Journal
DIABETES
Volume 60, Issue 3, Pages 899-908Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db10-0627
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- Heart and Stroke Foundation of Saskatchewan
- Canadian Institutes of Health Research (CIHR)
- Saskatchewan Health Research Foundation (SHRF)
- Heart Stroke Foundation of Canada
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OBJECTIVE-The incidence of high dietary carbohydrate-induced type 2 diabetes is increasing worldwide. Methylglyoxal (MG) is a reactive glucose metabolite and a major precursor of advanced glycation end products (AGEs). MG levels are elevated in diabetic patients. We investigated the effects of chronic administration of MG on glucose tolerance and p-cell insulin secreting mechanism in 12-week-old male Sprague-Dawley rats. RESEARCH DESIGN AND METHODS-MG (60 mg/kg/day) or 0.9% saline was administered by continuous infusion with a minipump for 28 days. We performed glucose and insulin tolerance tests and measured adipose tissue glucose uptake and insulin secretion from isolated pancreatic islets. We also used cultured INS-1E cells, a pancreatic beta-cell line, for molecular studies. Western blotting, quantitative PCR, immunohistochemistry, and transferase-mediated dUTP nick-end labeling (TUNEL) assay were performed. RESULTS-In rats treated with MG and MG + L-buthionine sulfoximine (BSO), MG levels were significantly elevated in plasma, pancreas, adipose tissue, and skeletal muscle; fasting plasma glucose was elevated, whereas insulin and glutathione were reduced. These two groups also had impaired glucose tolerance, reduced GLUT-4, phosphoinositide-3-kinase activity, and insulin-stimulated glucose uptake in adipose tissue. In the pancreatic beta-cells, MG and MG + BSO reduced insulin secretion, pancreatic duodenal homeobox-1, MafA, GLUT-2, and glucokinase expression; increased C/EBP beta, nuclear factor-kappa B, MG-induced AGE, N-epsilon-carboxymeythyllysine, and receptor for AGEs expression; and caused apoptosis. Alagebrium, an MG scavenger and an AGE-breaking compound, attenuated the effects of MG. CONCLUSIONS-Chronic MG induces biochemical and molecular abnormalities characteristic of type 2 diabetes and is a possible mediator of high carbohydrate-induced type 2 diabetes. Diabetes 60:899-908, 2011
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