Beta Cell Dysfunction Is a Hallmark of Early Type 2 Diabetes Pathogenesis

Dysfunction of Persisting β-Cells is a Key Feature of Early Type 2 Diabetes Pathogenesis. Cell Reports, 2020

The study utilizes pancreas tissue slices of metabolically phenotyped subjects undergoing pancreatectomy to assess beta cell pathogenesis in type 2 diabetes development. They reveal beta cell dysfunction as an early hallmark in type 2 diabetes pathogenesis, manifesting as increased basal and missing first-phase insulin secretion, although beta cell mass is maintained. © PLID

Already at an early stage of type 2 diabetes pathogenesis, the function of the insulin-producing beta cells deteriorates. The number of beta cells is unchanged at this stage. This is the result of a study recently published in Cell Reports by scientists of the German Center for Diabetes Research.

Type 2 diabetes is not only characterized by insulin resistance, but also by the fact that the pancreas produces less insulin. However, it has so far been unclear whether the insufficient insulin level during the development of the disease can be attributed to a dysfunction of the beta cells or to the loss of the beta cell mass. In order to gain new insights here, researchers led by Professor Stephan Speier have used a novel in situ platform for investigating the human pancreas in diabetes pathogenesis. Researchers from the DZD, the Paul Langerhans Institute in Dresden of Helmholtz Zentrum München and the Faculty of Medicine Carl Gustav Carus of TU Dresden, University Hospital Dresden and King's College London were involved in the study.

The group used freshly resected living pancreatic tissue to analyze the function of the beta cells in their original organ environment and to determine the beta cell volume. The tissues examined in this study came from donors from a larger patient cohort who had been metabolically phenotyped prior to pancreatectomy. The group included people without diabetes (ND), people with restricted glucose tolerance (IGT) and people with type 2 diabetes and thus represented the entire development spectrum of T2D pathogenesis. "After the production of 120 µm thick tissue sections, we were able to quantify glucose-induced insulin secretion in the tissue of test subjects under almost physiological conditions and, in parallel, examine the 3D cell morphology on adjacent sections," said the first author, Dr. Christian Cohrs from PLID and the DZD. This novel in situ approach for human pancreatic tissue sections made it possible for the first time to simultaneously investigate beta cell mass and function and to correlate these with the patients' diabetes status.

"Our data demonstrate that beta cells exhibit significant functional deterioration and exhaustion in early stages of T2D pathogenesis, when subjects have impaired glucose tolerance but are not yet diabetic. In contrast, beta cell numbers in the investigated tissues are maintained at this stage of the disease process," said Professor Speier, research  group leader at the Paul Langerhans Institute Dresden (PLID) and professor at the Institute of Physiology of TU Dresden. "Thus, our results identify beta cell dysfunction as an initial feature of diabetes development.”

Original publication:
Cohrs CM, Panzer JK, Drotar DM, Enos SJ, Kipke N, Chen C, Bozsak R, Schöniger E, Ehehalt F, Distler M, Brennand A, Bornstein SR, Weitz J, Solimena M, and Speier S. Dysfunction of Persisting β-Cells is a Key Feature of Early Type 2 Diabetes Pathogenesis. DOI: