Department of Internal Medicine, Division of Endocrinology, Eberhard Karls University Tübingen, Member of the German Centre for Diabetes Research DZD, Tübingen, Germany.
BMC Med Genet. 2010 Jun 9;11:86. doi: 10.1186/1471-2350-11-86.
Prohormone convertase 1 is involved in maturation of peptides. Rare mutations in gene PCSK1, encoding this enzyme, cause childhood obesity and abnormal glucose homeostasis with elevated proinsulin concentrations. Common single nucleotide polymorphisms (SNPs) within this gene, rs6232 and rs6235, are associated with obesity. We studied whether these SNPs influence the prediabetic traits insulin resistance, beta-cell dysfunction, or glucose intolerance.
We genotyped 1498 German subjects for SNPs rs6232 and rs6235 within PCSK1. The subjects were metabolically characterized by oral glucose tolerance test with glucose, insulin, proinsulin, and C-peptide measurements. A subgroup of 512 subjects underwent a hyperinsulinemic-euglycemic clamp.
The minor allele frequencies were 25.8% for SNP rs6235 and 6.0% for rs6232. After adjustment for sex and age, we found no association of SNPs rs6235 and rs6232 with BMI or other weight-related traits (all p >or= 0.07). Both minor alleles, adjusted for sex, age, BMI and insulin sensitivity were associated with elevated AUCproinsulin and AUCproinsulin/AUCinsulin (rs6235: p(additive) model <or= 0.009, effect sizes 8/8%, rs6232: pdominant model <or= 0.01, effect sizes 10/21%). Insulin secretion was not affected by the variants (different secretion parameters, all p >or= 0.08). The minor allele of SNP rs6232 was additionally associated with 15% higher OGTT-derived and 19% higher clamp-derived insulin sensitivity (pdom <or= 0.0047), 4.5% lower HOMAIR (pdom = 0.02) and 3.5% lower 120-min glucose (pdom = 0.0003) independently of BMI and proinsulin conversion. SNP rs6235 was not associated with parameters of glucose metabolism.
Like rare mutations in PCSK1, the more common variants tested determine glucose-stimulated proinsulin conversion, but not insulin secretion. In addition, rs6232, encoding the amino acid exchange N221D, influences insulin sensitivity and glucose homeostasis.
前激素转化酶 1 参与肽类的成熟。编码这种酶的 PCSK1 基因的罕见突变可导致儿童肥胖和葡萄糖稳态异常，同时伴有胰岛素原浓度升高。该基因内的常见单核苷酸多态性（SNP）rs6232 和 rs6235 与肥胖有关。我们研究了这些 SNP 是否影响糖尿病前期特征胰岛素抵抗、β细胞功能障碍或葡萄糖耐量异常。
我们对 1498 名德国受试者进行了 PCSK1 内 rs6232 和 rs6235 的基因分型。通过口服葡萄糖耐量试验测量葡萄糖、胰岛素、胰岛素原和 C 肽，对受试者进行代谢特征分析。一个 512 名受试者的亚组接受了高胰岛素-正葡萄糖钳夹。
SNP rs6235 的次要等位基因频率为 25.8%，rs6232 为 6.0%。调整性别和年龄后，我们发现 SNP rs6235 和 rs6232 与 BMI 或其他体重相关特征无关联（均 p>0.07）。两个次要等位基因，在调整性别、年龄、BMI 和胰岛素敏感性后，与 AUC 胰岛素原和 AUC 胰岛素原/AUC 胰岛素升高相关（rs6235：加性模型 p 值<0.009，效应大小 8/8%，rs6232：显性模型 p 值<0.01，效应大小 10/21%）。变异对胰岛素分泌没有影响（不同的分泌参数，均 p>0.08）。SNP rs6232 的次要等位基因还与 OGTT 衍生的胰岛素敏感性增加 15%和钳夹衍生的胰岛素敏感性增加 19%相关（p 值<0.0047），HOMA-IR 降低 4.5%（p 值<0.02），120 分钟血糖降低 3.5%（p 值<0.0003），与 BMI 和胰岛素原转化率无关。SNP rs6235 与葡萄糖代谢参数无关。
与 PCSK1 中的罕见突变一样，测试的更常见变体决定了葡萄糖刺激的胰岛素原转化，但不影响胰岛素分泌。此外，编码氨基酸替换 N221D 的 rs6232 还影响胰岛素敏感性和葡萄糖稳态。
