The Effect of Diabetes-Associated Variation in TCF7L2 on Postprandial Glucose Metabolism When Glucagon and Insulin Concentrations Are Matched

Background: The rs7903146 variant in the TCF7L2 gene is associated with defects in postprandial insulin and glucagon secretion and increased risk of type 2 diabetes. However, it is unclear if this variant has effects on glucose metabolism that are independent of islet function. Methods: We studied 54 nondiabetic subjects on two occasions where endogenous hormone secretion was inhibited by somatostatin. Twenty-nine subjects were homozygous for the diabetes-associated allele (TT) and 25 for the diabetes-protective allele (CC) at rs7903146, but otherwise matched for anthropometric characteristics. On 1 day, glucagon infused at a rate of 0.65 ng/kg/min, and at 0 min prevented a fall in glucagon (nonsuppressed day). On the contrary, infusion commenced at 120 min to create a transient fall in glucagon (suppressed day). Subjects received glucose (labeled with [3-3H]-glucose) infused to mimic the systemic appearance of oral glucose. Insulin was infused to mimic a prandial insulin response. Endogenous glucose production (EGP) was measured using the tracer dilution technique. Results: Lack of glucagon suppression increased postchallenge glucose concentrations and impaired EGP suppression. However, in the presence of matched insulin and glucagon concentrations, genetic variation in TCF7L2 did not alter glucose metabolism. Conclusion: These data suggest that genetic variation in TCF7L2 alters glucose metabolism through changes in islet hormone secretion.