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Chronic Hyperglycemia, Independent of Plasma Lipid Levels, Is Sufficient for the Loss of ß-Cell Differentiation and Secretory Function in the db/db Mouse Model of Diabetes

From the Diabetes and Obesity Research Program, Garvan Institute of Medical Research, St Vincent’s Hospital, Sydney, Australia

The ß-cell is a highly specialized cell with a unique differentiation that optimizes glucose-induced insulin secretion (GIIS). Here, we evaluated changes in gene expression that accompany ß-cell dysfunction in the db/db mouse model of type 2 diabetes. In db/db islets, mRNA levels of many genes implicated in ß-cell glucose sensing were progressively reduced with time, as were several transcription factors important for the maintenance of ß-cell differentiation. Conversely, genes normally suppressed in ß-cells, such as a variety of stress response mediators and inhibitor of differentiation/DNA binding 1, a gene capable of inhibiting differentiation, were markedly increased. We assessed whether this global alteration in the pattern of ß-cell gene expression was related more to chronic hyperglycemia or hyperlipidemia; db/db mice were treated with phlorizin, which selectively lowered plasma glucose, or bezafibrate, which selectively lowered plasma lipids. GIIS as well as the majority of the changes in gene expression were completely normalized by lowering glucose but were unaffected by lowering lipids. However, the restoration of GIIS was not accompanied by normalized uncoupling protein 2 or peroxisome proliferator–activated receptor mRNA levels, which were upregulated in db/db islets. These studies demonstrate that hyperglycemia, independent of plasma lipid levels, is sufficient for the loss of ß-cell differentiation and secretory function in db/db mice.

Abbreviations: ATF-3, activating transcription factor 3; B2/NeuroD, ß-cell E-box trans-activator 2; CPT-1, carnitine palmitoyl transferase 1; GIIS, glucose-induced insulin secretion; HNF1, hepatocyte nuclear factor 1; IAPP, islet amyloid polypeptide; ID-1, inhibitor of differentiation/DNA binding 1; KRHB, Krebs-Ringer HEPES buffer; mGPDH, mitochondrial glycerol phosphate dehydrogenase; NEFA, nonesterified fatty acid; PDX-1, pancreatic duodenal homeobox-1; PPAR, peroxisome proliferator–activated receptor; SNAP25, synaptosomal-associated protein of 25 kDa; UCP-2, uncoupling protein 2

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