Beta-Cell Compensation in Partial Pancreatectomy Mice

University Of Vermont & St Agric College, Burlington VT

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Abstract

PROJECT SUMMARY The islet [unreadable]-cell is the key regulatory element of the glucose homeostasis system. Changes in insulin sensitivity and/or [unreadable]-cell mass elicit precise adaptations from the remaining [unreadable]-cells so normoglycemia is maintained. How is that accomplished? What signaling pathways and [unreadable]-cell molecular processes are involved? This application continues our studies of the [unreadable]-cell adaptive mechanisms to a reduction in [unreadable]-cell mass such as occurs in evolving type 1 diabetes, likely also type 2 diabetes, using the experimental model of 60% pancreatectomy (Px) in normally insulin sensitive rodents. These rodents are normoglycemic following the reduction in [unreadable]-cell mass because of a multifacted adaptive response in islet [unreadable]-cells that results in maintenance of a normal level of secreted insulin. We plan to test a welldefined mechanistic schema for the adaptive responses that is based on findings from the prior funding period. Specifically, we propose an essential role for PPAR[unreadable] through its transcriptional regulation of key genes that impact [unreadable]-cell function and survival (Pdx-1), the incretin system (GIP receptor), and mitochondrial fuel metabolism (pyruvate carboxylase). Also, we propose upstream regulation of PPAR[unreadable] by the forkhead transcription factor FOXO1. This implies a broader role for this regulatory system than simply post-Px to include states of [unreadable]-cell adaptation that act through IRS-2/Akt such as insulin resistance. We will test these hypotheses in mice with genetically altered expression of key elements in the proposed regulatory pathways [unreadable] pancreas specific PPAR[unreadable] knockout and heterozygous FOXO1 knockout [unreadable] that undergo 60% Px or fat feeding. Parallel in vitro studies to identify the molecular details of the observed adaptive responses also will be performed. Aim #1 will determine the role of PPAR[unreadable] in the enhanced [unreadable]-cell function and survival following a reduction in [unreadable]-cell mass. We will test the hypothesis of a necessary role for PPAR[unreadable] in the post-Px [unreadable]cell adaptation by performing a 60% Px in pancreas-specific PPAR[unreadable] knockout mice, predicting hyperglycemia along with failed upregulation of the identified genes. Aim #2 will determine the molecular basis and functional significance of FOXO1 regulation of PPAR[unreadable] expression in [unreadable]-cells using in vitro siRNA studies for PPAR[unreadable] and FOXA2, and by determining the expression of Pdx-1 and PPAR[unreadable]-regulated genes following Akt activators (GLP-1 and insulin) in FOXO1 heterozygous knockout mice and normal mice. Aim #3 will determine the role of the FOXO1/PPAR[unreadable]/Pdx-1 pathway in the [unreadable]-cell adaptation to dietinduced obesity using fat feeding of FOXO1 heterozygous knockout mice and pancreas-specific PPAR[unreadable] knockout mice.