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.

Keywords: carbon stress; diabetes; glucotoxicity; hyperglycemic stress; pseudohypoxia; reactive oxygen species; redox imbalance.

Figure 1.

Major pathways upregulated by chronic hyperglycemia. These pathways include the polyol pathway, the hexosamine pathway, PKC activation, formation of advanced glycation end products (AGEs), and the enediol formation pathway. These pathways usually remain dormant under euglycemia conditions whereby majority of the body's glucose is combusted through glycolysis and TCA cycle.

Figure 2.

Regulation of glucose homeostasis and pathophysiology of hyperglycemia. Glucose is extracted from food stuff in the gastrointestinal tract and is then released to the blood stream. High level of blood glucose stimulates insulin secretion from islet β cell in the pancreas, leading to uptake of glucose by muscle and adipose tissues. Insulin also suppresses the gluconeogenesis in the liver. Excess glucose is stored in the liver and the muscle as glycogen, and in the adipose tissue as fat. This glucose uptake and storage process and the overall control of glucose homeostasis are impaired in diabetes.

Figure 3.

Summary of insulin-stimulated biological processes. Hyperglycemia-induced secretion of insulin can mediate numerous biological processes such as glucose uptake, activation of Na⁺/K⁺ pumps, synthesis of fatty acid from acetyl-CoA and glycogen from glucose, amino acid uptake, gene expression, and protein synthesis. Figure adapted from reference [58].

Figure 4.

Glucose disposal via the polyol pathway under chronic hyperglycemic conditions in diabetes. This pathway includes two-step reactions. The first one is glucose reduction by aldose reductase to form sorbitol; while the second reaction is sorbitol oxidation by sorbitol dehydrogenase to form fructose. Reducing equivalent is transferred from NADPH to NADH, leading to elevated level of NADH and reductive stress. The glycolytic pathway is also shown.

Figure 5.

Glucose disposal via the hexosamine pathway. This pathway involves activation of glutamine fructose-6-P amidotransferase that converts fructose 6-P to glucosamine 6-P. This is followed by the formation of UDP-GlcNAc that is the substrate for protein translational modifications. This pathway is known to be involved in insulin resistance and diabetes. The glycolytic pathway is also shown.

Figure 6.

Summary of events leading to redox imbalance between NADH and NAD⁺ in diabetes. On one hand, the polyol pathway produces excess NADH; on the other hand, the activation of poly ADP ribose polymerase could potentially deplete NAD⁺, leading to great pressure on mitochondrial complex I that is in charge of NADH oxidation and NAD⁺ production. NADH overload on complex I can lead to more ROS production. Therefore, complex I could be a pathogenic factor in diabetes and could also be a target for diabetic therapies.

Figure 7.

Sources and fates of acetyl-CoA. Acetyl-CoA is mainly generated by combustion of glucose, fatty acid, and proteins. When in excess, acetyl-CoA can be used to make sterols and fatty acids, and can also conjugate to proteins, forming acetylated protein products. In long term fasting or starvation, acetyl-CoA can be used to form ketone bodies that are needed for brain function [288, 289]. Under normal conditions, acetyl-CoA is metabolized to provide energy via TCA cycle and oxidative phosphorylation inside mitochondria.

Figure 8.

Excess acetyl-CoA produced by hyperglycemia and hyperlipidemia in diabetes can increase nonenzymatic acetylation of proteins via lysine residues. This modification can regulate protein function under stress conditions via sirtuins actions that remove the acetyl groups from the target proteins.