A Genome-Wide Association Study of IVGTT-Based Measures of First-Phase Insulin Secretion Refines the Underlying Physiology of Type 2 Diabetes Variants

Abstract

Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose-raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits.

Figure 1

IVGTT (peak insulin response)-based first-phase insulin secretion vs. OGTT-based insulin secretion (CIR) for known type 2 diabetes variants. Data are SD. Orange circles, SNP associated with both peak insulin response and CIR (P < 0.05); green circles, SNP associated with peak insulin response (P < 0.05); blue circles, SNP associated with CIR (P < 0.05); yellow circles; SNP not associated with either trait (P > 0.05). ISI, insulin sensitivity index.

Figure 2

ISR- vs. OGTT-based insulin secretion (CIR) for known type 2 diabetes variants. Data are SD. Orange circles, SNP associated with both ISR and CIR (P < 0.05); green circles, SNP associated with ISR (P < 0.05); blue circles, SNP associated with CIR (P < 0.05); yellow circles, SNP not associated with either trait (P > 0.05). ISI, insulin sensitivity index.

Figure 3

IVGTT (peak insulin response)-based first-phase insulin secretion vs. type 2 diabetes risk (OR) for known type 2 diabetes variants. The y-axis data are SD. Type 2 diabetes ORs are from Morris et al. (39), and some were reported from previous studies of East Asians (59,60). Orange circles, SNP associated with both peak insulin response and type 2 diabetes risk (P < 0.05); green circles, SNP associated with peak insulin response (P < 0.05); blue circles, SNP associated with type 2 diabetes risk (P < 0.05); yellow circles, SNP not associated with either trait (P > 0.05). T2D, type 2 diabetes.

Figure 4

ISR vs. type 2 diabetes risk for known type 2 diabetes variants. The y-axis data are SD. Orange circles, SNP associated with both ISR and type 2 diabetes risk (P < 0.05); green circles, SNP associated with ISR (P < 0.05); blue circles, SNP associated with type 2 diabetes risk (P < 0.05); yellow circles, SNP not associated with either trait (P > 0.05). T2D, type 2 diabetes.