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

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.) and insulin resistance (HOMA-IR, Matsuda-Index) were assessed.. on proinsulin-to-insulin conversion. These effects may also be related to neighboring regions of the genome

Associations of <i>PTBP1</i> SNPs rs736926 and rs123698 with insulin secretion and proinsulin conversion in non-diabetic subjects (N = 1502).

<p>Data represent means ±SD. For statistical analysis, data were ln-transformed and adjusted for gender, age, BMI, and insulin sensitivity. p₁ – p-values for the additive inheritance model; p₂ – p-values for the dominant inheritance model. AUC – area under the curve; BMI – body mass index; CIR – cleared insulin response; IGI – insulinogenic index; SNP – single nucleotide polymorphism.</p

Metabolic data in carriers of the PTBP1 SNP rs11085226 during the IVGTT.

<p>Shown are plasma insulin (A) and glucose (B) concentrations. Data are given as means +/− SEM. P-values for AUC of the ten minutes following glucose injection adjusted for gender, age, BMI, and clamp-derived insulin sensitivity are given. Arrows mark the time-point of glucose infusion. Black circles: homozygous carriers of the major allele; white circles: heterozygous and homozygous carrier of the minor allele.</p

Associations of <i>PTBP1</i> SNPs rs351974 and rs11085226 with insulin secretion and proinsulin conversion in non-diabetic subjects (N = 1502).

<p>Data represent means ±SD. For statistical analysis, data were ln-transformed and adjusted for gender, age, BMI, and insulin sensitivity. p₁ – p-values for the additive inheritance model; p₂ – p-values for the dominant inheritance model. AUC – area under the curve; BMI – body mass index; CIR – cleared insulin response; IGI – insulinogenic index; SNP – single nucleotide polymorphism.</p

Genomic region of human chromosome 19p13.3 harboring the PTBP1 gene and HapMap linkage disequilibrium data of common (MAF>5%) informative SNPs within this locus.

<p>The PTBP1 gene consists of 15 exons and 14 introns. It spans 14.92 kb from nucleotide 748,411 to 763,327. The analyzed locus included 5 kb of both the 5′- and the 3′-flanking regions. The locations of the four tagging SNPs are marked by frames. The upper panel shows D′ values and the lower panel shows r² values (black diamonds without values: r² = 1.0).</p