title: Glucose-raising genetic variants in MADD and ADCY5 impair conversion of proinsulin to insulin.
abstract: BACKGROUND
  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 Insulin(0-30)/AUC Glucose(0-30), AUC C-peptide(0-120)/AUC Glucose(0-120)), proinsulin-to-insulin conversion (fasting proinsulin, fasting proinsulin/insulin, AUC Proinsulin(0-120)/AUCInsulin(0-120)) 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Internal Medicine, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Eberhard Karls University Tübingen, Tübingen, Germany.
authors: Robert
authors: R
authors: Wagner
authors: Katarzyna
authors: K
authors: Dudziak
authors: Silke A
authors: SA
authors: Herzberg-Schäfer
authors: Fausto
authors: F
authors: Machicao
authors: Norbert
authors: N
authors: Stefan
authors: Harald
authors: H
authors: Staiger
authors: Hans-Ulrich
authors: HU
authors: Häring
authors: Andreas
authors: A
authors: Fritsche
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics*; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism*; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics*; D000090943:Delta-5 Fatty Acid Desaturase; D005260:Female; D020022:Genetic Predisposition to Disease; D005951:Glucose Tolerance Test; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011384:Proinsulin / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D053418:Death Domain Receptor Signaling Adaptor Proteins; D000090943:Delta-5 Fatty Acid Desaturase; D020662:Guanine Nucleotide Exchange Factors; C105852:MADD protein, human; D011384:Proinsulin; C000716847:FADS1 protein, human; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V