Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA.
Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
Diabetes. 2023 Dec 1;72(12):1809-1819. doi: 10.2337/db23-0465.
The importance of glucokinase (GK) in the regulation of insulin secretion has been highlighted by the phenotypes of individuals with activating and inactivating mutations in the glucokinase gene (GCK). Here we report 10 individuals with congenital hyperinsulinism (HI) caused by eight unique activating mutations of GCK. Six are novel and located near previously identified activating mutations sites. The first recognized episode of hypoglycemia in these patients occurred between birth and 24 years, and the severity of the phenotype was also variable. Mutant enzymes were expressed and purified for enzyme kinetics in vitro. Mutant enzymes had low glucose half-saturation concentration values and an increased enzyme activity index compared with wild-type GK. We performed functional evaluation of islets from the pancreata of three children with GCK-HI who required pancreatectomy. Basal insulin secretion in perifused GCK-HI islets was normal, and the response to glyburide was preserved. However, the threshold for glucose-stimulated insulin secretion in perifused glucokinase hyperinsulinism (GCK-HI) islets was decreased, and glucagon secretion was greatly suppressed. Our evaluation of novel GCK disease-associated mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response.
Our evaluation of six novel and two previously published activating GCK mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. These studies provide insights into the pathophysiology of GCK-hyperinsulinism and the dual role of glucokinase in β-cells and α-cells to regulate glucose homeostasis.
葡萄糖激酶（GK）在胰岛素分泌调节中的重要性已被具有葡萄糖激酶基因（GCK）激活和失活突变的个体表型所强调。在这里，我们报告了 10 名由 GCK 中的 8 个独特激活突变引起的先天性高胰岛素血症（HI）个体。其中 6 个是新发现的，位于先前确定的激活突变部位附近。这些患者的首次低血糖发作发生在出生至 24 岁之间，表型的严重程度也各不相同。突变酶被表达并在体外进行酶动力学纯化。与野生型 GK 相比，突变酶的葡萄糖半饱和浓度值较低，酶活性指数增加。我们对 3 名需要进行胰腺切除术的 GCK-HI 儿童的胰岛进行了功能评估。经灌注的 GCK-HI 胰岛的基础胰岛素分泌正常，对格列本脲的反应得以保留。然而，经灌注的葡萄糖激酶高胰岛素血症（GCK-HI）胰岛中葡萄糖刺激的胰岛素分泌的阈值降低，并且胰高血糖素分泌受到极大抑制。我们对新发现的 GCK 疾病相关突变的评估表明，这些突变对葡萄糖稳态的不利影响不仅归因于胰岛素分泌的葡萄糖阈值降低，而且归因于降低的抗胰岛素胰高血糖素分泌反应。
