Glucose-Raising Genetic Variants in MADD and ADCY5 Impair Conversion of Proinsulin to Insulin

PLOS ONE, Aug 2011

Introduction Recent meta-analyses of genome-wide association studies revealed new genetic loci associated with fasting glycemia. For several of these loci, the mechanism of action in glucose homeostasis is unclear. The objective of the study was to establish metabolic phenotypes for these genetic variants to deliver clues to their pathomechanism. Methods In this cross-sectional study 1782 non-diabetic volunteers at increased risk for type 2 diabetes underwent an oral glucose tolerance test. Insulin, C-peptide and proinsulin were measured and genotyping was performed for 12 single nucleotide polymorphisms (SNP) in or near the genes GCK (rs4607517), DGKB (rs2191349), GCKR (rs780094), ADCY5 (rs11708067), MADD (rs7944584), ADRA2A (rs10885122), FADS1 (rs174550), CRY2 (rs11605924), SLC2A2 (rs11920090), PROX1 (rs340874), GLIS3 (rs7034200) and C2CD4B (rs11071657). Parameters of insulin secretion (AUC Insulin0–30/AUC Glucose0–30, AUC C-peptide0–120/AUC Glucose0–120), proinsulin-to-insulin conversion (fasting proinsulin, fasting proinsulin/insulin, AUC Proinsulin0–120/AUCInsulin0–120) and insulin resistance (HOMA-IR, Matsuda-Index) were assessed. Results After adjustment for confounding variables, the effect alleles of the ADCY5 and MADD SNPs were associated with an impaired proinsulin-to-insulin conversion (p = 0.002 and p = 0.0001, respectively). GLIS3 was nominally associated with impaired proinsulin-to-insulin conversion and insulin secretion. The diabetogenic alleles of DGKB and PROX1 were nominally associated with reduced insulin secretion. Nominally significant effects on insulin sensitivity could be found for MADD and PROX1. Discussion By examining parameters of glucose-stimulated proinsulin-to-insulin conversion during an OGTT, we show that the SNP in ADCY5 is implicated in defective proinsulin-to-insulin conversion. In addition, we confirmed previous findings on the role of a genetic variant in MADD on proinsulin-to-insulin conversion. These effects may also be related to neighboring regions of the genome.

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Glucose-Raising Genetic Variants in MADD and ADCY5 Impair Conversion of Proinsulin to Insulin

et al. (2011) Glucose-Raising Genetic Variants in MADD and ADCY5 Impair Conversion of Proinsulin to Insulin. PLoS ONE 6(8): e23639. doi:10.1371/journal.pone.0023639 Glucose-Raising Genetic Variants in MADD and ADCY5 Impair Conversion of Proinsulin to Insulin Robert Wagner 0 Katarzyna Dudziak 0 Silke A. Herzberg-Scha fer 0 Fausto Machicao 0 Norbert Stefan 0 Harald Staiger 0 Hans-Ulrich Ha ring 0 Andreas Fritsche 0 Heike Muenzberg-Gruening, Louisiana State University, Pennington Biomedical Research Center, United States of America 0 1 Department of Internal Medicine, Division of Endocrinology , Diabetology, Angiology , Nephrology and Clinical Chemistry, Eberhard Karls University Tu bingen, Member of the German Center for Diabetes Research (DZD) , Tu bingen, Germany , 2 Department of Internal Medicine, Division of Nutritional and Preventive Medicine , Tu bingen , Germany Introduction: Recent meta-analyses of genome-wide association studies revealed new genetic loci associated with fasting glycemia. For several of these loci, the mechanism of action in glucose homeostasis is unclear. The objective of the study was to establish metabolic phenotypes for these genetic variants to deliver clues to their pathomechanism. Methods: In this cross-sectional study 1782 non-diabetic volunteers at increased risk for type 2 diabetes underwent an oral glucose tolerance test. Insulin, C-peptide and proinsulin were measured and genotyping was performed for 12 single nucleotide polymorphisms (SNP) in or near the genes GCK (rs4607517), DGKB (rs2191349), GCKR (rs780094), ADCY5 (rs11708067), MADD (rs7944584), ADRA2A (rs10885122), FADS1 (rs174550), CRY2 (rs11605924), SLC2A2 (rs11920090), PROX1 (rs340874), GLIS3 (rs7034200) and C2CD4B (rs11071657). Parameters of insulin secretion (AUC Insulin0-30/AUC Glucose0-30, AUC C-peptide0-120/AUC Glucose0-120), proinsulin-to-insulin conversion (fasting proinsulin, fasting proinsulin/insulin, AUC Proinsulin0-120/AUCInsulin0-120) and insulin resistance (HOMA-IR, Matsuda-Index) were assessed. Results: After adjustment for confounding variables, the effect alleles of the ADCY5 and MADD SNPs were associated with an impaired proinsulin-to-insulin conversion (p = 0.002 and p = 0.0001, respectively). GLIS3 was nominally associated with impaired proinsulin-to-insulin conversion and insulin secretion. The diabetogenic alleles of DGKB and PROX1 were nominally associated with reduced insulin secretion. Nominally significant effects on insulin sensitivity could be found for MADD and PROX1. Discussion: By examining parameters of glucose-stimulated proinsulin-to-insulin conversion during an OGTT, we show that the SNP in ADCY5 is implicated in defective proinsulin-to-insulin conversion. In addition, we confirmed previous findings on the role of a genetic variant in MADD on proinsulin-to-insulin conversion. These effects may also be related to neighboring regions of the genome. - . These authors contributed equally to this work. Introduction Type 2 diabetes is a multifactorial disease that arises from a complex interaction between environmental factors and genetic susceptibility. The major environmental causes are sedentary lifestyle and high energy intake [1]. A multitude of genes contributes to the overall predisposition of type 2 diabetes, but the genes have a rather small individual effect [2]. Most of the approximately 40 known genetic variants conferring increased risk for type 2 diabetes have been discovered by genome-wide association studies (GWAS) [3]. With this method, associations between genomic variants and diabetes prevalence or quantitative glycemic traits like increased fasting glucose (FG) can be established. The variants are single nucleotide polymorphisms (SNPs) harboured in different loci of the genome. Most of the recently discovered SNPs are located in non-coding DNA regions. They may regulate the expression of nearby or far away genes [4,5], however, the exact target genes and their function in glucose homeostasis are in most cases still elusive. Detailed metabolic characterization of these variants can provide further data to elucidate their mechanism of action. Hyperglycemia, the sine qua non of diabetes, results from a combination of impaired insulin secretion and impaired insulin action. Although their exact pathophysiologic relevance is unclear, measuring proinsulin, C-peptide and insulin levels can illuminate different aspects of beta-cell dysfunction. In the case of insulin, its level in venous plasma is influenced by extensive hepatic first-pass clearance and a short half-life [6] in combination with pulsatile secretion [7], while C-peptide levels seem to be somewhat more robust [8]. A decreased proinsulin-to-insulin ratio resulting from enhanced proinsulin-to-insulin conversion is supposed to indicate the adaptation of the healthy beta-cell to increased secretory demand after a glucose stimulus [9]. On the other hand, proinsulin-to-insulin ratio increases with age [10] (...truncated)


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Robert Wagner, Katarzyna Dudziak, Silke A. Herzberg-Schäfer, Fausto Machicao, Norbert Stefan, Harald Staiger, Hans-Ulrich Häring, Andreas Fritsche. Glucose-Raising Genetic Variants in MADD and ADCY5 Impair Conversion of Proinsulin to Insulin, PLOS ONE, 2011, Volume 6, Issue 8, DOI: 10.1371/journal.pone.0023639