Decreased tolbutamide-stimulated insulin secretion in healthy subjects with sequence variants in the high-affinity sulfonylurea receptor gene
Decreased tolbutamide-stimulated insulin secretion in healthy subjects with sequence variants in the high-affinity sulfonylurea receptor gene
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DOI：
10.2337/diabetes.47.4.598
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发表时间：
1998-04-01
期刊：
影响因子：
7.7
通讯作者：
Pedersen, O
中科院分区：
文献类型：
--
作者：
Hansen, T;Echwald, SM;Pedersen, O
磺酰脲受体（sunylurea receptor，SUR 1）是ATP敏感性钾通道的一个亚单位，是胰岛β细胞胰岛素分泌的重要调节因子。本研究的目的是检查SUR 1基因的遗传变异是否与NIDDM或胰腺β细胞功能改变有关。对63例NIDDM患者的所有39个SUR 1外显子（包括内含子-外显子边界）进行突变分析，发现2个错义变异，5个编码区沉默变异和4个内含子变异。两个错义变体（Asp 673 Asn和Ser 1369 Ala）和两个序列变体在一个随机的无关的，健康的，年轻的丹麦白人仅在1例NIDDM患者中发现了外显子14的Asp 673 Asn变异，而Ser 1369 Ala的等位基因频率在247例对照组（0.38 [95%CI 0.34-0.42]）和406例NIDDM患者（0.40 [0.37-0.43]）中相似。NIDDM患者（n = 392）和对照组（n = 246）中沉默外显子18 Thr 775 Thr变异的等位基因频率分别为0.051（0.035-0.067）和0.027（0.013-0.041）（χ 2 = 4.99，P = 0.03）。内含子变异的等位基因频率在NIDDM患者（0.45 [0.42-0.48]）和对照组（0.44 [0.40-0.48]）中相似。在386例NIDDM患者中，17例为外显子18 C/T和内含子-3c/-3t联合基因型（0.044 [0.024-0.064]），而243例对照组中有3例具有相同的组合基因型（0.012 [0-0.026]; chi（2）= 4.87，P = 0.03;比值比：3.69 [1.07-12.71]）。在380名无关的健康年轻丹麦白种人中，10名（0.026 [0.010-0.042]）具有合并的风险基因型。这些受试者在注射甲苯磺丁脲后血清C肽平均降低50%，血清胰岛素反应降低40%（分别为P = 0.002和P = 0.05），但在注射葡萄糖后血清C肽和胰岛素反应正常。总之，在丹麦高加索人群中，SUR 1基因外显子18的沉默多态性与NIDDM相关。与内含子变体组合时，相关性更高，并且基因内组合的年轻健康携带者对甲苯磺丁脲负荷的血清C肽和胰岛素反应降低。
The high-affinity sulfonylurea receptor (SUR1) is, as a subunit of the ATP-sensitive potassium channel, an important regulator of insulin secretion in the pancreatic beta-cell. The aim of this study was to examine if genetic variability of the SUR1 gene was associated with NIDDM or altered pancreatic beta-cell function. Mutational analysis of all the 39 SUR1 exons, including intron-exon boundaries, in 63 NIDDM patients revealed two missense variants, five silent variants in the coding region, and four intron variants. The two missense variants (Asp673Asn and Ser1369Ala) and two sequence variants (ACC --> ACT, Thr759Thr and a c --> t intron variant in position -3 of the exon 16 splice acceptor site) were examined for association with NIDDM and for a possible influence on insulin and C-peptide secretion after intravenous glucose and tolbutamide loads in a random sample of unrelated, healthy, young Danish Caucasians. The Asp673Asn variant in exon 14 was only identified in one NIDDM patient, and the allelic frequency of the Ser1369Ala was similar among 247 control subjects (0.38 [95% CI 0.34-0.42]) and 406 NIDDM patients (0.40 [0.37-0.43]). The allelic frequency of the silent exon 18 Thr775Thr variant was 0.051 (0.035-0.067) in NIDDM patients (n = 392) and 0.027 (0.013-0.041) in control subjects (n = 246; chi(2) = 4.99, P = 0.03). The allelic frequency of the intron variant was similar among NIDDM patients (0.45 [0.42-0.48]) and control subjects (0.44 [0.40-0.48]). Of 386 NIDDM patients, 17 had the combined genotype exon 18 C/T and intron -3c/-3t (0.044 [0.024-0.064]), whereas 3 of 243 control subjects had the same combined genotype (0.012 [0-0.026]; chi(2) = 4.87, P = 0.03; odds ratio: 3.69 [1.07-12.71]). Of 380 unrelated, healthy, young Danish Caucasians, 10 (0.026 [0.010-0.042]) had the combined at-risk genotype. These subjects had, on average, a 50% reduction in serum C-peptide and a 40% reduction in serum insulin responses upon tolbutamide injection (P = 0.002 and P = 0.05, respectively) but; normal serum C-peptide and insulin responses upon glucose injection. In conclusion, a silent polymorphism in exon 18 of the SUR1 gene is associated with NIDDM in a Danish Caucasian population. In combination with an intron variant, the association is higher, and young, healthy carriers of the intragenic combination have reduced serum C-peptide and insulin responses to a tolbutamide load.