Beta-cell compensation is an adaptive mechanism by which ?-cells increase insulin secretion to overcome insulin resistance or oxidative stress for maintaining euglycemia in obesity. Beta-cell compensation culminates in the expansion of ?-cell mass and/or upregulation of insulin synthesis/secretion. Failure of ?- cells to compensate for insulin resistance or oxidative stress contributes to insulin insufficiency and overt diabetes. How ?-cells compensate for insulin resistance or oxidative stress and what causes ?-cell failure are poorly understood. FoxO1 is a transcription factor that integrates insulin (or IGF-1) signaling to target genes in cell survival, proliferation, differentiation, metabolism and anti-oxidation. Human with genetic FoxO1 variants are associated with an increased risk of ?-cell dysfunction and type 2 diabetes. We show that transgenic mice with RIP (rat insulin promoter)-directed FoxO1 production in islets are protected against fat-induced glucose intolerance and streptozotocin-elicited diabetes. This effect is attributable to augmented glucose-stimulated insulin secretion and increased ?-cell mass in RIP-FoxO1 transgenic mice. FoxO1 activity is upregulated in islets, correlating with the physiological induction of ?-cell compensation in dietary obese mice. These new data underscore the importance of FoxO1 in ?-cell function, spurring the hypothesis that FoxO1 contributes to ?-cell compensation. To address this hypothesis, we propose three specific aims: 1) To determine the effect of FoxO1 gain-of-function on ?-cell compensation for insulin resistance;2) To address the mechanisms by which FoxO1 enhances ?-cell compensation for oxidative stress;and 3) To determine the effect of FoxO1 loss-of-function on ?-cell compensation in obesity and diabetes. To achieve these goals, we will employ gene transfer, transgenic expression, gene knockout and siRNA-mediated gene-silencing approaches to achieve ?-cell specific FoxO1 production and alternatively conditional FoxO1 depletion in mature islets in vivo as well as in human islets ex vivo, followed by determining the ability of ?-cells with FoxO1 gain- vs. loss-of-function to compensate for insulin resistance and oxidative stress. We have provided proof-of-principle and demonstrated the feasibility for the proposal. Accomplishing this project will deepen our understanding of the mechanisms of ?-cell compensation and ?- cell failure in diabetes.
Type 2 diabetes results from beta-cell failure, culminating in the inability of beta-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 the pathogenesis of beta-cell failure. Our goal is to characterize the genetic factor(s) that are responsible for coupling beta-cell compensation with nutrient signals to understand the underlying mechanism of beta-cell failure in diabetes.
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