Lifestyle intervention modifies the effect of the MC4R genotype on changes in insulin resistance among women with prior gestational diabetes: Tianjin Gestational Diabetes Mellitus Prevention Program

Abstract

Background: A history of gestational diabetes mellitus (GDM) has been related to an elevated risk of type 2 diabetes. The melanocortin-4 receptor (MC4R) genotype has been related to glycemic changes in women with prior GDM.

Objective: The objective of this study was to analyze whether lifestyle intervention modified the association between the MC4R genotype and changes in insulin sensitivity among women with prior GDM.

Methods: We genotyped MC4R rs6567160 and measured glucose and insulin in fasting plasma samples at baseline and during the first 2 follow-up visits in 1128 women with prior GDM. They were randomly assigned to either a 4-y lifestyle intervention involving both diet and physical activity or a control group from a randomized clinical trial, the Tianjin Gestational Diabetes Mellitus Prevention Program. We analyzed the interaction between the MC4R genotype and lifestyle intervention on changes in insulin resistance.

Results: From baseline to 1.28 y, the MC4R genotype was related to changes in fasting insulin, HOMA-IR, and homeostasis model assessment of β cell function (HOMA-B) in the intervention group. Each risk allele (C) of rs6567160 was associated with a 0.08-unit greater decrease in log(insulin), log(HOMA-IR), and log(HOMA-B) (P = 0.02, 0.04, and 0.04, respectively), whereas in the control group, each C allele tended to be associated with a greater increase in HOMA-IR (P = 0.09). We found significant interactions between the MC4R genotype and lifestyle intervention on 1.28-y changes in fasting insulin and HOMA-IR (P = 0.006 and 0.008, respectively), and such interaction remained significant when we analyzed the trajectory of changes in insulin and HOMA-IR from baseline to 2.55 y (both P = 0.03).

Conclusions: The exploratory results from the first 2 follow-up visits indicate that women with prior GDM carrying a diabetes-increasing MC4R genotype (CC or TC) may obtain better improvement than the TT genotype in insulin resistance through lifestyle intervention. This trial was registered at clinicaltrials.gov as NCT01554358.

Keywords: MC4R; gene–lifestyle interaction; gestational diabetes mellitus; insulin resistance; lifestyle intervention.

Copyright © American Society for Nutrition 2019.

Figures

FIGURE 1

Effects of the MC4R and lifestyle intervention on 1.28- and 2.55-y changes in insulin and HOMA-IR in women with prior GDM. Values are means ± SEs, adjusted for age, baseline BMI, weight change at 1.28 y, baseline values of the respective outcomes, monthly income (<$5000, $5000 to $8000, and ≥$8000), smoking (no, past, or current), drinking (no, past, or current), and family history of diabetes (no or yes) at baseline. Insulin and HOMA-IR were log transformed before analysis. At 1.28 y, for the intervention group: TT, n = 260; TC, n = 162; CC, n = 20; for the control group: TT, n = 268; TC, n = 162; CC, n = 21. At 2.55 y, for the intervention group: TT, n = 215; TC, n = 137; CC, n = 15; for the control group: TT, n = 222; TC, n = 137; CC, n = 19. (A) Changes in insulin at 1.28 y, (B) changes in HOMA-IR at 1.28 y, (C) changes in insulin at 2.55 y, and (D) changes in HOMA-IR at 2.55 y. GDM, gestational diabetes mellitus; MC4R, melanocortin-4 receptor. CC, TC, and TT are 3 genotypes of MC4R.

FIGURE 2

The effects of MC4R genotype on changes in insulin and HOMA-IR in response to lifestyle intervention from baseline to 2.55 y. GLMMs were used to test potential interactions between SNP rs6567160 and lifestyle interventions on the trajectory of changes in insulin and HOMA-IR from baseline to 2.55 y. P = 0.03 for both interactions. Values are means ± SEs after adjustment for age, baseline BMI, weight change, baseline values for respective phenotypes, monthly income (<$5000, $5000 to $8000, and ≥$8000), smoking (no, past, or current), drinking (no, past, or current), and family history of diabetes (no or yes). GLMMs were also used to calculate regression coefficients (β) of per additional copy of the rs6567160 C allele on changes in outcomes in intervention and control groups separately. Insulin and HOMA-IR were log transformed before analysis. At 1.28 y, for the intervention group: TT, n = 260; TC, n = 162; CC, n = 20; for the control group: TT, n = 268; TC, n = 162; CC, n = 21. At 2.55 years, for the intervention group: TT, n = 215; TC, n = 137; CC, n = 15; for the control group: TT, n = 222; TC, n = 137; CC, n = 19. (A) Changes in insulin in the lifestyle intervention group, (B) changes in insulin in the control group, (C) changes in HOMA-IR in the lifestyle intervention group, and (D) changes in HOMA-IR in the control group. GLMM, generalized linear mixed model; MC4R, melanocortin-4 receptor; SNP, single nucleotide polymorphism. CC, TC, and TT are 3 genotypes of MC4R.