Hyperglycemic Stress and Carbon Stress in Diabetic Glucotoxicity

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.

Redox imbalance stress in diabetes mellitus: Role of the polyol pathway

“…As glucose provides electrons that are mainly stored in NADH, the higher the blood glucose levels, the higher the NADH contents. This can tilt the redox balance between NADH and NAD + toward the side of NADH, resulting in redox imbalance . This is indeed what occurs in diabetes and the polyol pathway is known to play a major role in breaking the redox balance between NADH and NAD + …”

“…It impairs the biological function of many organs in the body. The underlying mechanism of diabetic pathogenesis is hyperglycemia‐induced chronic glucotoxicity, which impairs numerous pathways in the biological metabolome. During development and progression of diabetes, many pathways are upregulated in an attempt to handle the overflow of glucose in the body.…”

Redox imbalance and mitochondrial abnormalities in the diabetic lung

“…Diabetes is a problem of glucose metabolism and diabetes complications is the outcome of glucose toxicity, which is often manifested by increased protein glycation, activation of the polyol pathway and poly ADP ribose polymerase (PARP), and protein kinase C activation [1], [2], [3], [4], [5]. Mechanistically, all these hyperglycemia upregulated pathways can eventually lead to production of reactive oxygen species (ROS) that then induce oxidative stress, mitochondrial dysfunction, and cell death [6], [7].…”

N-Acetyl Cysteine Attenuated the Deleterious Effects of Advanced Glycation End-Products on the Kidney of Non-Diabetic Rats

“…The advanced glycation end-products (AGEs) are compounds derived from the Maillard reaction, in which reducing sugars react nonenzymatically with amino groups of proteins, nucleic acids or lipids [1]. The interest in AGEs in the pathogenesis of diseases in which hyperglycemia is not present lies in the fact that AGEs can be acquired exogenously through diet and tobacco [2,3].…”