Abstract
Diabetes and its complications are caused by chronic glucotoxicity driven by persistent hyperglycemia. In this article, we review the mechanisms of diabetic glucotoxicity by focusing mainly on hyperglycemic stress and carbon stress. Mechanisms of hyperglycemic stress include reductive stress or pseudohypoxic stress caused by redox imbalance between NADH and NAD(+) driven by activation of both the polyol pathway and poly ADP ribose polymerase; the hexosamine pathway; the advanced glycation end products pathway; the protein kinase C activation pathway; and the enediol formation pathway. Mechanisms of carbon stress include excess production of acetyl-CoA that can over-acetylate a proteome and excess production of fumarate that can over-succinate a proteome; both of which can increase glucotoxicity in diabetes. For hyperglycemia stress, we also discuss the possible role of mitochondrial complex I in diabetes as this complex, in charge of NAD(+) regeneration, can make more reactive oxygen species (ROS) in the presence of excess NADH. For carbon stress, we also discuss the role of sirtuins in diabetes as they are deacetylases that can reverse protein acetylation thereby attenuating diabetic glucotoxicity and improving glucose metabolism. It is our belief that targeting some of the stress pathways discussed in this article may provide new therapeutic strategies for treatment of diabetes and its complications.
Highlights
Diabetes and its complications are diseases originated from impaired glucose metabolism [1,2,3,4,5,6,7,8]
As glucose metabolism is tightly regulated by insulin, aberrant glucose metabolism can be regarded as the problems of insulin resistance or insulin deficiency [9,10,11,12,13]
If sirtuins have to be upregulated to cope with carbon stress, such approaches will certainly lead to more consumption of NAD+, the level of which is already low given the activation of poly ADP ribose polymerase and over production of NADH [36]
Summary
Diabetes and its complications are diseases originated from impaired glucose metabolism [1,2,3,4,5,6,7,8]. The process of glucose extraction from food is achieved in the gastrointestinal tract [42] This is followed by release of glucose into the blood stream and glucose stimulation of β cell insulin secretion that promotes uptake of glucose by muscle and adipose tissues [43]. Insulin promotes gene expression, protein synthesis, and amino acid uptake in all types of cells [58] All these processes are perturbed in diabetes, leading to progressive glucotoxicity [2, 20, 37, 59] that includes hyperglycemic stress and carbon stress as is to be discussed
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