Diabetes Risk Variants Associate With Impaired Insulin Sensitivity In Healthy Adults Following Bed Rest

Abstract

More than 80 genetic variants increase risk for type 2 diabetes. We hypothesized that increased genetic risk for diabetes may increase susceptibility to impaired insulin sensitivity following bed rest. PURPOSE: To determine whether type 2 diabetes genetic risk variants in healthy older adults are associated with impaired insulin sensitivity following bed rest. METHODS: 37 nondiabetic adults (65.9 ± 7.9 years, BMI 27.1 ± 3.0, 82.2 ± 6.4 mg/dL fasting blood glucose) completed bed rest studies at the University of Texas Medical Branch. The protocol consisted of a 3 day run-in period, 7 days of bed rest and 7 days of rehabilitation. OGTT (75g) were administered before and after bed rest protocol and following rehabilitation. Venous blood was collected at baseline, 0, 30, 60, 90, and 120 minutes, and the Matsuda Insulin Sensitivity Index (Mat-ISI), HOMA-IR, Insulinogenic Index (II), and the Disposition Index (DI) were calculated. DNA from whole blood was used to genotype for MTNR1B (rs10830963), NOTCH2 (rs10923931), RASGRP1 (rs7403531), PROX1 (rs2075423), HHEX (rs1111875), IGF2BP2 (rs4402960), CDKAL1 (rs7754840), SLC30A8 (rs13266634), ZFAND6 (rs11634397), and TCF7L2 (rs7903146) risk variants using TaqMan Assays. Results were collated into an unweighted risk score based on the total number of risk alleles (possible range from 0-20).SPSS version 26 (IBM, Chicago, IL) was used to build a multivariate model including all outcome indices and risk variants. RESULTS: Genetic risk scores ranged from 5 to 11. HOMA-IR and II were not associated with risk scores at any point in the study. Higher overall risk scores were inversely associated with the Mat-ISI and the DI only immediately after the completion of the bed rest period (p= 0.035 and p= 0.017, respectively), but not at baseline or after rehabilitation. Post-bed rest Mat-ISI ranged from 18.1 ± 11.6 for those in the lowest risk group vs. 6.8 ± 0.26 in the highest risk group. Post-bed rest DI was 16.8 ± 12.9 for those in the lowest risk group and 5.8 ± 3 in the highest risk group. CONCLUSION: These results indicate that people with a higher genetic risk for type 2 diabetes may be at increased risk of disuse-related loss of insulin sensitivity.The work was supported by the Claude D. Pepper Older Americans Independence Center (P30 AG024832).