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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetes mellitus ia very common disease with a high cardiovascular morbidity and mortality. This articles reviews the types of lipid disorders that can accompany diabetes mellitus and the evidence that treatment of dyslipidaemia improves primary and secondary endpoints, i.e. lipid levels, cardiovascular events, and mortality. Specific lipid-lowering strategies are discussed, including diet and exercise, treatment of hyperglycaemia, and the use of lipid-lowering therapy such as statins, fibric acid derivatives, bile acid sequestrants, nicotinic acid and its derivatives, fish oil and hormone replacement therapy. An approach to the patient with diabetes mellitus and dyslipidaemia is provided.
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PMID:Lipids and diabetes mellitus: a review of therapeutic options. 1236 20

This study evaluated the postprandial (PP) response to an oral fat load in 28 male patients with type 2 diabetes (mean HbA1c of 5.1%), all receiving metformin and performing physical exercise, compared with healthy subjects. The effects of micronized fenofibrate (200 mg once daily) on triglycerides (TG) and retinyl palmitate (RP) responses, lipoprotein mass concentrations, post-heparin lipase activities and coagulation factors were investigated after a 16-week double-blind, placebo-controlled period. Higher and delayed TG response after the oral fat load (P<0.001) corresponding to increases in both intestinally and endogenous TG-rich lipoproteins and lower lipoprotein lipase (LPL) activity 30 and 60 min post-heparin injection (P<0.05) were observed in the patients as compared with controls. Fasting PAI-1 activity, 6 h PP Factor VII and PAI-1 activities were higher in patients (P=0.036, P=0.032 and P=0.017, respectively). After fenofibrate treatment, TG and RP responses and peak LPL activity were no more significantly different from controls at baseline. Compared with placebo, fasting TG-rich lipoproteins and HDL(3) mass concentrations were significantly lower and higher, respectively; PP chylomicrons and very low density lipoprotein (VLDL) mass concentrations were lower; fasting and PP fibrinogen levels were significantly reduced after fenofibrate treatment. Diabetes control was unchanged throughout the study. Fenofibrate normalized the abnormal PP response and improved the fasting lipoprotein abnormalities in patients with type 2 diabetes and optimal glucose control.
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PMID:Micronized fenofibrate normalizes the enhanced lipidemic response to a fat load in patients with type 2 diabetes and optimal glucose control. 1248 62

Updated guidelines from the National Cholesterol Education Program give greater emphasis to lipoproteins other than low-density lipoprotein cholesterol (LDL) than previous guidelines. Although statins remain first-line therapy for most patients to lower LDL, combination therapy is the next logical step in achieving goals in patients with mixed dyslipidemia or elevated LDL despite statin therapy. As the prevalence of diabetes, metabolic syndrome, and atherogenic dyslipidemia rises, the importance of treating the total lipid profile becomes even more crucial. Niacin, fibrates, and bile acid sequestrants are effective in combination with statins in lowering LDL, triglycerides, and total cholesterol levels and increasing high-density lipoprotein cholesterol (HDL). Although combination therapies may increase the risk of myopathy, both fibrate-statin and niacin-statin combinations are considered safe. In addition, niacin-statin therapy reduces atherosclerotic progression and coronary events. New pharmacologic formulations exist that will further affect treatment: a single-tablet combination of lovastatin and extended-release niacin is available, as is ezetimibe, a cholesterol-absorption inhibitor. In all, both HDL and triglyceride levels correlate with cardiovascular risk and should be considered secondary targets of therapy. Combination therapy can be safe and effective and can be constructed to affect all lipoprotein parameters.
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PMID:Treating dyslipidemic patients with lipid-modifying and combination therapies. 1274 37

The efficacy and safety profiles of various forms of niacin for treating dyslipidemia are described. Niacin is well recognized for treating dyslipidemia in adults and has been shown to be effective in reducing coronary events. It has a broad range of effects on serum lipids and lipoproteins, including lowering total cholesterol, low-density-lipoprotein (LDL) cholesterol, and triglycerides. Niacin is the most effective lipid-modifying drug for raising high-density-lipoprotein (HDL) cholesterol levels and has been shown to lower Lp(a) lipoprotein. Niacin reduces triglycerides and very-low-density-lipoprotein and LDL cholesterol synthesis, primarily by decreasing fatty acid mobilization from adipose tissue. Niacin appears to raise HDL cholesterol by reducing hepatic apolipoprotein A-l clearance and enhancing reverse cholesterol transport. Niacin is metabolized through a conjugation or nicotinamide pathway. Standard immediate-release niacin is metabolized primarily through the conjugation pathway, which results in a high frequency of flushing. Long-acting niacin is metabolized through the nicotinamide pathway, which results in less flushing but increases the risk of hepatotoxicity. Extended-release niacin has a more balanced metabolism and causes fewer of both types of adverse effects. Improved serum lipid levels during niacin therapy have been associated with clinical and angiographic evidence of reduced coronary artery disease, especially when combined with statins. Niacin is particularly useful for managing high triglyceride and low HDL cholesterol levels as well as the lipid abnormalities associated with metabolic syndrome, including those commonly encountered in patients with diabetes. Several niacin products are available with significant differences in their safety and efficacy profiles. Health care providers must consider the differences between agents when recommending niacin for dyslipidemia treatment.
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PMID:Niacin for dyslipidemia: considerations in product selection. 1278 70

Niacin is the most effective medication in current clinical use for increasing high-density lipoprotein (HDL) cholesterol. It has the broadest effect on the lipid profile, reducing all atherogenic apolipoprotein (apo) B and increasing all antiatherogenic apo AI-containing lipoproteins, resulting in significant reduction in atherosclerotic complications and total mortality in trials. Recent research indicates novel major target sites of action in the liver to 1) directly inhibit diacylglycerol acyltransferase 2 (DGAT2), explaining its effect on triglycerides and apo B lipoproteins, and 2) inhibit the HDL apo AI catabolism pathway, resulting in higher HDL levels. Such information may lead to new drug discovery and supply the rationale for combination with other lipid regulators that are known to have different mechanisms of action. Trial evidence shows that niacin is not only safe to use in persons with diabetes, but that its combination with 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) is also safe and effective. Recently, a new formulation of niacin has made it easier to tolerate and administer. Clinical trials are needed to determine whether niacin in combination with other lipid-modulating agents decreases the risk of cardiovascular events beyond the approximately 30% that has been noted with monotherapy.
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PMID:Niacin, lipids, and heart disease. 1455 89

Increased circulating free fatty acids (FFAs) inhibit both hepatic and peripheral insulin action. Because the loss of effectiveness of glucose to suppress endogenous glucose production and stimulate glucose uptake contributes importantly to fasting hyperglycemia in type 2 diabetes, we examined whether the approximate twofold elevations in FFA characteristic of poorly controlled type 2 diabetes contribute to this defect. Glucose levels were raised from 5 to 10 mmol/l while maintaining fixed hormonal conditions by infusing somatostatin with basal insulin, glucagon, and growth hormone. Each individual was studied at two FFA levels: with (NA+) and without (NA-) infusion of nicotinic acid in nine individuals with poorly controlled type 2 diabetes (HbA(1c) = 10.1 +/- 0.7%) and with (LIP+) and without (LIP-) infusion of lipid emulsion in nine nondiabetic individuals. Elevating FFA to approximately 500 micro mol/l blunted the ability of glucose to suppress endogenous glucose production (LIP- = -48% vs. LIP+ = -28%; P < 0.01) and increased glucose uptake (LIP- = 97% vs. LIP+ = 51%; P < 0.01) in nondiabetic individuals. Raising FFA also blunted the endogenous glucose production response in 10 individuals with type 2 diabetes in good control (HbA(1c) = 6.3 +/- 0.3%). Conversely, normalizing FFA nearly restored the endogenous glucose production (NA- = -7% vs. NA+ = -41%; P < 0.001) and glucose uptake (NA- = 26% vs. NA+ = 64%; P < 0.001) responses to hyperglycemia in individuals with poorly controlled type 2 diabetes. Thus, increased FFA levels contribute substantially to the loss of glucose effectiveness in poorly controlled type 2 diabetes.
Diabetes 2003 Nov
PMID:Contribution of elevated free fatty acid levels to the lack of glucose effectiveness in type 2 diabetes. 1457 93

We used tracer and arteriovenous difference techniques in conscious dogs to determine the effect of nonesterified fatty acids (NEFAs) on net hepatic glucose uptake (NHGU). The protocol included equilibration ([3-(3)H]glucose), basal, and two experimental periods (-120 to -30, -30 to 0, 0-120 [period 1], and 120-240 min [period 2], respectively). During periods 1 and 2, somatostatin, basal intraportal insulin and glucagon, portal glucose (21.3 micromol.kg(-1).min(-1)), peripheral glucose (to double the hepatic glucose load), and peripheral nicotinic acid (1.5 mg.kg(-1).min(-1)) were infused. During period 2, saline (nicotinic acid [NA], n = 7), lipid emulsion (NA plus lipid emulsion [NAL], n = 8), or glycerol (NA plus glycerol [NAG], n = 3) was infused peripherally. During period 2, the NA and NAL groups differed (P < 0.05) in rates of NHGU (10.5 +/- 2.08 and 4.7 +/- 1.9 micromol.g(-1).min(-1)), respectively, endogenous glucose R(a) (2.3 +/- 1.4 and 10.6 +/- 1.0 micromol.kg(-1).min(-1)), net hepatic NEFA uptakes (0.1 +/- 0.1 and 1.8 +/- 0.2 micromol.kg(-1).min(-1)), net hepatic beta-hydroxybutyrate output (0.1 +/- 0.0 and 0.4 +/- 0.1 micromol.kg(-1).min(-1)), and net hepatic lactate output (6.5 +/- 1.7 vs. -2.3 +/- 1.2 micromol.kg(-1).min(-1)). Hepatic glucose uptake and release were 2.6 micro mol. kg(-1). min(-1) less and 3.5 micro mol. kg(-1). min(-1) greater, respectively, in the NAL than NA group (NS). The NAG group did not differ significantly from the NA group in any of the parameters listed above. In the presence of hyperglycemia and relative insulin deficiency, elevated NEFAs reduce NHGU by stimulating hepatic glucose release and suppressing hepatic glucose uptake.
Diabetes 2004 Jan
PMID:Nonesterified fatty acids and hepatic glucose metabolism in the conscious dog. 1469 95

Plasma levels of high-density lipoprotein-cholesterol (HDL-C) are a powerful independent cardiovascular risk factor, bearing an inverse relationship with atherosclerotic cardiovascular disease (with risk rising sharply when levels are <1.04 mmol/L). Apart from its protective role in atherosclerosis, HDL-C increases fibrinolysis, is an antioxidant to low density lipoprotein-cholesterol (LDL-C), and decreases platelet aggregability. Up to a third of patients with atherosclerotic cardiovascular disease have 'desirable' plasma levels of total cholesterol but low HDL-C levels. Benefits of treating low plasma HDL-C levels were clearly demonstrated in the Veterans Affairs HDL Intervention Trial (VA-HIT) where gemfibrozil reduced nonfatal infarcts and coronary deaths by 22%. This was achieved by a 6% increase in plasma HDL-C levels, and a 24.5% decrease in plasma levels of triglycerides, without any significant decrease in LDL-C levels. Multivariate analyses revealed the rise in plasma HDL-C levels after treatment, but not decreases in plasma levels of triglycerides or LDL-C, predicted coronary artery disease events. The typical patient under consideration in this article is one with plasma levels of HDL-C <1 mmol/L, LDL-C <3.37 mmol/L [either receiving therapeutic lifestyle changes or or LDL-C-lowering therapy comprising a hydroxymethylglutaryl coenzyme-A (HMG-CoA) reductase inhibitor or bile acid sequestrant] and fasting triglycerides <2.26 mmol/L. We propose this dyslipidemia be classified as Type VI phenotype following the Frederickson and Lees classification. High-risk patients (with >/=2 risk factors for atherosclerotic cardiovascular disease, or 10-year cardiovascular risk >20%), patients with established atherosclerotic cardiovascular disease, or type 2 diabetes mellitus, or metabolic syndrome should receive pharmacotherapy. Plasma HDL-C levels >1.16 mmol/L may be considered optimal and between 1 and 1.16 mmol/L as desirable. Fibric acid derivatives, nicotinic acid, HMG-CoA reductase inhibitors, estrogens, and ethanol (not recommended as therapy) increase plasma HDL-C levels. Nicotinic acid is the most potent agent and recent reports indicate that, in contrast to gemfibrozil, it selectively increases antiatherogenic HDL subfraction, lipoprotein (Lp) AI (without apolipoprotein AII), in patients with low plasma HDL-C levels. An extended-release formulation, administered once daily, has improved the tolerability of nicotinic acid. Recent evidence also indicates that nicotinic acid may effectively correct dyslipidemia in patients with diabetes mellitus without significantly compromising glycemic control. Fibric acid derivatives and estrogen raise plasma HDL-C levels by different mechanisms of action, and these agents may be used with nicotinic acid. Combination therapy (especially HMG-CoA reductase inhibitor and nicotinic acid) should be considered in patients with atherosclerotic cardiovascular disease and low plasma HDL-C levels.
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PMID:Optimal therapy of low levels of high density lipoprotein-cholesterol. 1472 46

Combined hyperlipidemia is increasing in frequency and is the most common lipid disorder associated with obesity, insulin resistance and diabetes mellitus. It is associated with other features of the metabolic syndrome including hypertension, hyperuricemia, hyperinsulinemia and highly atherogenic subfractions of lipoprotein remnant particles including small dense low density lipoprotein-cholesterol. This review examines the mechanisms by which combined hyperlipidemia arises and the various drugs including fibric acid derivatives, hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, and nicotinic acid which can be used either as monotherapy or in combination to manage it and to improve prognosis from atherosclerotic disease in diabetes mellitus, insulin resistant states and primary combined hyperlipidemia. The therapeutic approach to combined hyperlipidemia involves determination of whether the cause is hepatocyte damage or metabolic derangements. Combined hyperlipidemia due to hepatocyte damage should be treated by attention to the primary cause. In the case of metabolic dysfunction because of imbalance in glucose and fat metabolism, therapy of diabetes mellitus and obesity should be optimised prior to commencement of lipid lowering drugs. Both fibric acid derivatives and HMG-CoA reductase inhibitors can be used in the treatment of combined hyperlipidemia with fibric acid derivatives having greater effects on triglycerides and HMG-CoA reductase inhibitors on LDL-C though both have effects on the other cardiovascular risk factors. There is some evidence of benefit with both interventions in mild combined hyperlipidemias and large scale trials are underway. Fibric acid derivatives and HMG-CoA reductase inhibitor therapy can be combined with care, provided that gemfibrozil is avoided, fibric acid derivatives are given in the mornings and shorter half -life HMG-CoA reductase inhibitors are used at night. Combined hyperlipidemia emergencies occur with predominant hypertriglyceridemia in pregnancy or as a cause of pancreatitis. Therapy in the former should aim to reduce chylomicron production by a low fat diet and intervention to suppress VLDL-C secretion using omega-3 fatty acids. In the latter case, fluid therapy alone and medium chain plasma triglyceride infusions usually reduce levels satisfactorily though apheresis may be required. Blood glucose levels also need aggressive management in these conditions. Combined hyperlipidemia is likely to become an increasing problem with the increase in the prevalence of obesity and diabetes mellitus and needs aggressive management to reduce cardiovascular risk.
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PMID:Drug treatment of combined hyperlipidemia. 1472 15

Glucokinase (GK) has a major role in the control of blood glucose homeostasis and is a strong potential target for the pharmacological treatment of type 2 diabetes. We report here the mechanism of action of two novel and potent direct activators of GK: 6-[(3-isobutoxy-5-isopropoxybenzoyl)amino]nicotinic acid(GKA1) and 5-([3-isopropoxy-5-[2-(3-thienyl)ethoxy]benzoyl]amino)-1,3,4-thiadiazole-2-carboxylic acid(GKA2), which increase the affinity of GK for glucose by 4- and 11-fold, respectively. GKA1 increased the affinity of GK for the competitive inhibitor mannoheptulose but did not affect the affinity for the inhibitors palmitoyl-CoA and the endogenous 68-kDa regulator (GK regulatory protein [GKRP]), which bind to allosteric sites or to N-acetylglucosamine, which binds to the catalytic site. In hepatocytes, GKA1 and GKA2 stimulated glucose phosphorylation, glycolysis, and glycogen synthesis to a similar extent as sorbitol, a precursor of fructose 1-phosphate, which indirectly activates GK through promoting its dissociation from GKRP. Consistent with their effects on isolated GK, these compounds also increased the affinity of hepatocyte metabolism for glucose. GKA1 and GKA2 caused translocation of GK from the nucleus to the cytoplasm. This effect was additive with the effect of sorbitol and is best explained by a "glucose-like" effect of the GK activators in translocating GK to the cytoplasm. In conclusion, GK activators are potential antihyperglycemic agents for the treatment of type 2 diabetes through the stimulation of hepatic glucose metabolism by a mechanism independent of GKRP.
Diabetes 2004 Mar
PMID:Stimulation of hepatocyte glucose metabolism by novel small molecule glucokinase activators. 1498 35


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