High glucose inhibits glucose‐6‐phosphate dehydrogenase, leading to increased oxidative stress and β‐cell apoptosis

Abstract

Patients with type 2 diabetes lose beta cells, but the underlying mechanisms are incompletely understood. Glucose-6-phosphate dehydrogenase (G6PD) is the principal source of the major intracellular reductant, NADPH, which is required by many enzymes, including enzymes of the antioxidant pathway. Previous work from our laboratory has shown that high glucose impairs G6PD activity in endothelial and kidney cells, which leads to decreased cell survival. Pancreatic beta cells are highly sensitive to increased ROS. This study aimed to determine whether G6PD and NADPH play central roles in beta-cell survival. Human and mouse islets, MIN6 cell line, and G6PD deficient mice were studied. High glucose inhibited G6PD expression and activity. Inhibition of G6PD with siRNA led to increased ROS and apoptosis, decreased proliferation, and impaired insulin secretion. High glucose decreased insulin secretion, which was improved by overexpressing G6PD. G6PD-deficient mice had smaller islets and impaired glucose tolerance compared with control mice, which suggests that G6PD deficiency per se leads to beta-cell dysfunction and death. G6PD plays an important role in beta-cell function and survival. High-glucose-mediated decrease in G6PD activity may provide a mechanistic explanation for the gradual loss of beta cells in patients with diabetes.

Glucose-6-Phosphate Dehydrogenase Deficiency Improves Insulin Resistance With Reduced Adipose Tissue Inflammation in Obesity

“…Meanwhile, G6PD mut mice developed through ENU random mutagenesis with C3H mice are viable and display no apparent chronic hemolysis despite low G6PD activity (27). To date, G6PD mut mice have been studied for various pathological conditions such as sepsis, teratogenesis, cardiovascular diseases, myocardial dysfunction, and atherosclerosis (17,18,(20)(21)(22)(30)(31)(32)42,43). Because of their genetic background, C3H G6PD mut mice have some limitations for investigating obesity-mediated chronic inflammation and metabolic dysregulation.…”

“…In pathological conditions such as atherosclerosis, heart failure, and obesity, G6PD promotes cellular ROS production and proinflammatory signaling through increased availability of NADPH to ROS-producing enzymes (14)(15)(16)(17)(18)(19). On the other hand, in various cell types, including erythrocytes, cardiomyocytes, endothelial cells, and pancreatic b-cells, G6PD contributes to the clearance of cellular oxidative stress by NADPH-dependent ROS-scavenging enzymes (20)(21)(22)(23). We recently demonstrated that G6PD is highly expressed in the adipose tissues of obese and diabetic subjects (14,24).…”

“…As a potential animal model of human G6PD deficiency, a G6PD-deficient mutant (G6PD mut ) mouse model has been developed, which shows 10-15% of regular G6PD activity because of a reduction in G6PD protein expression by a splicing defect (27,28). Since the embryoprotective role of G6PD has been reported (20,29), various effects of G6PD deficiency on metabolic processes, immune responses, and organ development have been studied in G6PD mut mice (17,18,21,22,30). Furthermore, G6PD deficiency affects albuminuria and diet-induced cardiometabolic aberrations in G6PD mut mice (31,32).…”

High Frequency of Diabetes and Impaired Fasting Glucose in Patients with Glucose-6-Phosphate Dehydrogenase Deficiency in the Western Brazilian Amazon

“…Several mechanisms may be involved in the association between diabetes and G6PD deficiency, especially in the genes controlling insulin secretion and G6PD activity. 5 In addition, patients with diabetes and G6PD deficiency have a poorer prognosis. 6 The present study aimed to estimate the frequency of diabetes mellitus among G6PD-deficient persons in Manaus, in the Western Brazilian Amazon, and compare them with matched controls.…”

Vildagliptin and Insulin Combinatorial Therapy Drug Safety Monitoring in Diabetic Rats

“…There is a marked fall in the level of glucose 6-phosphate dehydrogenase which in turn decreases the formation of 14 CO 2 from glucose, which in turn leading to a decrease in the contribution of the Pentose Phosphate pathway. 21 The energy in the form of ATP and NADH is produced by Glucose-6-phosphate (G6P) in glycolysis and also it is used to store energy in the form of glycogen and also it is used by the pentose phosphate pathway. Significant decreases in G6PD [glucose-6-phosphate dehydrogenase] activity due to hyperglycemia or diabetes in all the cells and tissues of the body may lead to severe anaemia.…”