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Query: UMLS:C0011849 (diabetes)
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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

Starvation and experimental diabetes induce a stable increase in pyruvate dehydrogenase kinase (PDK) activity in skeletal muscle, which is largely due to a selective upregulation of PDK-4 expression. Increased free fatty acid (FFA) level has been suggested to be responsible for the upregulation. Because these metabolic states are also characterized by insulin deficiency, the present study was designed to examine whether insulin has a significant effect to regulate PDK mRNA expression in rat skeletal muscle. In study 1, overnight-fasted rats received an infusion of saline or insulin for 5 h (n = 6 each). During the insulin infusion, plasma glucose was clamped at basal levels (euglycemic hyperinsulinemic clamp). A third group (n = 6) received Intralipid infusion during the clamp to prevent a fall in plasma FFA. PDK-2 mRNA level in gastrocnemius muscle was not altered by insulin or FFA (i.e., Intralipid infusion). In contrast, PDK-4 mRNA level was decreased 72% by insulin (P < 0.05), and Intralipid infusion prevented only 20% of the decrease. PDK-4 protein level was decreased approximately 20% by insulin (P < 0.05), but this effect was not altered by Intralipid infusion. In study 2, overnight-fasted rats were refed or received an infusion of saline or nicotinic acid (NA, 30 micromol/h) for 5 h (n = 5 each). During the refeeding and NA infusion, plasma FFA levels were similarly (i.e., 60-70% vs. saline control) lowered. Muscle PDK-4 mRNA level decreased 77% after the refeeding (P < 0.05) but not after the NA infusion. In conclusion, the present data indicate that insulin had a profound effect to suppress PDK-4 expression in skeletal muscle and that, contrary to previous suggestions, circulating FFA had little impact on PDK-4 mRNA expression, at least within 5 h.
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PMID:Insulin suppresses PDK-4 expression in skeletal muscle independently of plasma FFA. 1502 5

Therapy with niacin (nicotinic acid) is unique in that it improves all lipoprotein abnormalities. It significantly reduces low-density lipoprotein cholesterol, triglyceride, and lipoprotein(a) levels, while increasing high-density lipoprotein cholesterol levels. This makes niacin ideal for treating a wide variety of lipid disorders, including the metabolic syndrome, diabetes mellitus, isolated low high-density lipoprotein cholesterol, and hypertriglyceridemia. Niacin-induced changes in serum lipid levels produce significant improvements in both coronary artery disease and clinical outcomes. Niacin is currently available in 3 formulations (immediate release, extended release, and long acting), which differ significantly with respect to their safety and efficacy profiles. Immediate-release niacin is generally taken 3 times a day and is associated with adverse flushing, gastrointestinal symptoms, and elevations in blood glucose levels. Long-acting niacin can be taken once daily and is associated with significantly reduced flushing, but its metabolism increases the risk of hepatotoxic effects. Extended-release niacin, also given once daily, has an absorption rate intermediate between the other formulations and is associated with fewer flushing and gastrointestinal symptoms without increasing hepatotoxic risk.
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PMID:New perspectives on the use of niacin in the treatment of lipid disorders. 1507 39

Enzyme activities along the kynurenine pathway were assayed in the tissues of New Zealand white rabbits made diabetic with alloxan treatment and hypercholesterolemic with a high-cholosterol diet. Activities are expressed as nmoles of product forming per min per mg of protein and per g of fresh tissue. Liver tryptophan 2,3-dioxygenase (TDO) was present only in holoenzyme form. This activity decreased in diabetic-hyperlipidemic and hyperlipidemic rabbits in comparison with healthy animals. Small intestine indole 2,3-dioxygenase was markedly higher than liver TDO in all rabbit groups, but did not show any significant difference in the values among the three groups. Mitochondrial kynurenine 3-monooxygenase activity was higher in liver than in kidney, but were unchanged with respect to controls. Kynureninase showed similar specific activities in the liver and kidney among groups, whereas the activity per g of fresh tissue was significantly lower in the liver of hyperlipidemic and kidney of diabetic-hyperlipidemic rabbits than in healthy animals. Kynurenine-oxoglutarate transaminase and kynureninase showed lower values in kidney, but not in liver, of diabetic-hyperlipidemic rabbits. However, 3-hydroxyanthranilate 3,4-dioxygenase activity was reduced in both liver and kidney of diabetic-hypercholesterolemic and hyperlipidemic rabbits compared with controls. Instead, aminocarboxymuconate-semialdehyde decarboxylase (picolinic carboxylase) activity was significantly higher in diabetic-hyperlipidermic rabbits in comparison with hyperlypidemic and control rabbits. Therefore, in diabetic rabbits, there is an alteration of tryptophan metabolism at the level of 3-hydroxyanthranilic acid --> nicotinic acid step, which has the effect of reducing the biosynthesis of NAD in diabetes.
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PMID:Metabolism of tryptophan along the kynurenine pathway in alloxan diabetic rabbits. 1520 55

Despite their inherited nature, familial dyslipidemias show large intra- and interfamilial variability in phenotypic expression, clinical presentations, and levels of abnormalities of serum lipid fractions. Once diagnosed, patients shall be considered at high cardiovascular risk and treated as per secondary prevention National Cholesterol Education Program III guidelines. Comorbidity treatments (ie, obesity, diabetes, and hypertension) are imperative. Lifestyle interventions shall soon be concomitantly followed by lipid-regulating drugs. The major aspects of the above interventions are the following: 1) therapeutic lifestyle change: regular aerobic exercises, conventional low-fat, low-cholesterol, low refined but high complex carbohydrates diet, avoidance of unproven fad diets (ie, Atkins); 2) plant stanols and sterol esters, 3) high-potency statins (eg, rosuvastatin, simvastatin, atorvastatin); 4) addition of nicotinic acid, bile acid binders, fibrates, or ezetimibe pending on the lipid fraction affected; 5) statins are the starting drug of choice with these exceptions: in isolated low-density lipoprotein cholesterol, niacin or fibrates may be preferable; in isolated severe hypertriglyceridemic conditions, fibrates or fish oil may be preferable; in children with isolated elevation of low-density lipoprotein cholesterol, ezetimibe or bile acid binders may be preferable; when serum lipoprotein (a) elevation is the most notable abnormality, niacin may be chosen as the initial drug for its unique effect on this fraction. Plasmapheresis, intestinal shunts, or liver transplantation are to be considered in that order as last resorts if the above fails to accomplish serum lipid level goals.
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PMID:Treatment of Familial Hypercholesterolemia and Other Genetic Dyslipidemias. 1521 22

The Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program issued an evidence-based set of guidelines on cholesterol management in 2001. Since the publication of ATP III, 5 major clinical trials of statin therapy with clinical end points have been published. These trials addressed issues that were not examined in previous clinical trials of cholesterol-lowering therapy. The present document reviews the results of these recent trials and assesses their implications for cholesterol management. Therapeutic lifestyle changes (TLC) remain an essential modality in clinical management. The trials confirm the benefit of cholesterol-lowering therapy in high-risk patients and support the ATP III treatment goal of low-density lipoprotein cholesterol (LDL-C) <100 mg/dL. They support the inclusion of patients with diabetes in the high-risk category and confirm the benefits of LDL-lowering therapy in these patients. They further confirm that older persons benefit from therapeutic lowering of LDL-C. The major recommendations for modifications to footnote the ATP III treatment algorithm are the following. In high-risk persons, the recommended LDL-C goal is <100 mg/dL, but when risk is very high, an LDL-C goal of <70 mg/dL is a therapeutic option, ie, a reasonable clinical strategy, on the basis of available clinical trial evidence. This therapeutic option extends also to patients at very high risk who have a baseline LDL-C <100 mg/dL. Moreover, when a high-risk patient has high triglycerides or low high-density lipoprotein cholesterol (HDL-C), consideration can be given to combining a fibrate or nicotinic acid with an LDL-lowering drug. For moderately high-risk persons (2+ risk factors and 10-year risk 10% to 20%), the recommended LDL-C goal is <130 mg/dL, but an LDL-C goal <100 mg/dL is a therapeutic option on the basis of recent trial evidence. The latter option extends also to moderately high-risk persons with a baseline LDL-C of 100 to 129 mg/dL. When LDL-lowering drug therapy is employed in high-risk or moderately high-risk persons, it is advised that intensity of therapy be sufficient to achieve at least a 30% to 40% reduction in LDL-C levels. Moreover, any person at high risk or moderately high risk who has lifestyle-related risk factors (eg, obesity, physical inactivity, elevated triglycerides, low HDL-C, or metabolic syndrome) is a candidate for TLC to modify these risk factors regardless of LDL-C level. Finally, for people in lower-risk categories, recent clinical trials do not modify the goals and cutpoints of therapy.
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PMID:Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. 1524 16


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