The Role of Somatostatin in the Deficient Glucagon Response to Acute and Recurrent Hypoglycemia in Type 2 Diabetes

Abstract

Treatment-induced hypoglycemia results from impaired glucagon counterregulation in a setting of intensive glucose-lowering therapies and remains the major clinical barrier to achieving optimal glycemic control in type 1 diabetes (T1D) and advanced type 2 diabetes (T2D). This dissertation establishes a role for paracrine somatostatin (SST) signaling in the pathogenesis of glucagon counterregulatory failure in diabetes based on data collected from rodent models in vivo and human donor islets in vitro. First, building on existing evidence from pre-clinical models of T1D, this work demonstrates that pharmacologic SSTR2 antagonism can restore physiologic glucagon counterregulation and resist hypoglycemia onset when administered before insulin overdose in rat models of recurrent hypoglycemia (Chapter 4) and pre-diabetes (Chapter 5). Second, when administered as a rescue agent after the onset of severe hypoglycemia in recurrently hypoglycemic rats, SSTR2 antagonism was shown to provide more gradual but sustained glycemic recovery compared to the relatively transient effect of high-dose exogenous glucagon (Chapter 6). Third, functional analysis of isolated human islets in vitro showed that deficient glucagon secretion from pancreatic α-cells under low glucose conditions corresponded with a marked hypersecretion of SST, as in T1D. Excess paracrine inhibition by SST may underscore the α-cell defect in T2D islets as evidenced by the restorative effect of SSTR2a antagonism on counterregulatory glucagon secretion (Chapter 7.1). These, and other findings from this thesis, suggest that inhibitory SST tone is typically alleviated under low glucose concentration in non-diabetic islets, providing a permissive paracrine signal for counterregulatory glucagon release that is compromised in T2D. Collectively, this work proposes that targeting SST secretion or action may represent a novel therapeutic strategy for improving glycemic control and reducing the risk of acute and recurrent hypoglycemia in advanced T2D.