Functional significance of the UCSNP-43 polymorphism in the CAPN10 gene for proinsulin processing and insulin secretion in nondiabetic Germans

Recently, an association of the G allele in UCSNP-43 of calpain 10 with typ e 2 diabetes and decreased glucose disposal was reported. Calpain 10 is als o expressed in pancreatic islets. It is not known, however, whether and how this polymorphism contributes to the biological variation of beta -cell fu nction. We studied 73 nondiabetic subjects from the southwest region of Ger many (G/G, n = 41; G/A, n = 29; and A/A, n = 3) using a modified hyperglyce mic clamp (10 mmol/l glucose, added glucagon-like peptide 1, final arginine bolus). The genotype distribution was not different between subjects with normal glucose tolerance (n = 56) and those with impaired glucose tolerance (n = 17; P = 0.74, chi (2) test). First-phase insulin secretion (adjusted for sex and insulin sensitivity from hyperglycemic clamp) was greater in G/ G (2,747 +/- 297 pmol/min) than in G/A + A/A (1,612 +/- 156 pmol/min, P = 0 .003). Insulin secretion in response to arginine (adjusted for insulin sens itivity) was also greater in G/G (9.648 +/- 1.186 pmol/min) than in G/A + A /A (5.686 +/- 720 pmol/min, P = 0.04). The acute poststimulus proinsulin-to -insulin ratio was lower in G/G (1.6 +/- 0.4% first phase; 1.6 +/- 0.2% arg inine) than in G/A + A/A (4.0 +/- 0.5% first phase, P < 0.001; 2.5 +/- 0.4% arginine, P = 0.03). In conclusion, it appears unlikely that any associati on of the UCSNP-43 polymorphism alone with type 2 diabetes involves impairm ent of insulin secretion in our population of German Caucasians. This may b e entirely different with specific haplotype combinations.