Effects of Genetic Susceptibility for Type 2 Diabetes on the Evolution of Glucose Homeostasis Traits Before and After Diabetes Diagnosis

OBJECTIVE To assess the impact of genetic susceptibility on evolution toward type 2 diabetes (T2D) by analyzing time trajectories of fasting glucose, glycated hemoglobin (HbA(1c)), insulin sensitivity (homeostasis model assessment [HOMA2%S]), and β-cell secretion (HOMA2%B) in a large nondiabetic cohort. We also examined whether baseline HbA(1c) modified the effect of genetic predisposition on the time trajectories. RESEARCH DESIGN AND METHODS Time trajectories were drawn in 4,744 participants from the French Data from an Epidemiological Study on the Insulin Resistance Syndrome (D.E.S.I.R.) cohort based on samples collected every 3 years over a 9-year follow-up. Trajectories were analyzed according to the TCF7L2 common variant, a family history of T2D, and a combination of at-risk alleles from nine T2D-associated genes. RESULTS There was a marked decrease in HOMA2%B in parallel to a steep increase in HbA(1c) over the 3 years before incident diabetes, which was not influenced by genetic predisposition when considered alone. However, after the onset of T2D, the TCF7L2 at-risk variant was associated with a greater decrease in HOMA2%B. There was a joint effect of a family history of T2D with the presence of the TCF7L2 risk allele with a greater rise in HbA(1c) conferred by the coexistence of a family history and the T risk allele. An HbA(1c) ≥5.7% at baseline was associated with a greater increase in both glycemia and HbA(1c) levels in the presence of a combination of diabetes at-risk alleles. CONCLUSIONS After incident T2D, TCF7L2 at-risk variants were associated with a faster decrease in β-cell function compared with those with the CC genotype. There was a joint effect of family history of T2D and TCF7L2 risk variant on the rise in glycemia and the decrease in insulin secretion at the end of follow-up, suggesting the joint influence of the combination of diabetes genetic predisposition with familial factors on the evolution of glycemia over time.