INSULIN SECRETORY ABNORMALITIES IN SUBJECTS WITH HYPERGLYCEMIA DUE TO GLUCOKINASE MUTATIONS
INSULIN SECRETORY ABNORMALITIES IN SUBJECTS WITH HYPERGLYCEMIA DUE TO GLUCOKINASE MUTATIONS
复制标题
DOI：
10.1172/jci117064
复制
发表时间：
1994-03-01
影响因子：
15.9
通讯作者：
POLONSKY, KS
中科院分区：
文献类型：
--
作者：
BYRNE, MM;STURIS, J;POLONSKY, KS
研究人员对 6 名具有葡萄糖激酶 (GCK) 突变的受试者进行了胰腺 β 细胞功能的研究，结果发现，与血糖正常对照相比，这些受试者的空腹和餐后血糖水平升高。胰岛素分泌率 (ISR) 是通过使用两室模型对外周 C 肽值进行解卷积以及生物合成人 C 肽静脉推注后获得的个体 C 肽动力学来估计的。在具有 GCK 突变的受试者和对照受试者中，对静脉注射葡萄糖的第一阶段胰岛素分泌反应和体重维持饮食 24 小时内的胰岛素分泌率没有差异。然而，在具有 GCK 突变的受试者中，在分级静脉葡萄糖输注期间获得的与葡萄糖和 ISR 相关的剂量反应曲线向右移动，并且在 5 至 9 mM 之间的葡萄糖范围内的平均 ISR 比对照组低 61%。在对照组中，β细胞对浓度在 5.5 至 6.0 mM 之间的葡萄糖增加最为敏感，而在 GCK 突变的患者中，最大反应点增加至 6.5 至 7.5 mM 之间。即使是导致体外酶活性轻度受损的突变也与 ISR 降低 > 50% 相关。以每分钟 4-6 毫克/公斤的速度静脉输注 42 小时葡萄糖后，突变受试者的 β 细胞对葡萄糖的反应性增加了 45%。在 144 分钟的振荡葡萄糖输注过程中，突变受试者的数据显示，与对照组相比，144 分钟时葡萄糖和 ISR 的光谱功率降低，表明外源葡萄糖夹带 β 细胞的能力下降。总之，GCK 突变的受试者表现出 β 细胞对葡萄糖的反应性降低，表现为葡萄糖 ISR 剂量反应曲线向右移动，以及外源性葡萄糖诱导胰岛素分泌超电振荡的能力降低。这些结果支持酶 GCK 在确定体内葡萄糖/ISR 剂量反应关系中的关键作用，并定义了 GCK 突变受试者中发生的 β 细胞反应性的改变。
Pancreatic beta-cell function was studied in six subjects with mutations in the enzyme glucokinase (GCK) who were found to have elevated fasting and postprandial glucose levels in comparison to sis normoglycemic controls. Insulin secretion rates (ISRs) were estimated by deconvolution of peripheral C-peptide values using a two-compartment model and individual Cpeptide kinetics obtained after bolus intravenous injections of biosynthetic human C-peptide. First-phase insulin secretory responses to intravenous glucose and insulin secretion rates over a 24-h period on a weight maintenance diet were not different in subjects with GCK mutations and controls. However, the dose-response curve relating glucose and ISR obtained during graded intravenous glucose infusions was shifted to the right in the subjects with GCK mutations and average ISRs over a glucose range between 5 and 9 mM were 61% lower than those in controls. In the controls, the beta cell was most sensitive to an increase in glucose at concentrations between 5.5 and 6.0 mM, whereas in the patients, with GCK mutations the point of maximal responsiveness was increased to between 6.5 and 7.5 mM. Even mutations that resulted in mild impairment of in vitro enzyme activity were associated with a > 50% reduction in ISR. The responsiveness of the beta cell to glucose was increased by 45% in the subjects with mutations after a 42-h intravenous glucose infusion at a rate of 4-6 mg/kg per min. During oscillatory glucose infusion with a period of 144 min, profiles from the subjects with mutations revealed reduced spectral power at 144 min for glucose and ISR compared with controls, indicating decreased ability to entrain the beta cell with exogenous glucose. In conclusion, subjects with mutations in GCK demonstrate decreased responsiveness of the beta cell to glucose manifest by a shift in the glucose ISR dose-response curve to the right and reduced ability to entrain the ultradian oscillations of insulin secretion with exogenous glucose. These results support a key role for the enzyme GCK in determining the in vivo glucose/ISR dose-response relationships and define the alterations in beta-cell responsiveness that occur in subjects with GCK mutations.