PWD/PhJ mice have a genetically determined increase in nutrient-stimulated insulin secretion

Abstract

PWD/PhJ (PWD) is a wild-derived inbred mouse strain unrelated to commonly studied strains, such as C57BL/6J (B6). A chromosome substitution panel with PWD chromosomes transferred into the B6 background is commercially available and will facilitate genetic analysis of this strain. We have previously shown that the PWD strain is a model of primary fasting hyperinsulinemia. To identify more specific phenotypes affected by the genetic variation in PWD compared to B6 mice, we examined physiological mechanisms that may contribute to their elevated insulin levels. PWD mice had increased nutrient-stimulated insulin secretion due to factors inherent to their pancreatic islets. Insulin secretion responses to glucose, palmitate, and the metabolic intermediate α-ketoisocaproate were increased ~2-fold in islets from PWD mice compared to B6 islets. In contrast, there were no strain differences in processes affecting insulin secretion downstream of β cell depolarization. PWD mice tended to have larger but fewer islets than B6 mice, resulting in similar insulin-staining areas and insulin content per unit of pancreatic tissue. However, pancreata of PWD mice were smaller, resulting in reduced total β cell mass and pancreatic insulin content compared to B6 mice. Combined, these data suggest that the elevated fasting insulin levels in PWD mice result from increased generation of metabolic signals leading to β cell depolarization and insulin secretion. Identification of the genetic differences underlying the enhanced nutrient-stimulated insulin secretion in this model may lead to new approaches to appropriately modulate insulin secretion for the treatment of obesity and type 2 diabetes.