Effects of common genetic variants associated with type 2 diabetes and glycemic traits on α- and β-cell function and insulin action in humans

Abstract

Although meta-analyses of genome-wide association studies have identified >60 single nucleotide polymorphisms (SNPs) associated with type 2 diabetes and/or glycemic traits, there is little information on whether these variants also affect α-cell function. The aim of the current study was to evaluate the effects of glycemia-associated genetic loci on islet function in vivo and in vitro. We studied 43 SNPs in 4,654 normoglycemic participants from the Finnish population-based Prevalence, Prediction, and Prevention of Diabetes-Botnia (PPP-Botnia) Study. Islet function was assessed, in vivo, by measuring insulin and glucagon concentrations during oral glucose tolerance test, and, in vitro, by measuring glucose-stimulated insulin and glucagon secretion from human pancreatic islets. Carriers of risk variants in BCL11A, HHEX, ZBED3, HNF1A, IGF1, and NOTCH2 showed elevated whereas those in CRY2, IGF2BP2, TSPAN8, and KCNJ11 showed decreased fasting and/or 2-h glucagon concentrations in vivo. Variants in BCL11A, TSPAN8, and NOTCH2 affected glucagon secretion both in vivo and in vitro. The MTNR1B variant was a clear outlier in the relationship analysis between insulin secretion and action, as well as between insulin, glucose, and glucagon. Many of the genetic variants shown to be associated with type 2 diabetes or glycemic traits also exert pleiotropic in vivo and in vitro effects on islet function.

FIG. 1.

Graphic representation of effects of genetic variants on the relationship between insulin secretion and insulin sensitivity in nondiabetic participants in the PPP-Botnia Study. Effect sizes are betas from linear regression adjusted for age, sex, and BMI. Whereas most genetic variants either increased insulin secretion or insulin sensitivity, those in MTNR1B, CDKAL1, and GCK were located to the lower left quadrant, reflecting both impaired insulin secretion and insulin sensitivity, with MTNR1B being the most extreme. In contrast, GIPR and FADS1 showed relatively high insulin sensitivity despite low insulin secretion. KCNQ1† represents rs2237895, and KCNQ1* represents rs231362. Black circles, P < 0.05; white circles, P > 0.05.

FIG. 2.

Graphic representation of effects of genetic variants on the relationship between glucose and insulin levels during OGTT in nondiabetic participants of the PPP-Botnia Study. Effect sizes are betas from linear regression adjusted for age, sex, and BMI. KCNQ1† represents rs2237895, and KCNQ1* represents rs231362. Black circles, P < 0.05; white circles, P > 0.05. A: The relationship between fasting insulin and fasting glucose. MTNR1B showed the highest effect on fasting glucose despite elevated insulin levels. CHCHD2P9 showed increased whereas FADS1 showed decreased fasting insulin. B: The relationship between 2-h insulin and 2-h glucose. GCK, CDKAL1, ZBED3, and MTNR1B all showed high postprandial glucose levels despite elevated insulin levels.

FIG. 3.

Graphic representation of effects of genetic variants on the relationship between glucose and glucagon levels during OGTT in nondiabetic participants of the PPP-Botnia Study. Effect sizes are betas from linear regression adjusted for age, sex, and BMI. KCNQ1† represents rs2237895, and KCNQ1* represents rs231362. Black circles, P < 0.05; white circles, P > 0.05. A: The relationship between fasting glucagon and fasting glucose. The highest fasting glucose level related to glucagon level was seen for MTNR1B. IGF2BP2 and CRY2 showed reduced glucagon secretion, whereas BCL11A and HHEX were associated with increased fasting glucagon. B: The relationship between 2-h glucagon and 2-h glucose. ZBED3, IGF1, and NOTCH2 showed elevated whereas KCNJ11 showed decreased postprandial glucagon secretion.

FIG. 4.

Relationship between glucagon and insulin secretion in human pancreatic islets at low and high glucose levels. A: Secretion at low glucose (1 mmol/L). The risk allele carriers of variants in CAMK1D, TCF7L2, GIPR, TSPAN8, and KLF14 showed lower glucagon secretion, whereas the risk allele carriers of CDKAL1, BCL11A, CRY2, FADS1, NOTCH2, HMGA2, and GCK showed glucagon levels above the expected 95% CI of the relationship between insulin and glucagon secretion. B: Secretion at high glucose (16.7 mmol/L). The risk allele carriers of DGKB, GIPR, JAZF1, CDKN2A/2B, HMGA2, and NOTCH2 remained high glucagon secretion, whereas those of FTO, CAMK1D, TCF7L2, KLF14, and ZBED3 had low glucagon.