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

With use of the alpha-glucosidase inhibitor bay g 5421 (acarbose), it is possible to improve glycemic profiles in diabetics without a concomitant increase in insulin levels or weight reduction. We have taken advantage of this feature to test whether an improvement in glycemic control alone can ameliorate some of the known abnormalities of type II diabetes (ie, impaired insulin secretion, elevated rate of basal hepatic glucose output, peripheral insulin resistance). We have studied eight type II diabetics (mean +/- SE fasting serum glucose 193 +/- 25 mg/dL) before and after 2 weeks of acarbose therapy (100 mg with each meal). Assessment of endogenous insulin secretion, peripheral and hepatic insulin sensitivity, and adipose tissue lipoprotein lipase (ATLPL) activity were performed. Results showed significant lowering of postprandial glucose excursions above basal but no change in basal serum glucose levels, marked reduction in fasting and day-long triglyceride levels and in spite of a reduction in ATLPL activity, an increase in hepatic sensitivity to insulin's ability to suppress hepatic glucose output, and no effect on peripheral insulin sensitivity. In conclusion, inhibition of carbohydrate digestion with alpha-glucosidase inhibitors ameliorates many of the metabolic abnormalities in type II (noninsulin-dependent diabetics), suggesting that agents of this type can be of therapeutic value.
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PMID:The effect of short-term alpha-glucosidase inhibition on carbohydrate and lipid metabolism in type II (noninsulin-dependent) diabetics. 355 48

Inhibition of carbohydrate digestion by the alpha-glucosidase inhibitor acarbose (BAY g 5421)reduces carbohydrate-induced postprandial blood glucose increase and insulin secretion. As a consequence, in feeding experiments sucrose-induced hyperinsulinemia and hypertriglyceridemia in genetically obese (fa,fa) "Zucker" rats were dose-dependently reduced by addition of acarbose to the diet (15-80 mg/100 g feed). The body weight gain was dose-dependently reduced. In short-term experiments with a fat-free diet acarbose not only prevented serum triglyceride and free fatty acid increase in spite of lowered insulin concentrations but also decreased their concentrations below the values obtained on standard feed. Under these conditions there were no significant effects on body weight. Hypertriglyceridemia induced by i.v. injection of the lipoprotein lipase inhibitor Triton WR 1339 was reduced without affecting body weight in "Zucker" rats after 3 days on a fat-free diet supplemented with acarbose. The triglyceride increase was even lower than in animals kept on standard feed. The data demonstrate that acarbose reduces sucrose-induced hypertriglyceridemia in (fa,fa) "Zucker" rats by diminishing VLDL production and/or secretion rather than by increasing VLDL removal from the blood.
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PMID:Reduction of carbohydrate-induced hypertriglyceridemia in (fa,fa) "Zucker" rats by the alpha-glucosidase inhibitor acarbose (BAY g 5421). 704 75

The mutations cld (combined lipase deficiency) and lec23 disrupt in a similar manner the expression of lipoprotein lipase (LPL). Whereas cld affects an unknown gene, lec23 abolishes the activity of alpha-glucosidase I, an enzyme essential for proper folding and assembly of nascent glycoproteins. The hypothesis that cld, like lec23, affects the folding/assembly of nascent LPL was confirmed by showing that in cell lines homozygous for these mutations (Cld and Lec23, respectively), the majority of LPL was inactive, displayed heterogeneous aggregation, and had a decreased affinity for heparin. While inactive LPL was retained in the ER, a small amount of LPL that had attained a native conformation was transported through the Golgi and secreted. Thus, Cld and Lec23 cells recognized and retained the majority of LPL as misfolded, maintaining the standard of quality control. Examination of candidate factors affecting protein maturation, such as glucose addition and trimming, proteins involved in lectin chaperone cycling, and other abundant ER chaperones, revealed that calnexin levels were dramatically reduced in livers from cld/cld mice; this finding was also confirmed in Cld cells. We conclude that cld may affect components in the ER, such as calnexin, that play a role in protein maturation. Whether the reduced calnexin levels per se contribute to the LPL deficiency awaits confirmation.
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PMID:cld and lec23 are disparate mutations that affect maturation of lipoprotein lipase in the endoplasmic reticulum. 1055 8

Mass spectrometry is a rapid, sensitive, and accurate quantitative approach for the direct monitoring of enzyme-catalyzed reactions that does not require a chromophore or radiolabeling and thus provides a viable alternative to existing analytical techniques. In this study the proteolysis of intact viral capsid proteins, the alpha-glucosidase-catalyzed hydrolysis of p-nitrophenyl-alpha-glucopyranoside and the lipoprotein lipase-catalyzed ester hydrolysis of resorufin were examined. Matrix-assisted laser desorption/ionization and electrospray ionization mass spectrometry were used to examine the proteolysis of viral protein capsids, providing information about capsid dynamics and the stabilizing force of viral protein/RNA interactions. In addition, k(cat) and K(m) values of enzyme-catalyzed hydrolysis were obtained (without the use of a chromophore). These results also demonstrate the effect an unnatural substrate can have on enzyme activity. Overall, mass spectrometry provides for efficient and quantitative analysis of enzyme-catalyzed reactions, as well as the direct observation of reaction dynamics.
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PMID:Monitoring enzyme catalysis with mass spectrometry. 1078 58

As compared to subcutaneous adipocytes, visceral adipocytes have high basal lipolysis, are highly sensitive to catecholamines, and are poorly sensitive to insulin; these traits are amplified when visceral adipocytes hypertrophy. As a result, enlarged visceral fat stores tend to flood the portal circulation with free fatty acids at metabolically inappropriate times when fatty acids are unlikely to be oxidized, thus exposing tissues to excessive free fatty acid levels and giving rise to the insulin resistance syndrome. A logical approach to preventing or correcting visceral obesity is to down-regulate the lipoprotein lipase (LPL) activity of visceral adipocytes relative to that expressed in subcutaneous adipocytes and skeletal muscle. IGF-I activity appears to be a primary determinant of visceral LPL activity in humans; systemic IGF-I activity is decreased when diurnal insulin secretion is low, when hepatocytes detect a relative paucity of certain essential amino acids, and when estrogens are administered orally. The ability of alpha-glucosidase inhibitor therapy to selectively reduce visceral adiposity suggests that down-regulation of diurnal insulin secretion and/or IGF-I activity may indeed have a greater impact on LPL activity in visceral fat than in subcutaneous fat. Thus, low-glycemic-index, vegan, high-protein, or hypocaloric diets can be expected to decrease visceral LPL activity, as can postmenopausal estrogen therapy. Furthermore, estrogen enhances the LPL activity of non-pathogenic gluteofemoral fat cells, whereas testosterone decreases visceral LPL activity in men; this may explain why sex hormone replacement in middle-aged people of both sexes has a favorable impact on visceral fat and insulin sensitivity. Beta-adrenergic activity suppresses transcription of LPL in adipocytes; this phenomenon may contribute to the favorable impact of exercise training on visceral obesity; conceivably, preadministration of safe drugs that boost catecholamine activity (caffeine, yohimbine) could potentiate this beneficial effect of exercise. Glucocorticoids selectively increase the LPL activity of visceral adipocytes; while there is currently no convincing evidence that psychological stress is a major determinant of visceral adiposity, or that stress management techniques can help to correct visceral obesity, reports that anxiolytic therapy can improve glycemic control in type 2 diabetes should encourage further research along these lines.
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PMID:Modulation of adipocyte lipoprotein lipase expression as a strategy for preventing or treating visceral obesity. 1146 Nov 72

Visceral obesity and insulin resistance are regarded as risk factors for atherosclerosis. Epidemiologic studies have demonstrated long-term anti-atherosclerotic effects with administration of alpha-glucosidase inhibitors. Alpha-glucosidase inhibitors also have been reported to enhance glucagon-like peptide 1 (GLP-1) secretion. We compared the postprandial effects of a single administration of miglitol and acarbose on glucose and lipid metabolism, on insulin requirement, on GLP-1 secretion, and on inflammatory and endothelial markers in viscerally obese subjects. Twenty-four viscerally obese subjects with relative insulin resistance participated in this study. Subjects were given a single dose of miglitol (50 mg), acarbose (100 mg), or placebo blindly and randomly before a meal in a crossover design. The meal loads after drug administration were tested 3 times within 2 weeks. We measured glucose, insulin, lipids, lipoprotein lipase, interleukin 6, intracellular adhesion molecule 1, vascular cell adhesion molecule 1, and active GLP-1 at before and various minutes after the meal. Single administration of both alpha-glucosidase inhibitors had several beneficial effects in improving postprandial hyperglycemia and reducing postprandial insulin requirement approximately 25% of placebo without adversely affecting lipid profiles. Although lipoprotein lipase levels within 2 hours after the meal did not show differences among miglitol, acarbose, and placebo administrations, miglitol significantly suppressed the increases in triglycerides, remnant-like particle triglycerides, and remnant-like particle cholesterol compared to acarbose and placebo in the early phase. Miglitol also significantly enhanced active GLP-1 secretion to a greater extent than acarbose (P < .01) and placebo (P < .001), and significantly suppressed the postprandial increase in interleukin 6 compared to placebo (P < .01). The results point to the potential suitability of miglitol as an anti-atherosclerotic effect in viscerally obese subjects, in preference to acarbose. Further studies are needed to elucidate the long-term effects on enhanced GLP-1 secretion and anti-atherosclerosis.
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PMID:Miglitol suppresses the postprandial increase in interleukin 6 and enhances active glucagon-like peptide 1 secretion in viscerally obese subjects. 1870 58