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

• Published in: Diabetes (New York, N.Y.) Vol. 54; no. 9; pp. 2755 - 2763
• Main Authors: KJØRHOLT, Cecilie, AKERFELDT, Mia C, BIDEN, Trevor J, LAYBUTT, D. Ross
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.09.2005
• Subjects: Aging; Animals; Biological and medical sciences; Blood lipids; Cell Differentiation - physiology; Diabetes Mellitus - physiopathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene Expression Regulation - physiology; Hyperglycemia; Hyperglycemia - physiopathology; Insulin - metabolism; Islets of Langerhans - cytology; Islets of Langerhans - metabolism; Lipids - blood; Medical sciences; Mice; Observations; Pancreatic beta cells; RNA, Messenger - metabolism; Australia; Endocrinopathy; Animal model; Diabetes mellitus; Langerhans islet; Rodentia; Lipids; Cell differentiation; Vertebrata; Chronic; Hyperglycemia; Mammalia; Mouse; Animal; β Cell; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.54.9.2755

Chronic Hyperglycemia, Independent of Plasma Lipid Levels, Is Sufficient for the Loss of β-Cell Differentiation and Secretory Function in the db/db Mouse Model of Diabetes Cecilie Kjørholt , Mia C. Åkerfeldt , Trevor J. Biden and D. Ross Laybutt From the Diabetes and Obesity Research Program, Garvan Institute of Medical Research, St Vincent’s Hospital, Sydney, Australia Address correspondence and reprint requests to Ross Laybutt, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst, Sydney 2010, Australia. E-mail: r.laybutt{at}garvan.org.au Abstract The β-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 β-cell dysfunction in the db/db mouse model of type 2 diabetes. In db/db islets, mRNA levels of many genes implicated in β-cell glucose sensing were progressively reduced with time, as were several transcription factors important for the maintenance of β-cell differentiation. Conversely, genes normally suppressed in β-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 β-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 γ 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 β-cell differentiation and secretory function in db/db mice. ATF-3, activating transcription factor 3 Β2/NeuroD, β-cell E-box trans-activator 2 CPT-1, carnitine palmitoyl transferase 1 GIIS, glucose-induced insulin secretion HNF1α, hepatocyte nuclear factor 1α 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 Footnotes The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted June 3, 2005. Received April 19, 2005. DIABETES