Hexosamines as mediators of nutrient sensing and regulation in diabetes.
High concentrations of glucose induce insulin resistance, impair insulin secretion, and affect hepatic glucose production in a manner that mirrors Type 2 diabetes, and hexosamines mimic many of these effects. This has led to the hypothesis that cells use hexosamine flux as a glucose- and satiety-sensing pathway. The hexosamine hypothesis for glucose sensing has been validated by overexpressing the rate-limiting enzyme for hexosamine synthesis, glutamine: fructose-6-phosphate amidotransferase (GFA) in several tissues including muscle, liver, fat, and beta cells. With overexpression of GFA in transgenic animals, skeletal muscle becomes insulin resistant, the liver synthesizes excess fatty acid, and the beta cell secretes excess insulin leading to hyperinsulinemia. Thus, excess hexosamine flux leads to a coordinated response whereby fuel is shunted toward long-term storage, mirroring the "thrifty phenotype." Chronically, however, these same adaptive changes result ultimately in obesity, hyperlipidemia, beta cell failure, and Type 2 diabetes. These results suggest a mechanism by which chronic overnutrition leads to the phenotype of Type 2 diabetes.
McClain
Donald A
DA
Department of Internal Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Utah and VA Medical Center, 50 N. Medical Drive, 4C116, Salt Lake City, UT 84132, USA. donald.mcclain@hsc.utah.edu
D000818:Animals; D003920:Diabetes Mellitus / Q000503:physiopathology*; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000235:genetics / Q000378:metabolism; D006595:Hexosamines / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D014280:Triglycerides / Q000097:blood
D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D006595:Hexosamines; D007328:Insulin; D014280:Triglycerides; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)