A key pathogenic feature of type 2 diabetes is loss of the beta-cell compensation to the insulin resistance that occurs in this disease. The biochemical and molecular nature of this beta-cell failure are poorly known, in part because of lack of animal models that faithfully reproduce the natural history of the human disease. This proposal makes use of a newly developed rat model, the 60% pancreatectomy Zucker rat that incorporates the characteristic features of human adipogenic diabetes - obesity, insulin resistance, and hyperlipidemia. They are characterized by a 3-week period of relative normoglycemia after the partial pancreatectomy (compensation phase) that is followed by the onset of beta-cell dysfunction and mild hyperglycemia (decompensation phase). We will use this model to test the hypothesis of this application that enhanced then impaired a-cell anaplerosis and lipid partitioning are the mechanistic basis for the beta-cell compensation and subsequent beta-cell failure in these rats. A notable aspect of this application is it stems as a joint effort from the laboratories of Drs. Jack Leahy (Burlington, VT) and Marc Prentki (Montreal, Canada) who have complimentary research expertise in the fields of beta cell anaplerosis/lipid partitioning and the beta cell failure in rodent models of type 2 diabetes.
Aim 1 will determine the cellular mechanisms and signaling pathways for beta-cell compensatory growth or loss of beta-cell mass in the 60% Px ZF rat model at different stages during the progression to diabetes.
Aim 2 will test the hypothesis that the mechanism of beta-cell decompensation in the 60% Px ZF rat model is related to failure of compensatory enhanced anaplerosis and lipid signaling processes.
Aim 3 will test the hypothesis that the beta-cell failure in 60% Px ZF rats is in part due to inadequate proinsulin synthesis relative to secretion. These studies will provide a better understanding of the molecular basis for beta-cell compensation and failure, and they hold considerable promise to provide targets for novel pharmaceutical approaches to the prevention or more effective treatment of type 2 diabetes.
| Delghingaro-Augusto, V; Nolan, C J; Gupta, D et al. (2009) Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass. Diabetologia 52:1122-32 |
| Gupta, Dhananjay; Jetton, Thomas L; Mortensen, Richard M et al. (2008) In vivo and in vitro studies of a functional peroxisome proliferator-activated receptor gamma response element in the mouse pdx-1 promoter. J Biol Chem 283:32462-70 |
| Peshavaria, Mina; Larmie, Brooke L; Lausier, James et al. (2006) Regulation of pancreatic beta-cell regeneration in the normoglycemic 60% partial-pancreatectomy mouse. Diabetes 55:3289-98 |
| Leahy, Jack L (2005) Pathogenesis of type 2 diabetes mellitus. Arch Med Res 36:197-209 |
