Chronic oxidative stress as a mechanism for glucose toxicity of the beta cell in Type 2 diabetes

Abstract

Type 2 diabetes is characterized by a relentless decline in pancreatic islet beta cell function and worsening hyperglycemia despite optimal medical treatment. Our central hypothesis is that residual hyperglycemia, especially after meals, generates reactive oxygen species (ROS), which in turn causes chronic oxidative stress on the beta cell. This hypothesis is supported by several observations. Exposure of isolated islets to high glucose concentrations induces increases in intracellular peroxide levels. The beta cell has very low intrinsic levels of antioxidant proteins and activities and thus is very vulnerable to ROS. Treatment with antioxidants protects animal models of type 2 diabetes against complete development of phenotypic hyperglycemia. The molecular mechanisms responsible for the glucose toxic effect on beta cell function involves disappearance of two important regulators of insulin promoter activity, PDX-1 and MafA. Antioxidant treatment in vitro prevents disappearance of these two transcription factors and normalizes insulin gene expression. These observations suggest that the ancillary treatment with antioxidants may improve outcomes of standard therapy of type 2 diabetes in humans.

Cancer Risk Among People With Type 1 and Type 2 Diabetes: Disentangling True Associations, Detection Bias, and Reverse Causation

“…Our results, instead, support the concept that hyperglycemia, found in both type 1 and type 2 diabetes, may be the mechanistic driver between diabetes and cancer. Hyperglycemia can induce DNA damage (26), downregulate expression of antioxidants (27), and increase reactive oxygen species generation (28). Although biologically plausible, results from epidemiological studies are conflicting.…”

Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Janus kinase‐2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling

“…The BCL family of proteins is a major regulator of the intrinsic mitochondrial cell death pathway [43]. Considering that both DEX and GLT mediate their toxic effects through the intrinsic cell death pathway [44,45], it is not surprising that BCLXL, an anti-apoptotic member of the BCL family, is protective against both cell death inducers. Thus, BCLXL is an important, although not the sole, mediator of the prosurvival effects of lactogens in rodent beta cells.…”

Cellular responses of novel human pancreatic β-cell line, 1.1B4 to hyperglycemia

“…1,2 Chronic hyperglycemia also causes other complications such as retinopathy, neuropathy, kidney failure, and macrovascular disease in diabetes. 3,4 Prolonged exposure to high glucose exerts toxicity on β cells by chronic oxidative stress via several mechanisms in the glycolysis pathway. These include loss of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) activity, production of diacylglycerol from dihydroxyacetone, formation of advanced glycation end products (AGE), alterations of sorbitol metabolism, formation of glucosamine from fructose-1, 6 bisphosphate and oxidative phosphorylation.…”