The effect of endogenous GLP-1 secretion on islet function in vivo

We have recently demonstrated that, in humans, islet function is dependent on Glucagon-Like Peptide-1 (GLP- 1), presumably originating in the α-cell. Islet GLP-1 regulates insulin and glucagon secretion and its effects seem to be more important in type 2 diabetes. However, these observations raise additional questions which we seek to address in this application. The first is whether the isolated defects in the regulation of fasting or postprandial glucose tolerance, seen in prediabetes, represent selective failure of islet GLP-1 to support islet function. Accordingly, we will use GLP-1 receptor blockade with exendin 9-39 to better understand the role (or lack thereof) of islet GLP-1 in the pathogenesis of prediabetes. At present we do not know how the system is regulated. Rodent models suggest that factors secreted by the β-cell in response to agonism of the β-cell’s GLP-1 receptors regulate expression of the prohormone convertase enzyme necessary to convert proglucagon to GLP-1. This is testable in humans with and without functional β-cells. Their response to exendin 9-39 will be compared before and after 4-week treatment with a GLP-1 receptor agonist. The experimental design will also establish if the system is affected by glycemic control and weight loss. Finally, a common genetic variant in TCF7L2 predisposes to type 2 diabetes through effects on α- and β-cell function. However, the mechanism by which it does so remains obscure. TCF7L2 is a transcription factor that mediates proglucagon gene expression in endocrine-derived cells, driving GLP-1 expression in enteroendocrine cells. Therefore, we will test the hypothesis that the diabetes-associated variant at this locus (rs7903146) impairs islet production of GLP-1 thereby impairing islet function. The proposed experiments will help to understand the role and regulation of islet GLP-1, furthering our ability to prevent type 2 diabetes.