The T-allele of TCF7L2 rs7903146 associates with a reduced compensation of insulin secretion for insulin resistance induced by 9 days of bed rest - PubMed (original) (raw)
The T-allele of TCF7L2 rs7903146 associates with a reduced compensation of insulin secretion for insulin resistance induced by 9 days of bed rest
Amra C Alibegovic et al. Diabetes. 2010 Apr.
Abstract
Objective: The aim of this study was to determine whether the type 2 diabetes-associated T-allele of transcription factor 7-like 2 (TCF7L2) rs7903146 associates with impaired insulin secretion to compensate for insulin resistance induced by bed rest.
Research design and methods: A total of 38 healthy young Caucasian men were studied before and after bed rest using the hyperinsulinemic-euglycemic clamp technique combined with indirect calorimetry preceded by an intravenous glucose tolerance test. The TCF7L2 rs7903146 was genotyped using allelic discrimination performed with an ABI 7900 system. The genetic analyses were done assuming a dominant model of inheritance.
Results: The first-phase insulin response (FPIR) was significantly lower in carriers of the T-allele compared with carriers of the CC genotype before bed rest, with and without correction for insulin resistance. The incremental rise of FPIR in response to insulin resistance induced by bed rest was lower in carriers of the T-allele (P < 0.001). Fasting plasma glucagon levels were significantly lower in carriers of the T-allele before and after bed rest. While carriers of the CC genotype developed increased hepatic insulin resistance, the TCF7L2 rs7903146 did not influence peripheral insulin action or the rate of lipolysis before or after bed rest.
Conclusions: Healthy carriers of the T-allele of TCF7L2 rs7903146 exhibit a diminished increase of insulin secretion in response to intravenous glucose to compensate for insulin resistance as induced by bed rest. Reduced paracrine glucagon stimulation may contribute to the impairment of beta-cell function in the carriers TCF7L2 rs7903146 T-allele associated with increased risk of type 2 diabetes.
Figures
FIG. 1.
Schematic presentation of the experimental day(s). Whole-body glucose metabolism was measured by a hyperinsulinemic-euglycemic clamp technique. Steady-state measurements of plasma glucose and plasma glycerol enrichments were performed during the basal period (before the insulin stimulation) to determine hepatic glucose production and whole-body lipolysis rate. Arrows show points for collecting of blood samples for basal-state determination of stable isotope kinetics.
FIG. 2.
AUC0–10 min for plasma insulin during IVGTT before bed rest. Data are presented as means ± SE in carriers of the risk T-allele (●) and carriers of low-risk CC genotype (○) and AUC0–10 min for plasma C-peptide during IVGTT before bed rest. Data are presented as means ± SE in carriers of the risk T-allele (▼) and carriers of low-risk CC genotype (△).
FIG. 3.
AUC0–10 min for plasma insulin during IVGTT after bed rest. Data are presented as means ± SE in carriers of the risk T-allele (●) and carriers of low-risk CC genotype (○) and AUC0–10 min for plasma C-peptide during IVGTT after bed rest. Data are presented as means ± SE in carriers of the risk T-allele (▼) and carriers of low-risk CC genotype (△). *P < 0.05; **P < 0.01.
FIG. 4.
Plasma insulin concentration during 9 days of bed rest; *P < 0.05. Data are presented as means ± SE in carriers of the risk T-allele (△) and carriers of low-risk CC genotype (▼). _P_ANOVAday1 = 0.93; _P_day2 = 0.41; _P_day3 = 0.75; _P_day5 = 0.15; _P_day7 = 0.24; _P_day9 = 0.02. Plasma C-peptide concentration during 9 days of bed rest; *P < 0.05. Data are presented as means ± SE in carriers of the risk T-allele (○) and carriers of low-risk CC genotype (●). _P_ANOVAday1 = 0.63; _P_day2 = 0.24; _P_day3 = 0.39; _P_day5 = 0.14; _P_day7 = 0.39; _P_day9 = 0.02.
Similar articles
- Effect of TCF7L2 on the relationship between lifestyle factors and glycemic parameters: a systematic review.
Hosseinpour-Niazi S, Mirmiran P, Hosseini S, Hadaegh F, Ainy E, Daneshpour MS, Azizi F. Hosseinpour-Niazi S, et al. Nutr J. 2022 Sep 26;21(1):59. doi: 10.1186/s12937-022-00813-w. Nutr J. 2022. PMID: 36155628 Free PMC article. Review. - Impact of TCF7L2 rs7903146 on insulin secretion and action in young and elderly Danish twins.
Wegner L, Hussain MS, Pilgaard K, Hansen T, Pedersen O, Vaag A, Poulsen P. Wegner L, et al. J Clin Endocrinol Metab. 2008 Oct;93(10):4013-9. doi: 10.1210/jc.2008-0855. Epub 2008 Jul 8. J Clin Endocrinol Metab. 2008. PMID: 18611970 - The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men.
Pilgaard K, Jensen CB, Schou JH, Lyssenko V, Wegner L, Brøns C, Vilsbøll T, Hansen T, Madsbad S, Holst JJ, Vølund A, Poulsen P, Groop L, Pedersen O, Vaag AA. Pilgaard K, et al. Diabetologia. 2009 Jul;52(7):1298-307. doi: 10.1007/s00125-009-1307-x. Epub 2009 Mar 14. Diabetologia. 2009. PMID: 19288077 - Interactions between TCF7L2 genotype and growth hormone-induced changes in glucose homeostasis in small for gestational age children.
de Kort SW, Mook-Kanamori DO, Jaddoe VW, Hokken-Koelega AC. de Kort SW, et al. Clin Endocrinol (Oxf). 2010 Jan;72(1):47-52. doi: 10.1111/j.1365-2265.2009.03635.x. Epub 2009 May 18. Clin Endocrinol (Oxf). 2010. PMID: 19473183 - TCF7L2 genetic defect and type 2 diabetes.
Cauchi S, Froguel P. Cauchi S, et al. Curr Diab Rep. 2008 Apr;8(2):149-55. doi: 10.1007/s11892-008-0026-x. Curr Diab Rep. 2008. PMID: 18445358 Review.
Cited by
- The crucial role and mechanism of insulin resistance in metabolic disease.
Zhao X, An X, Yang C, Sun W, Ji H, Lian F. Zhao X, et al. Front Endocrinol (Lausanne). 2023 Mar 28;14:1149239. doi: 10.3389/fendo.2023.1149239. eCollection 2023. Front Endocrinol (Lausanne). 2023. PMID: 37056675 Free PMC article. - Effect of TCF7L2 on the relationship between lifestyle factors and glycemic parameters: a systematic review.
Hosseinpour-Niazi S, Mirmiran P, Hosseini S, Hadaegh F, Ainy E, Daneshpour MS, Azizi F. Hosseinpour-Niazi S, et al. Nutr J. 2022 Sep 26;21(1):59. doi: 10.1186/s12937-022-00813-w. Nutr J. 2022. PMID: 36155628 Free PMC article. Review. - The T allele of TCF7L2 rs7903146 is associated with decreased glucose tolerance after bed rest in healthy older adults.
Fry JL, Munson BD, Thompson KL, Fry CS, Paddon-Jones D, Arentson-Lantz EJ. Fry JL, et al. Sci Rep. 2022 Apr 27;12(1):6897. doi: 10.1038/s41598-022-10683-1. Sci Rep. 2022. PMID: 35477971 Free PMC article. - Interventions outside the workplace for reducing sedentary behaviour in adults under 60 years of age.
Murtagh EM, Murphy MH, Milton K, Roberts NW, O'Gorman CS, Foster C. Murtagh EM, et al. Cochrane Database Syst Rev. 2020 Jul 17;7(7):CD012554. doi: 10.1002/14651858.CD012554.pub2. Cochrane Database Syst Rev. 2020. PMID: 32678471 Free PMC article. - Transcription factor 7-like 2 gene links increased in vivo insulin synthesis to type 2 diabetes.
Jainandunsing S, Koole HR, van Miert JNI, Rietveld T, Wattimena JLD, Sijbrands EJG, de Rooij FWM. Jainandunsing S, et al. EBioMedicine. 2018 Apr;30:295-302. doi: 10.1016/j.ebiom.2018.03.026. Epub 2018 Mar 30. EBioMedicine. 2018. PMID: 29631902 Free PMC article. Clinical Trial.
References
- Vaag A: On the pathophysiology of late onset non-insulin dependent diabetes mellitus: current controversies and new insights. Danish Med Bull 1999; 46: 197– 234 - PubMed
- Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, MacDougald OA: Inhibition of adipogenesis by Wnt signaling. Science 2000; 289: 950– 953 - PubMed
- Papadopoulou S, Edlund H: Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function. Diabetes 2005; 54: 2844– 2851 - PubMed
- Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K: Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 2006; 38: 320– 323 - PubMed
- Wiltshire S, Hattersley AT, Hitman GA, Walker M, Levy JC, Sampson M, O'Rahilly S, Frayling TM, Bell JI, Lathrop GM, Bennett A, Dhillon R, Fletcher C, Groves CJ, Jones E, Prestwich P, Simecek N, Rao PV, Wishart M, Bottazzo GF, Foxon R, Howell S, Smedley D, Cardon LR, Menzel S, McCarthy MI: A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q. Am J Hum Genet 2001; 69: 553– 569 - PMC - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical