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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 .    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.

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