The T-allele of TCF7L2 rs7903146 associates with a reduced compensation of insulin secretion for insulin resistance induced by 9 days of bed rest

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.

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.

AUC_{0–10 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 AUC_{0–10 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.

AUC_{0–10 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 AUC_{0–10 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.