Effects of genetic susceptibility for type 2 diabetes on the evolution of glucose homeostasis traits before and after diabetes diagnosis: data from the D.E.S.I.R. Study

Abstract

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.

FIG. 1.

Trajectories of HbA_1c in participants screened with incident diabetes at year 0 and in participants without diabetes, after adjustment for age, sex, BMI, and recruitment center.

FIG. 2.

Trajectories of HbA_1c (A) and HOMA2%B (B) in the 167 participants with incident diabetes, after adjustment for age, sex, BMI, and recruitment center, according to TCF7L2 variants. Data after diabetes diagnosis in those treated by sulfonylureas are not included. *P < 0.05 for each time point. P values for the interactions between the two groups and trajectories over time are given for the entire time: from year −9 to +6, from year −9 to 0 before diabetes, and from year 0 to +6 after diabetes.

FIG. 3.

Trajectories of HbA_1c (A) and HOMA2%B (B) in the 167 participants with incident diabetes, after adjustment for age, sex, BMI, and recruitment center, according to family history of diabetes. Data after diabetes diagnosis in those treated by sulfonylureas are not included. *P < 0.05 for each time point. P values for the interactions between the two groups and trajectories over time are given for the entire time: from year −9 to +6, from year −9 to 0 before diabetes, and from year 0 to +6 after diabetes.

FIG. 4.

Trajectories over the 9 years of follow-up of HbA_1c in all participants (n = 4,080 at baseline), stratified by the presence of a family history of diabetes, after adjustment for age, sex, BMI, and recruitment center, according to TCF7L2 risk variant. *P < 0.05 for each time point. P_trajectories is the P value for the interaction between values within each group.

FIG. 5.

Trajectories of HOMA2%B in the 146 participants with incident diabetes, after adjustment for age, sex, BMI, and recruitment center, according to a genetic score based on 12 at-risk variants. Data after diabetes diagnosis in those treated by sulfonylureas are not included. There were no differences between data at the six time points and no interaction between group and time.

FIG. 6.

Trajectories over the 9 years of follow-up of fasting glucose (A) and HbA_1c (B) in all participants (n = 4,080 at baseline), stratified by baseline HbA_1c <5.7 or >5.7%, after adjustment for age, sex, BMI, and recruitment center, according to a genetic score based on nine at-risk variants. Data after diabetes diagnosis in those treated by sulfonylureas are not included. *P < 0.05 for each time point. P_trajectories is the P value for the interaction between values within HbA_1c strata.