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By the Might of a Lash Against Bad Blood Sugar Levels

If the cilia on the pancreatic beta cells do not function properly, glucose intolerance and type 2 diabetes develop. In 'Nature Communications', a research team from the DZD partner Helmholtz Zentrum München now described the underlying mechanisms. The team found that the hair-like structures regulate insulin secretion into the pancreas using direct cell-cell communication pathways. The researchers hope that these findings will provide them with a long-term therapeutic target for both ciliopathies and diabetes.

Links: Langerhanssche Insel aus der Maus. Insulin aus den Betazellen grün, Zilien in Rot. Rechts: Elektronenmicrograph einer Betazelle, Zilium gekennzeichnet mit rotem Pfeil. ©Helmholtz Zentrum München, Yan Xiong/ Andreas Müller

 

Ciliopathies are genetic disorders of the ciliated cells. Cilia are lash-like cell protuberances that sensor mechanical or chemical stimuli. Cilia defects can cause a number of severe symptoms. “Rare cilia defects are associated with type 2 diabetes in humans,” says Dr. Jantje M. Gerdes. These include the Bardet-Biedl and the Alström syndrome*, both of which can be traced back to mutations in specific genes. Gerdes is head of the junior research group “Primary Cilia and Energy Metabolism” at the Institute for Diabetes and Regeneration Research at Helmholtz Zentrum München. Through her research on ciliopathies, she hopes to gain new insights into the mechanisms of type 2 diabetes. “Our research contributes to an even better understanding of the biology of beta and other cells in metabolically active tissues,” Gerdes explains.

Mouse model clarifies open questions on diabetes and ciliopathies
Prof. Dr. Hans-Ulrich Häring from the Institute for Diabetes Research and Metabolic Diseases at Helmholtz Zentrum München in Tübingen provided patient data for the current project. Correspondingly Gerdes and her team analyzed a mouse model that does not form functional cilia on beta cells. They found that glucose tolerance** and insulin release deteriorated significantly over twelve weeks. All phenomena were conveyed by so-called ephrin receptors, i.e. special binding sites on beta cells. EphA/Ephrin signals are upregulated and in turn suppress insulin secretion. Researchers observed similar reactions with islet cells from organ donors. The research group also evaluated data from a small cohort of 19 patients and found a correlation between ciliopathy genes and blood sugar levels.

From mouse to human
“In a mouse model we were able to show that in the pancreas cilia regulate direct cell-cell communication pathways and in that way control blood sugar levels,” summarized Francesco Volta, a member of Gerdes' junior research group. “Until now the regulatory role of cilia in beta cells has been underestimated,” stated Volta. “In that respect, our study closes a knowledge gap and could provide the basis for future therapies, both for ciliopathies and diabetes.”

Diabetes mellitus affects every eleventh adult worldwide. Most patients suffer from type 2 diabetes mellitus with insulin resistance. They have to take antidiabetics orally or inject insulin. Worldwide researchers are looking for new targets for pharmacotherapy.

 

*The Bardet–Biedl syndrome (BBS) and the Alström syndrome (AS) are two very rare genetic disorders. Patients are affected by a number of symptoms, such as excessive appetite, obesity and a higher-than-average risk of type 2 diabetes.

** In patients with impaired glucose tolerance, oral intake of carbohydrates leads to higher blood sugar levels than in healthy people. This can be regarded as a preliminary stage of diabetes mellitus.

Original publication:
F. Volta et al., 2019: Glucose homeostasis is regulated by pancreatic β-cell cilia via endosomal EphA-processing. Nature Communications, doi: 10.1038/s41467-019-12953-5