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

Abstract

IntroductionRecent 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.MethodsIn 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.ResultsAfter 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.DiscussionBy 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.

Beta cell connectivity in pancreatic islets: a type 2 diabetes target?

“…Although the former is partly due to impaired insulin processing (i.e., proinsulin ? insulin conversion) [149], islets depleted for ADCY5 also displayed impaired glucose-but not GLP-1-induced increases in cAMP, and consequent impairments in glucose-induced metabolism (ATP:ADP ratios). Moreover, ADCY5-silenced islets showed more stochastic long-term evolutions in coordinated beta cell activity following glucose exposure [148].…”

The rs10885122 polymorphism of the adrenoceptor alpha 2A (ADRA2A) gene in Euro-Brazilians with type 2 diabetes mellitus

“…Polymorphisms of the ADRA2A gene have been primarily studied by meta-analysis (25). The G allele of the ADRA2A rs10885122 polymorphism was described as a risk factor associated with higher fasting glucose and reduced insulin secretion in non-diabetic subjects (14,17,26,27). In contrast, others studies did not find an association of this polymorphism with T2D in European Caucasians (17,19,25), Japanese (28), Chinese (25), and several other ethnicities (29).…”

A Type 2 Diabetes–Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus

“…ADCY5 variant alleles associated with higher glucose levels were also associated with lower birth weight (rs9883204, LD r 2 = 0.826 with rs11708067, 1000 Genomes phase 3 EUR, P < 5 × 10 −8 ) (14). The type 2 diabetes–, fasting glucose–, and 2-h glucose–associated variant, rs11708067, was also associated ( P = 2.0 × 10 −3 ) with impaired proinsulin-to-insulin conversion as individuals homozygous for the type 2 diabetes risk A allele showed higher proinsulin levels and a higher proinsulin/insulin ratio after an oral glucose tolerance test (15). Transethnic fine-mapping studies (11) and credible set analyses suggest rs11708067 is a functional variant at this locus.…”