Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.2.1.20 (alpha-glucosidase)
 4,237 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The JCR:LA-cp rat is one of a number of strains incorporating the autosomal recessive cp gene that induces obesity. This strain is unique in the development of not only a profound insulin resistance, but an accompanying cardiovascular disease that correlates strongly with hyperinsulinemia. The hyperinsulinemia develops rapidly after 4 weeks of age, with an age at half-maximum of 5.5 weeks. This reflects postprandial plasma insulin levels that peak at 1000 mU/l in a standardized meal tolerance test. Defective acetylcholine-mediated vascular relaxation develops with a 1-week lag over the developing hyperinsulinemia. The frequency of staining for the vascular adhesion molecules, VCAM-1 and ICAM, does not show either age or genotype variation, although plasma levels do show an age variation. Treatment of the rats with the alpha-glucosidase inhibitor, miglitol (Bay m1099), obviates the exaggerated postprandial glucose and, especially, the insulin responses of the cp/cp rat. This causes an improvement in insulin sensitivity, prevention of the impaired vascular relaxation, and reduction in plasma levels of advanced glycated end-products. Arterial wall morphology, as visualized by both scanning and transmission electron microscopy, shows abnormal endothelium, adherent macrophages, and activated migrating smooth muscle cells in the intima. Oil-Red-O staining reveals lipid deposits in the intimal spaces, as confirmed by the presence of foam cells. The lesions resemble fatty streaks or modest atherosclerosis in man, rather than the extensive cholesterol-laden lesions seen in familial hypercholesterolemia or cholesterol-fed rabbit models. The lean rats of the strain show similar, but less marked, intimal abnormalities. The vasculopathy in this animal model appears to be precipitated by the developing hyperinsulinemia, but also requires an underlying abnormality of vascular smooth muscle and possibly also of the endothelium.
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PMID:Vasculopathy and insulin resistance in the JCR:LA-cp rat. 967 79

Ultrasonographic scanning of carotid arteries allows non-invasive detection of atherosclerotic changes. This technique has been used to investigate changes in the thickness of the intimal plus medial (IM) complex, in patients with type 2 diabetes, type 1 diabetes and those in the pre-diabetic state of impaired glucose tolerance (IGT). IM thickness (IMT) increases with age, but this process was found to be considerably accelerated in patients with type 2 diabetes. In addition, IMT was significantly greater in patients with cerebral lacunar infarctions, and in those with detectable coronary artery stenosis. A study in patients with type 1 diabetes found that IMT correlates with duration of diabetes as well as age. The correlation with duration of diabetes suggests that hyperglycaemia contributes to the progression of atherosclerosis. IMT was also found to be increased in individuals with hyperinsulinaemic IGT, compared with control individuals with normal glucose tolerance. These results suggest that even relatively small increases in postprandial blood glucose levels can lead to increases in IMT and, hence, increased risk of cardiovascular disease. Further analysis revealed a correlation between hyperinsulinaemia (i.e. insulin resistance) and increased IMT. These results provide a clear rationale for the therapeutic use of alpha-glucosidase inhibitors, such as acarbose, which attenuate postprandial hyperglycaemia-induced hyperinsulinaemia.
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PMID:Asymptomatic hyperglycaemia and early atherosclerotic changes. 974 May 1

Fasting blood glucose level is usually used to diagnose diabetes, but is not a good predictor of postprandial hyperglycaemia, which is a more accurate measure of the metabolic defect underlying type 2 diabetes. Postprandial blood glucose levels may be elevated while fasting levels are normal, constituting an early stage in type 2 diabetes that can be termed 'postprandial diabetes'. Prevention of postprandial hyperglycaemia is important, as it is implicated in the development of macro- and microvascular complications associated with diabetes. The risk of cardiovascular disease is higher in individuals with postprandial hyperglycaemia, even without diabetes, than in individuals with normal postprandial blood glucose levels. Furthermore, postprandial hyperglycaemia is implicated in the development of type 2 diabetes. Even modest postprandial hyperglycaemia may lead to beta-cell dysfunction. Agents that reduce postprandial hyperglycaemia have a key role in the treatment of type 2 diabetes and pre-diabetic states. Most anti-diabetic agents that are currently available reduce fasting blood glucose levels, but have little impact on postprandial glycaemic excursions and thus do not normalize postprandial hyperglycaemia. However, new agents that control postprandial hyperglycaemia have been developed, for example, the alpha-glucosidase inhibitor acarbose. Such agents have a potential to reduce the progression of diabetes as well as macro- and microvascular complications.
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PMID:Postprandial hyperglycaemia and alpha-glucosidase inhibitors. 974 May 3

The JCR:LA-cp rat is one of a number of strains that carry the mutant autosomal recessive cp gene. Animals, of all strains, that are homozygous, for the gene (cp/cp) become obese, insulin resistant, and hypertriglyceridemic. Heterozygotes or homozygous normal rats (+/+) are lean and metabolically normal. The JCR:LA-cp rat is unique in the development of a frank vasculopathy with atherosclerotic lesions and associated ischemic myocardial lesions. The cardiovascular disease is strongly correlated with the hyperinsulinemia, which develops as the animals mature from 4 to 8 weeks of age. The hyperinsulinemia can be decreased by marked food restriction, ethanol consumption, or reduction of the postprandial glucose and insulin responses through the use of alpha-glucosidase inhibitors. Any treatment that reduces plasma insulin levels is associated with a reduction in cardiovascular disease. In contrast, a reduction in plasma triglyceride concentrations, alone, has no effect on end-stage lesions. JCR:LA-cp rats, particularly those that are cp/cp, are, however, sensitive to cholesterol in the diet, unlike other strains that are highly resistant. Further, the rats have abnormal vascular smooth muscle cells that, especially in the cp/cp animals, are hyperplastic and activated and migrate into the intimal space. Our findings suggest that susceptibility to cardiovascular disease requires hypermsulinemic stress coupled with excessive dietary intake and the presence of one or more other necessary, but not sufficient, genetic factors. One of these may be a genetic abnormality of vascular smooth muscle cells. A similar situation may occur in humans.
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PMID:Cardiovascular disease in the JCR:LA-cp rat. 982 17

The prevalence of Type 2 diabetes rises steeply with age and involves beta-cell dysfunction and diminished sensitivity to insulin. beta-cell dysfunction is important in the development of hyperglycaemia while insulin resistance seems to play a major role in the atherogenic process resulting in cardiovascular disease. Current therapeutic options include lifestyle adjustments (exercise and diet), oral hypoglycaemic agents (sulphonylureas, newer beta-cell mediated insulin releasing drugs, alpha-glucosidase inhibitors, biguanides and thiazolidinediones) and insulin treatment. Oral hypoglycaemic agents are effective only temporarily in maintaining good glycaemic control, their efficacy should be determined from changes in fasting and postprandial glucose levels. Recent studies have shown that the early initiation of insulin therapy can establish good glycaemic control.
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PMID:Current therapeutic options in type 2 diabetes. 1038 6

The UK Prospective Diabetes Study (UKPDS) provides the first conclusive proof for the importance of intensifying diabetes control in individuals with type 2 diabetes mellitus. However, reduction in cardiovascular disease risk with intensive therapy was modest and did not reach statistical significance. Metformin therapy in obese individuals with type 2 diabetes mellitus was associated with reduced cardiovascular death. These observations should be re-evaluated to determine whether various therapeutic agents available for treatment of type 2 diabetes mellitus have different effects on cardiovascular complications of diabetes. The addition of alpha-glucosidase inhibitor, acarbose, improved glycaemic control irrespective of concomitant therapy for diabetes, although compliance with this agent was poor. The tight blood pressure control study embedded in UKPDS reaffirms the importance of lowering the blood pressure below 150/85 to reduce microvascular and macrovascular complications of diabetes.
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PMID:Implications of the UK prospective diabetes study: questions answered and issues remaining. 1080 56

Despite the growing consensus that postprandial glucose levels provide a more accurate and valuable early marker of diabetes symptoms than fasting plasma glucose, the ability to forestall diabetic complications by managing postprandial hyperglycemia has not been proved. Patients who are not considered to have diabetes mellitus may have impaired glucose tolerance (and increased risk for developing cardiovascular disease), and targeting nonfasting glucose can reduce insulin requirements for patients with insulin-dependent diabetes mellitus (type 1 diabetes mellitus). The challenge now is to determine what fasting glucose levels merit intervention, when and how they should be determined, and who should measure them. After outlining the discrepancies and lack of consensus between measurement guidelines developed by different professional organizations, the author then reviews options for treating postprandial hyperglycemia, including prepackaged meals, alpha-glucosidase inhibitors, acarbose therapy, and fast-acting insulin preparations.
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PMID:Postprandial hyperglycemia: implications for practice. 1157 24

Several epidemiological studies have shown an association between postprandial hyperglycemia and mortality from cardiovascular disease. Postprandial hyperglycemia is frequently associated with visceral obesity which plays a key role in metabolic abnormalities such as dyslipidemia and hypertension. Inhibitors of alpha-glucosidase and nateglinide have beneficial effects on the metabolic syndrome associated with visceral obesity. Voglibose in combination with diet therapy reduces visceral fat deposition and ameliorates insulin resistance. Acarbose slightly reduces blood pressure of hypertensive diabetic patients. Nateglinide, a rapidly acting insulin secretagogue, lowers postprandial glucose levels without significant body weight gain. These drugs may protect pancreatic beta-cells from postprandial glucose toxicity and prevent the progression of diabetes.
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PMID:[Pharmacological treatment of postprandial hyperglycemia in hypertensive patients with type 2 diabetes mellitus]. 1287 88

Genetically modified laboratory animals provide a powerful approach for studying gene expression and regulation and allow one to directly examine structure-function and cause-and-effect relationships in pathophysiological processes. Today, transgenic mice are available as a research tool in almost every research institution. On the other hand, the development of a relatively large mammalian transgenic model, transgenic rabbits, has provided unprecedented opportunities for investigators to study the mechanisms of human diseases and has also provided an alternative way to produce therapeutic proteins to treat human diseases. Transgenic rabbits expressing human genes have been used as a model for cardiovascular disease, AIDS, and cancer research. The recombinant proteins can be produced from the milk of transgenic rabbits not only at lower cost but also on a relatively large scale. One of the most promising and attractive recombinant proteins derived from transgenic rabbit milk, human alpha-glucosidase, has been successfully used to treat the patients who are genetically deficient in this enzyme. Although the pronuclear microinjection is still the major and most popular method for the creation of transgenic rabbits, recent progress in gene targeting and animal cloning has opened new avenues that should make it possible to produce transgenic rabbits by somatic cell nuclear transfer in the future. Based on a computer-assisted search of the studies of transgenic rabbits published in the English literature here, we introduce to the reader the achievements made thus far with transgenic rabbits, with emphasis on the application of these rabbits as human disease models and live bioreactors for producing human therapeutic proteins and on the recent progress in cloned rabbits.
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PMID:Transgenic rabbits as therapeutic protein bioreactors and human disease models. 1295 Nov 61

Numerous clinical trials have been completed to evaluate interventions aimed to prevent or delay the development of diabetes in high risk populations and ultimately to reduce the risk of CVD. There have been several trials emphasizing lifestyle modification, including weight reduction and increased physical activity, such as the Da Qing Study, the Finnish Diabetes Prevention Study and the Diabetes Prevention Program. Pharmacologic agents such as metformin, alpha-glucosidase inhibitors, and TZDs have also been shown to reduce the risk of developing type 2 diabetes.
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PMID:[Clinical trials to evaluate interventions aimed to prevent or delay the development of diabetes in high risk IGT]. 1520 57


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