Hexosamines regulate sensitivity of glucose-stimulated insulin secretion in beta-cells Export

@article{citeulike:4251938, abstract = {Hexosamines serve a nutrient-sensing function through enzymatic O-glycosylation of proteins. We previously characterized transgenic (Tg) mice with overexpression of the rate-limiting enzyme in hexosamine production, glutamine:fructose-6-phosphate amidotransferase, in {beta}-cells. Animals were hyperinsulinemic, resulting in peripheral insulin resistance. Glucose tolerance deteriorated with age, and males developed diabetes. We therefore examined islet function in these mice by perifusion in vitro. Young (2-mo-old) Tg animals had enhanced sensitivity to glucose of insulin secretion. Insulin secretion was maximal at 20 mM and half maximal at 9.9 {+/-} 0.5 mM glucose in Tg islets compared with maximal at 30 mM and half maximal at 13.5 {+/-} 0.7 mM glucose in wild type (WT; P < 0.005). Young Tg animals secreted more insulin in response to 20 mM glucose (Tg, 1,254 {+/-} 311; WT, 425 {+/-} 231 pg{middle dot}islet-1{middle dot}35 min-1; P < 0.01). Islets from older (8-mo-old) Tg mice became desensitized to glucose, with half-maximal secretion at 16.1 {+/-} 0.8 mM glucose, compared with 11.8 {+/-} 0.7 mM in WT (P < 0.05). Older Tg mice secreted less insulin in response to 20 mM glucose (Tg, 2,256 {+/-} 342; WT, 3,493 {+/-} 367 pg{middle dot}islet-1{middle dot}35 min-1; P < 0.05). Secretion in response to carbachol was similar in WT and Tg at both ages. Glucose oxidation was blunted in older Tg islets. At 5 mM glucose, islet CO2 production was comparable between Tg and WT. However, WT mice increased islet CO2 production 2.7 {+/-} 0.4-fold in 20 mM glucose, compared with only 1.4 {+/-} 0.1-fold in Tg (P < 0.02). Results demonstrate that hexosamines are involved in nutrient sensing for insulin secretion, acting at least in part by modulating glucose oxidation pathways. Prolonged excess hexosamine flux results in glucose desensitization and mimics glucose toxicity. 10.1152/ajpendo.00265.2005}, author = {Cooksey, Robert C. and Pusuluri, Sumitha and Hazel, Mark and Mcclain, Donald A.}, citeulike-article-id = {4251938}, citeulike-linkout-0 = {http://dx.doi.org/10.1152/ajpendo.00265.2005}, citeulike-linkout-1 = {http://ajpendo.physiology.org/cgi/content/abstract/290/2/E334}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/16188910}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=16188910}, day = {1}, doi = {10.1152/ajpendo.00265.2005}, journal = {Am J Physiol Endocrinol Metab}, keywords = {gfat, hexosamine-pathway}, month = {February}, number = {2}, pages = {E334--340}, posted-at = {2009-04-01 04:47:04}, priority = {2}, title = {Hexosamines regulate sensitivity of glucose-stimulated insulin secretion in {beta}-cells}, url = {http://dx.doi.org/10.1152/ajpendo.00265.2005}, volume = {290}, year = {2006} }

TY - JOUR ID - citeulike:4251938 L3 - citeulike-article-id:4251938 N2 - Hexosamines serve a nutrient-sensing function through enzymatic O-glycosylation of proteins. We previously characterized transgenic (Tg) mice with overexpression of the rate-limiting enzyme in hexosamine production, glutamine:fructose-6-phosphate amidotransferase, in {beta}-cells. Animals were hyperinsulinemic, resulting in peripheral insulin resistance. Glucose tolerance deteriorated with age, and males developed diabetes. We therefore examined islet function in these mice by perifusion in vitro. Young (2-mo-old) Tg animals had enhanced sensitivity to glucose of insulin secretion. Insulin secretion was maximal at 20 mM and half maximal at 9.9 {+/-} 0.5 mM glucose in Tg islets compared with maximal at 30 mM and half maximal at 13.5 {+/-} 0.7 mM glucose in wild type (WT; P < 0.005). Young Tg animals secreted more insulin in response to 20 mM glucose (Tg, 1,254 {+/-} 311; WT, 425 {+/-} 231 pg{middle dot}islet-1{middle dot}35 min-1; P < 0.01). Islets from older (8-mo-old) Tg mice became desensitized to glucose, with half-maximal secretion at 16.1 {+/-} 0.8 mM glucose, compared with 11.8 {+/-} 0.7 mM in WT (P < 0.05). Older Tg mice secreted less insulin in response to 20 mM glucose (Tg, 2,256 {+/-} 342; WT, 3,493 {+/-} 367 pg{middle dot}islet-1{middle dot}35 min-1; P < 0.05). Secretion in response to carbachol was similar in WT and Tg at both ages. Glucose oxidation was blunted in older Tg islets. At 5 mM glucose, islet CO2 production was comparable between Tg and WT. However, WT mice increased islet CO2 production 2.7 {+/-} 0.4-fold in 20 mM glucose, compared with only 1.4 {+/-} 0.1-fold in Tg (P < 0.02). Results demonstrate that hexosamines are involved in nutrient sensing for insulin secretion, acting at least in part by modulating glucose oxidation pathways. Prolonged excess hexosamine flux results in glucose desensitization and mimics glucose toxicity. 10.1152/ajpendo.00265.2005 IS - 2 JF - Am J Physiol Endocrinol Metab EP - 340 TI - Hexosamines regulate sensitivity of glucose-stimulated insulin secretion in {beta}-cells VL - 290 SP - E334 KW - gfat KW - hexosamine-pathway AU - Cooksey, Robert AU - Pusuluri, Sumitha AU - Hazel, Mark AU - Mcclain, Donald PY - 2006/02/01/ UR - http://dx.doi.org/10.1152/ajpendo.00265.2005 ER -