Insulin resistance causes increased beta-cell mass but defective glucose-stimulated insulin secretion in a murine model of type 2 diabetes

Abstract

Aims/hypothesis: Although insulin resistance induces compensatory increases in beta cell mass and function to maintain normoglycaemia, it is not clear whether insulin resistance can precipitate beta cell dysfunction and hyperglycaemia without a pre-existing beta cell susceptibility. We therefore examined the beta cell phenotype in the MKR mouse, a model in which expression of a dominant-negative IGF 1 receptor (IGF1R) in skeletal muscle leads to systemic insulin resistance and diabetes. Materials and methods: Circulating glucose, insulin and glucagon concentrations were measured. Insulin sensitivity, glucose tolerance and insulin release in vivo were assessed by i.p. insulin and glucose tolerance tests. Beta cell function was assessed via insulin secretion from isolated islets and the glucose gradient in the perfused pancreas. Beta cell morphology was examined via immunohistochemistry. MKR mice were fed a high-fat diet containing sucrose (HFSD) to test metabolic capacity and beta cell function. Results: Insulin-resistant MKR mice developed hyperglycaemia and a loss of insulin responsiveness in vivo. Basal insulin secretion from the perfused pancreas was elevated, with no response to glucose. Despite the demand on insulin secretion, MKR mice had increased pancreatic insulin content and beta cell mass mediated through hyperplasia and hypertrophy. The HFSD worsened hyperglycaemia in MKR mice but, despite increased food intake in these mice, failed to induce the obesity observed in wild-type mice. Conclusions/interpretation: Our studies demonstrate that insulin resistance of sufficient severity can impair glucose-stimulated insulin secretion, thereby undermining beta cell compensation and leading to hyperglycaemia. Moreover, because insulin stores were intact, the secretory defects reflect an early stage of beta cell dysfunction.

Exendin-4 and exercise promotes β-cell function and mass through IRS2 induction in islets of diabetic rats

“…Glucokinase serves as a glucose sensor in pancreatic β-cells and regulates glucose-stimulated insulin release (Matschinsky, 2002). Increased insulin resistance due to a high fat diet, obesity and other conditions is known to reduce both GLUT-2 and glucokinase expression, thereby impairing glucose-stimulated insulin secretion (Cerf, 2007;Asghar et al, 2006). Furthermore, a high fat diet and other conditions increased insulin resistance, inducing oxidative stress and apoptosis, which reduce β-cell mass and compromises β-cell function (Cerf, 2007).…”

MKR mice have increased dynamic glucose disposal despite metabolic inflexibility, and hepatic and peripheral insulin insensitivity

“…Previously MKR mice have been shown to have exaggerated basal and glucose-stimulated insulin secretion due to beta cell hyperplasia, mediated by an increased number of proliferating beta cells [3] and by beta cell dysfunction [20]. While basal glucose levels are similar, whether or not [U- 13 C 6 ]glucose is infused, the higher basal insulin seen in our MKR mice during stable isotope infusion studies (Tables 2 and 3) may be secondary to the response of insulin-resistant MKR mice to the mass of glucose in the stable isotope infusion itself.…”

An insulin signaling feedback loop regulates pancreas progenitor cell differentiation during islet development and regeneration

“…The failure of β cell compensation to meet insulin demand results in diabetes mellitus, a metabolic disease of insufficient insulin signaling that is characterized by uncontrolled hyperglycemia and its associated morbid complications. While compensation can be transiently mediated in part via increased insulin production and release from existing β cells, long term β cell compensation involves the expansion of β cell mass by multiple mechanisms (Asghar et al, 2006; Wang et al, 2015; Weir and Bonner-Weir, 2004). For instance, in mice physiological stresses like over-nutrition and pregnancy can accelerate β cell replication (Kim et al, 2010; Lee and Nielsen, 2009; Tanaka and Wands, 1996).…”