This is a renewal application. During the previous funding period, we have made significant progress toward our understanding of pancreatic ?-cell compensation ? an adaptive mechanism by which ?-cells increase insulin secretion to overcome insulin resistance for maintaining euglycemia in obesity. ?-cell compensation also ensues during pregnancy to override maternal insulin resistance for accommodating the rising metabolic demand of insulin from the fetus and mother. Failure of ?-cells to compensate for obesity- or pregnancy-elicited insulin resistance results in insulin insufficiency, contributing to the onset of type 2 diabetes or gestational diabetes. It remains elusive how ?-cells compensate for insulin resistance and what causes ?-cell failure. Our studies characterize FoxO1 as a pivotal factor for ?-cell compensation. FoxO1 loss-of-function impairs ?-cell compensation, resulting in fat-induced diabetes, whereas FoxO1 gain-of-function augments ?-cell compensation, preventing glucose disorder in dietary obese male mice. Female mice with ?-cell FoxO1 depletion maintain euglycemia, but during pregnancy, all female ?-cell FoxO1-knockout mice develop fasting hyperglycemia and glucose intolerance and abnormal glucose-stimulated insulin secretion, characteristic of gestational diabetes. To deepen our understanding of the mechanism by which FoxO1 regulates the adaptive changes of ?-cell mass and function in response to overnutrition or pregnancy, we proposed two aims: 1) To determine the mechanisms by which FoxO1 integrates nutrient and insulin signals to ?-cell compensation for insulin resistance in diet-induced obesity, and 2) To characterize FoxO1 in gestational ?-cell compensation for maternal insulin resistance and determine the contribution of FoxO1 deregulation to gestational diabetes. Accomplishing this project will provide potential therapeutic avenues for augmenting ?-cell compensation to prevent the onset of diabetes in at-risk subjects with morbid obesity or gestational diabetes.
Type 2 diabetes results from ?-cell failure, culminating in the disability of ?-cells to compensate for insulin resistance in at-risk subjects with obesity. The fact that diabetes develops in some but not all insulin resistant subjects with obesity forebodes an intricate interplay between genetic and nutritional cues in ?-cell failure. Our goal is to characterize the genetic factor(s) that integrate ?-cell compensation with nutrient signals to understand the mechanism of ?-cell failure in diabetes.
