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• W4328049359 abstract "Type 2 diabetes (T2D) is characterized by a progressive deterioration of β-cell function with a continuous decline in insulin secretion. Glucokinase (GCK) facilitates the rate-limiting step of glycolysis in pancreatic β-cells, to acquire the proper glucose-stimulated insulin secretion. Multiple glucokinase activators (GKAs) have been developed and clinically tested. However, the dynamic change of human pancreatic GCK expression during T2D progression has not been investigated.We evaluated GCK expression by measuring the average immunoreactivity of GCK in insulin+ or glucagon+ cells from pancreatic sections of 11 nondiabetic subjects (ND), 10 subjects with impaired fasting glucose (IFG), 9 with well-controlled T2D (wT2D), and 5 individuals with poorly controlled T2D (uT2D). We also assessed the relationship between GCK expression and adaptive unfolded protein response (UPR) in human diabetic β-cells.We did not detect changes of GCK expression in IFG islets. However, we found β-cell GCK levels were significantly increased in T2D with adequate glucose control (wT2D) but not in T2D with poor glucose control (uT2D). Furthermore, there was a strong positive correlation between GCK expression and adaptive UPR (spliced X-box binding protein 1 [XBP1s] and activating transcription factor 4 [ATF4]), as well as functional maturity marker (urocortin-3 [UCN3]) in human diabetic β-cells.Our study demonstrates that inductions of GCK enhanced adaptive UPR and UCN3 in human β-cells, which might be an adaptive mechanism during T2D progression. This finding provides a rationale for exploring novel molecules that activate β-cell GCK and thereby improve pharmacological treatment of T2D.背景:2型糖尿病(T2D)以胰岛β细胞功能进行性恶化和胰岛素分泌持续下降为特征。葡萄糖激酶(GCK)促进胰岛β细胞糖酵解的限速步骤, 以获得适当的葡萄糖刺激的胰岛素分泌。多种葡萄糖激酶激活剂(GKA)已经被研发出来并进行了临床测试, 但在T2D进展过程中, 人胰腺GCK表达的动态变化尚未被研究。 方法:我们通过测定11名非糖尿病受试者(ND)、10名空腹血糖受损(IFG)受试者、9名血糖控制良好的2型糖尿病患者和5名血糖控制不佳的2型糖尿病患者胰腺切片中胰岛素细胞或胰高血糖素分泌细胞中GCK的平均免疫反应性来评估GCK的表达。我们还评估了GCK表达与糖尿病患者β细胞适应性未折叠蛋白反应(UPR)之间的关系。 结果:我们没有检测到空腹血糖受损患者胰岛中GCK表达的变化, 但是我们发现β细胞GCK水平在血糖控制良好的T2D (wT2D)中显著增加, 而在血糖控制不佳的T2D (uT2D)中却没有。此外, 在糖尿病患者β细胞中, GCK的表达与适应性UPR (XBP1s和ATF4)以及功能性成熟标记物(UCN3)呈强正相关。 结论:我们的研究表明, GCK的诱导增强了人β细胞的适应性UPR和UCN3, 这可能是T2D进展中的一种适应性机制。这一发现为探索激活β细胞GCK的新分子以及改善T2D的药物治疗提供了理论基础。." @default.
• W4328049359 created "2023-03-22" @default.
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• W4328049359 date "2023-03-20" @default.
• W4328049359 modified "2023-10-15" @default.
• W4328049359 title "β‐Cell glucokinase expression was increased in type 2 diabetes subjects with better glycemic control" @default.
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• W4328049359 doi "https://doi.org/10.1111/1753-0407.13380" @default.
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