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)

Besides genetic predisposition, obesity is the most important risk factor for the development of type 2 diabetes mellitus. Even modest weight reduction can improve blood glucose control in overweight subjects. After failure of lifestyle modifications, antiobesity drugs such as orlistat, a potent and selective inhibitor of gastric and pancreatic lipases that reduces lipid intestinal absorption, or sibutramine, a noradrenaline and 5-hydroxytryptamine reuptake inhibitor that regulates food intake, may be considered to favour weight loss and/or weight maintenance. Several placebo-controlled studies have recently demonstrated that both drugs are able to promote weight loss in obese type 2 diabetic patients treated with diet alone, sulphonylureas, metformin or insulin. The greater weight reduction as compared to placebo was associated with a significant reduction of glycated haemoglobin levels and/or of the doses of classical antihyperglycaemic agents, especially in good responders who lost at least 10% of initial body weight. In addition, vascular risk factors associated to insulin resistance were also reduced after weight loss. These antiobesity agents may also contribute to delay or prevent the progression from impaired glucose tolerance to overt type 2 diabetes in at risk obese individuals ("Xenical in the prevention of diabetes in obese subjects" trial). Large long-term prospective studies, such as the "Sibutramine cardiovascular and diabetes outcome study" should better determine the place of pharmacological anti-obesity strategy in the overall management of obese patients with impaired glucose tolerance or type 2 diabetes.
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PMID:New antiobesity agents in type 2 diabetes: overview of clinical trials with sibutramine and orlistat. 1252 23

Type 2 diabetes is becoming very common and is closely linked to physical inactivity and obesity. It is associated with clustering of coronary risk factors and 60-80% of cases have hypertension. The first therapeutic action is appropriate adjustment of life style. Anti-hypertensive therapies such as diuretics, ACE inhibitors and calcium antagonists have been effective in reducing cardiovascular events in type 2 diabetes, though calcium antagonists may be less effective than older therapies and ACE-inhibitors in reducing the risk of heart attacks and heart failure (but possibly more effective in stroke reduction). Beta-blockers (BBs) have a poor image as a potential therapy due to apparent adverse effects on surrogate end-points such as insulin-resistance. However large, controlled trials have shown BBs to be highly effective in reducing the risk of cardiovascular events and death in post myocardial infarction patients with diabetes. The UKPDS study in type 2 diabetics with hypertension showed first-line beta-blockade to be at least as effective as ACE-inhibition in preventing all primary macrovascular and microvascular end-points. The active ingredient appears to be beta-1 blockade, acting not only to lower blood pressure but also to prevent sudden death and cardiovascular damage stemming from chronic beta-1 stimulation associated with raised noradrenaline activity. By contrast, in the LIFE study atenolol was less effective than the angiotensin receptor antagonist losartan in reducing cardiovascular events and all-cause mortality in mainly elderly hypertensives with diabetes. Thus the best beta-blocker results in reducing hard cardiovascular end-points occur in hypertension studies (including the UKPDS study) involving younger/middle aged (say less than 60-65 years) patients, with relatively high sympathetic activity, relatively compliant/elastic arteries (narrow pulse-pressure) and normally functioning beta-1 receptors. In elderly hypertensive patients beta-blockers may be given as second-line therapy on the back of a low-dose diuretic (but possibly as first line agent in elderly hypertensives with prior myocardial infarction). Thus inappropriate attention to surrogate end-points can lead to faulty prescribing habits. Beta-blockers, currently severely underprescribed, should be considered as a first line therapeutic option for all diabetics with ischaemic heart disease or younger/middle aged diabetics with hypertension (but co-prescribed with low dose diuretic therapy in the elderly). The active ingredient for cardiovascular protection appears to be beta-1 blockade; optimal efficacy in lowering blood pressure and safety e.g. reducing risk of bronchoconstriction, is achieved by choosing an agent with high beta-1 selectivity.
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PMID:Beta-blockers and diabetes: the bad guys come good. 1265 16

In many industrialized nations, obesity is now considered an epidemic, resulting in accelerated morbidity and mortality. Obesity is associated with an increased risk of coronary artery disease as well as the metabolic syndrome comprising abdominal obesity, increased fasting blood glucose levels, dyslipidemia and hypertension, which are all recognized cardiovascular risk factors. Diet, exercise, and lifestyle changes constitute important recommendations for treatment. Unfortunately, although effective in some individuals, these recommendations have proven to be ineffective in adequately addressing the broad, enlarging scope of this public health problem. Drug treatment is often indicated but is somewhat limited by the minimal number of well tolerated drugs that have proven to have long-term efficacy in maintaining bodyweight loss. For example, phentermine may result in modest bodyweight loss through suppression of appetite, but potential cardiovascular adverse effects exist and the efficacy is mainly short-term. Sibutramine, an inhibitor of serotonin and norepinephrine (noradrenaline) reuptake, may increase satiety and result in modest bodyweight loss. However, cardiovascular adverse effects may occur in susceptible patients. Nonetheless, sibutramine is one of the few drugs that has been approved by the US Food and Drug Administration (FDA) for bodyweight loss. Orlistat, a lipase inhibitor, is also approved by the FDA for bodyweight loss but may have bothersome gastrointestinal adverse effects, especially among patients who do not adhere to the recommended low-fat diet. Ongoing studies continue to evaluate other drug treatments that may result in bodyweight reduction through a number of different mechanisms. It is anticipated that the development of effective and well tolerated antiobesity drugs will elevate the pharmacologic treatment of obesity to the status of other cardiovascular risk factors and metabolic disorders. This may be especially important given that dyslipidemia, hypertension and type 2 diabetes mellitus are often secondary to, or exacerbated by, obesity.
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PMID:Pharmacotherapy of obesity: currently marketed and upcoming agents. 1472 70

We used the partial protection exerted by suitable dosages of nicotinamide against the beta-cytotoxic effect of streptozotocin (STZ) to create an experimental diabetic syndrome in adult rats that appears closer to type II diabetes mellitus than other available animal models. The dosage of 230 mg/kg of nicotinamide given intraperitoneally 15 min before STZ administration (65 mg/kg i.v.) yielded animals with hyperglycemia (187.8 +/- 17.8 vs. 103.8 +/- 2.8 mg/dL in controls; P < 0.001) and preservation of plasma insulin levels. This study assessed the relationship between endothelial dysfunction and agonist-induced contractile responses in such rats. In the thoracic aorta, the acetylcholine (ACh) induced relaxation was significantly reduced and the noradrenaline (NA) induced contractile response was significantly increased in diabetic rats compared with age-matched control rats. In the superior mesenteric artery, the ACh-induced relaxation was similar in magnitude between diabetic and age-matched control rats; however, the ACh-induced endothelium-derived hyperpolarizing factor (EDHF) type relaxation was significantly weaker in diabetic rats than in the controls. The phenylephrine (PE) induced contractile response was not different between the two groups. The plasma concentration of NOx (NO2- + NO3-) was significantly lower in diabetic rats than in control rats. We conclude that vasomotor activities in conduit arteries are impaired in this type II diabetes model.
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PMID:Alterations in vascular endothelial function in the aorta and mesenteric artery in type II diabetic rats. 1505 83

The beta3-adrenergic receptor (beta3-AR) may play a key role in the regulation of lipid metabolism and glucose homeostasis. Adrenaline and noradrenaline beta3-AR stimulate lipolysis and thermogenesis in human fat cells and increase glucose uptake in skeletal muscle. Therefore, the beta3-AR gene may be associated with obesity and related diseases, such as type 2 diabetes, coronary heart disease and hypertension. Many studies in different ethnic groups showed an association of beta3-AR gene polymorphism with insulin resistance, obesity and its metabolic disorders such as type 2 diabetes, coronary heart disease and hypertension. A Trp64Arg mutation in the beta3-AR gene has been reported to be correlated with the occurrence of those disorders among obese. Several studies revealed also the influence of the Trp/Arg polymorphism on carcinogenesis and its contribution to the link between cancer and obesity. Since obesity is a serious problem as a civilization-related disease, it is very important to investigate genes suspected to be connected with it.
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PMID:[Beta3-adrenergic receptor]. 1620 45

Hypothalamic neuronal activities of noradrenaline, dopamine and serotonin were investigated in the GK (Goto-Kakizaki) rats, a model for type 2 diabetes, and the streptozotocin (STZ)-induced diabetic rats, a model for type 1 diabetes. Each neuronal activity was assessed from a ratio of the concentrations of the major metabolite to those of its precursor monoamine itself or the metabolite concentrations itself. In the GK rats, hypothalamic noradrenaline and dopamine activities were significantly increased, and serotonin activity was unchanged. In the STZ-induced diabetic rats, hypothalamic dopamine and serotonin activities were significantly decreased, and noradrenaline activity was unchanged. In these two diabetic rats, hypothalamic noradrenaline and dopamine activities correlated significantly with serum insulin concentrations, whereas hypothalamic serotonin activity correlated significantly with serum glucose concentrations. These findings suggest that hypothalamic monoamine metabolism of the GK rats is quite different from that of the STZ-induced diabetic rats, and that not only hyperglycemia but also serum insulin concentrations have an influence on the hypothalamic monoamine metabolism in these diabetic rats.
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PMID:Hypothalamic monoamine metabolism is different between the diabetic GK (Goto-Kakizaki) rats and streptozotocin-induced diabetic rats. 1642 25

Insulin secretagogues and insulin sensitizers can be combined with one another as well as with other treatments (described below). Alpha-glucosidase inhibitors delay intestinal absorption of carbohydrates and reduce postprandial glycemia. Orlistat and sibutramine improve insulin sensitivity by helping patients lose weight. Orlistat inhibits hydrolysis of dietary triglycerides. Sibutramine, a noradrenaline and serotonin reuptake inhibitor, reinforces feelings of satiety and increases energy expenditure. After approximately 10 years, insulin therapy is usually required together with oral antidiabetic agents (except glitazones) or alone if HbA(1c) (glycosylated hemoglobin) is>6.5%. New guidelines for management of type 2 diabetes were published in 2006.
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PMID:[Drug treatment in type 2 diabetes (part 2)]. 1733 55

Islet function is regulated by a number of different signals. A main signal is generated by glucose, which stimulates insulin secretion and inhibits glucagon secretion. The glucose effects are modulated by many factors, including hormones, neurotransmitters and nutrients. Several of these factors signal through guanine nucleotide-binding protein (G protein)-coupled receptors (GPCR). Examples of islet GPCR are GPR40 and GPR119, which are GPCR with fatty acids as ligands, the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), the receptors for the islet hormones glucagon and somatostatin, the receptors for the classical neurotransmittors acetylcholine (ACh; M(3) muscarinic receptors) and noradrenaline (beta(2)- and alpha(2)-adrenoceptors) and for the neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP; PAC(1) and VPAC(2) receptors), cholecystokinin (CCK(A) receptors) and neuropeptide Y (NPY Y1 receptors). Other islet GPCR are the cannabinoid receptor (CB(1) receptors), the vasopressin receptors (V1(B) receptors) and the purinergic receptors (P(2Y) receptors). The islet GPCR couple mainly to adenylate cyclase and to phospholipase C (PLC). Since important pharmacological strategies for treatment of type 2 diabetes are stimulation of insulin secretion and inhibition of glucagon secretion, islet GPCR are potential drug targets. This review summarizes knowledge on islet GPCR.
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PMID:G-protein-coupled receptors and islet function-implications for treatment of type 2 diabetes. 1790 Jul

This review summarizes data on currently used antiobesity drugs and new compounds under clinical development. Three antiobesity drugs are currently accepted for long-term use. Sibutramine is a noradrenaline and serotonin reuptake inhibitor which reduces body weight by about 4-5 kg but increases heart rate and arterial blood pressure. Orlistat is a gastrointestinal lipase inhibitor which results in mean weight loss by about 3 kg and reduces the incidence of type 2 diabetes in patients with impaired glucose tolerance; however, adverse gastrointestinal effects have been observed. Rimonabant is an endocannabinoid CB1 receptor antagonist which induces a 4-5 kg mean weight loss and improves glycemic and lipid profiles, but it induces anxiety and depressive disorders. Unfortunately, there are no data on the chronic administration of these drugs. Other drugs can induce weight loss, e.g. some antidepressants, antiseizure agents, and antidiabetic drugs. The moderate efficacy of currently used antiobesity drugs has led to an intense effort to identify new, safe antiobesity drugs with better therapeutic profiles. The new antiobesity drugs under clinical development include: 1) agents that affect neurotransmitters in the central nervous system, including noradrenaline and dopamine reuptake inhibitors (bupropion, radafaxine), selective 5HT2C receptor agonists (lorcaserin), and selective 5HT6 receptor antagonists, 2) agents that modulate the activity of neuropeptides influencing food intake, including leptin analogues, human ciliary neurotrophic factor (Axokine), neuropeptide Y antagonists, and melanine-concentrating hormone antagonists, 3) agents that affect the peripheral satiety signals and brain-gut axis, e.g. selective cholecystokinin receptor A agonists, PYY3-36, agents decreasing ghrelin activity, 4) thermogenic agents, e.g. selective beta3 receptor agonists and selective thyroid hormone receptor beta agonists, and 5) others, e.g. human growth hormone fragment (AOD9604) and gastrointestinal lipase inhibitor (cetilistat).
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PMID:[Obesity: a review of currently used antiobesity drugs and new compounds in clinical development]. 1797 63

Moderate elevations in blood pressure translate to significant increases in cardiovascular and cerebro vascular risk. Beneficially, this relationship allows small decreases in blood pressure to be associated with risk reduction. Both the renin-angiotensin system and the sympathetic nervous system are involved in hypertension, hence targeting these systems is likely to be of benefit in the treatment of hypertension. Angiotensin II type 1 receptor blockers (ARBs) are used for controlling blood pressure and treating heart failure in a broad range of patients, including those with diabetes and the elderly. Not only have ARBs shown good efficacy and tolerability, they also appear to have a protective effect that goes beyond that expected from the reduction of blood pressure. The ARB eprosartan is a nonbiphenyl nontetrazole angiotensin II type 1 receptor (AT1) antagonist, which acts to decrease total peripheral resistance. Eprosartan acts at vascular AT1 receptors (postsynaptically) and at presynaptic AT1 receptors, where it inhibits noradrenaline release. In clinical studies, eprosartan has been shown to significantly reduce cardiovascular and cerebrovascular events, whilst avoiding the persistent cough that commonly occurs with the use of angiotensin-converting enzyme inhibitors. Eprosartan can also be differentiated from other ARBs due to its noradrenergic effects, which other ARBs used at therapeutic doses do not possess. Eprosartan, therefore, represents a useful therapeutic option in the management of patients with hypertension, including those with a history of stroke or with co-morbid type 2 diabetes mellitus.
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PMID:Introduction: The pharmacological profile of eprosartan--implications for cerebrovascular and cardiovascular risk reduction. 1809 7


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