Mechanisms of defective insulin secretion in type 2 diabetes

Defective insulin secretion from the pancreatic B-cells is a central feature in type 2 diabetes (T2D). There is a strong hereditary component in type T2D, but the underlying pathophysiology remains largely unknown. This thesis uses a combination of gene network analysis and cell-physiological techniques to explore the genetic and cellular basis for impaired insulin secretion in T2D.
We found that genetic variants for type 2 diabetes near TCF7L2 and ADRA2A were associated with reduced glucose-induced insulin secretion. Moreover, susceptibility variants near ADRA2A, KCNJ11, KCNQ1, and TCF7L2 were associated with reduced depolarization-evoked insulin exocytosis. We combined our results to create a novel genetic risk score for B-cell dysfunction that includes aberrant granule docking, decreased Ca2+ sensitivity of exocytosis, and reduced insulin release. Individuals with a high risk score displayed an impaired response to intravenous glucose and deteriorating insulin secretion over time.
To obtain a more global view of the pathophysiology of T2D we next analyzed gene expression from microarray data of human pancreatic islets. A group of coexpressed genes (module), enriched for interleukin-1-related genes, was associated with T2D and reduced insulin secretion. One of the module genes that was highly overexpressed in islets from T2D patients is SFRP4, which encodes secreted frizzled-related protein 4. SFRP4 expression correlated with inflammatory markers, and its release from islets was stimulated by interleukin-1B. Elevated systemic SFRP4 caused reduced glucose tolerance through decreased islet expression of Ca2+ channels and suppressed insulin exocytosis. SFRP4 thus provides the first molecular link between islet inflammation and impaired insulin secretion. Moreover, the protein was increased in serum from diabetic patients several years before the diagnosis, suggesting that SFRP4 could be a potential biomarker for islet dysfunction in T2D.
We have also identified a gene co-expression module in human pancreatic islets that is enriched for genes with islet-specific open chromatin. In individuals with T2D this module displays an expression pattern that is reminiscent of a B-cell dedifferentiation profile. We have studied key transcription factors that may regulate this module.
Taken together, the findings shed new light on the pathophysiology of T2D and show the potential of combining genetics, bioinformatics and cell-physiology to better understand complex polygenic diseases.