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)

NEFAs characteristically are elevated in obese NIDDM patients in both the basal state and after insulin. This elevation might aggravate glycemic control both by decreasing peripheral glucose disposal (glucose-fatty acid cycle), and by increasing HGO. Thus, lowering plasma NEFA levels might improve carbohydrate metabolism. We therefore measured HGO and fuel use (by indirect calorimetry) both in the basal state and during the last 30 min of a hyperinsulinemic clamp (0.025U.kg-1.h-1) in 8 obese NIDDM patients (BMI 34.8 +/- 1.0 kg/m2) after complete overnight suppression of plasma NEFA levels with acipimox, a new nicotinic acid analogue. After acipimox, mean basal plasma NEFA and glycerol levels were lower than control values (0.11 +/- 0.02 vs. 0.65 +/- 0.04 mM, P < 0.001; and 16 +/- 3 vs. 68 +/- 7 microM, P = 0.004, respectively) and were accompanied by a fall in lipid oxidation (acipimox vs. placebo: 16.1 +/- 1.2 vs. 38.8 +/- 2.4 mg.m-2 x min-1; P < 0.001) and a rise in glucose oxidation (91.1 +/- 6.2 vs. 54.1 +/- 9.0 mg.m-2 x min-1; P = 0.002). Basal HGO and fasting plasma glucose levels were lower (94.1 +/- 9.2 vs. 118.5 +/- 9.5 mg.m-2 x min-1, P = 0.01; and 8.3 +/- 1.2 vs. 9.8 +/- 1.2 mM; P < 0.001), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Metabolic effects of suppression of nonesterified fatty acid levels with acipimox in obese NIDDM subjects. 139 16

Because the supplementation of pyridoxine (vitamin B6) improves the glucose tolerance in gestational diabetes and adult onset diabetes, pyridoxine deficiency has been considered to be one of the factors that cause diabetes mellitus. We produced pyridoxine deficient rats by giving pyridoxine-free food with deoxypyridoxine which competitively the activity of pyridoxal phosphate. In these pyridoxine deficient rats plasma insulin during the glucose tolerance test was significantly low as compared with controls. In vitro experiments of pancreas perfusion showed that secretion of insulin and glucagon was impaired in the pyridoxine deficiency. Since the restriction of diet-calorie caused a decrease in arginine-induced secretion of insulin and glucagon from the isolated pancreas, the impairment of the endocrine pancreas may depend on malnutrition. Pyridoxine deficiency is surely one of the factors that impair the endocrine pancreas by multifactorial derangement of metabolism besides the tryptophan-nicotinic acid pathway.
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PMID:The endocrine pancreas in pyridoxine deficient rats. 703 87

We determined whether overnight inhibition of lipolysis by a long-acting nicotinic acid derivative (acipimox) decreases gluconeogenesis from lactate in NIDDM patients. For this purpose, 250 mg of acipimox or placebo was administered in a double-blind crossover study at 2400, 0400, and 0800 to 8 NIDDM patients (54 +/- 4 yr of age, body mass index 29.5 +/- 1.3 kg/m2, fasting plasma glucose 11 +/- 1 mM). The next morning, total hepatic glucose production (glucose Ra) and gluconeogenesis from lactate were determined using primed, continuous infusions of [3-3H]glucose and [U-14C]acetate. Glucose and lipid oxidation rates were measured using indirect calorimetry. Mean overnight serum free fatty acid concentrations averaged 242 +/- 8 microM after acipimox and 721 +/- 30 microM after placebo (P < 0.001). Inhibition of lipolysis decreased lipid oxidation from 33 +/- 3 to 22 +/- 2 J.kg-1 x min-1 (P < 0.001) and increased carbohydrate oxidation from 15 +/- 3 to 23 +/- 2 mumol.kg-1.min-1 (P < 0.005). Gluconeogenesis from lactate decreased by approximately 40%, from 6.2 +/- 0.6 to 3.8 +/- 0.5 mumol.kg-1 x min-1 (P < 0.005); lactate oxidation increased from 5.6 +/- 0.8 to 7.9 +/- 1.1 mumol.kg-1 x min-1 (P < 0.005), with no change in plasma lactate concentrations or total lactate Rd. Fasting plasma glucose concentrations were comparable at 2400 (10.0 +/- 1.1 vs. 10.6 +/- 1.3 mM, acipimox vs. placebo) and between 0900 and 1000 (10.6 +/- 1.3 and 11.3 +/- 1.3 mM, respectively). Also, total glucose production rates remained unchanged (14.0 +/- 1.2 vs. 14.9 +/- 1.3 mol.kg-1 x min-1, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of lipolysis decreases lipid oxidation and gluconeogenesis from lactate but not fasting hyperglycemia or total hepatic glucose production in NIDDM. 824 14

An increased supply of FFAs for oxidation leads to a reduced rate of glucose oxidation and interferes with the inhibitory action of insulin on hepatic glucose production. Available evidence indicates that in humans skeletal muscle is a site for such substrate competition, which involves both pyruvate oxidation and glycogen synthesis. The insulin resistance of obesity is thought to be mostly of metabolic origin, and fully reversible. A reduction in FFA supply by weight reduction can, however, reverse this defect. The insulin resistance associated with NIDDM is thought to be primary, with a strong genetic basis, and partially irreversible. Patients with NIDDM are unable to increase their glucose oxidation normally in response to insulin to meet the energy demands of the body. Increased oxidation of lipids represents a compensatory phenomenon to meet these demands. Therapeutic use of the glucose-FFA cycle to lower blood glucose levels has yielded conflicting results. Studies are in progress to develop agents that inhibit gluconeogenesis by interfering with FFA oxidation. Nicotinic acid derivatives seem to enhance glycogen synthesis acutely by activating glycogen synthetase. Whether these or similar agents can be used to restore impaired glycogen synthesis, the most characteristic genetic defect in NIDDM, cannot be answered until the effect has been proven in chronic studies. The existence of substrate competition between amino acids and glucose, and an intrinsic hypoaminoacidaemic property of amino acids, makes it possible to expand the Randel cycle into a glucose-FFA-amino acid cycle, which integrates control of substrate disposition at the whole body level.
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PMID:Insulin action and substrate competition. 830 11

Blood levels of intermediary metabolites were measured and indirect calorimetry was performed in 10 otherwise healthy, non-insulin-dependent diabetic (NIDDM) patients before, during, and after 30 minutes of moderate exercise on three occasions in random order at weekly intervals with (1) heparin treatment to increase preexercise plasma nonesterified fatty acid (NEFA) levels (HEPARIN); (2) acipimox, a nicotinic acid analogue, to reduce preexercise plasma NEFA levels (ACIPIMOX); and (3) no manipulation of preexercise plasma NEFA levels (NIL). With ACIPIMOX, preexercise blood levels were significantly reduced for NEFAs and glycerol (P < .01) and marginally reduced for acetoacetate and 3-hydroxybutyrate (NS) compared with preexercise levels for the other two treatments; these low levels seen with acipimox treatment increased only slightly during exercise and the postexercise period. Plasma NEFA levels increased by approximately 150% (P < .001) with HEPARIN at the same times. The levels of ketone bodies during either NIL or HEPARIN increased rapidly postexercise by approximately 90% to 110% for both acetoacetate and 3-hydroxybutyrate (both P < .01). Plasma insulin levels tended to be lowest (despite similar plasma glucose levels during the three treatments) with ACIPIMOX, while growth hormone (hGH) and, perhaps, noradrenaline levels were highest both during and after exercise. The respiratory quotient (RQ) was highest with ACIPIMOX (P < .05 for exercise and postexercise periods compared with the other two treatments), which, compared with NIL, reduced fat oxidation by 27% and 60% and increased carbohydrate oxidation by 29% and 74% during and after exercise, respectively (all P < .05). These changes in substrate oxidation due to ACIPIMOX were almost opposite to those observed with HEPARIN.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effects of changes in plasma nonesterified fatty acid levels on oxidative metabolism during moderate exercise in patients with non-insulin-dependent diabetes mellitus. 848 64

Non-insulin-dependent diabetes mellitus (NIDDM) is associated with approximately two fold increase in coronary heart disease (CHD) in men and fourfold increase in CHD in women. In most studies, the duration of diabetes and severity of glycemia are only weakly related to CHD in NIDDM, suggesting that the prediabetic period may be important for the increased CHD in NIDDM subjects. Both hyperinsulinemia and/or insulin resistance predict the development of NIDDM. A number of studies have shown that increased cardiovascular risk factors (especially high triglyceride, blood pressure, and small dense low-density lipoprotein (LDL) and low high-density liproprotein (HDL) cholesterol) precede the onset of NIDDM. Recent data from the San Antonio Heart Study suggest that the atherogenic pattern of cardiovascular risk factors is more marked in prediabetic women than in prediabetic men, thus partially explaining the higher risk of CHD in prediabetic women than in prediabetic men. The atherogenic changes in cardiovascular risk factors appear to be mainly due to increased hyperinsulinemia and insulin resistance in nondiabetic subjects. Interventions to reduce cardiovascular disease in NIDDM subjects should emphasize the primary prevention of NIDDM and very aggressive treatment of traditional cardiovascular risk factors in prediabetic subjects. Treatment of hypertension and dyslipidemia in high-risk patients for NIDDM should avoid agents that further worsen insulin resistance (nicotinic acid, beta blockers, and thiazides), as subjects with hypertension and dyslipidemia are already at increased risk of NIDDM.
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PMID:The prediabetic problem: development of non-insulin-dependent diabetes mellitus and related abnormalities. 910 90

Usual risk factors for coronary artery disease account for only 25-50% of increased atherosclerotic risk in diabetes mellitus. Other obvious risk factors are hyperglycemia and dyslipidemia. However, hyperglycemia is a very late stage in the sequence of events from insulin resistance to frank diabetes, whereas lipoprotein abnormalities are manifested during the largely asymptomatic diabetic prodrome and contribute substantially to the increased risk of macrovascular disease. The insulin-resistant diabetes course affects virtually all lipids and lipoproteins. Chylomicron and very-low-density lipoprotein (VLDL) remnants accumulate, and triglycerides enrich high-density lipoprotein (HDL) and low-density lipoprotein (LDL), leading to high levels of potentially atherogenic particles and low levels of HDL cholesterol. Hyperglycemia eventually impairs removal of triglyceride-rich lipoproteins, the accumulation of which accentuates hypertriglyceridemia. As triglycerides increase-still within the so-called normal range-abnormalities in HDL and LDL became more apparent. Thus, when triglycerides are >200 mg/dL, LDL particles are small and dense (when they are <90 mg/dL, the particles are of the large, buoyant variety). The atherogenicity of small, dense LDL particles is attributed to their increased susceptibility to oxidation, but in many patients they may be a marker for insulin resistance or the presence of atherogenic VLDL. Hypertriglyceridemia is associated with atherosclerosis because (1) it is a marker for insulin resistance and atherogenic metabolic abnormalities; and (2) the small size of triglyceride-enriched lipoproteins enables them to infiltrate the blood vessel wall where they are oxidized, bind to receptors on macrophages, and ingested, leading to the development of the atherosclerotic lesion. Various studies (primary prevention with gemfibrozil: Helsinki Heart Study; secondary prevention with simvastatin and pravastatin: Scandinavian Simvastatin Survival Study [4S] and Cholesterol and Recurrent Events [CARE], respectively) have demonstrated that lipid-lowering therapy in type 2 diabetes is effective in decreasing the number of cardiac events. Risk reduction was 22% to 50% (statins) and approximately 65% (fibrate) relative to placebo. It was also noted (in 4S and CARE) that the risk of major coronary events in untreated diabetic patients was 1.5-1.7-fold greater than in untreated nondiabetic patients. Although gemfibrozil (fibric acid derivative) is more effective in decreasing triglycerides and increasing HDL cholesterol in diabetic patients than the statins, it does not change and may even increase LDL-cholesterol levels (fenofibrate may be an exception, decreasing LDL cholesterol by 20-25% in some studies). However, gemfibrozil does increase LDL particle size. Nevertheless, the statins are the current lipid-lowering drugs of choice because the change in LDL-cholesterol-to-HDL-cholesterol ratio is better than with gemfibrozil. Moreover, the diabetic patient may be more likely to benefit from statin therapy than the nondiabetic patient. It should be noted that, in theory, nicotinic acid can correct or improve all lipid or lipoprotein abnormalities in patients with type 2 diabetes. Unfortunately, it is relatively contraindicated because it causes insulin resistance and may precipitate or aggravate hyperglycemia (in addition to its other well-known side effects such as flushing, gastric irritation, development of hepatotoxicity, and hyperuricemia). It is unknown at present whether newer formulations such as once-daily Niaspan may be better tolerated in diabetes. In any case, most patients with type 2 diabetes have risk factors for coronary artery disease and qualify for aggressive LDL cholesterol-lowering therapy. At the same time, it is presently unknown whether improved glycemic control decreases coronary artery disease risk in such patients.
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PMID:Diabetic dyslipidemia. 991 65

The objective of this study was to assess the role of free fatty acids (FFAs) as insulin secretagogues in patients with type 2 diabetes. To this end, basal insulin secretion rates (ISR) in response to acute increases in plasma FFAs were evaluated in patients with type 2 diabetes and in age- and weight-matched nondiabetic control subjects during 1) intravenous infusion of lipid plus heparin (L/H), which stimulated intravascular lipolysis, and 2) the FFA rebound, which followed lowering of plasma FFAs with nicotinic acid (NA) and was a consequence of increased lipolysis from the subject's own adipose tissue. At comparable euglycemia, diabetic patients had similar ISR but higher plasma beta-hydroxybutyrate (beta-OHB) levels during L/H infusion and higher plasma FFA and beta-OHB levels during the FFA rebound than nondiabetic control subjects. Correlating ISR with plasma FFA plus beta-OHB levels showed that in response to the same changes in FFA plus beta-OHB levels, diabetic patients secreted approximately 30% less insulin than nondiabetic control subjects. In addition, twice as much insulin was secreted during L/H infusion as during the FFA rebound in response to the same FFA/beta-OHB stimulation by both diabetic patients and control subjects. Glycerol, which was present in the infused lipid (272 mmol/l) did not affect ISR. We concluded that 1) assessment of FFA effects on ISR requires consideration of effects on ISR by ketone bodies; 2) ISR responses to FFA/beta-OHB were defective in patients with type 2 diabetes (partial beta-cell lipid blindness), but this defect was compensated by elevated plasma levels of FFAs and ketone bodies; and 3) approximately two times more insulin was released per unit change in plasma FFA plus beta-OHB during L/H infusion than during the FFA rebound after NA. The reason for this remains to be explored.
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PMID:Effects of fatty acids and ketone bodies on basal insulin secretion in type 2 diabetes. 1007 59

NIDDM is characterized by a decrease in insulin sensitivity of the liver, the muscles and adipocytes. Diet, exercise and control of excess body weight are the first step of the treatment; they are even able to prevent NIDDM. In this paper the drugs that may improve insulin sensitivity are described with their different specific action on liver, muscles, or adipocytes. Drugs from the thiazolidinedione class act by enhancing the sensitivity to insulin of adipose tissue; they are high-affinity ligands for peroxisome proliferator-activated receptor gamma 2 (PPAR gamma 2 being the predominant form expressed in adipocytes) Hepatotoxicity and weight gain are sides effects of thiazolidinedione. Acipimox (a nicotinic acid analogue) is a NEFA lowering drug that suppress lipolysis, but after a few days of utilisation there is a compensatory free fatty acid rise. Recent data on Metformin action on hepatic insulin sensitivity are discussed and combination with Troglitazone is presented. Vanadyl sulfate may also improve insulin sensitivity but there is no long term human studies.
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PMID:[Insulin resistance: therapeutic approaches]. 1052 Apr 9

The effect of 3 days of intensive treatment with acipimox, an antilipolytic nicotinic acid derivative, on plasma leptin levels was studied in eight patients with Type 2 diabetes mellitus in a double-blind, placebo-controlled, cross-over study. Acipimox reduced plasma free fatty acids (FFA) markedly and lowered plasma triglycerides, glucose and insulin. Plasma leptin levels were elevated in all eight patients during 3 days of acipimox treatment (mean increase+/-s.e.: 2.38+/-0.57ng/ml, P<0.005) and the 24h mean effect of acipimox on leptin levels increased during the experimental period (P<0.03). The effect on plasma insulin and glucose resembled a mirror image of the effect on plasma leptin during 3 days of treatment. The suggestion that leptin mediates insulin resistance and may be involved in the development of the diabetic syndrome cannot be supported by the present results. It has been reported that FFA stimulates leptin secretion. Surprisingly, despite a markedly reduced FFA level, leptin concentration increased in the present study. We suggest that a primary acipimox effect is to increase leptin secretion, and that this prevails over the reduced FFA stimulus.
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PMID:The nicotinic acid analogue acipimox increases plasma leptin and decreases free fatty acids in type 2 diabetic patients. 1102 82


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