Chronic Methylglyoxal Infusion by Minipump Causes Pancreatic β-Cell Dysfunction and Induces Type 2 Diabetes in Sprague-Dawley Rats

Abstract

OBJECTIVEThe 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 β-cell insulin secreting mechanism in 12-week-old male Sprague-Dawley rats.RESEARCH DESIGN AND METHODSMG (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 β-cell line, for molecular studies. Western blotting, quantitative PCR, immunohistochemistry, and transferase-mediated dUTP nick-end labeling (TUNEL) assay were performed.RESULTSIn 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 β-cells, MG and MG + BSO reduced insulin secretion, pancreatic duodenal homeobox-1, MafA, GLUT-2, and glucokinase expression; increased C/EBPβ, nuclear factor-κB, MG-induced AGE, Nε-carboxymeythyllysine, and receptor for AGEs expression; and caused apoptosis. Alagebrium, an MG scavenger and an AGE-breaking compound, attenuated the effects of MG.CONCLUSIONSChronic MG induces biochemical and molecular abnormalities characteristic of type 2 diabetes and is a possible mediator of high carbohydrate-induced type 2 diabetes.

Methylglyoxal impairs insulin signalling and insulin action on glucose-induced insulin secretion in the pancreatic beta cell line INS-1E

“…Previous reports have shown that MGO alters insulin secretion [17,19,21]. Our current study on INS-1E cells further documents the inhibitory effect of MGO on glucoseinduced insulin secretion, but clearly goes beyond by providing decisive insight into the mechanisms involved.…”

“…We have also shown that MGO induces insulin resistance in skeletal muscle cells through direct chemical modification of IRS proteins [15]. Finally, MGO is thought to exert deleterious effects on insulin secretion [16][17][18][19][20][21]. However, the molecular mechanisms involved in the effect of MGO on the regulation of insulin release remains to be clarified.…”

Glyphosate, pathways to modern diseases IV: cancer and related pathologies

“…We have already noted that excess methylglyoxal exposure can lead to diabetes. Direct evidence of this was obtained when methylglyoxal injection into Sprague Dawley rats caused pancreatic β-cell dysfunction [164]. We earlier discussed the rôle of excess iron deposition in the destruction of pancreatic β cells [134].…”

Aging: Drugs to Eliminate Methylglyoxal, a Reactive Glucose Metabolite, and Advanced Glycation Endproducts

“…More direct evidence of interaction of alagebrium and MG using mass spectrometry would be very useful. We have also recently shown that alagebrium significantly attenuated the deleterious effects of chronic MG administration for 4 wks on glucose tolerance and pancreatic islet -cell function in male Sprague-Dawley rats [72].…”

“…Sprague-Dawley rats [72]. Elevated MG levels are linked to the development of microvascular complications of diabetes such as retinopathy and nephropathy, and other conditions such as atherosclerosis and neurodegenerative diseases [73][74][75][76][77].…”