitagliptin, they are already known from other GLP-1RA and in many cases temporary, so that GLP-1RA are considered safe.
Rosenstock J, Allison D, Birkenfeld AL, Blicher TM, Deenadayalan S, Jacobsen JB, Serusclat P, Violante R, Watada H, Davies M; PIONEER 3 Investigators. Effect of Additional Oral Semaglutide vs Sitagliptin on Glycated Hemoglobin in Adults With Type 2 Diabetes Uncontrolled With Metformin Alone or With Sulfonylurea: The PIONEER 3 Randomized Clinical Trial. JAMA. 2019 Mar 23. doi: 10.1001/jama.2019.2942. [Epub ahead of print]
Link to publication:
Well-regulated Blood Sugar Levels Lower the Risk for Cardiovascular Disease
The regulation of blood glucose should be part of cardiovascular prevention and health promotion measures and be included in evidence-based practice guidelines. This is the result of an extensive systematic umbrella review conducted by DZD researchers at the Paul Langerhans Institute Dresden (PLID) and published in the Journal of the American College of Cardiology (JACC).
Too-high blood sugar (hyperglycemia) as occurs in type 2 diabetes is considered one of the key risk factors for the development of cardiovascular diseases. But how does a blood sugar level that is well regulated by medication or lifestyle changes affect the cardiovascular system? Can this help to prevent diseases of the cardiovascular system such as heart attack or stroke? In order to answer these questions, researchers systematically reviewed current studies on preventive approaches in the field of diabetes and cardiovascular diseases. The analysis was based on three separate systematic literature searches with a total of 2,343 reviews and meta-analyses.
People with type 2 diabetes have a two to three times higher risk of developing cardiovascular disease. The current study shows that well-regulated blood glucose levels through medication can reduce the risk of cardiovascular disease in people with type 2 diabetes. The analysis also shows that individual lifestyle interventions such as a healthy diet and exercise can help to effectively reduce blood sugar levels and thus indirectly lower the risk of cardiovascular disease.
Population-level intervention strategies reduce the risk both directly and indirectly: Physical activity in the workplace helps to avoid dangerous cardiometabolic events. In addition, measures to reduce obesity in people with type 2 diabetes also help to reduce a major risk of cardiovascular disease.
"Our results suggest that it makes sense to develop multicomponent standardized procedures for diabetes prevention and management as well as for the prevention of cardiovascular diseases," said first author Professor Peter Schwarz from the Paul Langerhans Institute Dresden of Helmholtz Zentrum München at the University Hospital Carl Gustav Carus of TU Dresden. The DZD scientist and further authors of the paper suggest that the regulation of blood glucose levels should also be included in evidence-based practice guidelines.
Peter E.H. Schwarz et al. 2018: Blood Sugar Regulation for Cardiovascular Health Promotion and Disease Prevention, JACC Health Promotion Series, Journal of the American College of Cardiology 2018, https://doi.org/10.1016/j.jacc.2018.07.081
How a protein promotes the healing of inflammation
The protein DEL-1, is a central actor that ensures that excessive inflammation subsides. Scientists were able to demonstrate the importance and basic function of this protein. Their work could provide new approaches for the treatment of diseases such as multiple sclerosis, metabolic diseases, inflammatory bone diseases or cancer.
The protein DEL-1, is a central actor that ensures that excessive inflammation subsides. Scientists were able to demonstrate the importance and basic function of this protein. Their work could provide new approaches for the treatment of diseases such as multiple sclerosis, metabolic diseases, inflammatory bone diseases or cancer. The results of the study were now published in the journal "Nature Immunology" (www.nature.com, DOI /10.1038/s41590-018-0249-1).
Inflammatory processes are a natural defense reaction of the immune system against pathogens. Inflammation can spread like a fire and last for a long time if it is not effectively combated. The protein DEL-1 plays a central role in the body's own fire brigade. "We were able to show that DEL-1 decisively regulates the immune defense. Figuratively speaking, the protein controls a large part of the extinguishing and clean-up work. Understanding this mechanism could in future contribute to better treatments for various inflammatory diseases," said Prof. Triantafyllos Chavakis, Director of the Institute of Clinical Chemistry and Laboratory Medicine (IKL) at the TU Dresden and group leader at the Paul Langerhans Institute Dresden.
At the beginning of an inflammatory process, certain immune cells, so-called neutrophils, migrate into the affected tissue. There they drive the inflammation as well as another cell type of the immune defense - so-called macrophages or scavenger cells - which produce inflammation-promoting substances. The protein DEL-1 forms a kind of bridge between macrophages and dying neutrophils. On the one hand, this causes the macrophages to eat dying neutrophils in a kind of clearing up action. On the other hand, DEL-1 reprograms the macrophages to produce anti-inflammatory substances. "Both are important processes that reduce inflammation and restore a healthy balance in the tissue," emphasize Dr. Ioannis Kourtzelis and Dr. Ioannis Mitroulis, scientists at IKL and NCT/UCC Dresden.
"Understanding the mode of action of DEL-1 is an important basis for developing new therapies against metabolic diseases," says DZD-Reseacher Dr. Ünal Coskun of the Paul Langerhans Institute Dresden, which is operated jointly by Helmholtz Zentrum München and the University Hospital at the Technical University of Dresden. Due to its fundamental importance for the inflammatory balance, DEL-1 not only acts as a bridge between immune cells, but also connects research on various diseases.
Kourtzelis et al. DEL-1 promotes macrophage efferocytosis and clearance of inflammation. Nat Immunol. 2018 Nov 19. doi: 10.1038/s41590-018-0249-1. [Epub ahead of print]
Leptin resistance causes overweight
Many overweight people lack the feeling of being full. It was long thought that this was due to the disrupted transport of the satiety hormone leptin to the brain. That is not the case, as a group of DZD scientists was able to show using a new 3D imaging method. The cause seems to lie in the nerve cells, as the researchers describe in an article in the "International Journal of obesity".
"In obese mice and humans, leptin is released from fatty tissue into the bloodstream in high concentrations but fails to activate the satiety centers in the brain. It has long been assumed that leptin resistance is caused by a disrupted transport process," explains Luke Harrison, a doctoral student at Helmholtz Zentrum München and lead author of the study. As the ability of leptin to cross the blood-brain barrier is limited, so the theory goes, less of it reaches the satiety centers. The innovative 3D technique enabled the researchers to visualize the transport of leptin for the first time and to investigate whether this theory holds up.
Working with biologists, pathologists and structural biologists, Harrison was able to disprove this assumption. Thanks to the new imaging method, the research team headed by Dr. Paul Pfluger, a partner in the German Center for Diabetes Research (DZD), showed that leptin reaches the brain in sufficient quantities both in thin and in obese mice. The cause of the eating disorder must therefore lie in the nerve cells themselves. "We can now narrow down the cause of leptin resistance and focus our research on the molecular mechanisms within nerve cells," says Dr. Paul Pfluger. "
Luke Harrison et. al.: Fluorescent blood brain barrier tracing shows intact leptin transport in obese mice. International Journal of obesity. DOI:10.1038/s41366-018-0221-z
Atlas of Circadian Metabolism
As part of a large-scale study, researchers constructed 24-hour metabolic profiles of mouse tissues and organs under conditions of energy balance and high-fat diet. Their findings provide an overview of how the various metabolic pathways in the body are interconnected and also reveal suitable time frames for anti-obesity therapies. The study was conducted under the aegis of the Helmholtz Zentrum München and the University of California Irvine in collaboration with the German Center for Diabetes Research (DZD). The results have now been published in 'Cell'.
The scientists generated 24 hour metabolic profiles of eight different tissues simultaneously. These included the suprachiasmatic nucleus in the hypothalamus (regarded as the principal circadian pacemaker in mammals), in addition to prefrontal cortex, skeletal muscle, liver, brown and white adipose tissue, blood and sperm.
To understand how diet impacts tissue synchronization and 24 hour metabolism the scientists compared all this data under normal and high-fat diets. High-fat food is known to disrupt circadian rhythms and cause metabolic diseases like obesity and diabetes. This temporal view of tissue metabolism enabled a better insight into how metabolism is changed in metabolic diseases, for example, in the case of obesity and diabetes.
Excess calories from fat upset metabolic rhythms
The researchers were also able to observe how high-fat food consumption disrupts tissue metabolism. In muscle tissue, for instance, they noticed that energy generation from fat and sugar occurred separately and in a very orderly sequence under conditions of energy balance. Under high fat diet, this typical pattern broke down completely and fat metabolism dominated. These changes have major implications for how diet can contribute to development of muscle insulin resistance.
Overall, the study provides an overview of the metabolic processes taking place in the respective tissue at any given time, and also reveals previously unknown links. From that, the authors say, one can also deduce the most promising time frames for administering metabolically effective medication.
Dyar, KA. et al. (2018): Atlas of Circadian Metabolism Reveals System-wide Coordination and Communication between Clocks. Cell, DOI: 10.1016/j.cell.2018.08.042
New Biomarkers of Inflammation Identified as Risk Factors for Neuropathy
Although polyneuropathy is present in about 30% of people with diabetes, it often remains undiagnosed. Scientists from DZD, have now been able to show for the first time that six biomarkers of inflammation indicate the risk of polyneuropathy. The results were published in the current issue of the journal "Diabetes".
Many patients suffer from polyneuropathy, relatively little is currently known about its development, which also limits the therapeutic options. It is known that inflammatory processes contribute to other diabetic complications such as heart attack or stroke. The aim of this new study was therefore the extensive analysis of biomarkers that characterize inflammatory processes as a risk factor for distal sensory polyneuropathy (DSPN). Both people with type 2 diabetes and people in the elderly general population were examined.
Study – Procedure and Design
The study included 513 men and women of the population-based KORA (Cooperative Health Research in the Region of Augsburg) F4/FF4 cohort aged 62 to 81 years who had no distal sensory polyneuropathy at the beginning of the study. Of these individuals, 127 developed a DSPN during the 6.5 year follow-up period. The serum level of 71 biomarkers of inflammation was measured using the new proximity extension assay technology. The serum level of 26 of these 71 biomarkers was higher in people who developed polyneuropathy during the study than in people without polyneuropathy. After statistical correction for multiple testing, higher concentrations of six biomarkers remained associated with the DSPN risk. Three of these proteins (MCP-3/CCL7, MIG/CXCL9, IP-10/CXCL10) were chemokines, while the other three (DNER, CD40, TNFRSF9) were soluble forms of transmembrane receptors.
"In our study, we identified novel biomarkers that indicate the risk of polyneuropathy. For the first time, we were also able to find indications that in addition to the innate immune system, the adaptive immune system could be involved in the development of the disease," said Professor Christian Herder, MD, head of the study at the German Diabetes Center (DDZ).
Herder C, Kannenberg J, Carstensen-Kirberg M, Strom A, Bönhof G, Rathmann W, Huth C, Koenig W, Heier M, Krumsiek J, Peters A, Meisinger C, Roden M, Thorand B, Ziegler D. A Systemic Inflammatory Signature Reflecting Crosstalk Between Innate and Adaptive Immunity Is Associated With Incident Polyneuropathy: KORA F4/FF4 Study. Diabetes. 2018 Aug 16. db180060. DOI: 10.2337/db18-0060 [Epub ahead of print]
Restrictive lung diseases - late consequence of diabetes?
Breathlessness and conditions of restrictive lung disease (RLD), such as pulmonary fibrosis, may be a late complication of type 2 diabetes. These are the key findings of a joint study undertaken by researchers from the German Center for Diabetes Research (DZD) and the German Center for Lung Research (DZL) under the leadership of the University Hospital Heidelberg.
The research team comprised 110 patients with long-term type 2 diabetes, 29 patients with newly diagnosed type 2 diabetes, 68 patients with pre-diabetes and 48 non-diabetic patients (controls). The study participants were examined for metabolic control, diabetes-related complications, breathlessness, and lung function. It was found that people with type 2 diabetes are significantly more likely to suffer from breathlessness and RLD than the control group. RLD was found in 27% of patients with long-term type 2 diabetes, in 20% of patients with newly diagnosed diabetes, and in 9% of patients with pre-diabetes. Patients with pronounced symptoms and RLD also showed CT-morphologically a fibrosating interstitial lung disease. There were also differences in the morphological analysis of the lung tissue of subjects with and without diabetes. Patients with diabetes had increased pulmonary fibrosis. In addition, the study showed that RLD is associated with albuminuria. In the disease, urinary albumin levels are elevated. This may be an indication that lung disease and kidney disease may be associated with diabetic kidney disease (nephropathy).
The researchers suspect that restrictive lung disease (RLD) is a late consequence of type 2 diabetes
Stefan Kopf, Jan B. Groener, Zoltan Kender, Thomas Fleming, Maik Brune, Christin Riedinger, Nadine Volk, Esther Herpel, Dominik Pesta, Julia Szendrödi, Mark O. Wielpütz, Hans-Ulrich Kauczor, Hugo A. Katus, Michael Kreuter, Peter P. Nawroth. Breathlessness and Restrictive Lung Disease: An Important Diabetes-Related Feature in Patients with Type 2 Diabetes. Respiration 2018, DOI: 10.1159/000488909
New adipokine promotes insulin resistance
In cases of severe obesity, visceral fat cells release a protein that promotes insulin resistance and chronic inflammation. This was discovered by an international team led by scientists from the German Center for Diabetes Research (DZD).
The researchers were able to show for the first time how the protein molecule Wingless-type signaling pathway protein-1 (WISP1) directly impairs the insulin effect in muscle cells and in the liver and thus leads to insulin insensitivity.
The study shows that WISP1 cancels insulin-induced inhibition of glucose production (gluconeogesis) in murine hepatocytes and glycogen synthesis in human muscle cells. The synthesis quantity of the WISP1 protein correlates with the blood glucose levels in the oral glucose tolerance test (OGTT) and with the circulating level of heme oxygenase-1 (HO-1), an enzyme that promotes systemic inflammation, especially in obesity.
The researchers suspect that an increased production of WISP1 from the abdominal fat could be one of the reasons why overweight people often have a disturbed glucose metabolism.
Hörbelt, T., Tacke, C., Markova, M. et al. (2018): The novel adipokine WISP1 associates with insulin resistance and impairs insulin action in myotubes and hepatocytes. Diabetologia https://doi.org/10.1007/s00125-018-4636-9
Increased Glucagon Secretion Not Indispensable Prerequisite for the Development of Diabetes
Only one subgroup of type 2 diabetes (T2D) has elevated glucagon levels. This is the finding of a study conducted by DZD researchers in Munich. The scientists studied glucagon levels in young women with different levels of risk for T2D during an oral glucose tolerance test*. They discovered four patterns of glucagon dynamics that did not match the metabolic phenotypes. The results have now been published in the “Journal of Clinical Endocrinology & Metabolism”.
It is known that glucagon is the main antagonist of insulin, but just what role the hormone plays in the onset of type 2 diabetes is still under debate among scientists. A research team compared glucagon secretion in young women with three different metabolic phenotypes during an oral glucose tolerance test. The groups were: a healthy control group (93 women), metabolically healthy women after gestational diabetes (high-risk group for type 2 diabetes, 121 women) and 71 women who were newly diagnosed with diabetes or prediabetes.
The analysis showed that there are four patterns of glucagon dynamics but that the found patterns did not match the three different metabolic groups. However, one pattern – elevated fasting glucagon levels with delayed glucagon suppression – was particularly common in women with diabetes and prediabetes (21 percent), but this cluster was also discovered in 8 percent of healthy women. Conversely, the majority of women in the prediabetes / diabetes group (n = 39; 55%) had glucagon levels in the normal range with low fasting glucagon and rapid suppression. In addition, in the cluster of high fasting glucagon and poor glucagon suppression, there were increased symptoms of metabolic syndrome (high blood pressure, visceral obesity, and high blood lipids).
The authors of the study therefore assume that increased glucagon secretion in a subgroup can contribute to the development of type 2 diabetes, but this is not an indispensable prerequisite for the development of diabetes.
The study of the DZD, the Medical Center of the University of Munich and Helmholtz Zentrum München was published in the March issue of Journal of Clinical Endocrinology & Metabolism.
Gar, C. et al. (2018): Patterns of Plasma Glucagon Dynamics Do Not Match Metabolic Phenotypes in Young Women. J Clin Endocrinol Metab; DOI: 10.1210/jc.2017-02014
Oral Glucose Tolerance Test (oGTT)
The oGTT provides evidence of the body's ability to break down a defined amount of glucose within a given period of time. For this purpose, 75 g of glucose are consumed as a sugar solution on an empty stomach. Subsequently, blood is taken at certain intervals and tested for sugar content.
Visualization of the function of the insulin receptor
Insulin was discovered almost 100 years ago. Now, a German-American research team with DZD involvement was able to show how the hormone activates its receptor. The results and images have been published in the' Journal of Cell Biology'.
Insulin is an important hormone for metabolism in the human body. It is mainly used to channel glucose from the blood into the cells. The hormone acts as a key that opens the cells for the glucose molecules. Insulin docks to the insulin receptors on the cell surface. The receptors then change their shape on the inside of the cell to transmit the signal. However, the exact nature of the structural change has not been known so far.
In order to gain an insight into receptor activation, the researchers have purified complete human insulin receptors and embedded them in nanodiscs. These are disk-shaped miniature membranes, which are just a few nanometers in size and could be made visible directly under the electron microscope. They were able to observe the insulin receptor in an artificial membrane and its structural changes.
In the absence of insulin, the receptor exhibits an inverted U-shaped ectodomain conformation and well-separated transmembrane domains. Insulin binding results in structural rearrangements of the receptor. The receptor takes on a T-shaped structure that allows the transmembrane domains to come together. That's probably what triggers the signal transmission.
“These nanodisc-embedded receptors provide a novel platform to address further questions regarding insulin receptor regulation and eventually to test therapeutic agents”, said Dr. Ünal Coskun, co-senior author of the study and group leader at the DZD - Paul-Langerhans-Institute Dresden of the Helmholtz-Zentrum München at the University Hospital and the Medical Faculty Carl Gustav Carus of the TU Dresden.
Researchers from PLID and Rockefeller University collaborated on the study.
Gutmann, Kim et al. (2018): Visualization of ligand-induced transmembrane signaling in the full-length human insulin receptor. Journal of Cell Biology, DOI: 10.1083/jcb.201711047
Largest collection of islet cells reveals new diabetes genes
Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes.
A collaborative study has identified a novel cluster of dysregulated genes in the pancreatic islets of patients with type 2 diabetes. The study is part of the EU-Innovative Medicine Initiative (IMI) research consortium IMIDIA.
The goal of the IMIDIA consortium, which involved 14 European academic institutions, large pharma companies and biotech firms from 2010 to 2016, was to identify novel pathways for the regeneration, maintenance and protection of insulin-producing pancreatic beta cells as a mean to expedite the discovery of more effective strategies to prevent and treat diabetes. A main task of the study led by Prof. Michele Solimena, DZD-Speaker, was to define which genes are abnormally expressed in islets of diabetic subjects compared to islets of non-diabetic subjects. The altered expression of these genes could account for beta cell failure in diabetes.
For the first time, the investigators based their comparative gene expression analysis not only on islets collected from non-diabetic and diabetic organ donors, for which the availability of clinical information is limited, but also on islets from patients undergoing pancreatic surgery. The investigators identified nineteen genes the expression of which was altered in islets of both diabetic organ donors as well as diabetic surgical patients. Notably, nine of these nineteen genes had never been shown previously to be dysregulated in diabetic islets. On the other hand, the study could not find evidence for any of these genes to be dysregulated in islets of prediabetic subjects, hence suggesting that their altered expression is a consequence rather than the cause of beta cell failure in diabetes.
Solimena et al., Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes. Diabetologia. 2017 Nov 28. doi: 10.1007/s00125-017-4500-3.
Insulin pump therapy is associated with reduced risks of short-term diabetes complications
Among young patients with type 1 diabetes, insulin pump therapy, compared with insulin injection therapy, was associated with lower risks of severe hypoglycemia and diabetic ketoacidosis and with better glycemic control during the most recent year of therapy. These are the results of a population-based cohort study published in the „Journal of the American Medical Association“.
Type 1 diabetes is the most common metabolic disease in children and adolescents. Insulin pump therapy may improve metabolic control in young patients with type 1 diabetes, but the association with short-term diabetes complications is unclear. Are the rates of severe hypoglycemia and diabetic ketoacidosis lower with insulin pump therapy than with insulin injection therapy in young patients with type 1 diabetes?
To answer these questions researcher conducted a population-based observational study between January 2011 and December 2015 in 350 diabetes centers in Germany, Austria, and Luxembourg. Patients using pump therapy (n = 9814) were matched with 9814 patients using injection therapy.
The Findings: In this population-based observational study including 30 579 young patients with type 1 diabetes, pump therapy, compared with injection therapy, was associated with significantly lower rates of severe hypoglycemia (9.55 vs 13.97 per 100 patient-years) and ketoacidosis (3.64 vs 4.26 per 100 patient-years), and with lower hemoglobin A1c levels (8.04% vs 8.22%) in a propensity score–matched cohort. Also total daily insulin doses were lower for pump therapy compared with injection therapy (0.84 U/kg vs 0.98 U/kg1). There was no significant difference in body mass index between both treatment regimens.
Beate Karges et al: Association of Insulin Pump Therapy vs Insulin Injection Therapy With Severe Hypoglycemia, Ketoacidosis, and Glycemic Control Among Children, Adolescents, and Young Adults With Type 1 Diabetes. JAMA 2017; DOI:10.1001/jama.2017.13994
Elevated hepatic DPP4 activity promotes non-alcoholic fatty liver disease
Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease. Molecular Metabolism, 2017
Increased hepatic expression of dipeptidyl peptidase 4 (DPP4) is associated with non-alcoholic fatty liver disease (NAFLD). Whether this is causative for the development of NAFLD is not yet clarified. DZD-researchers investigate the effect of hepatic DPP4 overexpression on the development of liver steatosis in a mouse model of diet-induced obesity.
In mice that are given a high-fat diet, an increased production of the enzyme DPP4* by the liver promotes an increase in body fat, the development of fatty liver disease and insulin resistance. These were the findings of a current study by DZD-researchers in Potsdam and Tübingen."In combination with our observations from additional human and cell studies, these results indicate that increased DPP4 production by the liver is the cause rather than the consequence of a fatty liver and insulin resistance," says the head of the study, Annette Schürmann from the German Institute for Human Nutrition Research (DIfE), a partner of the German Center for Diabetes Research (DZD). The research team led by Schürmann has now published its findings in Molecular Metabolism.
Christian Baumeier et al: Elevated hepatic DPP4 activity promotes insulin resistance and non-alcoholic fatty liver disease. Molecular Metabolism 2017; DOI: 10.1016/j.molmet.2017.07.016
Fetuin-A leads to pathological changes of the kidney
The protective effect of human renal sinus fat on glomerular cells is reversed by the hepatokine fetuin-A. Scientific Reports 7, 2017
Adipose tissue is not harmful per se. It can even have protective effects. For example, adipose tissue located around blood vessels or the kidney has regenerative properties. "The factor that leads to pathological changes is fetuin-A, which is produced by the fatty liver," said Professor Dorothea Siegel-Axel, DZD scientist at the Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Zentrum München at the Eberhard-Karls-University of Tuebingen.
As a result, instead of protecting tissue as before, the adipose tissue now elicits inflammatory processes. This leads to a restriction of renal function. This is demonstrated by studies on arteries and the kidney, which have recently been published by the working group in the journal Scientific Reports (Nature Group).
Background: DZD scientists in Tuebingen discovered several years ago that especially a fatty liver can cause damage to other organs. The cause for this is the altered secretion behavior of the fatty liver. It increasingly produces glucose, unfavorable fats and proteins, such as the hepatokine fetuin-A, all of which it releases into the bloodstream. Thus, the secreted substances of the fatty liver enter other organs and trigger reactions there (organ crosstalk).
Wagner R. et al (2017): The protective effect of human renal sinus fat on glomerular cells is reversed by the hepatokine fetuin-A. Scientific Reports, DOI: 10.1038/s41598-017-02210-4
Insulin in the Brain Influences the Metabolism in the Body
Hypothalamic and striatal insulin action suppresses endogenous glucose production and may stimulate glucose uptake during hyperinsulinemia in lean but not in overweight men. Diabetes, 2017
Insulin acts in certain regions of the human brain. If the hormone is administered via an intranasal spray, the insulin is delivered to the brain directly. In lean people, the administration of intranasal insulin results in an improvement of insulin action in the whole body by suppressing endogenous glucose production, causing more glucose to be absorbed by the tissue. In overweight subjects these effects did not occur. These were the results of a study by DZD scientists from Tübingen and Düsseldorf, which was published in the journal Diabetes.
In order to measure the endogenous glucose production and the glucose uptake of the tissue, the 21 study participants underwent two hyperinsulinemic-euglycemic clamps with labeled glucose infusion (method for determining insulin sensitivity). In addition, the participants were administered an intranasal insulin spray or a placebo spray. The researchers investigated brain activity by means of functional magnetic resonance tomography (fMRI).
After the insulin administration, the endogenous glucose production decreased and glucose uptake in the tissue increased in the lean subjects. In addition, the researchers also observed increased activity in the hypothalamus and striatum (part of the basal ganglia, which belong to the cerebrum). No such effects were detected in the overweight participants. This could be due to insulin resistance in the brain of overweight people, which has been known for some time. This insulin resistance of the brain consequently has negative effects on the metabolism in the body, the researchers suspect.
The study was conducted by the Institute for Diabetes Research and Metabolic Diseases of Helmholtz Zentrum München at the University of Tübingen and the German Diabetes Center in Düsseldorf, both partners of the German Center for Diabetes Research (DZD).
Martin Heni, Robert Wagner, Stephanie Kullmann, Sofiya Gancheva, Michael Roden, Andreas Peter, Norbert Stefan, Hubert Preissl, Hans Ulrich Haring, Andreas Fritsche. Hypothalamic and striatal insulin action suppresses endogenous glucose production and may stimulate glucose uptake during hyperinsulinemia in lean but not in overweight men. Diabetes, 2017; db161380. https://doi.org/10.2337/db16-1380
mIndy affects hepatic lipid metabolism
The Human Longevity Gene Homolog INDY and Interleukin-6 Interact in Hepatic Lipid Metabolism. Hepatology, 2017
Reduced expression of the Indy (‘I am Not Dead, Yet') gene in lower organisms promotes longevity in a manner akin to caloric restriction. The mammalian homolog of Indy (mIndy, Slc13a5) affects hepatic lipid metabolism. In obese, insulin resistant patients with NAFLD, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis.
Liver microarray analysis showed that high mIndy expression was associated with pathways involved in hepatic lipid metabolism and immunological processes. Interleukin-6 (IL-6) was identified as a regulator of mIndy by binding to its cognate receptor. Studies in human primary hepatocytes confirmed that IL-6 markedly induced mIndy transcription. Activation of the IL-6-Stat3 pathway stimulated mIndy expression, enhanced cytoplasmic citrate influx and augmented hepatic lipogenesis in vivo. These data show that mIndy is increased in liver of obese humans and non-human primates with NALFD. Targeting human mINDY may have therapeutic potential in obese patients with NAFLD.
von Loeffelholz et al., The Human Longevity Gene Homolog INDY and Interleukin-6 Interact in Hepatic Lipid Metabolism, Hepatology 2017 http://dx.doi.org/10.1002/hep.29089
People with prediabetes should avoid high-Carbohydrate Foods in the evening
The effect of diurnal distribution of carbohydrates and fat on glycaemic control in humans: a randomized controlled trial. Scientific Reports 7, 2017
The internal clock influences how people with impaired glucose metabolism react to carbohydrate-rich food. Men with prediabetes, abundant consumption of foods containing starch and sugar in the evening had a negative effect on their blood glucose regulation. These are the results of a nutrition study led by the German Institute of Human Nutrition (DIfE).
Furthermore, in the affected men the researchers observed an altered secretion of the intestinal hormones glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), which contribute to the regulation of the glucose metabolism or body weight and whose secretion is subject to a particular circadian rhythm. Thus, the blood levels of the two hormones decreased significantly parallel to the pronounced decrease of glucose tolerance in the afternoons in the affected persons in contrast to the healthy participants.
“The circadian rhythm of the hormonal release thus influences the way we react to carbohydrates,” said endocrinologist Pfeiffer, who heads the Department of Clinical Nutrition at DIfE.
Kessler, K. et al. The effect of diurnal distribution of carbohydrates and fat on glycaemic control in humans: a randomized controlled trial. Sci. Rep. 7, 44170; doi: 10.1038/srep44170 (2017).
Pancreas lineage allocation and specification are regulated by S1p
Pancreas lineage allocation and specification are regulated by sphingosine-1-phosphate signalling.
PLoS Biol., 2017
Sphingosine-1-phosphate has a key role in mouse pancreas progenitor survival and the generation of the endocrine and acinar lineages. S1p signaling promotes endocrine specification by stabilizing YAP and attenuating Notch signaling.
The pancreas develops from a field of progenitor cells localised in a restricted region of the embryonic endoderm. These progenitor cells proliferate and eventually differentiate to generate the three distinct lineages comprising the endocrine (which include insulin-producing β cells), acinar, and ductal cells. DZD-Reseachers show that a phospholipid, sphingosine-1-phosphate (S1p), generated by the progenitor cells themselves, acts as a signal necessary to define the acinar and endocrine lineage. They observe that in the absence of S1p only duct cells are generated and the survival of pancreas progenitors is compromised.
The function of this signalling pathway in the generation of the endocrine cells is two-fold. Firstly, it stabilizes yes-associated protein (YAP), a transcriptional gene coactivator known to regulate pancreatic progenitor proliferation. The reseachers show that this stability is necessary for the activation of the endocrine specification program. Secondly, it attenuates Notch signalling, allowing the generation of endocrine and acinar cells. Notch attenuation is necessary for the stabilisation of the transcription factor Ngn3, which is required for the generation of endocrine cells.
The DZD-Reseachers conclude that S1p acts as an autocrine signal regulating YAP stabilization and Notch attenuation to mediate pancreas specification. Understanding lineage allocation and specification in the pancreas will shed light on the origins of pancreatic diseases and may suggest novel therapeutic approaches.
Serafimidis I., Rodriguez-Aznar E., Lesche M., Yoshioka K., Takuwa Y., Dahl A., Pan D., Gavalas A.
Pancreas lineage allocation and specification are regulated by sphingosine-1-phosphate signalling.
PLoS Biol. 2017 Mar 1;15(3):e2000949. doi: 10.1371/journal.pbio.2000949. eCollection 2017.
Even One High-Fat Meal Can Harm the Metabolism
Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance. Journal of Clinical Investigation, 2017
A single ingestion of a large quantity of palm oil suffices to reduce the body's sensitivity to insulin and also to induce increased fat deposits and changes in the energy metabolism of the liver.
DZD researchers from the German Diabetes Center, together with scientists from Helmholtz Zentrum München and Portuguese colleagues, have published a study in "The Journal of Clinical Investigation" on the effects of high-fat intake in healthy, lean male participants. Each participant randomly received a flavored palm oil drink or a glass of clear water as a control experiment. The palm oil drink contained a similar amount of saturated fat as two cheeseburgers with bacon and a large portion of French fries or two pepperoni pizzas. The scientists showed that this single high-fat meal sufficed to reduce the insulin action, i.e., to induce insulin resistance and to increase the fat content of the liver. In addition, alterations in the energy metabolism of the liver were detected. The observed metabolic changes are similar to the changes observed in people with type 2 diabetes or non-alcoholic fatty liver disease (NAFLD).
The study results provide information about the earliest alterations in the liver metabolism, which in the case of overweight and diabetes can, over the long term, lead to fatty liver diseases.
Elisa Álvarez Hernández, Sabine Kahl, Anett Seelig, Paul Begovatz, Martin Irmler, Yuliya Kupriyanova, Bettina Nowotny, Peter Nowotny, Christian Herder, Cristina Barosa, Filipa Carvalho, Jan Rozman, Susanne Neschen, John G. Jones, Johannes Beckers, Martin Hrabě de Angelis and Michael Roden, Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance, J Clin Invest. 2017., 23. Januar 2017. doi:10.1172/JCI89444.
Correlative light and electron microscopy for quantitative studies
A Global Approach for Quantitative Super Resolution and Electron Microscopy on Cryo and Epoxy Sections Using Self-labeling Protein Tags. Scientific Reports 7, 2017
Correlative light and electron microscopy (CLEM) is a powerful approach to investigate the molecular ultrastructure of labeled cell compartments. However, quantitative CLEM studies are rare, mainly due to small sample sizes and the sensitivity of fluorescent proteins to strong fixatives and contrasting reagents for EM. DZD-Reseachers show that fusion of a self-labeling protein to insulin allows for the quantification of age-distinct insulin granule pools in pancreatic beta cells by a combination of super resolution and transmission electron microscopy on Tokuyasu cryosections. In contrast to fluorescent proteins like GFP organic dyes covalently bound to self-labeling proteins retain their fluorescence also in epoxy resin following high pressure freezing and freeze substitution, or remarkably even after strong chemical fixation. This enables for the assessment of age-defined granule morphology and degradation. Finally, we demonstrate that this CLEM protocol is highly versatile, being suitable for single and dual fluorescent labeling and detection of different proteins with optimal ultrastructure preservation and contrast.
F.l.: (a) SIM image of Epon section of SOFIA mouse beta cells labeled with 505-Star (green) and TMR-Star (magenta) fixed by HPF followed by FS. As fiducial markers fluorescent beads (blue) were added to the section prior to imaging. Punctate SGs can be unequivocally distinguished by SIM. (b) CLEM image of boxed area in (a). (c) CLEM detail of boxed area in (c) showing perfect overlay of 505+ and TMR+ SGs. Scale bars: (a) 10 µm. (b+c) 1 µm.
Andreas Müller, Martin Neukam, Anna Ivanova, Anke Sönmez, Carla Münster, Susanne Kretschmar, Yannis Kalaidzidis, Thomas Kurth, Jean-Marc Verbavatz & Michele Solimena. A Global Approach for Quantitative Super Resolution and Electron Microscopy on Cryo and Epoxy Sections Using Self-labeling Protein Tags. Scientific Reports 7, Article number: 23 (2017). doi:10.1038/s41598-017-00033-x
Overweight Affects DNA Methylation
Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature 2016
High BMI leads to epigenetic changes at nearly 200 loci of the genome – with effects on gene expression. This is the result of a large-scale international study coordinated by Helmholtz Zentrum München, a partner in the German Center for Diabetes Research.
An international research team led by Dr. Christian Gieger and Dr. Harald Grallert (as well as Jaspal Kooner and John Chambers of Imperial College London) examined possible correlations between body mass index (BMI) and epigenetic changes.
The scientists examined the blood samples of over 10,000 women and men from Europe. A large proportion of these were inhabitants of London of Indian ancestry, who according to the authors are at high risk for obesity and metabolic diseases. In a first step with 5,387 samples, the research team identified 207 gene loci that were epigenetically altered dependent on the BMI. They then tested these candidate loci in blood samples of an additional 4,874 subjects and were able to confirm 187 of these. Further studies and long-term observations also indicated that the changes were predominantly a consequence of being overweight – not the cause.
Significant changes were found in the expression of genes responsible for lipid metabolism and substrate transport, but inflammation-related gene loci were also affected. From the data, the team was also able to identify epigenetic markers that could predict the risk of type 2 diabetes.
Wahl, S. et al. (2016): Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity. Nature, doi:10.1038/nature20784
Friendly Fire in the Pancreas
miRNA92a targets KLF2 and PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity.
Type 1 diabetes is an autoimmune disease in which the body destroys its own beta cells in the pancreas. Researchers are still seeking to find out what causes this malfunction of the immune system in order to intervene therapeutically in the processes. A team led by Dr. Carolin Daniel, group leader at the Institute of Diabetes Research (IDF) of Helmholtz Zentrum München, has now discovered a further piece in solving this puzzle.
“For the first time, we were able to show that in the affected children an increased number of specific immune cells are found in the blood at the beginning of the autoimmune response,” said Daniel. She and her team had previously analyzed blood samples of children in a biobank established by Professor Anette-Gabriele Ziegler, director of the IDF, within the framework of large-scale cohort studies.
According to the authors, these special immune cells are so-called insulin-specific T follicular helper cells (TFH). They appear in the lymph nodes, among other organs, and initiate attacks of the immune system by promoting the production of antibodies by B cells. Now the scientists have found increased frequencies of these cells in samples of children with recent onset of islet cell autoimmunity – an early stage of type 1 diabetes.
In the search for the causes of the increase in TFH cells during autoimmune activation in children, the scientists discovered a previously unknown signaling pathway. The analyses showed that a molecule called miRNA92a triggers a chain of molecular events, which ultimately leads to the increase in these immune cells.
To check whether this newly discovered mechanism is suitable for therapeutic intervention, the scientists investigated the effect of a so-called antagomir, which specifically binds to miRNA92a molecules and blocks their effect. In an experimental model of type 1 diabetes and in the humanized model, this treatment resulted in a significantly lower autoimmune response. (see figure: Treatment with an antagomir directed against miR92a results in reduced attacks of immune cells (green) on the insulin (white) producing beta cells directly in the pancreas. Moreover, the treatment leads to more regulatory T cells (red) able to protect the beta cells.)
Serr, I. et al. (2016). miRNA92a targets KLF2 and PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity, DOI: 10.1073/pnas.160664611
High-Protein Diets Reduce Liver Fat
Isocaloric Diets High in Animal or Plant Protein Reduce Liver fat and Inflammation in Individuals with Type 2 Diabetes.
According to a new nutritional study conducted by the German Institute of Human Nutrition (DIfE) on individuals with type 2 diabetes, high-protein diets reduced liver fat by up to 48 percent within six weeks. It did not matter whether the diet was mainly based on plant or animal protein.
Nonalcoholic fatty liver disease is the most common chronic liver disease in Europe and the U.S. “When left untreated, fatty liver is an important step progress to type 2 diabetes and can develop into liver cirrhosis, which can have life-threatening effects,” said endocrinologist Andreas F. H. Pfeiffer of DIfE, who led the study. "Since the number of affected persons is increasing, it is therefore more important than ever to work together with our partners to develop effective dietary strategies that prevent the disease," he added.
Researchers at DIfE investigated in the current study the effects of two high-protein diets on the metabolism of 37 female and male subjects between the ages of 49 and 78 years suffering from type 2 diabetes and, in most cases, from fatty liver. The two diets differed only in the protein sources, which were either mainly plant or animal origin.
The results: All study participants benefited from the high-protein diet, whether based on plant or animal protein. Liver fat content decreased significantly, in half of the study participants by more than 50 percent. Negative effects on renal function or glucose metabolism were not observed.
The team of scientists led by Mariya Markova, Olga Pivovarova, Silke Hornemann and Andreas F. H. Pfeiffer of DIfE, a partner of the German Center for Diabetes Research (DZD), has published its findings in the journal "Gastroenterology".
Markova et al. 2016. Isocaloric Diets High in Animal or Plant Protein Reduce Liver fat and Inflammation in Individuals with Type 2 Diabetes, Gastroenterology 2016. DOI: http://dx.doi.org/10.1053/j.gastro.2016.10.007
Calcineurin: Key molecule in energy metabolism
Pfluger PT, Kabra DG, Aichler M, Schriever SC, Pfuhlmann K, García VC, Lehti M, Weber J, Kutschke M, Rozman J, Elrod JW, Hevener AL, Feuchtinger A, Hrabě de Angelis M, Walch A, Rollmann SM, Aronow B, Müller TD, Perez-Tilve D, Jastroch M, De Luca M, Molkentin JD, Tschöp MH. Calcineurin Links Mitochondrial Elongation with Energy Metabolism.
doi: 10.1016/j.cmet.2015.08.022. Cell Metabolism. Sep 23, 2015
Our body consistently adjusts its energy management to changes in the supply of nutrients or physical activity. Malfunctioning in this process plays an essential role in the genesis of metabolic disorders like adiposity and diabetes. Scientists at the Helmholtz Zentrum München now report that in this process the protein calcineurin assumes a central function by optimising cellular respiration. Genetic as well as pharmacological calcineurin inhibition protects from diet-induced obesity in both a fly and mouse animal models.
The evolutionary highly conserved role of calcineurin in fly and mouse energy metabolism suggests a similar function in humans. It would therefore be an obvious conclusion to suppress the function of calcineurin through medication in order to treat obesity. Corresponding inhibitors have been deployed in high dosages in the clinic for years in order to prevent rejection reactions after tissue transplants but due to numerous side effects have not been above criticism. Effects from low-dosage calcineurin inhibitors on the body weight of adipose patients have, however, not yet been studied clinically. Corresponding new approaches are currently being tested. They could play a role in future diabetes therapies.
Pfluger PT, Kabra DG, Aichler M, Schriever SC, Pfuhlmann K, García VC, Lehti M, Weber J, Kutschke M, Rozman J, Elrod JW, Hevener AL, Feuchtinger A, Hrabě de Angelis M, Walch A, Rollmann SM, Aronow B, Müller TD, Perez-Tilve D, Jastroch M, De Luca M, Molkentin JD, Tschöp MH. Calcineurin Links Mitochondrial Elongation with Energy Metabolism. doi: 10.1016/j.cmet.2015.08.022. Cell Metabolism. Sep 23, 2015
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Diabetes prevention: Who benefits from lifestyle modification?
Stefan N, Staiger H, Wagner R, Machann J, Schick F, Häring HU, Fritsche A. A high-risk phenotype associates with reduced improvement in glycaemia during a lifestyle intervention in prediabetes.
doi: 10.1007/s00125-015-3760-z. Diabetologia. September 24, 2015
DZD scientists at the University of Tübingen identified a phenotype among patients with prediabetes that is associated with nonresponse to lifestyle modification in the Tübingen Lifestyle Intervention Program (TULIP). These participants showed a lack of reversal of prediabetes (impaired glucose tolerance and/or impaired fasting glucose) to normal glucose regulation (NGR) despite reduction of body weight. Characteristics of non-responders were low insulin secretion relative to insulin resistance or insulin-resistant nonalcoholic fatty liver disease (= high-risk phenotype). The odds ratio for reaching the status NGR was 4.54 (95% CI 2.08, 9.94) for participants having the low-risk phenotype.
In future, stratification of individuals with prediabetes at baseline into a high-risk and a low-risk phenotype may help to determine the effectiveness of a lifestyle intervention to revert individuals to NGR. The next question is: Can a reduced response to a standard
lifestyle intervention in individuals with the identified high-risk phenotype be overcome by an intensified lifestyle intervention? The German Prediabetes Lifestyle Intervention Study (PLIS) has been started in eight centres throughout Germany to investigate this issue.
Stefan N, Staiger H, Wagner R, Machann J, Schick F, Häring HU, Fritsche A. A high-risk phenotype associates with reduced improvement in glycaemia during a lifestyle intervention in prediabetes. doi: 10.1007/s00125-015-3760-z. Diabetologia. September 24, 2015
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Study on healthy aging: Knockdown of Indy/CeNac2 extends Caenorhabditis elegans life span
Schwarz F, Karadeniz Z, Fischer-Rosinsky A, Willmes DM, Spranger J, Birkenfeld AL. Knockdown of Indy/CeNac2 extends Caenorhabditis elegans life span by inducing AMPK/aak-2.
Aging. August 20, 2015
DZD scientists of the group of Prof. Andreas Birkenfeld at the University Clinic Carl Gustav Carus, TU Dresden, were able to shed a new light on the controversial data on life span extension in C. elegans.
It has been known that reduced expression of the Indy (“I am Not Dead Yet”) gene in Drosophila melanogaster promotes longevity. Now, the researchers could show that the knockdown of Indy/CeNAC2 using a specific siRNA extended the life span of C. elegans along with the activation of the intracellular energy sensor AMP-activated protein Kinase A (AMPK). Mean life span was extended by 22±3 % upon knockdown of Indy/CeNAC2, while whole body fat content was reduced by nearly 50%. This finding might also be interesting for future diabetes therapies in humans.
The study provides a rationale for the molecular mechanisms mediating longevity when Indy/CeNAC2 is reduced. It further supports the hypothesis that activation of AMPK and inactivation of Indy are attractive targets to promote healthy ageing and, possibly, to extend life span also in higher eukaryotes.
Schwarz F, Karadeniz Z, Fischer-Rosinsky A, Willmes DM, Spranger J, Birkenfeld AL. Knockdown of Indy/CeNac2 extends Caenorhabditis elegans life span by inducing AMPK/aak-2. Aging. August 20, 2015 Link to the Publication
Stool microbiota of high-risk people for type 2 diabetes
Fugmann M, Breier M, Rottenkolber M, Banning F, Ferrari U, Sacco V, Grallert H, Parhofer KG, Seissler J, Clavel T, Lechner A. The stool microbiota of insulin resistant women with recent gestational diabetes, a high risk group for type 2 diabetes. doi: 10.1038/srep13212.
Nature Scientific Reports. August 17, 2015
The gut microbiota influences metabolic health and has already been linked to diabetes. DZD scientist from Munich now investigated the microbiome of young adults at risk for type 2 diabetes. They compared stool microbiota of insulin resistant women with previous gestational diabetes – a high risk group for type 2 diabetes – and women after a normoglycemic pregnancy (controls).
Significantly more women in the previous gestational diabetes group showed a Prevotellaceae-dominated intestinal microbiome. Prevotella are mucin degrading bacteria, which may be associated with increased gut permeability and low-grade inflammation with decreased insulin sensitivity. This could explain the link between Prevotellaceae and diabetes.
The study suggests that distinctive features of the intestinal microbiota are already present
in young adults at risk for type 2 diabetes. These results warrant further investigation in larger human cohorts and other clinical settings, as well as examination of the underlying molecular mechanisms. Considering that the gut microbiota can be influenced by diet, this might be a suitable way to prevent type 2 diabetes in people at risk.
Fugmann M, Breier M, Rottenkolber M, Banning F, Ferrari U, Sacco V, Grallert H, Parhofer KG, Seissler J, Clavel T, Lechner A. The stool microbiota of insulin resistant women with recent gestational diabetes, a high risk group for type 2 diabetes. doi: 10.1038/srep13212. Nature Scientific Reports. August 17, 2015
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New diabetes-related genes discovered
Hrabě de Angelis, M. et al. Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics.
Nature Genetics. doi: 10.1038/ng.3360. September 1, 2015
The role of 300 genes has been revealed by DZD scientists in cooperation with colleagues of the European Mouse Disease Clinic (EUMODIC) to understand the part they play in disease and biology. In order to study gene function, they analyzed mouse lines which each had a single gene removed. 160 disease-related genes were discovered. Some of them play a role in diabetes and are promising candidates for further diabetes research.
EUMODIC was the first step towards the creation of a database of all mouse gene functions, a vision now being realized by the International Mouse Phenotyping Consortium (IMPC). The published data set is available on the IMPC website for other scientists to use it in their own research. This will allow to understand more about genes we currently know very little about, and open up new ways for research into the genetics of human disease.
Hrabě de Angelis, M. et al. Analysis of mammalian gene function through broad-based phenotypic screens across a consortium of mouse clinics. Nature Genetics. doi: 10.1038/ng.3360. September 1, 2015
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New surgically reversible diabetes subtype
Ehehalt F, Sturm D, Rösler M, Distler M, Weitz J, Kersting S, Ludwig B, Schwanebeck U, Saeger HD, Solimena M, Grützmann R. Blood Glucose Homeostasis in the Course of Partial Pancreatectomy – Evidence for Surgically Reversible Diabetes Induced by Cholestasis.
PLoS One. August 6, 2015
DZD scientists at the Paul Langerhans Institute Dresden characterized a new reversible, tumor-associated diabetes subtype: Cholestasis-induced diabetes. This surgically reversible blood glucose dysregulation diagnosed concomitantly with a (peri-)pancreatic tumor appears secondary to compromised liver function due to tumor compression of the common bile duct and the subsequent increase in insulin resistance.
Individuals undergoing elective partial pancreatic resection were recruited into this trial. They were assigned into three groups: deteriorated, stable or improved glucose homeostasis three months after surgery.
Stability and improvement of glucose homeostasis were associated with tumor resection and postoperative normalization of recently diagnosed glucose dysregulation, preoperatively elevated tumor markers and markers for common bile duct obstruction, acute pancreatitis and liver cell damage.
These data enable the pancreatic surgeon to estimate the postoperative metabolic consequences in the course of partial pancreatic resection and to improve his patient’s information accordingly. Furthermore, “new-onset diabetes” in elderly patients (age >50 years) and temporary surveillance of bile duct, pancreas and liver cell parameters during the first months after the diagnosis of impaired glucose metabolism in the elderly might serve as an effective and practical filter for pancreatic cancer screening.
Ehehalt F, Sturm D, Rösler M, Distler M, Weitz J, Kersting S, Ludwig B, Schwanebeck U, Saeger HD, Solimena M, Grützmann R. Blood Glucose Homeostasis in the Course of Partial Pancreatectomy – Evidence for Surgically Reversible Diabetes Induced by Cholestasis.
doi: 10.1371/journal.pone.0134140. PLoS One. August 6, 2015
Link to the Publication
Positive side effect: Metformin lowers LDL cholesterol levels
Xu T, Brandmaier S, Messias AC, Herder C, Draisma HH, Demirkan A, Yu Z, Ried JS, Haller T, Heier M, Campillos M, Fobo G, Stark R, Holzapfel C, Adam J, Chi S, Rotter M, Panni T, Quante AS, He Y, Prehn C, Roemisch-Margl W, Kastenmüller G, Willemsen G, Pool R, Kasa K, van Dijk KW, Hankemeier T, Meisinger C, Thorand B, Ruepp A, Hrabé de Angelis M, Li Y, Wichmann HE, Stratmann B, Strauch K, Metspalu A, Gieger C, Suhre K, Adamski J, Illig T, Rathmann W, Roden M, Peters A, van Duijn CM, Boomsma DI, Meitinger T, Wang-Sattler R. Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes. doi: 10.2337/dc15-0658.
Besides affecting the blood sugar levels, the substance Metformin also has an impact on blood fat levels. This was elucidated by an interdisciplinary team of the DZD headed by Dr. Rui Wang-Sattler of the Helmholtz Zentrum München. Especially LDL cholesterol can be reduced.
The DZD-researchers at Helmholtz Zentrum München and German Diabetes Center Düsseldorf analyzed more than 1.800 blood samples of participants, who joined the German large-scale study KORA*. Using a comprehensive approach, the scientists investigated metabolic products (metabolites) as well as genetics of these participants. They found that the administration of Metformin in patients suffering from type 2 diabetes led to a change in metabolite levels. This was associated with a decreased level of LDL cholesterol, which is under strong suspicion to promote cardiovascular diseases by causing atherosclerosis.
The study suggests that Metformin might have an additional beneficial effect with regards to cardiovascular diseases among diabetes patients. The exact mechanism of Metformin will be further investigated.
* For more than 20 years, the Cooperative Health Research in the Region of Augsburg (KORA) has been examining the health of thousands of citizens in Augsburg and environs.
Xu T, Brandmaier S, Messias AC, Herder C, Draisma HH, Demirkan A, Yu Z, Ried JS, Haller T, Heier M, Campillos M, Fobo G, Stark R, Holzapfel C, Adam J, Chi S, Rotter M, Panni T, Quante AS, He Y, Prehn C, Roemisch-Margl W, Kastenmüller G, Willemsen G, Pool R, Kasa K, van Dijk KW, Hankemeier T, Meisinger C, Thorand B, Ruepp A, Hrabé de Angelis M, Li Y, Wichmann HE, Stratmann B, Strauch K, Metspalu A, Gieger C, Suhre K, Adamski J, Illig T, Rathmann W, Roden M, Peters A, van Duijn CM, Boomsma DI, Meitinger T, Wang-Sattler R. Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes. doi: 10.2337/dc15-0658. Diabetes Care. August 5, 2015
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Intake of Lactobacillus reuteri improves incretin and insulin secretion
Simon MC, Strassburger K, Nowotny B, Kolb H, Nowotny P, Burkart V, Zivehe F, Hwang JH, Stehle P, Pacini G, Hartmann B, Holst JJ, MacKenzie C, Bindels LB, Martinez I, Walter J, Henrich B, Schloot NC, Roden M. Intake of Lactobacillus reuteri Improves Incretin and Insulin Secretion in Glucose Tolerant Humans: A Proof of Concept. doi: 10.2337/dc14-2690.
Diabetes Care. June 17, 2015
Alterations in gut microbiota occur in obesity and type 2 diabetes. DZD scientists at the German Diabetes Center in Düsseldorf and an international research team analyzed the effects of daily intake of Lactobacillus reuteri. The prospective, double-blind, randomized trial was performed in 21 glucose tolerant humans. L. reuteri increased glucose-stimulatedGLP-1 and GLP-2 release by 76% and 43%, respectively, compared with placebo, along with 49% higher insulin and 55% higher C-peptide secretion. However, the intervention did not alter peripheral and hepatic insulin sensitivity, body mass, ectopic fat content, orcirculating cytokines.
The authors conclude that enrichment of gut microbiota with L. reuteri increases insulin secretion, possibly due to augmented incretin release, but does not directly affect insulin sensitivity or body fat distribution. This suggests that oral ingestion of one specific strain may
serve as a novel therapeutic approach to improve glucose-dependent insulin release.
Simon MC, Strassburger K, Nowotny B, Kolb H, Nowotny P, Burkart V, Zivehe F, Hwang JH, Stehle P, Pacini G, Hartmann B, Holst JJ, MacKenzie C, Bindels LB, Martinez I, Walter J, Henrich B, Schloot NC, Roden M. Intake of Lactobacillus reuteri Improves Incretin and Insulin Secretion in Glucose Tolerant Humans: A Proof of Concept. doi: 10.2337/dc14-2690. Diabetes Care. June 17, 2015
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Effects of aging on insulin in the brain
Sartorius T, Peter A, Heni M, Maetzler W, Fritsche A, Häring HU, Hennige AM. The brain response to peripheral insulin declines with age: a contribution of the blood-brain barrier? doi: 10.1371/journal.pone.0126804.
PLoS One. May 12, 2015
DZD scientists at the Institute for Diabetes Research and Metabolic Diseases (IDM) and scientists at the German Center for Neurodegenerative Diseases (DZNE) investigated the effect of aging on insulin concentrations in the periphery and the central nervous system as well as its impact on insulin-dependent brain activity.
In humans, glucose and insulin concentrations in cerebrospinal fluid (CSF) were tightly correlated with the respective serum/plasma concentrations. The CSF/serum ratio for insulin was reduced in older subjects while the CSF/serum ratio for albumin increased with age like for most other proteins. Insulin-mediated cortical brain activity instantly increased in young mice subcutaneously injected with insulin but was significantly reduced and delayed in aged mice during the treatment period. However, when insulin was applied intracerebroventricularly into aged animals, brain activity was readily improved.
An inadequate insulin transport into the central nervous system across the blood-brain barrier may contribute to impaired insulin action in elderly subjects, which finally harms glucose homeostasis and neuronal function. This information is crucial for more efficient preventive and therapeutic interventions like specific insulin sensitizing agents in an aging population.
Sartorius T, Peter A, Heni M, Maetzler W, Fritsche A, Häring HU, Hennige AM. The brain response to peripheral insulin declines with age: a contribution of the blood-brain barrier? doi: 10.1371/journal.pone.0126804. PLoS One. May 12, 2015
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Visualization of digestion and microbial metabolism – better understanding of metabolic diseases
Heinzmann SS, Schmitt-Kopplin P. Deep metabotyping of the murine gastrointestinal tract for the visualization of digestion and microbial metabolism. doi: 10.1021/acs.jproteome.5b00034.
J Proteome Res. May 1, 2015
Obesity and diabetes are influenced by gastrointestinal metabolism. To gain a better understanding of the interdependencies DZD scientists at the Helmholtz Zentrum München analyzed the metabolic and physiological functions of different sections of the gut. The aim was to define a comprehensive list of characteristic metabolites for the physiological gut sections and to quantify the selected pathways. They investigated the metabolic composition of seven different gut sections using high-resolution NMR spectroscopy, which returned a comprehensive metabolite overview with a single analytical measurement per sample.
The created list delivers characteristic metabolites, describes metabolite changes along the gut, and highlights the site specificity for selected metabolite pathways. The largest metabolic changes happened in the cecum, where the microbiome produces microbial metabolites. Furthermore, the evolution of bile acids along the gut was shown and their site-specific conversion was described. A metabolic basis was established for future investigations of metabolic perturbations, which can be introduced by dietary challenges or gene knockouts and provide valuable information for tailored study design and targeted sample collection.
These results provide the fundamental analytical and metabolic basis for the investigation of the gut metabolism. Better knowledge of site-specific gastrointestinal metabolism will lead to improved understanding of systemic diseases such as diabetes and obesity and advance dietary, drug intervention and surgical procedure outcomes and guide the way to new therapeutic targets.
Heinzmann SS, Schmitt-Kopplin P. Deep metabotyping of the murine gastrointestinal tract for the visualization of digestion and microbial metabolism. doi: 10.1021/acs.jproteome.5b00034. J Proteome Res. May 1, 2015
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Association between red meat intake and type 2 diabetes risk
Wittenbecher C, Mühlenbruch K, Kröger J, Jacobs S, Kuxhaus O, Floegel A, Fritsche A, Pischon T, Prehn C, Adamski J, Joost HG, Boeing H, Schulze MB. Amino acids, lipid metabolites, and ferritin as potential mediators linking red meat consumption to type 2 diabetes. doi: 10.3945/ajcn.114.099150.
Am J Clin Nutr. June 1, 2015
Habitual red meat consumption is related to a higher risk of type 2 diabetes in observational studies. An interdisciplinary team of DZD scientists at the German Institute of Human Nutrition Potsdam-Rehbrücke, the Helmholtz Zentrum München and the University of Tübingen identified blood metabolites that possibly relate red meat consumption to the occurrence of type 2 diabetes. Analyses were conducted in the European Prospective Investigation into Cancer and Nutrition-Potsdam cohort (n = 27,548), applying a nested case-cohort design (n = 2681, including 688 incident diabetes cases). Six biomarkers (ferritin, glycine, diacyl phosphatidylcholines 36:4 and 38:4, lysophosphatidylcholine 17:0, and hydroxy-sphingomyelin 14:1) in serum samples from baseline were associated with red meat consumption and diabetes risk.
Heme iron intake from red meat is related to higher ferritin levels. The underlying mechanisms that link elevated iron status to the risk of diabetes likely include oxidative stress and modulation of intracellular signaling cascades. Glycine is part of the body’s defense systems against oxidative stress and might ameliorate inflammatory processes. An inverse association of glycine with diabetes risk was previously described. Circulating lipid metabolites partly reflect the nutrient uptake and metabolic processes in the liver. In the literature, several lines of evidence relate a disturbed hepatic lipid metabolism to the pathogenesis of type 2 diabetes.
This is the first study evaluating a large set of metabolites as potential mediators of the association between red meat intake and diabetes risk. The results cannot prove
causality of the observed associations but they hint towards plausible biological pathways linking red meat intake to type 2 diabetes risk. Not least the results provide valuable information for the design and the biomarker assessment of interventional studies.
Wittenbecher C, Mühlenbruch K, Kröger J, Jacobs S, Kuxhaus O, Floegel A, Fritsche A, Pischon T, Prehn C, Adamski J, Joost HG, Boeing H, Schulze MB. Amino acids, lipid metabolites, and ferritin as potential mediators linking red meat consumption to type 2 diabetes. doi: 10.3945/ajcn.114.099150. Am J Clin Nutr. June 1, 2015
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Hepatic mitochondrial flexibility lost in patients with steatohepatitis
Koliaki C, Szendroedi J, Kaul K, Jelenik T, Nowotny P, Jankowiak F, Herder C, Carstensen M, Krausch M, Knoefel WT, Schlensak M, Roden M. Adaptation of Hepatic Mitochondrial Function in Humans with Non-Alcoholic Fatty Liver Is Lost in Steatohepatitis. doi: 10.1016/j.cmet.2015.04.004,
Cell Metabolism May 5, 2015
DZD scientists showed that obese individuals without steatohepatitis (NASH) have increased mitochondrial respiratory rates compared to lean ones, suggesting hepatic mitochondrial flexibility at early stages of obesity-related insulin resistance. This adaptation is, however, lost in patients with NASH, who have lower maximal respiration, despite higher mitochondrial mass.
These results have been obtained by direct measurement of hepatic mitochondrial content and capacity in humans. The discovered ‘‘hepatic mitochondrial flexibility’’ which is associated with early stages of human obesity could serve as future target for the prevention and treatment of non-alcoholic fatty liver disease (NAFLD).
Koliaki C, Szendroedi J, Kaul K, Jelenik T, Nowotny P, Jankowiak F, Herder C, Carstensen M, Krausch M, Knoefel WT, Schlensak M, Roden M. Adaptation of Hepatic Mitochondrial Function in Humans with Non-Alcoholic Fatty Liver Is Lost in Steatohepatitis. doi: 10.1016/j.cmet.2015.04.004, Cell Metabolism May 5, 2015
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Successful first step for the prevention of type 1 diabetes
Bonifacio E, Ziegler AG, Klingensmith G, Schober E, Bingley PJ, Rottenkolber M, Theil A, Eugster A, Puff R, Peplow C, Buettner F, Lange K, Hasford J, Achenbach P. Pre-POINT Study Group. Effects of High-Dose Oral Insulin on Immune Responses in Children at High Risk for Type 1 Diabetes: The Pre-POINT Randomized Clinical Trial. doi: 10.1001/jama.2015.2928,
JAMA April 21, 2015
In the international Pre-POINT study, published in the renowned scientific journal JAMA, DZD scientists at the Paul Langerhans Institute Dresden and the Helmholtz Zentrum München achieved a breakthrough in the prevention of type 1 diabetes together with researchers from Vienna, Bristol and Denver (USA): They completed the first step in development of an insulin vaccine successfully.
The study, a double-blind, placebo-controlled, dose-escalation, assessed the immune responses and adverse events associated with orally administered insulin in autoantibody-negative, genetically at-risk children. The immune response to insulin was measured as serum IgG and saliva IgA binding to insulin, and CD4+ T-cell proliferative responses to insulin. In this pilot study of children at high risk for type 1 diabetes, daily oral administration of 67.5 mg of insulin, compared with placebo, resulted in an immune response without hypoglycemia. These findings support the need for a phase 3 trial to determine whether oral insulin can prevent islet autoimmunity and diabetes in such children.
Bonifacio E, Ziegler AG, Klingensmith G, Schober E, Bingley PJ, Rottenkolber M, Theil A, Eugster A, Puff R, Peplow C, Buettner F, Lange K, Hasford J, Achenbach P. Pre-POINT Study Group. Effects of High-Dose Oral Insulin on Immune Responses in Children at High Risk for Type 1 Diabetes: The Pre-POINT Randomized Clinical Trial. doi: 10.1001/jama.2015.2928, JAMA April 21, 2015
Link to the publication:http://jama.jamanetwork.com/article.aspx?articleid=2275446
Innovative approach provides new insights into human metabolism
Wahl S, Vogt S, Stückler F, Krumsiek J, Bartel J, Kacprowski T, Schramm K, Carstensen M, Rathmann W, Roden M, Jourdan C, Kangas AJ, Soininen P, Ala-Korpela M, Nöthlings U, Boeing H, Theis FJ, Meisinger C, Waldenberger M, Suhre K, Homuth G, Gieger C, Kastenmüller G, Illig T, Linseisen J, Peters A, Prokisch H, Herder C, Thorand B, Grallert H. Multi-omic signature of body weight change: results from a population-based cohort study. doi:10.1186/s12916-015-0282-y
BMC Medicine March 9, 2015
Until now there have been few molecular epidemiological studies regarding the effects of weight changes on metabolism in the general population. In a study published in the journal BMC Medicine, DZD scientists at the Helmholtz Zentrum München, the German Diabetes Center Düsseldorf (DDZ) and the German Institute of Human Nutrition Potsdam-Rehbrücke evaluated molecular data of the KORA study*. The applied techniques, metabolomics and transcriptomics, allow the simultaneous determination of a variety of low molecular weight metabolites and gene activities, respectively. This integrated metabolomics and transcriptomics approach improves e.g. the understanding of molecular mechanisms underlying the association of weight gain with changes in insulin sensitivity.
*For more than 20 years the Cooperative Health Research in the Region of Augsburg (KORA) platform has been examining the health of thousands of citizens in Augsburg and environs.
Wahl S, Vogt S, Stückler F, Krumsiek J, Bartel J, Kacprowski T, Schramm K, Carstensen M, Rathmann W, Roden M, Jourdan C, Kangas AJ, Soininen P, Ala-Korpela M, Nöthlings U, Boeing H, Theis FJ, Meisinger C, Waldenberger M, Suhre K, Homuth G, Gieger C, Kastenmüller G, Illig T, Linseisen J, Peters A, Prokisch H, Herder C, Thorand B, Grallert H. Multi-omic signature of body weight change: results from a population-based cohort study. doi:10.1186/s12916-015-0282-y,
BMC Medicine March 9, 2015
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Cough suppressant improves symptoms of type 2 diabetes
Marquard J., Otter S., Welters A., Stirban A., Fischer A., Eglinger J., Herebian D., Kletke O., Klemen M.S., Stožer A., Wnendt S., Piemonti L., Köhler M., Ferrer J., Thorens B., Schliess F., Rupnik M.S., Heise T., Berggren PO., Klöcker N., Meissner T., Mayatepek E., Eberhard D., Kragl M., Lammert E. Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. doi: 10.1038/nm.3822
Nature Medicine March 16, 2015
Dextromethorphan, an over-the-counter cough suppressant, and its metabolites may improve diabetic complications in mice and humans, according to research published in Nature Medicine. These results suggest a potential adjunct treatment for type 2 diabetes.
Dextromethorphan is an active ingredient, with only a few minor adverse side effects, found in many over-the-counter cough medications and it acts by inhibiting N-Methyl-D-Aspartate (NMDA) receptors. These receptors are expressed in tiny clusters of insulin-producing beta cells in the pancreas, but their physiological role has not been clear.
DZD scientist Eckhard Lammert and colleagues found that genetic deletion of a key part of this class of receptors, or their pharmacological inhibition by drugs such as dextromethorphan, results in more potent glucose-stimulated insulin secretion in a sample of normal mouse and human pancreatic tissue. In addition, the researchers found that dextromethorphan protects pancreatic islets from cell death under certain experimental conditions, which could be of interest to patients with type 1 diabetes.
These results, as well as improved glucose control, were - observed in a mouse model of type 2 diabetes on administration of dextromethorphan. In a small, phase 2a, clinical trial involving 20 volunteers with type 2 diabetes, the authors confirmed that dextromethorphan increases serum insulin concentrations and lowers blood glucose. Long-term clinical studies are now needed to study the benefits of dextromethorphan for patients with diabetes in more depth.
Marquard J., Otter S., Welters A., Stirban A., Fischer A., Eglinger J., Herebian D., Kletke O., Klemen M.S., Stožer A., Wnendt S., Piemonti L., Köhler M., Ferrer J., Thorens B., Schliess F., Rupnik M.S., Heise T., Berggren PO., Klöcker N., Meissner T., Mayatepek E., Eberhard D., Kragl M., Lammert E. Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. doi: 10.1038/nm.3822
Nature Medicine March 16, 2015
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