Chronic diabetes complication

The Diabetes Control and Complications Trial (DCCT), the Stockholm Diabetes Intervention Study (DIS), the United Kingdom Prospective Diabetes Study (UKPDS), and the Japanese Kumamoto study show unequivocally that vigorous treatment of diabetes can decrease both the morbidity and mortality of the disease by reducing chronic complications. 

As noted previously, available therapies moderate the hyperglycemia of diabetes, but fail to completely normalize metabolism. The long-stand-hg elevation of blood glucose causes the chronic complications of diabetes—premature atherosclerosis, retinopathy, nephropathy, and neuropathy. Intensive treatment with insulin (see p. 339) delays the onset and slows the progression of these long-term complications. For example, the incidence of retinopathy decreases as control of blood glu-... 

L. Kennedy and J. W. Baynes, Nonenzymatic glycosylation and the chronic complications of diabetes An overview, Diabetologia, 1984, 26, 93-98. 

In Ayurveda and folklore medicines, cinnamon is used in the treatment of diabetes. Cinnamon is reported to reduce the blood glucose level in non-insulin-dependent diabetics. Therapeutic studies have proved the potential of cinnamaldehyde as an antidiabetic agent. Cinnamaldehyde inhibits aldose reductase, a key enzyme involved in the polyol pathway. This enzyme catalyses the conversion of glucose to sorbitol in insulin-insensitive tissues in diabetic patients. This leads to accumulation of sorbitol in chronic complications of diabetes, such as cataract, neuropathy and retinopathy. Aldose-reductase inhibitors prevent conversion of glucose to sorbitol, thereby preventing several diabetic complications (Lee, 2002). 

A 27-year-old woman with diabetes mellitus, complicated by diabetic retinopathy and chronic renal insufficiency with anemia, developed methemoglobinemia (11%) after peribulbar blockade with prilocaine 80 mg, bupivacaine 30 mg, hyaluronidase, and napha-zoline (325). She recovered uneventfully after methylthioninium chloride 1.5 mg/kg. 

The complication risk in Type-I diabetes is related not only to duration of the disease but also to the degree of glycaemic control, blood pressure and genetic susceptibility (Hanssen, 1991). The most frequent chronic complication in Type-I diabetes is diabetic background retinopathy, with a near-100% occurrence rate after 15 years diabetes duration. Manifestations of diabetes, however, can be found in all ocular structures (Table 1). 

Patients with both type 1 and type 2 diabetes are at high risk for the development of chronic complications. Diabetes-specific microvascular pathology in tlie retina, renal glomerulus, and peripheral nerve produces retinopathy, nephropathy, and neuropathy. As a result of these microvascular complications, diabetes is the most frequent cause of new cases of bfindness in the industrialized world in persons between 25 and 74 years and the leading cause of end-stage renal disease.Diabetes is also associated with a marked increase in atherosclerotic macrovascular disease involving... 

The Amadori sugar-amino acid residue adducts in proteins are produced with prolonged hyperglycemia and undergo progressive nonenzymatic reactions involving dehydration, condensation, and cyclization. These compounds are collectively known as advanced glycosylation end products and are involved in the chronic complications of diabetes mellitus (cataracts and nephropathy) (Chapter 22). 

One of the chronic complications of diabetes mellitus is diabetic nephropathy, which leads to end-stage renal disease. An initial biochemical parameter of diabetic nephropathy in the asymptomatic state is a persistent... 

Diabetes mellitus is a group of metabolic diseases characterized by an increased blood glucose level secondary to defects in insulin secretion and/or action. According to the American Diabetes Association, as of 2002, the United States diabetes prevalence is 18.2 million people (6.3% of the population). Diabetics suffer from acute complications of the disease such as diabetic ketoacidosis and hyperosmolar nonketotic syndrome as well as chronic complications ranging from microvascular disease (nephropathy, neuropathy, retinopathy) to macrovascular disease (1). 

Since alrestatin, albeit at relatively high doses, showed clinical efficacy in the treatment of chronic complications of diabetes [24,25], Ayerst Research Laboratories continued the search for another, more potent, orally active AR inhibitor. Initial attempts were directed towards analogues of alrestatin, and a series was synthesized [124] Table 8.10). Substitution at the 6-position generally increased potency, the highest in vitro being obtained with the readily... 

Substituted spiro[imidazolidine-4,4 (T/0quinazoline]-2,2, 5(3 /0-triones (713) (Scheme 109) have been prepared and tested as aldose reductase inhibitors, which are of therapeutic interest in counteracting chronic complications of diabetes (retinopathy, neuropathy, nephropathy, cataracts). The spiro derivatives (713) were prepared from 1-carbamoylisatins (711) and S-ethylisothiouronium bromide with subsequent treatment of the 4-(2-ethyl-2-isothioureido)carbonyl-3,4-dihydro-4-hyd-roxy-2(l/f)quinazolinone (712) with acid <91CPB1694>. 

Sorbinil 282 is a compound of potential therapeutic interest, because it prevents or alleviates the chronic complications of diabetes mellitus, due to its ability to inhibit the enzyme aldose reductase. Sarges et al. prepared 282 and its enantiomer by the reaction sequence shown in Scheme 12.71, involving a brucine resolution of the racemic hydantoin precursor 284. " The free base of brucine forms a crystalline complex with 282, whereas the other enantiomer of 282 only forms a crystalline complex with brucine hydrochloride. Since this resolution technique does not work with certain congeners of sorbinil, a synthesis via an asymmetric induction sequence (Scheme 12.72) has also been developed that seems generically applicable to optically active spiro hydantoins. Both methodsrequired 2,3-dihydro-6-fluoro-47/-l-benzopyran-4-one 283 and the introduction of the amino acid functionality... 

Chronic Complications - A great deal of interest has been generated in recent years, regarding the possibility that polyol accumulation may be fundamental to the development of diabetic complications in certain tissues. While sorbitol accumulation in the lens has long been implicated as being causally related to diabetic cataract formation , more recent work has provided compelling evidence that a similar situation may exist for the development of diabetic neuropathy " and macroangio-pathy. ... 

Protein giycation. Modest increases in the blood glucose concentration result in glucose reacting non-enzymically with the free amino groups of amino acid residues in cellular and extracellular proteins. They are associated with the development of the chronic complications associated with diabetes such as neuropathy, nephropathy and retinopathy (Chapter 28). 

Pancreatic islet transplantation normalizes the metabolic control of blood glucose to prevent the development of chronic complications is an efficacious treatment for Type 1 diabetes [1]. Although limited donor sources prevent islet transplantation from becoming a major treatment option [2]. Using xenogeneic species as donor sources may solve the problem of an insufficient donor supply [3]. However, xenogeneic islets are subject to immune rejection in humans because of the extensive antigenic differences [4]. Therefore, immune rejection remains a major restriction to xenotransplantation. 

Diabetes mellitus is a complicated, chronic disorder characterized by either insufficient insulin production by the beta cells of die pancreas or by cellular resistance to insulin. Insulin insufficiency results in elevated blood glucose levels, or hyperglycemia As a result of the disease, individuals with diabetes are at greater risk for a number of disorders, including myocardial infarction, cerebrovascular accident (stroke), blindness, kidney disease, and lower limb amputations. 

Diabetes continues to be a major cause of excessive morbidity, severe disability and premature death in Western populations. In developed countries, the cost of diabetes to society may be estimated to be as high as 5% of the total health costs, much of which relates to the chronic vascular complications of this disorder (Williams, 1991). The vascular lesion in diabetes consists of (1) microangiopathy, distinguished by thickening of capillary basement membranes resulting in increased vascular permeability, which is clinically manifested as diabetic retinopathy (Fig. 12.1a) and/or nephropathy (Fig. 12.1b), and (2) macroangiopathy (Fig. 12.2),... 

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