Older adults with TCF7L2 rs7903146T risk variants are more likely to have increased 2-hour OGTT blood glucose following seven days of bed rest. TCF7L2 is a transcription factor belonging to the Wnt signaling pathway present in pancreas, liver, and other tissues [12, 13]. Whole-genome chromatinimmunoprecipitation (ChIP) combined with massively parallel DNA sequencing (ChIP-Seq) analyses show that TCF7L2 binds directly to several genes involved in glucose metabolism, including PCK1, FBP1, IRS1, IRS2, AKT2, ADIPOR1, PDK4 AND CPT1A . Carriers of the rs7903146T allele exhibit impaired proinsulin conversion, higher proinsulin:insulin ratios, and greater likelihood of developing insulin-dependent type 2 diabetes [15–18], but not hepatic or extrahepatic insulin resistance [19, 20]. Paradoxically, some evidence indicates that liver and other tissues appear to be involved in TCF7L2 rs7903146T-associated glucose intolerance and insulin secretion .
TCF7L2 risk alleles are associated with elevated post-OGTT and nocturnal blood glucose in nondiabetic adults [17, 18, 22, 23]. The rs7903146T allele also associates with impaired glucose tolerance in adults with metabolic syndrome  and obese adolescents . Healthy, middle-aged and older nondiabetic participants with rs7903146T also exhibit higher nocturnal glucose . However, similar to our findings, prior studies indicate that rs7903146T does not affect fasting blood glucose in healthy middle-aged adults . This suggests that fasting blood glucose may not be an optimal biomarker to screen individuals with rs7903146T for risk of developing prediabetes and type 2 diabetes.
Young, healthy Caucasian men with TCF7L2 rs7903146T risk alleles exhibit a lower first-phase insulin response (FPIR) to an intravenous glucose tolerance test (IGTT) compared with those with the homozygous C genotype both before and after 9 days of bed rest (p = 0.01 and p = 0.0001, respectively) . Following bed rest, the participants with the TCF7L2 rs7903146 risk variants also fail to show an incremental rise of FPIR in response to insulin resistance. Though FPIR is not a concept that is directly translatable outside of the context of an IGTT, the ability to rapidly secrete insulin in response to an OGTT in the early phase (up to 30 minutes after consumption of glucose) is a similar concept . The liver responds to a robust early phase insulin response by reducing release of glucose, thereby limitng the overall blood glucose response to an OGTT or a meal, and this physiological trait that is lost in the development of type 2 diabetes . Here we did not observe any relationship between rs7903146T risk alleles and insulin measures or calculated insulin sensitivity at point after a 75 g glucose load, but we completed 2-hour OGTT, which are not directly comparable to the IGTT or the FPIR.
Periods of physical inactivity promote insulin resistance in healthy adults [28, 29]. If the reduced glucose tolerance we observed following a 7 day period of inactivity in healthy, nondiabetic adults persists, patients having rs7903146T variants could be especially susceptible to long-term impairments in glucose metabolism following inpatient stays. Future research should evaluate how rs7903146T affects blood glucose throughout hospital stay in both critically ill and non-critically ill hospital patients. Moreover, follow up studies should evaluate if rs7903146T predicts long-term glucose intolerance following an extended period of disuse in clinical populations in patients after discharge. Finally, utilizing and OGTT, rather than fasting blood glucose, may be more appropriate for patients carrying the rs7903146T allele.
Our analysis showed a clinically relevant association between the TCF7L2 rs7903146T allele and risk of glucose intolerance after physical disuse; however, there were limitations. This study was not initially designed to test genotype-phenotype relationships. We recruited volunteers to test the effect of nutrition and physicial activity on a broad range of outcomes following bed rest. We feel confident that the genotype-phenotype relationship between TCF7L2 rs7903146T and 2-hour OGTT blood glucose described here was not affected by the group assignment, however (Supplemental Table S4). This small study was conducted in generally healthy older adults and woud not be generalizable to other aged groups or those with acute or chronic illness.