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Effect of Blood Glucose Concentrations on the Development of Chronic Complications of Diabetes Mellitus

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Effect of Blood Glucose Concentrations on the Development of Chronic Complications of Diabetes Mellitus Effect of Blood Glucose Concentrations on the Development of Chronic Complications of Diabetes Mellitus Sahar Z. Swidan, Pharm.D., and Patricia A. Montgomery, Pharm.D. Diabetes is associated with increased risk of cardiovascular disease, coronary heart disease, stroke, acute myocardial infarction, blindness, and renal failure. Strategies to reduce their occurrence are an essential focus of patient care. More than one pathogenic process is involved, and genetics influence the risk. Hyperglycemia is a factor in the development of microvascular and possibly macrovascular complications. Two possible mechanisms of glucose damage are glycation of proteins and the polyol pathway. Research led to the identification of drugs that block parts of the pathways. In clinical trials, intensive control of blood glucose concentrations decreased the risk of microvascular complications. Adverse effects associated with intensive therapy, however, include hypoglycemia and weight gain. (Pharmacotherapy 1998;18( 5):96 1-972) OUTLINE for diabetes are based on the relationship Mechanisms of Damage from Hyperglycemia between hyperglycemia and retinopathy, Glycation of Proteins nephropathy, and macrovascular di~ease.~The Polyol Pathway and Myoinositol degree of glycemic control contributes to the risk Clinical Trials of nephropathy and retinopathy in patients with Type 1 Diabetes Mellitus type 1 disease.'j Approximately 25% of people Type 2 Diabetes Mellitus with diabetes never develop chronic complications Special Patient Populations regardless of glycemic control, whereas Conclusion approximately 5% develop severe complications within a few years of diagnosis.' Hypertension Diabetes mellitus is associated with 2-3 times and hyperlipidemia occur frequently and the risk of cardiovascular disease, coronary heart contribute to vascular disease.' disease and stroke' and is implicated in 25% of acute myocardial infarctiom2 It is the leading Mechanisms of Damage from Hyperglycemia cause of blindness in the United States and of renal failure.2, Individuals with diabetes are 2.5 Identifying the mechanisms by which glucose times more likely to be hospitalized than those causes damage may be helpful in developing without the disease.2 Overall, it is estimated that ways to prevent complications. It is likely that the cost of diabetes in the United States is $92 more than one pathogenic process is involved, billion/year.2 and the critical process may vary with the Epidemiologic and clinical data showed an compli~ation.~Furthermore, there is an apparent association between hyperglycemia and the genetic influence on the risk of complications. complications of diabetes.3d Diagnostic criteria Many physiologic abnormalities have been associated with hyperglycemia. Acute effects From the Department of Pharmaceutical Services, include elevated protein kinase C activity, Chelsea Community Hospital, Chelsea Michigan (Dr. hyperlipidemia, alterations in renal hemodynamics, Swidan); and the Department of Pharmacy, University of abnormalities in prostacyclin activity, rheologic Michigan College of Pharmacy, Ann Arbor, Michigan (both abnormalities, and hypersensitivity of platelets.l~12 authors). Many of these disorders are reversible with Address reprint requests to Sahar Z. Swidan, Department of Pharmaceutical Services, Chelsea Community Hospital, correction of hyperglycemia.l0,l1 Therefor;, it is 775 South Main Street, Chelsea, MI 48118. not known why they may progress, or even 962 PHARMACOTHERAPY Volume 18, Number 5,1998 appear for the first time, after glucose is Reactions involved in formation of Amadori corrected. l3 Two possible mechanisms of long- compounds are also reversible, although slower, term glucose toxicity are glycation of proteins reaching equilibrium in several weeks. The and the polyol pathway. Research into each concentration of Amadori compounds is related mechanism has been the impetus for the to mean blood glucose concentration over the development of new drugs. previous weeks. Amadori products eventually degrade, resulting in carbonyl compounds that Glycation of Proteins are highly reactive with free amino groups. These ultimately form complexes known as Glucose and proteins undergo a complex series intermediate and advanced glycated end products of reactions that ultimately results in irreversible (AGEs) or advanced glycated proteins (AGPs). alterations in tissue structure and interference Once AGEs have formed, the process is irreversible. with normal protein function. For this reason, Therefore, the concentration of AGEs is a reflection glycation of proteins was proposed as an of overall glucose concentration throughout life. explanation for so-called hyperglycemic memory, These reactions occur in everyone to an extent or continued destruction of tissues after determined by blood glucose concentrations. restoration of glycemic contr01.l~ Some Normally, the process may be involved in tissue individuals may produce enzymes capable of remodeling and removal of aging macrom~lecules metabolizing precursors of glycated proteins to from the circulation.16 This may explain why result in less harmful m01ecules.l~ This is also a some chronic pomplications of diabetes resemble possible explanation for genetic differences in acceleration of the aging process. risk of complications; that is, those who can Several mechanisms have been identified by efficiently clear glycated proteins may be at which AGEs interfere with normal tissue decreased risk compared with those who cannot. function. Some abnormalities in diabetes may Decreased renal clearance of glycated proteins result from AGEs attaching to proteins of the may be involved in acceleration of some extracellular matrix. The extracellular matrix is complications in patients with declining renal widened in all types of vessels in diabetes, function. The glycation sequence, which is not including basement membranes of the retinal and completely described, begins when sugar vasa nervorum, and mesangial matrix of the molecules undergo nucleophilic addition glomerulu~.~’Alterations in the structure of reactions with free amino groups on proteins to basement membrane may result in part by form molecules called Schiff bases (Figure l).15 binding of AGEs to type IV collagen and laminin, Because the reaction is nonenzymatic and interfering with their ability to self-assemble and reversible, these early glycated proteins are associate with other basement membrane formed in proportion to the surrounding glucose macromolecules. l9 Other consequences of concentration. The reaction is rapid and reaches glycation cause the basement membrane to be equilibrium within hours. l5 These compounds less susceptible to normal proteolytic degradation are unstable and undergo further rearrangement and inactivation of nitric to the Amadori product (1-amino-l-deoxy-D- Further problems are caused by AGEs on ketose).13 collagen in vessel walls that have increased binding to low-density lipoprotein (LDL) and immunoglobulin G (IgG).23v24 Bound LDL and Protein-NH2 IgG are likely to react further with glucose and + H- rNH-Protein glycated proteins to form additional AGEs. H- -OH Thickening of vessel walls is in part a direct Advancsd OH- -H Glycation consequence of the accumulation of these bound t- - Endpmduct proteins.17 In addition, macrophages and H- -OH monocytes have receptors that interact with H-IzOH -OH AGEs, triggering release of cytokines such as tumor necrosis factor and interleukin-1, and ultimately the release of growth factors.16 These processes are involved in formation of athero- [Glucooe*ProtsinI pGq pizzzz- sclerotic plaques.25 Release of these factors and Figure 1. Proposed steps in the formation of glycated end diminished activity of nitric oxide may also products. contribute to the cellular proliferation associated GLUCOSE CONCENTRATIONS & DIABETES COMPLICATIONS Swidan and Montgomery 963 with retinopathy, nephropathy, and ne~ropathy.'~,26 glycation of proteins. Sorbitol is more likely to Binding of AGEs to receptors on endothelial exist in the reactive open form of sugars than is cells induces changes in coagulation pathways glucose. Therefore, in cells with high concentrations that promote thrombosis and stimulates of sorbitol, reactions between sugars and proteins production of endothelial-1, which has vaso- are accelerated.l4 In addition, accumulation of constrictive activity. A separate mechanism of the reduced form of nicotinamide adenine AGE-induced damage involves glycation of DNA dinucleotide may contribute to complications by and RNA, which results in mutations and altering the redox state and allowing a rise in the abnormal expression of genes in experimental concentration of diacylglycerol (DAG), and models.27-29 increased activation of some isoforms of protein Several agents were investigated for activity in kinase C (PKC).39 Activation of PKC causes inhibiting AGE development. Pimagedine is an effects such as reduced Na', K-ATPase activity investigational drug that interferes with and changes in vascular c~ntractility.~~!40 Other formation of AGEs and may have other actions as abnormalities associated with polyol pathway well.30 Its efficacy was shown in studies in activity are diminished nitric oxide synthetase animal models of retinopathy and nephropathy. and some structural lesions.38,41 In an open label study in 18 humans with Aldose reductase inhibitors were developed to diabetes, hemoglobin AGE concentrations interfere with accumulation of sorbitol in decreased significantly during 1 month of
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