Title: Hyperglycaemia & Diabetic Complications
Key words: Diabetes, aldose reductase, glycation, glycoxidation, complications, antioxidants, aldose reductase inhibitors
Date: March 1999
Category: 13. Specific Conditions
Author: Dr van Rhijn
Hyperglycaemia & Diabetic Complications
Mechanisms of Chronic Complications in Diabetes Mellitus
Developing chronic tissue complications of diabetes cause great anxiety among patients. Tthe complications seem to be proportional to the degree and duration of the hyperglycaemia1. Several mechanisms are proposed by which glucose and other sugars can damage tissues. These are discussed briefly below.
Excess glucose is converted to the polyalcohol sorbitol by aldose reductase2. This enzyme is present in the retina, lens, glomerulus and Schwann cells of nerves, which are therefore the areas affected. Excess sorbitol formation may promote cataract formation in the lens probably via excessive osmotic stress3. It may also interfere with the synthesis of myo-inositol and thus intracellular signalling involving inositol phosphates, resulting in delayed conduction and neuropathy.
Glycation and Glycoxidation
Glucose (straight-chain form) is able to behave as an aldehyde, therefore binding to various proteins, amino-lipids and DNA, slowly modifying them in the process referred to as non-enzymatic Glycosylation (Maillard browning). Glycation products can be oxidised to irreversible Advanced Glycation End-products (AGEs), which can impair organ function when accumulated in tissues4. In collagen, they decrease the elasticity of connective tissue (blood vessels) and damage basement membranes (kidneys/retina). They can also cause excessive proliferation of blood vessels in diabetic retinopathy. This neovascularisation is also facilitated by hypoxia, which releases vascular endothelial-cell growth factor (VEGF). AGEs are also present on circulating low density lipoproteins (LDLs) and endothelial5 cells, contributing to injury and atherosclerotic lesions via scavenger receptor mediated uptake of LDL's by endothelium macrophages. Cell adhesion and a procoagulation state is also promoted.
Glycation is facilitated at higher glucose levels, and glycosylated haemoglobin (HbA1/HbA1c) levels are used as an index of how well blood glucose has been controlled over the last 4-6 weeks.
Both glycated and AGE-modified proteins can lead to oxidative stress by releasing superoxide and hydrogen peroxide (O2 and H2O2 ) and activating phagocytes. Several cells (monocytes & macrophages) use a cell-surface receptor for AGE (RAGE) that is distinct from scavenger receptors, to recognise and engulf glycosylated erythrocytes. RAGE is also present in endothelial cells, and exposure to AGEs up-regulates adhesion molecule production and decreases GSH levels. Oxidative stress in diabetes results from a combination of altered metabolism (carbohydrates & lipids), increased generation of ROS (glycation & lipid oxidation), elevated F2-isoprostanes, raised 8-hydroxydeoxyguanosine and activated NFkB in circulating leucocytes, as well as decreased levels of erythrocyte antioxidant defences6 (GSH) and reduced plasma concentrations of vitamin C.
Chronic diabetic complications are usually classified as:
Microvascular disease: The common features are basement membrane thickening and increased capillary permeability of the microcirculation, leading to the formation of haemorrhages7, leakage of fibrin and oedema with subsequent thickening of the vessel walls and eventual closure. This is an essential characteristic component of retinopathy, nephropathy and less certainly, peripheral neuropathy8.
Macrovascular disease: (coronary/cerebral/peripheral): Poor conversion of n-3 and n-6 essential fatty acids to their longer-chain metabolites via the insulin-dependent desaturation step9. The result is a lack of prostaglandins, responsible for normal platelet function and clot clearance from arterial walls, possibly leading to coronary artery disease, cerebrovascular disease and peripheral vascular disease.
The significance in the disease pathology remains still uncertain regarding oxidative stress and the other mechanisms mentioned above. Tight glycaemic10, 11, 12 control and the possible use of several antioxidants13, 14 and inhibitors of aldose reductase may have beneficial therapeutic effect by reducing long term microvascular complications.