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 pertinent literature on the prevalence, clinical manifestations and pathogenic mechanisms of sleep apnoea (SA) in endocrine diseases, namely acromegaly, Cushing syndrome, hypothyroidism and diabetes mellitus was reviewed. An increased prevalence is well documented in patients with active and treated acromegaly. While most authors report peripheral obstruction, due to hypertrophy of tongue and pharyngeal tissues, to be the cause of SA in acromegaly, some findings argue for a role of hormone-induced changes of central respiratory control. SA is also more common in hypothyroidism, especially when myxedema is present. The associated edema and myopathy appear to be of pathogenic importance. Thyroxin substitution is frequently effective for the treatment of SA but nCPAP can be necessary initially and in some patients even after remission of clinical signs of hypothyroidism. In Cushing disease and syndrome, parapharyngeal fat accumulation can cause SA, but no epidemiological information is available. In non insulin dependent diabetes (NIDDM), obesity is the common risk factor for both, nocturnal hypoxia and insulin resistance. In IDDM, the development of autonomic neuropathy may predispose to SA. Where treatment of the underlying endocrine disease is unable cure the associated SA, nCPAP is usually the treatment of first choice. More prospective studies are clearly needed to establish prevalences and resolve the controversies regarding pathogenesis.
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PMID:Sleep apnoea in endocrine diseases. 961 23

Insulin resistance is a common metabolic disorder. It plays an important role in the metabolic syndrome (or syndrome X), type 2 diabetes, obesity and in the lipodystrophic syndromes recently described, associated with treatments of HIV disease and represent a worrying cardiovascular risk. However, its pathophysiology remains poorly understood in these situations. Syndromes of major insulin resistance, although rare, allow investigations of the mechanisms leading to alterations in the insulin transduction pathways. Mutations of the insulin receptor gene have been discovered in rare patients. Therefore alterations at the post-receptor level are probably causative in other cases. Furthermore, the role of body fat repartition seems determinant in the apparition of insulin resistance, as attested by the clinical characteristics of lipodystrophies, either congenital or acquired. The two lipodystrophic syndromes which molecular defect is identified are the familial partial lipodystrophy of the Dunnigan type, due to mutations of the lamin A/C gene, and the congenital generalized lipodystrophy, linked to alterations in the protein seipin. However, their physiopathology remains mysterious. Lamin A/C is indeed an ubiquitous nuclear protein, which is also mutated in a genetic squelettic and/or cardiac myopathy, and seipin is a protein of unknown function mainly expressed in brain. Progresses in the understanding of these syndromes, in particular lipodystrophies which can be considered as caricatural models of the metabolic syndrome, will probably allow to clarify the physiopathology of the more common forms of insulin resistance.
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PMID:[Major insulin resistance syndromes: clinical and physiopathological aspects]. 1183 62

Cardiovascular disease is responsible for a large proportion of morbidity and mortality in people with type 2 diabetes, who typically have a clustering of risk factors for coronary heart disease (CHD), including dyslipidaemia. Intensive single-factor interventions to lower blood glucose have not eliminated the increased risk of adverse cardiovascular outcomes in patients with diabetes. In comparison, multifactorial interventions, which include normalizing blood lipids with statins, appear to be more effective in reducing CHD. However, risk reductions in patients with type 2 diabetes are often no better than those seen in people without diabetes, despite the much greater baseline risk in the former group. High-density lipoprotein cholesterol (HDL-C) is an independent risk factor for CHD, but is only minimally improved by statin therapy. Additional interventions aimed at increasing HDL-C can further reduce cardiovascular morbidity and mortality in patients with type 2 diabetes. However, use of fibrates in combination with statins may pose an unacceptable risk of myopathy. Therefore, other strategies for combination therapy are needed to normalize lipids in patients with type 2 diabetes or metabolic syndrome.
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PMID:Is dyslipidaemia important if we control glycaemia? 1605 91

Because of their wide range of actions on glucose homeostasis, lipid metabolism and vascular inflammation, peroxisome proliferator-activated receptors (PPARs) are promising targets for the development of new drugs for the treatment of metabolic disorders such as diabetes, dyslipidemia and atherosclerosis. In clinical practice, PPARalpha agonists, such as the already available fibrates, improve dyslipidemia, while PPARgamma agonists, such as thiazolidinediones, improve insulin resistance and diabetes. The complementary action of simultaneous activation of each PPAR in patients suffering from metabolic syndrome and type 2 diabetes has led to new pharmacological strategies focused on the development of agonists targeting more than one receptor such as the dual PPARalpha/gamma agonists. However, despite the proven benefits of targeting PPARs, safety concerns have recently led to late stage development failures of various PPAR agonists including novel specific PPARgamma agonists and dual PPARalpha/gamma agonists. These safety concerns include potential carcinogenicity in rodents, signs of myopathy and rhabdomyolysis, increase in plasma creatinine and homocysteine, weight gain, fluid retention, peripheral edema and potential increased risk of cardiac failure. Although the discontinued compounds shared common side effects, the reason for discontinuation was always compound specific and the toxicological or adverse effects which have motivated the discontinuation could be either due to the activation of PPARgamma, PPARalpha or both (class effect) or due to a PPAR unrelated effect. Thus, the risk evaluation of each adverse effect should be viewed on a case by case basis considering both the PPAR profile of the drug, its absorption/distribution profile, the nature of the side effect and the putative PPAR-related mechanism of action. This review mainly focuses on the preclinical and clinical adverse events of PPAR agonists that could be of concern when considering the development of new PPAR agonists. The selective modulation of PPAR activities is a promising approach to develop new drugs with preserved efficacy but diminished adverse effects.
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PMID:Safety issues and prospects for future generations of PPAR modulators. 1742 30

Clinical guidelines highlight the importance of dyslipidaemia management for reducing the risk of cardiovascular disease in patients with type 2 diabetes and metabolic syndrome. While statins represent the main focus of therapy, there is increasing evidence that the addition of a fibrate such as fenofibrate provides further reduction in risk. Fenofibrate also offers a number of benefits beyond lipid modification; these are mediated by peroxisome proliferator-activated receptor-alpha (PPARalpha) activation and appear to be independent of effects of glucose and lipid metabolism. Furthermore, as shown by the Fenofibrate Intervention for Event Lowering in Diabetes (FIELD) study, fenofibrate treatment has promising effects in preventing progression of diabetes-related microvascular complications. PPARalpha is critical to lipid metabolism in the liver. Recent findings which showed that pioglitazone, a PPARgamma agonist with weak PPARalpha activity, improved fatty liver disease in patients with non-alcoholic steatohepatitis (NASH) and metabolic syndrome or type 2 diabetes have prompted interest in whether more potent PPARalpha agonists, such as fenofibrate, may have a role in the management of non-alcoholic fatty liver disease (NAFLD). The combination of fenofibrate and a statin is well tolerated, with no apparent increase in the risk of myopathy, unlike gemfibrozil-statin combination therapy. In overview, the available evidence indicates that the combination of fenofibrate with a statin is a useful approach for optimising reduction in the risk of cardiovascular disease in patients with type 2 diabetes and metabolic syndrome, as well as delaying the progression of diabetes-related microvascular complications. Data are awaited from the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study to evaluate the outcome benefits of this approach.
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PMID:The role of fenofibrate in clinical practice. 1793 56

Evidence of the effectiveness of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) within continuum of atherothrombotic conditions and particularly in the treatment and prevention of coronary heart disease (CHD) is well established. Large-scale, randomized, prospective trials involving patients with CHD have shown that statins reduce the clinical consequences of atherosclerosis, including cardiovascular deaths, nonfatal myocardial infarction and stroke, hospitalization for acute coronary syndrome and heart failure, as well as the need for coronary revascularization. Direct testing of varying degrees of low-density lipoprotein (LDL)- cholesterol lowering has now been carried out in 4 large outcomes trials: PROVE IT-TIMI 22, A to Z, TNT and IDEAL. However, the question whether more aggressive LDL-cholesterol lowering by high-dose statins monotherapy is an appropriate strategy is still open: higher doses of statins are more effective mainly for the prevention of the nonfatal cardiovascular events but such doses are associated with an increase in hepatotoxicity, myopathy and concerns regarding noncardiovascular death. Moreover, despite the increasing use of statins, a significant number of coronary events still occur and many such events take place in patients presenting with type 2 diabetes and metabolic syndrome. More and more attention is now being paid to combined atherogenic dyslipidemia which typically presented in patients with type 2 diabetes and metabolic syndrome. This mixed dyslipidemia (or 'lipid quartet') - hypertriglyceridemia, low high-density lipoprotein (HDL)-cholesterol levels, a preponderance of small, dense LDL particles and an accumulation of cholesterol-rich remnant particles - emerged as the greatest 'competitor' of LDL-cholesterol among lipid risk factors for cardiovascular disease. Most recent extensions of the fibrates trials (BIP, HHS, VAHIT and FIELD) give further support to the hypothesis that patients with insulin-resistant syndromes such as diabetes and/or metabolic syndrome might be the ones to derive the most benefit from therapy with fibrates. However, different fibrates may have a somewhat different spectrum of effects. Other lipid-modifying strategies included using of niacin, ezetimibe, bile acid sequestrants, CETP inhibitors and omega-3 fatty acids. Particularly, ezetimibe/statins combinations provide superior lipid-modifying benefits compared Tenenbaum/Fisman/Motro/Adler 128 with any statins monotherapy in patients with atherogenic dyslipidemia. Atherogenic dyslipidemia is associated with increased levels of chylomicrons and their remnants containing 3 main components: apolipoprotein B-48, triglycerides and cholesterol ester of intestinal origin. Reduction in accessibility for one of them (specifically cholesteryl ester lessening due to ezetimibe administration) could lead to a decrease of the entire production of chylomicrons and result in a decrease of the hepatic body triglycerides pool as confirmed in number of clinical studies. However, the ENHANCE study showed no difference in the progression of carotid atherosclerosis between ezetimibe/simvastatin vs. simvastatin alone over a 2-year period. Conclusions regarding ezetimibe/statins combinations should not be made until the three large clinical outcome trials will be completed within the next 2-3 years. In addition, bezafibrate as a pan-PPAR activator has clearly demonstrated beneficial pleiotropic effects related to glucose metabolism, insulin sensitivity and pancreatic beta cell protection. Because fibrates, niacin, ezetimibe, omega-3 fatty acids and statins each regulate serum lipids by different mechanisms, combination therapy - selected on the basis of their safety and effectiveness, could be more helpful in achieving a comprehensive lipid control as compared with statins monotherapy.
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PMID:Optimal management of combined dyslipidemia: what have we behind statins monotherapy? 1823 Sep 60

A 44-year-old woman with mitochondrial encephalomyopathy noticed weakness of the lower extremities at the age of 30 years. She also has type 2 diabetes mellitus, posterior subcapsular cataracts in both eyes, and corpus callosum atrophy. Family history showed that a maternal cousin had a myopathy, 3 maternal aunts had diabetes mellitus, and her mother and 2 maternal aunts had cataracts. External ophthalmoplegia, proximal myopathy, and absent deep tendon reflexes were noted. The mitochondrial DNA 3243 point mutation was negative. Muscle biopsy showed ragged-red fibers, cytochrome c oxidase (COX)-positive fibers, and COX-negative fibers.
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PMID:Mitochondrial encephalomyopathy associated with diabetes mellitus, cataract, and corpus callosum atrophy. 1831 Sep 79

Patients with type 2 diabetes or metabolic syndrome remain at high residual risk of cardiovascular events even after intensive statin therapy. While treatment guidelines recommend the addition of a fibrate to statin therapy in this setting, concerns about the potential for myopathy may limit the use of this combination in clinical practice. These concerns are certainly justified for gemfibrozil, which interferes with statin glucuronidation, leading to elevation in statin plasma concentrations and an increased risk of myotoxicity in combination with a range of commonly prescribed statins. However, the available evidence refutes suggestions that this is a class effect for fibrates. Fenofibrate does not adversely influence the metabolism or pharmacokinetics of any of the commonly prescribed statins. This in turn translates to a reduced potential for myotoxicity in combination with a statin. Data are awaited from the ongoing Action to Control Cardiovascular Risk in Diabetes (ACCORD) study to evaluate the efficacy and safety of fenofibrate plus simvastatin combination therapy in type 2 diabetes patients.
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PMID:Combination statin-fibrate therapy: safety aspects. 1851 91

The weak peroxisome proliferator activated receptor-alpha (PPAR-alpha) agonists gemfibrozil and fenofibrate achieve only small increases in high-density lipoprotein (HDL) cholesterol. CP-778,875 is a more potent PPAR-alpha agonist developed to produce greater HDL cholesterol increases. This randomized, multicenter, double-blinded, placebo-controlled study evaluated the efficacy and safety of CP-778,875 in subjects with mixed dyslipidemia and type 2 diabetes. Eight-six subjects with low HDL cholesterol (< or =45 mg/dl for men and < or =55 mg/dl for women) and increased triglycerides (150 to 500 mg/dl) who had coexisting type 2 diabetes were randomized. Subjects received CP-778,875 doses of 0.5, 2, or 6 mg/day or placebo for 6 weeks. Any other lipid-altering therapy was stopped at screening. The primary end point was percent change in HDL cholesterol from baseline. The 2-mg/day dose of CP-778,875 significantly increased HDL cholesterol by 14%. The 2-mg dose also increased concentrations of apolipoprotein (apo) A-I, HDL(2) cholesterol, and HDL(3) cholesterol by 13%, 12%, and 19%, respectively. An unusual dose-response pattern was observed in that at 6 mg/day CP-778,875 only increased HDL cholesterol by 3% and decreased HDL(2) cholesterol by 24%. Fasting triglyceride levels were significantly decreased to a similar extent (26%) by all 3 doses of CP-778,875. CP-778,875 significantly increased homocysteine levels. There was no significant relation between change in homocysteine and change in apoA-I or HDL cholesterol. No subjects developed myopathy. In conclusion, CP-778,875 2 mg/day significantly increased HDL cholesterol, significantly lowered fasting triglycerides, and increased apoA-I and HDL subfractions. The clinical relevance of the increase in homocysteine levels is unknown.
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PMID:Efficacy and safety of a potent and selective peroxisome proliferator activated receptor alpha agonist in subjects with dyslipidemia and type 2 diabetes mellitus. 1867 1

Even with optimal statin therapy, many patients with type 2 diabetes mellitus or metabolic syndrome fail to achieve all lipid targets and remain at high risk of cardiovascular events. Add-on lipid-modifying therapy that is effective in improving the triglyceride and high-density lipoprotein (HDL) cholesterol abnormalities characteristic of these conditions is a recommended approach to reduce this risk. Fibrates or niacin is a logical option, supported by clinical studies showing improved lipid control in combination with a statin. Of the fibrates, fenofibrate may offer microvascular benefits in type 2 diabetes--as demonstrated by the Diabetes Atherosclerosis Intervention Study (DAIS) and the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study--as well as a low risk of myopathy when combined with statins compared with gemfibrozil. Although there is good evidence that both agents favorably affect clinical outcome, we need to evaluate their impact against a baseline of statin therapy. We await data from ongoing large-scale studies to evaluate the efficacy and safety of these combinations and to determine the most appropriate option for reducing residual cardiovascular risk in this important patient population.
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PMID:Expert perspective: reducing cardiovascular risk in metabolic syndrome and type 2 diabetes mellitus beyond low-density lipoprotein cholesterol lowering. 1908 89


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