Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of various treatments on acetylation status measured by caffeine metabolites was investigated in 17 subjects with non-insulin dependent diabetes mellitus (NIDDM). The test drugs, caffeine (200 mg), antipyrine (20 mg/kg) and coumarin (5 mg), were given simultaneously, and urinary 5-acetylamino-6-formyl-amino-3-methyluracil/1-methylxanthine (AFMU/1X) molar ratio was measured before and after 8 weeks of therapy. The urinary AFMU/1X molar ratio decreased (p < 0.05) after 8 weeks of therapy with glipizide (2.5 mg), but remained unaltered in those treated with placebo or those who self-monitored blood glucose (SMBG) by glucometer. Antipyrine and coumarin decreased (p < 0.05) the AFMU/1X molar ratio both in diabetics and healthy volunteers. Our data demonstrate that glipizide, antipyrine and coumarin may interfere with the classification of acetylator status measured by caffeine metabolites.
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PMID:Antipyrine, coumarin and glipizide affect n-acetylation measured by caffeine test. 757

Oral glucose tolerance was tested in a heterogeneous group of 108 patients with liver cirrhosis. Data were compared with those from 181 subjects without liver disease (44% normal, 35% impaired glucose tolerance and 21% type 2 diabetes mellitus). In cirrhosis, 27% of the patients had normal, 36% had impaired glucose tolerance, and 37% were diabetic. There was no association between glucose intolerance or diabetes and the aetiology of cirrhosis, the duration of the disease, the biochemical indicators of hepatocyte damage, cholestasis and/or liver function. Only weak associations were found between the results of quantitative liver functions tests (caffeine, xylocaine, indocyanine green) and basal and post load glucose and insulin concentrations. Cirrhotics with 1st degree relatives with type 2 diabetes mellitus (n = 16) did not show an increased prevalence of diabetes. Older and/or malnourished patients were more frequently glucose intolerant. Using the plasma glucose concentration 120 minutes after glucose load as the dependent variable, multivariate regression analysis showed that 54% of its variance is associated with the following variables: basal plasma glucose (36%) and free fatty acid concentration (5%), age (3%), basal glucose oxidation rate (3%), muscle mass (3%) and plasma free glycerol at 120 minutes after glucose load (3%). By contrast, the clinical state of the patients (i.e. the CHILD-Pugh score) accounted for only 2% of the variance. We conclude that glucose tolerance is variable in cirrhosis. After manifestation of liver disease, glucose intolerance or diabetes cannot be explained by the clinical, histological or biochemical signs of liver disease.
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PMID:Glucose intolerance in liver cirrhosis: role of hepatic and non-hepatic influences. 786 13

An inhibitor of human liver glycogen phosphorylase a (HLGPa) has been identified and characterized in vitro and in vivo. This substance, [R-(R*, S*)]-5-chloro-N-[3-(dimethylamino)-2-hydroxy-3-oxo-1-(phenylmethyl)pr opyl]-1H-indole-2-carboxamide (CP-91149), inhibited HLGPa with an IC50 of 0.13 microM in the presence of 7.5 mM glucose. CP-91149 resembles caffeine, a known allosteric phosphorylase inhibitor, in that it is 5- to 10-fold less potent in the absence of glucose. Further analysis, however, suggests that CP-91149 and caffeine are kinetically distinct. Functionally, CP-91149 inhibited glucagon-stimulated glycogenolysis in isolated rat hepatocytes (P < 0.05 at 10-100 microM) and in primary human hepatocytes (2.1 microM IC50). In vivo, oral administration of CP-91149 to diabetic ob/ob mice at 25-50 mg/kg resulted in rapid (3 h) glucose lowering by 100-120 mg/dl (P < 0.001) without producing hypoglycemia. Further, CP-91149 treatment did not lower glucose levels in normoglycemic, nondiabetic mice. In ob/ob mice pretreated with 14C-glucose to label liver glycogen, CP-91149 administration reduced 14C-glycogen breakdown, confirming that glucose lowering resulted from inhibition of glycogenolysis in vivo. These findings support the use of CP-91149 in investigating glycogenolytic versus gluconeogenic flux in hepatic glucose production, and they demonstrate that glycogenolysis inhibitors may be useful in the treatment of type 2 diabetes.
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PMID:Discovery of a human liver glycogen phosphorylase inhibitor that lowers blood glucose in vivo. 946 93

Obesity is characterised by pathophysiological defects affecting both sides of the energy balance equation. Individuals with a predisposition to obesity have impaired appetite control when diets are fat-rich and energy dense. They also exhibit a lower than expected resting metabolic rate (RMR). A low RMR, in concert with a sedentary lifestyle, contributes to a low total energy output, which may lead to obesity if continued over a period of years. A low metabolic rate seems to be genetically determined, and is partly caused by low sympathetic nervous system activity. Classical treatment programmes for obesity do not provide a satisfactory long-term outcome for the majority of patients. Patients who achieve only a small weight loss during dietary therapy, and have a tendency to weight regain, are characterised by lower energy expenditure, lower sympathetic activity, and a reduced ability to mobilise fat stores, compared with patients who are more successful at losing weight. It is reasonable to improve or normalise these traits by supporting the dietary approach with pharmacological manipulation of central and peripheral pathways. Agents which stimulate adrenergic neurons are particularly suitable because they offer mechanisms for inhibiting hunger and for stimulating energy expenditure, lipolysis and fat oxidation. Sympathomimetic compounds can reduce appetite and increase energy expenditure. Energy expenditure can be increased by 5-10% via stimulation of a combination of beta-adrenoceptors; beta3-adrenoceptors may predominate during chronic therapy. This increased energy expenditure increases the relative proportion of fat oxidation; as this is not fully compensated by increased energy intake, a negative energy balance occurs. This mechanism may be responsible for the long-term weight loss efficiency of agents like ephedrine/caffeine and sibutramine. Pharmacotherapy can be used to support short-term induction of weight loss or long-term weight maintenance. In the latter case, adrenergic agents enable a greater proportion of patients to maintain a satisfactory weight loss, compared with patients treated with conventional programmes alone. Pharmacotherapy which stabilises the size of fat stores at a lower level contributes indirectly to a pronounced improvement of risk factors, leading to a decreased potential for cardiovascular disease, type 2 diabetes and associated morbidity.
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PMID:What do pharmacological approaches to obesity management offer? Linking pharmacological mechanisms of obesity management agents to clinical practice. 979 79

Glucagon-like peptide-1 (GLP-1) is an intestinally derived insulinotropic hormone currently under investigation for use as a novel therapeutic agent in the treatment of type 2 diabetes mellitus. In vitro studies of pancreatic islets of Langerhans demonstrated that GLP-1 interacts with specific beta-cell G protein-coupled receptors, thereby facilitating insulin exocytosis by raising intracellular levels of cAMP and Ca2+. Here we report that the stimulatory influence of GLP-1 on Ca2+ signaling results, in part, from cAMP-dependent mobilization of ryanodine-sensitive Ca2+ stores. Studies of human, rat, and mouse beta-cells demonstrate that the binding of a fluorescent derivative of ryanodine (BODIPY FL-X ryanodine) to its receptors is specific, reversible, and of high affinity. Rat islets and BTC3 insulinoma cells are shown by reverse transcriptase polymerase chain reaction analyses to express mRNA corresponding to the type 2 isoform of ryanodine receptor-intracellular Ca2+ release channel (RYR2). Single-cell measurements of [Ca2+]i using primary cultures of rat and human beta-cells indicate that GLP-1 facilitates Ca2+-induced Ca2+ release (CICR), whereby mobilization of Ca2+ stores is triggered by influx of Ca2+ through L-type Ca2+ channels. In these cells, GLP-1 is shown to interact with metabolism of D-glucose to produce a fast transient increase of [Ca2+]i. This effect is reproduced by 8-Br-cAMP, but is blocked by a GLP-1 receptor antagonist (exendin-(9-39)), a cAMP antagonist ((Rp)-cAMPS), an L-type Ca2+ channel antagonist (nimodipine), an antagonist of the sarco(endo)plasmic reticulum Ca2+ ATPase (thapsigargin), or by ryanodine. Characterization of the CICR mechanism by voltage clamp analysis also demonstrates a stimulation of Ca2+ release by caffeine. These findings provide new support for a model of beta-cell signal transduction whereby GLP-1 promotes CICR by sensitizing intracellular Ca2+ release channels to the stimulatory influence of cytosolic Ca2+.
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PMID:cAMP-dependent mobilization of intracellular Ca2+ stores by activation of ryanodine receptors in pancreatic beta-cells. A Ca2+ signaling system stimulated by the insulinotropic hormone glucagon-like peptide-1-(7-37). 1031 32

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

Coffee is a major source of caffeine, which has been shown to acutely reduce sensitivity to insulin, but also has potentially beneficial effects. We prospectively investigated the association between coffee consumption and risk of clinical type 2 diabetes in a population-based cohort of 17111 Dutch men and women aged 30-60 years. During 125774 person years of follow-up, 306 new cases of type 2 diabetes were reported. After adjustment for potential confounders, individuals who drank at least seven cups of coffee a day were 0.50 (95% CI 0.35-0.72, p=0.0002) times as likely as those who drank two cups or fewer a day to develop type 2 diabetes. Coffee consumption was associated with a substantially lower risk of clinical type 2 diabetes.
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PMID:Coffee consumption and risk of type 2 diabetes mellitus. 1260 1

Caffeine ingestion negatively affects insulin sensitivity during an oral glucose tolerance test (OGTT) in lean and obese men, but this has not been studied in individuals with type 2 diabetes. We examined the effects of caffeine ingestion on insulin and glucose homeostasis in obese men with type 2 diabetes. Men (n = 12) with type 2 diabetes (age = 49 +/- 2 y, BMI = 32 +/- 1 kg/m(2)) underwent 2 trials, 1 wk apart, in a randomized, double-blind design. Each trial was conducted after withdrawal from caffeine, alcohol, exercise, and oral hypoglycemic agents for 48 h and an overnight fast. Subjects randomly ingested caffeine (5 mg/kg body weight) or placebo capsules and 1 h later began a 3 h 75 g OGTT. Caffeine increased (P < 0.05) serum insulin, proinsulin, and C-peptide concentrations during the OGTT relative to placebo. Insulin area under the curve was 25% greater (P < 0.05) after caffeine than after placebo ingestion. Despite this, blood glucose concentration was also increased (P < 0.01) in the caffeine trial. After caffeine ingestion, blood glucose remained elevated (P < 0.01) at 3 h postglucose load (8.9 +/- 0.7 mmol/L) compared with baseline (6.7 +/- 0.4 mmol/L). The insulin sensitivity index was lower (14%, P = 0.02) after caffeine than after placebo ingestion. Overall, despite elevated and prolonged proinsulin, C-peptide, and insulin responses after caffeine ingestion, blood glucose was also increased, suggesting an acute caffeine-induced impairment in blood glucose management in men with type 2 diabetes.
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PMID:Caffeine ingestion before an oral glucose tolerance test impairs blood glucose management in men with type 2 diabetes. 1546 42

Recent prospective epidemiology links heavy coffee consumption to a substantial reduction in risk for type 2 diabetes. Yet there is no evidence that coffee improves insulin sensitivity and, at least in acute studies, caffeine has a negative impact in this regard. Thus, it is reasonable to suspect that coffee influences the risk for beta cell "failure" that precipitates diabetes in subjects who are already insulin resistant. Indeed, there is recent evidence that coffee increases production of the incretin hormone glucagon-like peptide-1 (GLP-1), possibly owing to an inhibitory effect of chlorogenic acid (CGA -- the chief polyphenol in coffee) on glucose absorption. GLP-1 acts on beta cells, via cAMP-dependent mechanisms, to promote the synthesis and activity of the transcription factor IDX-1, crucial for maintaining the responsiveness of beta cells to an increase in plasma glucose. Conversely, the "glucolipotoxicity" thought to initiate and sustain beta cell dysfunction in diabetics can suppress expression of this transcription factor. The increased production of GLP-1 associated with frequent coffee consumption could thus be expected to counteract the adverse impact of chronic free fatty acid overexposure on beta cell function in overweight insulin resistant subjects. CGA's putative impact on glucose absorption may reflect the ability of this compound to inhibit glucose-6-phosphate translocase 1, now known to play a role in intestinal glucose transport. Delayed glucose absorption may itself protect beta cells by limiting postprandial hyperglycemia -- though, owing to countervailing effects of caffeine on plasma glucose, and a paucity of relevant research studies, it is still unclear whether coffee ingestion blunts the postprandial rise in plasma glucose. More generally, diets high in "lente carbohydrate", or administration of nutraceuticals/pharmaceuticals which slow the absorption of dietary carbohydrate, should help preserve efficient beta cell function by boosting GLP-1 production, as well as by blunting the glucotoxic impact of postprandial hyperglycemia on beta cell function.
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PMID:A chlorogenic acid-induced increase in GLP-1 production may mediate the impact of heavy coffee consumption on diabetes risk. 1569 6

Weight reduction has been shown to improve glycemic control and cardiovascular risk factors associated with insulin resistance in obese individuals with type 2 diabetes mellitus. Therapeutic options for these patients include promoting weight loss (non-pharmacologic and pharmacologic treatment) and improving glycemic control, as well as treating common associated risk factors such as arterial hypertension and dyslipidemias. This article provides an overview of anti-obesity drugs used in the treatment of obese individuals with type 2 diabetes. The most widely investigated drugs, sibutramine and orlistat, result in modest, clinically worthwhile weight loss, with demonstrable improvements in many co-morbidities, among them, type 2 diabetes. Clinical trials with these anti-obesity medications in cohorts of obese diabetic patients have been reviewed as well as cathecolaminergic agents (diethylpropion [amfepramone], fenproporex, mazindol, ephedrine-caffeine combination), serotoninergic drugs (fenfluramine, dexfenfluramine, fluoxetine), and other drugs that have some action on weight loss (the antidiabetic agent metformin, anti-epileptic agents topiramate and zonisamide, and the antidepressive bupropion [amfebutamone]). These trials show variable benefits in terms of effects on glucose profiles.
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PMID:Diabesity: are weight loss medications effective? 1578 44


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