A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1
A new subtype of autosomal dominant diabetes attributable to a mutation in the gene for sulfonylurea receptor 1
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DOI：
10.1016/s0140-6736(03)12325-2
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发表时间：
2003-01-25
期刊：
影响因子：
168.9
通讯作者：
Laakso, M
中科院分区：
文献类型：
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作者：
Huopio, H;Otonkoski, T;Laakso, M
背景：ATP敏感性钾(K-ATP)通道是葡萄糖诱导的胰腺P细胞胰岛素分泌的主要调节因子。我们描述了一个芬兰家庭的磺脲受体1(SUR1)基因(ABCC8)的一个显性杂合突变E1506K，该突变由于K-ATP通道活性降低而导致先天性高胰岛素血症。方法对11例E1506K杂合子成人和19例对照组进行口服葡萄糖耐量试验、静脉葡萄糖耐量试验和高血糖钳夹试验检测胰岛素分泌、高胰岛素正葡萄糖钳夹试验检测胰岛素敏感性，发现4例E1506K杂合子患者合并糖尿病，5例糖耐量受损，1例空腹血糖受损，1例糖耐量正常。在SUR1 E1506K突变杂合子10岁以下儿童中，虽然葡萄糖诱导的第一时相胰岛素分泌正常(n=2；66和334pmol/L)，但在青春期后迅速下降(n=3；12-32pmol/L)，并在成年后几乎完全消失(n=11；12-32pmol/L)。此外，这些杂合子携带者在高血糖钳夹期间(非糖尿病携带者422pmol/L；糖尿病携带者97pmol/L)的最大葡萄糖刺激胰岛素分泌显著减少。相反，在没有糖尿病的E1506K突变携带者中，胰岛素敏感性(M/I值)是正常的，而在糖尿病杂合子携带者中胰岛素敏感性(M/I值)降低了15%(无糖尿病者为0.07，有糖尿病者为0.05，与对照组无显著差异)。SUR1基因E1506K杂合突变在婴儿期导致先天性高胰岛素血症，在成年早期导致胰岛素分泌能力丧失，在中年导致糖尿病。该变异代表了常染色体显性糖尿病的一种新亚型。
Background ATP-sensitive potassium (K-ATP) channels are major regulators of glucose-induced insulin secretion in pancreatic P cells. We have described a dominant heterozygous mutation-E1506K-in the sulfonylurea receptor 1 (SUR1) gene (ABCC8) in a Finnish family, which leads to congenital hyperinsulinaemia due to reduction of K-ATP-channel activity. We aimed to characterise glucose metabolism in adults heterozygous for the E1506K mutation.Methods Glucose tolerance was assessed by an oral glucose tolerance test, insulin secretion by the intravenous glucose tolerance test and hyperglycaemic clamp, and insulin sensitivity by hyperinsulinaemic euglycaemic clamp in 11 people heterozygous for the E1506K mutation and 19 controls.Findings Four people who were heterozygous for the SUR1 E1506K mutation had diabetes, five had impaired glucose tolerance, one had impaired fasting glucose, and one had normal glucose tolerance. Although glucose-induced, first-phase insulin secretion was normal in children younger than 10 years of age who were heterozygous for the SUR1 E1506K mutation (n=2; 66 and 334 pmol/L), it fell rapidly after puberty (n=3; 12-32 pmol/L), and was almost completely lost in adulthood (n=11; 12-32 pmol/L). Furthermore, these heterozygous people had a substantial reduction in maximum glucose-stimulated insulin secretion during hyperglycemic clamp (carriers without diabetes 422 pmol/L; carriers with diabetes 97 pmol/L). By contrast, insulin sensitivity (M/I value) was normal in carriers of the E1506K mutation who did not have diabetes and was reduced by 15% in those who were heterozygous with diabetes (0.07 in those without diabetes and 0.05 in those with the disorder; not significantly different from controls).Interpretation Heterozygous E1506K substitution in the SUR1 gene causes congenital hyperinsulinism in infancy, loss of insulin secretory capacity in early adulthood, and diabetes in middle-age. This variant represents a new subtype of autosomal dominant diabetes.