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Chronic Methylglyoxal Infusion by Minipump Causes Pancreatic β-Cell Dysfunction and Induces Type 2 Diabetes in Sprague-Dawley Rats
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 chro...
Autores principales: | , , , , |
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Formato: | Texto |
Lenguaje: | English |
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American Diabetes Association
2011
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046851/ https://www.ncbi.nlm.nih.gov/pubmed/21300844 http://dx.doi.org/10.2337/db10-0627 |
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author | Dhar, Arti Dhar, Indu Jiang, Bo Desai, Kaushik M. Wu, Lingyun |
author_facet | Dhar, Arti Dhar, Indu Jiang, Bo Desai, Kaushik M. Wu, Lingyun |
author_sort | Dhar, Arti |
collection | PubMed |
description | 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 β-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 β-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 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, N(ε)-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. |
format | Text |
id | pubmed-3046851 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-30468512012-03-01 Chronic Methylglyoxal Infusion by Minipump Causes Pancreatic β-Cell Dysfunction and Induces Type 2 Diabetes in Sprague-Dawley Rats Dhar, Arti Dhar, Indu Jiang, Bo Desai, Kaushik M. Wu, Lingyun Diabetes Pathophysiology 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 β-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 β-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 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, N(ε)-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. American Diabetes Association 2011-03 2011-02-21 /pmc/articles/PMC3046851/ /pubmed/21300844 http://dx.doi.org/10.2337/db10-0627 Text en © 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Pathophysiology Dhar, Arti Dhar, Indu Jiang, Bo Desai, Kaushik M. Wu, Lingyun Chronic Methylglyoxal Infusion by Minipump Causes Pancreatic β-Cell Dysfunction and Induces Type 2 Diabetes in Sprague-Dawley Rats |
title | Chronic Methylglyoxal Infusion by Minipump Causes Pancreatic β-Cell Dysfunction and Induces Type 2 Diabetes in Sprague-Dawley Rats |
title_full | Chronic Methylglyoxal Infusion by Minipump Causes Pancreatic β-Cell Dysfunction and Induces Type 2 Diabetes in Sprague-Dawley Rats |
title_fullStr | Chronic Methylglyoxal Infusion by Minipump Causes Pancreatic β-Cell Dysfunction and Induces Type 2 Diabetes in Sprague-Dawley Rats |
title_full_unstemmed | Chronic Methylglyoxal Infusion by Minipump Causes Pancreatic β-Cell Dysfunction and Induces Type 2 Diabetes in Sprague-Dawley Rats |
title_short | Chronic Methylglyoxal Infusion by Minipump Causes Pancreatic β-Cell Dysfunction and Induces Type 2 Diabetes in Sprague-Dawley Rats |
title_sort | chronic methylglyoxal infusion by minipump causes pancreatic β-cell dysfunction and induces type 2 diabetes in sprague-dawley rats |
topic | Pathophysiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046851/ https://www.ncbi.nlm.nih.gov/pubmed/21300844 http://dx.doi.org/10.2337/db10-0627 |
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