AIMS/HYPOTHESIS: The aim of the study was to evaluate the relationship between insulin sensitivity, beta cell function and glucose tolerance, and its dependence on variants in the newly identified Type 2 diabetes susceptibility gene, calpain-10 ( CAPN10). METHODS: We studied 203 men of the same age but with varying degrees of glucose tolerance. These men participated in (i) an oral glucose tolerance test, (ii) a euglycaemic clamp combined with indirect calorimetry and infusion of [3-(3)H]-glucose and (iii) a stepwise assessment of acute insulin response to arginine (AIR) at three different glucose concentrations (fasting, 14 and 28 mmol/l). RESULTS: There was a linear increase in NEFA levels ( p<0.0005) and WHR ( p<0.0005) and decrease in glucose uptake due to a reduction in glucose storage over the entire range of glucose tolerance ( r=-0.404; p<0.005). No increase in endogenous glucose production (EGP) was seen until patients had manifest diabetes. However, when EGP was expressed relative to fasting insulin concentrations, there was a linear deterioration of basal hepatic insulin sensitivity ( r=-0.514; p<0.005). The AIR followed a bell-shaped curve with an initial rise and subsequent decrease. However, AIR adjusted for insulin sensitivity (disposition index) showed a linear decrease with increasing glucose concentrations ( r=-0.563; p<0.001) starting already in subjects with normal glucose tolerance. There was an inverse correlation between increase in WHR and NEFA and peripheral as well as hepatic insulin sensitivity. Subjects with the genotype combination of CAPN10 consisting of SNP44 TT and SNP43 GG genotypes had significantly lower insulin-stimulated glucose uptake than carriers of the other genotype combinations (5.3+/-0.4 vs 7.2+/-0.4 mg.ffm kg(-1).min(-1).mU.l(-1); p<0.005). CONCLUSIONS/ INTERPRETATION: We conclude that the pre-diabetic state is characterised by a similar linear deterioration of peripheral and hepatic insulin sensitivity as beta cell function and that variants in the CAPN10 gene modify this relationship. These findings are compatible with a common defect in muscle, liver and beta cells in the pathogenesis of Type 2 diabetes.
AIMS/HYPOTHESIS: The aim of the study was to evaluate the relationship between insulin sensitivity, beta cell function and glucose tolerance, and its dependence on variants in the newly identified Type 2 diabetes susceptibility gene, calpain-10 ( CAPN10). METHODS: We studied 203 men of the same age but with varying degrees of glucose tolerance. These men participated in (i) an oral glucose tolerance test, (ii) a euglycaemic clamp combined with indirect calorimetry and infusion of [3-(3)H]-glucose and (iii) a stepwise assessment of acute insulin response to arginine (AIR) at three different glucose concentrations (fasting, 14 and 28 mmol/l). RESULTS: There was a linear increase in NEFA levels ( p<0.0005) and WHR ( p<0.0005) and decrease in glucose uptake due to a reduction in glucose storage over the entire range of glucose tolerance ( r=-0.404; p<0.005). No increase in endogenous glucose production (EGP) was seen until patients had manifest diabetes. However, when EGP was expressed relative to fasting insulin concentrations, there was a linear deterioration of basal hepatic insulin sensitivity ( r=-0.514; p<0.005). The AIR followed a bell-shaped curve with an initial rise and subsequent decrease. However, AIR adjusted for insulin sensitivity (disposition index) showed a linear decrease with increasing glucose concentrations ( r=-0.563; p<0.001) starting already in subjects with normal glucose tolerance. There was an inverse correlation between increase in WHR and NEFA and peripheral as well as hepatic insulin sensitivity. Subjects with the genotype combination of CAPN10 consisting of SNP44 TT and SNP43 GG genotypes had significantly lower insulin-stimulated glucose uptake than carriers of the other genotype combinations (5.3+/-0.4 vs 7.2+/-0.4 mg.ffm kg(-1).min(-1).mU.l(-1); p<0.005). CONCLUSIONS/ INTERPRETATION: We conclude that the pre-diabetic state is characterised by a similar linear deterioration of peripheral and hepatic insulin sensitivity as beta cell function and that variants in the CAPN10 gene modify this relationship. These findings are compatible with a common defect in muscle, liver and beta cells in the pathogenesis of Type 2 diabetes.
Authors: S K Sreenan; Y P Zhou; K Otani; P A Hansen; K P Currie; C Y Pan; J P Lee; D M Ostrega; W Pugh; Y Horikawa; N J Cox; C L Hanis; C F Burant; A P Fox; G I Bell; K S Polonsky Journal: Diabetes Date: 2001-09 Impact factor: 9.461
Authors: Søren K Rasmussen; Søren A Urhammer; Lars Berglund; Jan N Jensen; Lars Hansen; Søren M Echwald; Knut Borch-Johnsen; Yukio Horikawa; Hirosato Mashima; Hans Lithell; Nancy J Cox; Torben Hansen; Graeme I Bell; Oluf Pedersen Journal: Diabetes Date: 2002-12 Impact factor: 9.461
Authors: G W Cline; K F Petersen; M Krssak; J Shen; R S Hundal; Z Trajanoski; S Inzucchi; A Dresner; D L Rothman; G I Shulman Journal: N Engl J Med Date: 1999-07-22 Impact factor: 91.245
Authors: L J Baier; P A Permana; X Yang; R E Pratley; R L Hanson; G Q Shen; D Mott; W C Knowler; N J Cox; Y Horikawa; N Oda; G I Bell; C Bogardus Journal: J Clin Invest Date: 2000-10 Impact factor: 14.808
Authors: A Dresner; D Laurent; M Marcucci; M E Griffin; S Dufour; G W Cline; L A Slezak; D K Andersen; R S Hundal; D L Rothman; K F Petersen; G I Shulman Journal: J Clin Invest Date: 1999-01 Impact factor: 14.808
Authors: Cullen M Taniguchi; Thien T Tran; Tatsuya Kondo; Ji Luo; Kohjiro Ueki; Lewis C Cantley; C Ronald Kahn Journal: Proc Natl Acad Sci U S A Date: 2006-07-31 Impact factor: 11.205
Authors: Willeke de Haan; Alpana Bhattacharjee; Piers Ruddle; Martin H Kang; Michael R Hayden Journal: J Lipid Res Date: 2014-01-17 Impact factor: 5.922
Authors: Alberto O Chavez; Subhash Kamath; Rucha Jani; Lokendra K Sharma; Adriana Monroy; Muhammad A Abdul-Ghani; Victoria E Centonze; Padma Sathyanarayana; Dawn K Coletta; Cristopher P Jenkinson; Yidong Bai; Franco Folli; Ralph A Defronzo; Devjit Tripathy Journal: J Clin Endocrinol Metab Date: 2009-10-28 Impact factor: 5.958