Functional Significance of the UCSNP-43 Polymorphism in the CAPN10 Gene for Proinsulin Processing and Insulin Secretion in Nondiabetic Germans
Author:
Stumvoll Michael1, Fritsche Andreas1, Madaus Alexander1, Stefan Norbert1, Weisser Melanie1, Machicao Fausto1, Häring Hans1
Affiliation:
1. Department of Endocrinology and Metabolism, Eberhard-Karls-Universität, Tübingen, Germany
Abstract
Recently, an association of the G allele in UCSNP-43 of calpain 10 with type 2 diabetes and decreased glucose disposal was reported. Calpain 10 is also expressed in pancreatic islets. It is not known, however, whether and how this polymorphism contributes to the biological variation of β-cell function. We studied 73 nondiabetic subjects from the southwest region of Germany (G/G, n = 41; G/A, n = 29; and A/A, n = 3) using a modified hyperglycemic 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, χ2 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 sensitivity) 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% arginine) 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 association of the UCSNP-43 polymorphism alone with type 2 diabetes involves impairment of insulin secretion in our population of German Caucasians. This may be entirely different with specific haplotype combinations.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
Reference13 articles.
1. Hanis CL, Boerwinkle E, Chakraborty R, Ellsworth DL, Concannon P, Stirling B, Morrison VA, Wapelhorst B, Spielman RS, Gogolin Ewens KJ, Shepard JM, Williams SR, Risch N, Hinds D, Iwasaki N, Ogata M, Omori Y, Petzold C, Rietzch H, Schroder HE, Schulze J, Cox NJ, Menzel S, Boriraj VV, Chen X, et al: A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet 13:161–166, 1996 2. Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner TH, Mashima H, Schwarz PE, del Bosque-Plata L, Oda Y, Yoshiuchi I, Colilla S, Polonsky KS, Wei S, Concannon P, Iwasaki N, Schulze J, Baier LJ, Bogardus C, Groop L, Boerwinkle E, Hanis CL, Bell GI: Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26:163–175, 2000 3. Baier LJ, Permana PA, Yang X, Pratley RE, Hanson RL, Shen G-Q, Mott D, Knowler WC, Cox NJ, Horikawa Y, Oda N, Bell GI, Bogardus C: A calapin-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest 106:R69–73, 2000 4. Polonsky KS, Sturis J, Bell GI: Seminars in Medicine of the Beth Israel Hospital, Boston: non-insulin-dependent diabetes mellitus - a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med 334:777–783, 1996 5. Larsson H, Ahren B: Relative hyperproinsulinemia as a sign of islet dysfunction in women with impaired glucose tolerance. J Clin Endocrinol Metab 84:2068–2074, 1999
Cited by
52 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献
|
|