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...
"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...
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...
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 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...
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...
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.
New genes and regulatory elements discovered that can lead to metabolic disorders
An international team of researchers led by Prof. Martin Hrabě de Angelis has identified a network of genes that can play an important role in the...
An international team of researchers led by Prof. Martin Hrabě de Angelis has identified a network of genes that can play an important role in the development of metabolic diseases.
The development of metabolic diseases like diabetes is a complex process. The underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. In order to find out which genes are involved in metabolic processes, the researchers investigated the metabolic functions of mouse models, each of which lacked a precisely selected gene. The work was carried out within the framework of the International Mouse Phenotyping Consortium (IMPC). Using this method, researchers are trying to establish whether the missing gene is involved in important metabolic processes and can be linked to human diseases.
"Our analysis of the phenotyping data has identified a total of 974 genes whose loss has strong effects on glucose and lipid metabolism," said Hrabě de Angelis, Board of German Center for Diabetes Research (DZD) and Director of the Institute for Experimental Genetics (IEG) at the Helmholtz Zentrum München and the chair of the same name at the TU Munich. In 429 genes, no correlation with the metabolism has been known so far. 51 of the found metabolic genes were completely unknown.
When compared with genome data collected in humans, they found that 23 of these also appear to play a role in human diabetes. There is no data for the rest.
The research team also discovered a new regulatory code: Many candidate genes had common regulatory elements in promotors. The scientists therefore assume that these genes are a network.
The work published in' Nature Communications' was produced under the leadership of a team from the Helmholtz Zentrum München and the DZD.
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...
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...
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...
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...
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
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
Smart drug clears fat from liver and blood
Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease.
The constant rise in obesity and diabetes represents a major burden of our society. Fatty liver and atherosclerosis are frequent consequences of these metabolic diseases, but an efficient and safe medicine, which would reverse obesity, insulin resistance, fatty liver and atherosclerosis remains a major scientific challenge of global priority.
Scientists of DZD partner Helmholtz Zentrum München and Technische Universität München have developed a ‘smart’ drug that safely clears the liver of fat and prevents blood vessels from clogging up. Similar to a trojan horse, the drug enters the liver with a trick: It uses the pancreatic hormone glucagon as vehicle to shuttle thyroid hormone T3 the live while keeping it away from other organs, thereby improving cholesterol and lipid metabolism while avoiding typical side effects of thyroid hormone.
The international team led by metabolism experts Matthias Tschöp (Helmholtz Zentrum München / Technische Universität Müchen), Richard diMarchi (Indiana University) and Timo Müller (Helmholtz Zentrum München) report in the journal ‘Cell’ that liver-specific delivery of the thyroid hormone T3 using glucagon corrects obesity, glucose intolerance, fatty liver disease and atherosclerosis without causing adverse effects in other tissues. “While the ability of T3 to lower cholesterol is known for centuries, deleterious effects, in particular on the skeleton and the cardiovascular system, do so far limit its medicinal utility”, says Brian Finan, the first author of the manuscript.
Finan, B.& Clemmensen, C. et al. (2016): Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease. Cell, DOI: 10.1016/j.cell.2016.09.014
Higher risk of diabetes due to two mutations
Interaction between the obesity-risk gene FTO and the dopamine D2 receptor gene ANKK1/TaqIA on insulin sensitivity.
In the development of obesity and diabetes, signals from the brain play an important role. Here an important neurotransmitter is dopamine. DZD scientists from Tübingen and Munich, together with Swedish and American colleagues, have investigated how mutations in the obesity risk gene FTO and variants of the dopamine D2 receptor gene interact. Their results suggest that people in whom both genes are altered have a higher risk of developing obesity and diabetes.
“Our studies show that when both genes are mutated, this can have a far-reaching effect on health. If due to the ANKK1 polymorphism there are fewer dopamine D2 receptors, those affected with mutated FTO have a higher percentage of body fat, more abdominal fat and low sensitivity to insulin in the body. In addition, in the caudate nucleus, the brain region that is important for dopamine metabolism, insulin sensitivity was altered,” said PD Dr. med. Martin Heni of the Institute for Diabetes Research and Metabolic Diseases (IDM) of Helmholtz Zentrum München at the University of Tübingen, summarizing the results.
Heni et al. (2016) Interaction between the obesity-risk gene FTO and the dopamine D2 receptor gene ANKK1/TaqIA on insulin sensitivity. Diabetologia, DOI 10.1007/s00125-016-4095-0
Molecule prevents positive effect of sport
TGFβ contributes to impaired exercise response by suppression of mitochondrial key regulators in skeletal muscle.
Physical exercise improves insulin sensitivity and thus reduces the risk for type 2 diabetes. However, every fifth person fails to improve after physical excercise intervention. Researchers from the German Center for Diabetes Research (DZD) found out why. They discovered that the signaling molecule TGFß is activated in the muscles of non-responders. TGFß inhibits genes that are involved in the glucose and fat oxidation and reduces insulin sensitivity. The DZD study involved 20 people with a high risk for type 2 diabetes who participated in a two-month long exercise program. They all lost weight and became more fit, yet in eight participants the insulin sensitivity did not improve. It may be that personalized training could help to lower the diabetes risk in these non-responders.
Böhm, A., et al. (2016) TGFβ contributes to impaired exercise response by suppression of mitochondrial key regulators in skeletal muscle. Diabetes, DOI: 10.2337/db15-1723
New Marker for Subpopulations of Beta Cells
Identification of proliferative and mature β-cells in the islet of Langerhans.
A recent DZD study has identified the protein Flattop as a marker to distinguish between mature beta cells and their precursors in the pancreas. (See figure: Flattop-positive beta cells (green), precursor cells without Flattop (red).)Approximately 80% of beta cells produce insulin; the remaining 20% form a highly proliferative reserve pool. Flattop is only present in mature beta cells. When blood glucose levels rise, these mature beta cells secrete insulin to keep glucose levels in equilibrium. In contrast, the cells without Flattop do not respond as well to glucose and secrete less insulin. Instead, they are capable of proliferating up to four times more often than beta cells expressing Flattop. They have a particularly high division rate during pregnancy and in the expansion phase during the neonatal period. This suggests that they are precursor cells of the beta cells that can serve as a reserve pool. By means of in vitro and in vivo genetic lineage tracing experiments, the DZD scientists confirmed that insulin-producing beta cells with Flattop develop from beta cells without Flattop. To carry out the study, the researchers introduced a genetic modification to cells and to a mouse line: The DZD scientists replaced the Flattop gene with a gene encoding a fluorescent reporter protein. When the gene was activated to express Flattop, the cells fluoresced green.Flattop itself is not causally involved in the maturation of beta cells. In mice that cannot generate Flattop, neither the maturation of beta cells nor the regulation of the glucose homeostasis is impaired. However, the DZD researchers showed that factors that regulate Flattop can also influence the maturation of beta cells and their activity.These findings provide an important basis for new therapeutic approaches in diabetes: First, they can contribute to the development of cell replacement therapy, in which mature beta cells are derived in the laboratory from stem cells. Second, they provide targets for new drugs that induce the regeneration of beta cell tissue by stimulating the conversion of immature precursor cells into insulin-secreting beta cells.
Bader, E. et al. (2016). Identification of proliferative and mature β-cells in the islet of Langerhans, Nature, DOI: 10.1038/nature18624
The Genetic Architecture of Type 2 Diabetes
The genetic architecture of type 2 diabetes.
Genetic disease or a question of lifestyle? So far, the question of hereditary components in type 2 diabetes has remained open. A paper published in ‘Nature’ now concludes that, contrary to model predictions, the influence of rare sequence variants in the human genome on diabetes risk is low. Rather, most genetic risk factors occur in regions that exist in a similar way in many people.
A team of more than 300 experts, including scientists from the German Center for Diabetes Research (DZD) at Helmholtz Zentrum München, analyzed the genome of 120,000 people with genetic origins in Europe, South and East Asia, North and South America and Africa. In the study they compared the sequence data of people with and without type 2 diabetes.
The sequence analysis of the whole genome as well as the exome – the subset of DNA that encodes proteins – in 15,700 test subjects resulted in 126 sequence variants that are significantly associated with diabetes risk. These DNA regions are in four genes: TCF7L2, ADCY5, CCND2 and EML4, whereby the first three have already been shown to be associated with diabetes risk.
The investigation of variants in the coding sequence sections in the DNA of more than 90,000 people also confirmed the results of previous genome-wide association studies (GWAS). For a single additional gene, MTMR3, the scientists were able to show a previously unknown association of a coding sequence variant with diabetes.
The results of these comprehensive analyses suggest that the genetic causes for diabetes risk in the population can be ascribed to frequent sequence variants in the DNA.
The genetic architecture of type 2 diabetes.
Fuchsberger C., et. al. Nature (2016). Jul 11. doi: 10.1038/nature18642.
Biomarker for Figure Type: Weight Gain in the Abdomen or at the Hips?
Specific Metabolic Markers Are Associated with Future Waist-Gaining Phenotype in Women.
PLoS One 2016
All body fat is not equal. The ratio of waist circumference to hip circumference is a significant predictor of the risk of diabetes or cardiovascular disease. With regard to body fat distribution, scientists differentiate between the metabolically more dangerous apple-shaped figure type with visceral (abdominal) fat and fat in the organs and the more harmless pear-shaped figure type with fat around the hips (peripheral fat) and under the skin.
When individuals gain weight over the years, they show a greater increase in waist circumference compared to hip circumference. This phenomenon was observed by DZD scientists in collaboration with the Competence Network Obesity in 4,126 adults in the German population studies KORA1, EPIC-Potsdam2 and DEGS3. A blood test can determine whether someone will accumulate more abdominal fat than peripheral fat. In the analysis of the metabolome the researchers found 21 abnormal metabolites in women. According to the researchers’ conclusions, a low concentration of lecithin in the blood is associated with the figure type with increased accumulation of fat at the waist. Conversely, a high level of lecithin favors the deposit of fat at the hips, which has a significantly lower risk; these women had significantly fewer abnormal metabolites.
In men the results were less clear. This could also be due to the fact that when men gain weight, they tend to deposit fat at the waist. Therefore a metabolic comparison of fat deposits in the abdomen versus hips has less significance. Earlier studies by the DZD already showed sex-specific differences in the metabolic profile (LINK).
1 KORA Study (Cooperative Health Research in the Region of Augsburg in der Region Augsburg) of HMGU
2 EPIC-Potsdam (European Prospective Investigation into Cancer and Nutrition) at DIfE
3 Study on the Health of Adults in Germany of the Robert Koch Institute
Original publicationMerz B, Nöthlings U, Wahl S, Haftenberger M, Schienkiewitz A, Adamski J, Suhre K, Wang-Sattler R, Grallert H, Thorand B, Pischon T, Bachlechner U, Floegel A, Peters A, Boeing H. Specific Metabolic Markers Are Associated with Future Waist-Gaining Phenotype in Women. PLoS One (2016). 11(6):e0157733.http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157733
New target in diabetes prevention
Alterations in β-cell calcium dynamics and efficacy outweigh islet mass adaptation in compensation of insulin resistance and prediabetes onset....
The majority of obese people with insulin resistance do not develop type 2 diabetes; their pancreas is able to compensate for the metabolic problems. But when does this compensation fail? For an answer, researchers from the German Center for Diabetes Research (DZD) investigated how pancreas cells in living animals change during the development of type 2 diabetes. Initially, the function of the insulin-producing beta cells in the islets of Langerhans become more active. Subsequently, the islet mass also gradually expands. Prior to prediabetes, beta-cell function decreases, whereas the islet continues to grow. Thus, the first step plays the more significant role in the compensation. Since this heightened activity is based on an increased calcium efficacy in the beta-cells, the scientists see the possibility of new pharmacological approaches in the prevention of type 2 diabetes.
Chunguang Chen et al., Alterations in β-cell calcium dynamics and efficacy outweigh islet mass adaptation in compensation of insulin resistance and prediabetes onset. dx.doi.org/10.2337/db15-1718. Diabetes 2016
Link to publicationhttp://diabetes.diabetesjournals.org/content/early/2016/04/07/db15-1718.article-info
High-fat diet starves the brain
Myeloid-Cell-Derived VEGF maintains brain glucose uptake and limits cognitive impairment in obesity. doi: 10.1016/j.cell.2016.03.033. Cell 2016
A high-fat diet of three days in mice leads to a reduction in the amount of glucose that reaches the brain. This finding was reported by a Research Group led by Jens Brüning, Director at the Max Planck Institute for Metabolism Research in Cologne and associated DZD partner. The mouse brain restored its glucose level after four weeks.
Responsible is the protein GLUT-1, which is the most important glucose transporter at the blood-brain barrier: Possible triggers for the reduction of the GLUT-1 transporter are free saturated fatty acids.
The brain responds to compensate its lack of energy. Specialized cells in the immune system produce the growth factor VEGF, which induces the production of GLUT-1. After four weeks glucose levels of the mice brain are normalized.
If there is a lack of VEGF and the fat uptake remains high, the brain provides itself with glucose at the cost oft he rest of the body. It stimulates the body’s appetite for sweets and prevents the glucose uptake in muscels and fat. The cells in the musculature become resistent to insulin, which normally regulates the glucose uptakte in these cells. This may lead to the development of diabetes.
Brüning Jens C et al., Myeloid-Cell-Derived VEGF maintains brain glucose uptake and limits cognitive impairment in obesity. doi: 10.1016/j.cell.2016.03.033. Cell 2016
Link to the publication
FigureCross-section through the brain of a mouse: regions with reduced uptake of glucose after three days of a high-fat diet© MPI f. Metabolism Research
Epigenetic modification precedes fatty liver
Early hypermethylation of hepatic Igfbp2 results in its reduced expression preceding fatty liver in mice. doi: 10.1093/hmg/ddw121. Hum Mol Genet....
An epigenetic modification increases the likelihood of obesity and precedes fatty liver disease. This was discovered by DZD scientists led by the German Institute of Human Nutrition (DIfE). They fed genetically identical mice a high-fat diet, whereupon a portion of the mice developed fatty livers. The researchers detected an epigenetic modification of the Igfbp2 gene, an increased methylation in specific sections of the DNA, already before the mice developed a fatty liver. The DZD scientists also found this change in blood cells of obese humans. It is possible that this modification already occurs during fetal development. An early detection of the modification could lead to the development of appropriate measures to lower the risk of obesity and fatty liver disease.
Kammel A, Saussenthaler S, Jähnert M, Jonas W, Stirm L, Hoeflich A, Staiger H, Fritsche A, Häring HU, Joost HG, Schürmann A, Schwenk RW. Early hypermethylation of hepatic Igfbp2 results in its reduced expression preceding fatty liver in mice. doi: 10.1093/hmg/ddw121. Hum Mol Genet. April 28, 2016
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New target for the treatment of fatty liver and diabetes
Fasting-induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health. doi: 10.15252/emmm.201505801. EMBO Mol Med. May 3,...
What happens at the molecular level when we go hungry? Scientists at Helmholtz Zentrum München in cooperation with the Deutsches Zentrum für Diabetesforschung (German Center for Diabetes Research - DZD) and the Deutsches Krebsforschungszentrum (German Cancer Research Center - DKFZ) were able to show that upon deprivation of food a certain protein is produced that adjusts the metabolism in the liver.
Prof. Stephan Herzig and colleagues wanted to answer the question why an intermittent fasting diet can help to whip the metabolism back into shape. They looked for liver cell genetic activity differences that were caused by fasting and they were able to show that especially the gene for the protein GADD45β was often read differently depending on the diet: the greater the hunger, the more frequently the cells produced the molecule. GADD45β is responsible for controlling the absorption of fatty acids in the liver. A low GADD45β level is accompanied by increased fat accumulation in the liver and an elevated blood sugar level.
The researchers now want to use the new findings for therapeutic intervention in the fat and sugar metabolism so that the positive effects of food deprivation might be translated for treatment.
Fuhrmeister J, Zota A, Sijmonsma TP, Seibert O, Cıngır Ş, Schmidt K, Vallon N, de Guia RM, Niopek K, Berriel Diaz M, Maida A, Blüher M, Okun JG, Herzig S, Rose AJ. Fasting-induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health. doi: 10.15252/emmm.201505801. EMBO Mol Med. May 3, 2016
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Respiratory infections as a risk factor for type 1 diabetes
Infections in Early Life and Development of Type 1 Diabetes. doi: 10.1001/jama.2016.2181. JAMA. May 3, 2016
DZD researchers at the Helmholtz Zentrum München found a further piece in the puzzle of understanding how type 1 diabetes develops. They show that viral respiratory infections during the first six months of life are associated with an increased risk for type 1 diabetes.
The scientists headed by Prof. Anette-Gabriele Ziegler examined data from almost 300,000 children born in Bavaria. Their findings show that viral respiratory tract disorders during the first six months of life significantly increase the risk of children developing type 1 diabetes. Infections that occurred later or that involved other organs were not associated with a significantly higher risk.
In the future the scientists want to determine whether there is actually a causal relationship and if yes, exactly which pathogens are involved and how they trigger this effect. This could then serve as a basis for attempting to develop an appropriate vaccine.
Beyerlein A, Donnachie E, Jergens S, Ziegler AG. Infections in Early Life and Development of Type 1 Diabetes. doi: 10.1001/jama.2016.2181. JAMA. May 3, 2016
Optimized approach for the prevention of type 1 diabetes
Type 1 diabetes vaccine candidates promote human Foxp3(+)Treg induction in humanized mice. doi: 10.1038/ncomms10991. Nature Communications. March 15,...
DZD scientists at Helmholtz Zentrum München are exploring new strategies to prevent the onset of type 1 diabetes. They have shown in a preclinical model that specifically modified insulin mimetopes may lead to an immune tolerance.
Dr. Carolin Daniel and colleagues investigated the effect of specifically modified insulin mimetopes on the immune system. Previous studies had shown that insulin mimetopes were significantly more efficient in inducing a tolerance through regulatory T cells towards insulin than their natural counterparts (epitopes). In young mice, the induction of insulin mimetopes at low doses completely halted the development of type 1 diabetes.
The next step was achieved in the study that has just been published: In a so-called humanized mouse model, whose immune system is very similar to that of humans, the scientists were able to confirm the results. In the long term the scientists want to further develop the method for preventive treatment of children at high risk for type 1 diabetes and to test the new therapy clinically.
Serr I, Fürst RW, Achenbach P, Scherm MG, Gökmen F, Haupt F, Sedlmeier EM, Knopff A, Shultz L, Willis RA, Ziegler AG, Daniel C. Type 1 diabetes vaccine candidates promote human Foxp3(+)Treg induction in humanized mice. doi: 10.1038/ncomms10991. Nature Communications. March 15, 2016
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Lifestyle is hereditary
Epigenetic germline inheritance of diet induced obesity and insulin resistance. doi: 10.1038/ng.3527. Nature Genetics. March 14, 2016
Parents could play an important role for the prevention of diabetes. DZD scientists at Helmholtz Zentrum München have shown that diet-induced obesity and diabetes can be epigenetically* inherited by the offspring.
For this study, Prof. Martin Hrabě de Angelis, Prof. Johannes Beckers and colleagues used mice that had become obese and had developed type 2 diabetes due to a high-fat diet. Their offspring were obtained solely through in vitro fertilization (IVF) from isolated oocytes and sperm, so that changes in the offspring could only be passed on via these cells. The offspring were carried and born by healthy surrogate mothers. The results showed that both oocytes and sperm passed on epigenetic information, which particularly in the female offspring led to severe obesity. In the male offspring, by contrast, the blood glucose level was more affected than in the female siblings.
This kind of epigenetic inheritance of a metabolic disorder due to an unhealthy diet could be another major cause for the dramatic global increase in the prevalence of diabetes. Since epigenetic inheritance – as opposed to genetic inheritance - is in principle reversible, new possibilities to influence the development of obesity and diabetes arise from these observations.
*Epigenetics: In contrast to genetics, the term epigenetics refers to the inheritance of traits that are not determined in the primary sequence of the DNA (the genes).
Huypens, P. et al. Epigenetic germline inheritance of diet induced obesity and insulin resistance. doi: 10.1038/ng.3527. Nature Genetics. March 14, 2016
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Genetic switch for the regulation of satiety and body weight
Hypothalamic Leptin Action is Mediated by Histone Deacetylase 5. doi: 10.1038/NCOMMS10782. Nature Communications. February 29, 2016
Why do we get fat and why is it so difficult for so many people to keep off excess weight? DZD scientists at the Helmholtz Zentrum München, in collaboration with colleagues of Technische Universität München, have identified a new mechanism that regulates the effect of the satiety hormone leptin. The study identified the enzyme HDAC5 as key factor in our control of body weight and food intake and potential target against the Yoyo dieting effect.
The enzyme histone deacetylase 5 (HDAC5) has a significant influence on the effect of the hormone leptin. This hormone plays a crucial role in triggering satiety and thus on how the body adapts to a changing food environment. Mice unable to produce HDAC5 respond significantly worse to leptin – a condition referred to as leptin resistance. They show a continuously increased food intake and they get fat. Through targeted activation of HDAC5 the team was able to reverse this effect, and thereby enabling obese animals to loose fat mass and body weight.
The restoration of leptin sensitivity is an important step on the path towards sustainable weight loss and towards combating type 2 diabetes. However, it remains to be seen in the coming years whether HDAC5 will be a suitable target in humans.
Kabra, DG et al. Hypothalamic Leptin Action is Mediated by Histone Deacetylase 5. doi: 10.1038/NCOMMS10782. Nature Communications. February 29, 2016
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Type 2 diabetes: Isomaltulose better than table sugar
Effects of Palatinose and Sucrose Intake on Glucose Metabolism and Incretin Secretion in Subjects With Type 2 Diabetes. doi: 10.2337/dc15-1891....
Like sucrose (table sugar), the natural disaccharide isomaltulose (PalatinoseTM) consists of glucose and fructose, but it is apparently more suitable for people with type 2 diabetes with regard to regulating blood glucose levels. This has now been confirmed in a new DZD study carried out by the German Institute of Human Nutrition (DIfE). The study showed for the first time on subjects with type 2 diabetes that the favorable metabolic effect of isomaltulose is due to the almost opposing release profiles of the gut hormones GLP-1 and GIP.
The researchers investigated the effect of 50 g isomaltulose and 50 g sucrose in a crossover study of 10 adults with type 2 diabetes. The mean peak blood glucose concentrations after isomaltulose ingestion were 20 percent lower. Insulin secretion was even 55 percent lower. Isomaltulose in the intestine reduces GIP secretion, increases GLP-1 secretion, and at the same time preserves a certain measure of insulin secretion, thus preventing severe fluctuations in blood glucose levels.
The scientists assume that the different metabolic effects of the two disaccharides, which are composed of one molecule of glucose and fructose, are due to the different chemical bond of the monosaccharides. While the digestive enzymes cleave sucrose quite rapidly into glucose and fructose, this process takes longer with isomaltulose. However, patients should be aware that isomaltulose provides the same number of calories as other types of sugar but it doesn’t taste as sweet.
Keyhani-Nejad F, Kemper M, Schueler R, Pivovarova O, Rudovich N, Pfeiffer AF. Effects of Palatinose and Sucrose Intake on Glucose Metabolism and Incretin Secretion in Subjects With Type 2 Diabetes. doi: 10.2337/dc15-1891. Diabetes Care. December 30, 2015
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Height Influences Risk of Cardiovascular Disease, Diabetes, and Cancer
Divergent associations of height with cardiometabolic disease and cancer: epidemiology, pathophysiology, and global implications. Lancet Diabetes &...
Tall people have a lower risk for cardiovascular disease and type 2 diabetes, but a higher risk of cancer. In recent decades the height of children and adults has steadily increased throughout the world. The increasing consumption of high caloric food and especially milk and dairy products seems to be one reason.
An analysis of DZD scientists in collaboration with US colleagues shows that height has an important impact on the mortality from certain common diseases, irrespective of body fat mass and other modulating factors. Per 6.5 cm increase in height the risk of cardiovascular mortality decreases by six percent, but cancer mortality, by contrast, increases by four percent.
The increase in body height might be a marker of overnutrition of high-calorie food rich in animal protein during stages of growth. Thus, already in utero, lifelong programming might take place that until now has mainly been established for the insulin-like growth factor 1 and 2 (IGF-1/2) system. Activation of this system causes the body to become more sensitive to insulin action and influences the lipid metabolism positively. Accordingly, new DZD data show that tall people are more sensitive to insulin and have lower fat content in the liver, which may explain their lower risk for cardiovascular disease and type 2 diabetes.
However, this activation of the IGF-1/2 system and other signaling pathways may be related to an increased risk of certain cancers, especially breast cancer, colon cancer, and melanoma.
Divergent associations of height with cardiometabolic disease and cancer: epidemiology, pathophysiology, and global implications. Lancet Diabetes & Endocrinology 2016 [epub ahead of print]
Genetic fine mapping for decoding causal mechanisms in type 2 diabetes
Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. Nature Genetics. doi: 10.1038/ng.3437....
To learn more about causal mechanisms in type 2 diabetes, DZD scientists and international colleagues investigated genes that are associated with diabetes. The researchers performed fine mapping of 39 established type 2 diabetes loci in 27,206 cases and 57,574 controls of European ancestry within the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) consortium. They identified 49 distinct association signals at these loci. Most of the T2D association signals are primarily driven by noncoding alleles, with effects that are mediated through gene regulation.
The study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. Nature Genetics. doi: 10.1038/ng.3437. December 1, 2015
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New approach for the study of metabolic diseases
Forcisi S, Moritz F, Lucio M, Lehmann R, Stefan N, Schmitt-Kopplin P. Solutions for Low and High Accuracy Mass Spectrometric Data Matching: A...
While very high mass accuracy is the first prerequisite for proper compound annotation, it is not compatible to state of the art high resolution liquid chromatography (the most frequently used technique in metabolomics). This incompatibility furthermore impairs the capacity of common metabolomics workflows to integrate data generated on both, high resolution/accuracy mass spectrometry (e.g. Fourier transform ion cyclotron resonance mass spectrometry: FT-ICR/MS) and ultra-high performance liquid chromatography coupled to mass spectrometry (UHPLC-MS) platforms. DZD scientists from the Research Unit Analytical BioGeoChemistry (BGC) at the Helmholtz Zentrum München have devised a data-driven retention time (RT) based strategy, which allows for high confidence annotations on UHPLC-MS data. Interestingly, the workflow is independent on column chemistry, and therefore it is resistant to sample matrix based alterations of the chemistry a given UHPLC separation is based on.
The strategy is demonstrated on the basis of samples from the Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Zentrum München at the University of Tübingen. Within the so called TULIP study, lifestyle intervention study of a cohort in Tübingen, they investigated plasma metabolome trends that mirror Insulin sensitivity in non-alcoholic fatty liver diseased (NAFLD) specimens. The strategy showed that UHPLC-MS and FT-ICR/MS address metabolome snapshots of largely differing composition. Still, the same compound classes were found to be relevant for the NAFLD phenotype. This comparison was only possible due to the retention-time-mass-difference network based annotation strategy, as UHPLC-MS signals are normally too inaccurate to perform robust and consistent sum formula assignments.
Forcisi S, Moritz F, Lucio M, Lehmann R, Stefan N, Schmitt-Kopplin P. Solutions for Low and High Accuracy Mass Spectrometric Data Matching: A Data-Driven Annotation Strategy in Nontargeted Metabolomics. doi: 10.1021/acs.analchem.5b02049. Analytical Chemistry. September 1, 2015
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Importance of insulin in the human brain
Linder K, Schleger F, Kiefer-Schmidt I, Fritsche L, Kümmel S, Heni M, Weiss M, Häring HU, Preissl H, Fritsche A. Gestational Diabetes Impairs Human...
In a newly published study, DZD scientists at the Tübingen University Hospital have shown for the first time that gestational diabetes slows the fetal brain response after the expectant mother consumes a meal. In this case already in utero, the fetus may have insulin resistance of the brain, which increases the probability that the child may become overweight later in life and develop diabetes.
Forty pregnant women participated in the study, including 12 who had gestational diabetes. The participants ingested a sugar solution (75 g glucose). One hour after the glucose uptake, the researchers found a significantly slower fetal brain response to the auditory stimuli in the group of women with gestational diabetes (measured by fetal magnetoencephalography). The authors conclude that the mother’s metabolism directly affects the brain function of the fetus and that gestational diabetes may induce insulin resistance in the brain already of the unborn child.
The current state of research on the importance of insulin in the human brain and the effects of insulin resistance there was summarized by the research group in an overview article in the prestigious journal Nature Reviews Endocrinology.
Linder K, Schleger F, Kiefer-Schmidt I, Fritsche L, Kümmel S, Heni M, Weiss M, Häring HU, Preissl H, Fritsche A. Gestational Diabetes Impairs Human Fetal Postprandial Brain Activity. doi: 10.1210/jc.2015-2692. J Clin Endocrinol Metab. October 14, 2015
Heni M, Kullmann S, Preissl H, Fritsche A, Häring HU. Impaired insulin action in the human brain: causes and metabolic consequences. doi: 10.1038/nrendo.2015.173. Nat Rev Endocrinol. October 13, 2015
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,...
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...
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...
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...
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.
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...
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
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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,...
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...
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...
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....
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....
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...
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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Insulin resistance in brain areas of obese
Kullmann S, Heni M, Veit R, Scheffler K, Machann J, Häring HU, Fritsche A, Preissl H. Selective Insulin Resistance in Homeostatic and Cognitive...
For the first time DZD scientists evaluated the specific brain areas affected by insulin resistance. They compared the cerebral blood flow (CBF) of lean and overweight/obese participants after application of intranasal insulin. Dr. Stephanie Kullmann, Dr. Hubert Preißl and colleagues (Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the Eberhard-Karls-University of Tübingen) found a significant CBF decrease in the hypothalamus in both lean and overweight/obese participants compared with placebo. The magnitude of this response correlated with visceral adipose tissue independent of other fat compartments. Furthermore, they observed a differential response in the lean compared with the overweight/obese group in the prefrontal cortex, resulting in an insulin-induced CBF reduction in lean participants only. This prefrontal cortex response significantly correlated with peripheral insulin sensitivity and eating behavior measures as disinhibition and food craving. Behaviorally, a significant reduction for the wanting of sweet foods after insulin application was observed in lean men only.
The identification of hormone-brain interactions that modulate food intake can potentially aid in the development of effective obesity therapies. Reduction of body weight would also contribute to the prevention of type 2 diabetes.
Kullmann S, Heni M, Veit R, Scheffler K, Machann J, Häring HU, Fritsche A, Preissl H. Selective Insulin Resistance in Homeostatic and Cognitive Control Brain Areas in Overweight and Obese Adults. doi: 10.2337/dc14-2319, Diabetes Care March 20, 2015
Link to the publication:http://care.diabetesjournals.org/content/early/2015/03/19/dc14-2319.long
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,...
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,...
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...
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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Granule age is critical for their mobility, exocytosis and intracellular degradation
Hoboth, P., Müller, A., Ivanova A., Mziaut H., Dehghany J., Sönmez A., Lachnit M., Meyer-Hermann M., Kalaidzidis Y., Solimena M. Aged insulin granules...
Independent lines of evidence suggest that newly generated insulin secretory granules (SGs) are preferentially secreted and more mobile than their older counterparts. However, mechanisms governing differential mobility and propensity to undergo exocytosis of age-distinct SGs were unknown. The work of Prof. Solimenas lab shows that aged SGs display reduced competence for glucose-stimulated microtubule-mediated transport and are disposed within actin-positive multigranular bodies. These results highlight the link between SG age and mobility and thus are relevant for better understanding insulin secretion in health and diabetes.
Hoboth, P., Müller, A., Ivanova A., Mziaut H., Dehghany J., Sönmez A., Lachnit M., Meyer-Hermann M., Kalaidzidis Y., Solimena M. Aged insulin granules display reduced microtubule-dependent mobility and are disposed within actin-positive multigranular bodies. doi: 10.1073/pnas.1409542112
PNAS February 2, 2015
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