Dysfunction of Persisting β Cells Is a Key Feature of Early Type 2 Diabetes Pathogenesis

• Published in: Cell reports (Cambridge) Vol. 31; no. 1; p. 107469
• Main Authors: Cohrs, Christian M., Panzer, Julia K., Drotar, Denise M., Enos, Stephen J., Kipke, Nicole, Chen, Chunguang, Bozsak, Robert, Schöniger, Eyke, Ehehalt, Florian, Distler, Marius, Brennand, Ana, Bornstein, Stefan R., Weitz, Jürgen, Solimena, Michele, Speier, Stephan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.04.2020; Elsevier
• Subjects: Aged; beta cell function; beta cell mass; Blood Glucose - metabolism; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Female; Glucose - metabolism; human pancreas; Humans; Insulin - metabolism; Insulin Resistance - physiology; insulin secretion; Insulin Secretion - physiology; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Islets of Langerhans - metabolism; Male; Middle Aged; Pancreas - metabolism; Type 2 diabetes; Type 2 diabetes; insulin secretion; beta cell function; human pancreas; beta cell mass
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.03.033

Type 2 diabetes is characterized by peripheral insulin resistance and insufficient insulin release from pancreatic islet β cells. However, the role and sequence of β cell dysfunction and mass loss for reduced insulin levels in type 2 diabetes pathogenesis are unclear. Here, we exploit freshly explanted pancreas specimens from metabolically phenotyped surgical patients using an in situ tissue slice technology. This approach allows assessment of β cell volume and function within pancreas samples of metabolically stratified individuals. We show that, in tissue of pre-diabetic, impaired glucose-tolerant subjects, β cell volume is unchanged, but function significantly deteriorates, exhibiting increased basal release and loss of first-phase insulin secretion. In individuals with type 2 diabetes, function within the sustained β cell volume further declines. These results indicate that dysfunction of persisting β cells is a key factor in the early development and progression of type 2 diabetes, representing a major target for diabetes prevention and therapy. [Display omitted] •Pancreas tissue slices from surgical resections allow study of β cells in T2D•β cell dysfunction develops early and deteriorates further in T2D pathogenesis•Basal and first-phase insulin is altered in impaired glucose-tolerant donor tissue•β cell mass in tissue slices appears intact throughout the progression to T2D Cohrs et al. utilize pancreas tissue slices of metabolically phenotyped subjects undergoing pancreatectomy to assess β cell pathogenesis in type 2 diabetes development. They reveal β cell dysfunction as an early hallmark in type 2 diabetes pathogenesis, manifesting as increased basal and missing first-phase insulin secretion, although β cell mass is maintained.