acipimox and Diabetes-Mellitus--Type-2

Topics: Animals; Biological Transport; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucose; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Insulin; Insulin Resistance; Lipolysis; Models, Biological; Niacin; Obesity; Pyrazines

The authors give summary on the pathogenesis of hyperlipoproteinaemia in patients with diabetes mellitus. They investigated the effects of acid nicotinic derivate acipimox on lipid metabolism in these patients. They treated with acipimox 15 patients who suffered from non-insulin-dependent diabetes mellitus, as well as II/B, IV type hyperlipoproteinaemia by Fredrickson. They investigated the effect of acipimox on the lipoprotein content and quality in the sera and uric acid and carbohydrate metabolism. The authors found decreased cholesterol, triglyceride, apolipoprotein-B, glycosilated haemoglobin, glucose and uric acid levels in the sera and they found that the atherogenic index decreased too. During the treatment they could not recognise a change in the low-density lipoprotein level of the sera while the high density lipoprotein and apo-A1 level increased.

Topics: Adult; Diabetes Mellitus, Type 2; Female; Humans; Hyperlipoproteinemias; Hypolipidemic Agents; Male; Middle Aged; Pyrazines

Exercise combined with adipose tissue lipolytic inhibition augments intramuscular lipid and glycogen use in type 2 diabetes patients. The present study investigates the impact of adipose tissue lipolytic inhibition during exercise on subsequent postprandial glycemic control in type 2 diabetes patients.. Sixty minutes of endurance-type exercise (at 45% W. Collectively, exercise with adipose tissue lipolytic inhibition reduces postprandial blood glucose and insulin excursions and, as such, further improves glycemic control in male type 2 diabetes patients.

Topics: Adipose Tissue; Administration, Oral; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Exercise; Fatty Acids; Glycogen; Humans; Hypolipidemic Agents; Insulin; Lactic Acid; Lipid Metabolism; Male; Middle Aged; Pyrazines; Triglycerides

To investigate the effect of lowering the plasma glucose and free fatty acid (FFA) concentrations with dapagliflozin and acipimox, respectively, on insulin sensitivity and insulin secretion in T2DM individuals.. Fourteen male T2DM patients received an oral glucose tolerance test and euglycemic hyperinsulinemic clamp at baseline and were treated for 3 weeks with dapagliflozin (10 mg per day). During week 3, acipimox (250 mg four times per day) treatment was added to dapagliflozin. The oral glucose tolerance test and insulin clamp were repeated at the end of weeks 2 and 3.. Dapagliflozin caused glucosuria and significantly lowered the plasma glucose concentration (by 35 mg/dL; P < .01), whereas the fasting plasma FFA concentration was unaffected. Acipimox caused a further decrease in the fasting plasma glucose concentration (by 20 mg/dL; P < .01) and a significant decrease in the fasting plasma FFA concentration. Compared to baseline, insulin-mediated glucose disposal increased significantly at week 2 (from 4.48 ± 0.50 to 5.30 ± 0.50 mg/kg · min; P < .05). However, insulin-mediated glucose disposal at week 3 (after the addition of acipimox) did not differ significantly from that at week 2. Glucose-stimulated insulin secretion at week 2 increased significantly compared to baseline, and it increased further and significantly at week 3 compared to week 2.. Lowering the plasma glucose concentration with dapagliflozin improves both insulin sensitivity and β-cell function, whereas lowering plasma FFA concentration by addition of acipimox to dapagliflozin improves β-cell function without significantly affecting insulin sensitivity.

Topics: Adult; Aged; Benzhydryl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Glucose Clamp Technique; Glucose Tolerance Test; Glucosides; Humans; Hypolipidemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Pyrazines; Young Adult

Type 2 diabetes (T2DM) is closely associated with the development of heart failure, which might be related with impaired substrate metabolism and accumulation of myocardial lipids (MYCL). The aim of this study was to investigate the impact of an acute pharmacological inhibition of adipose tissue lipolysis leading to reduced availability of circulating FFA on MYCL and heart function in T2DM.. 8 patients with T2DM (Age: 56 ± 11; BMI: 28 ± 3.5 kg/m(2); HbA1c: 7.29 ± 0.88%) were investigated on two study days in random order. Following administration of Acipimox or Placebo MYCL and heart function were measured by (1)H-magnetic-resonance-spectroscopy and tomography at baseline, at 2 and at 6 h. Acipimox reduced circulating FFA by -69% (p < 0.001), MYCL by -39 ± 41% (p < 0.001) as well as systolic heart function (Ejection Fraction (EF): -13 ± 8%, p = 0.025; Cardiac Index: -16 ± 15%, p = 0.063 compared to baseline). Changes in plasma FFA concentrations strongly correlated with changes in MYCL (r = 0.707; p = 0.002) and EF (r = 0.651; p = 0.006). Diastolic heart function remained unchanged.. Our results indicate, that inhibition of adipose tissue lipolysis is associated with a rapid depletion of MYCL-stores and reduced systolic heart function in T2DM. These changes were comparable to those previously found in insulin sensitive controls. MYCL thus likely serve as a readily available energy source to cope with short-time changes in FFA availability.

Topics: Adipose Tissue; Aged; Austria; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Down-Regulation; Energy Metabolism; Fatty Acids, Nonesterified; Female; Humans; Hypolipidemic Agents; Lipolysis; Magnetic Resonance Imaging; Male; Middle Aged; Myocardium; Proton Magnetic Resonance Spectroscopy; Pyrazines; Risk Factors; Single-Blind Method; Stroke Volume; Systole; Time Factors; Treatment Outcome; Ventricular Function, Left

Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD(+)) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We hypothesize that the nicotinic acid derivative acipimox, an NAD(+) precursor, would directly affect mitochondrial function independent of reductions in nonesterified fatty acid (NEFA) concentrations. In a multicenter randomized crossover trial, 21 patients with type 2 diabetes (age 57.7 ± 1.1 years, BMI 33.4 ± 0.8 kg/m(2)) received either placebo or acipimox 250 mg three times daily dosage for 2 weeks. Acipimox treatment increased plasma NEFA levels (759 ± 44 vs. 1,135 ± 97 μmol/L for placebo vs. acipimox, P < 0.01) owing to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene sets and a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response. Further studies in C2C12 myotubes confirmed a direct effect of acipimox on NAD(+) levels, mitonuclear protein imbalance, and mitochondrial oxidative capacity. To the best of our knowledge, this study is the first to demonstrate that NAD(+) boosters can also directly affect skeletal muscle mitochondrial function in humans.

Topics: Cross-Over Studies; Diabetes Mellitus, Type 2; Female; Humans; Hypolipidemic Agents; Insulin Resistance; Male; Middle Aged; Mitochondria, Muscle; Muscle, Skeletal; Pyrazines

Elevated plasma FFA cause beta-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% (P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or DeltaC-peptide/Deltaglucose AUC (+177%, P = 0.02), an index of improved beta-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 +/- 5% (P < 0.04). First- (+19 +/- 6%, P = 0.1) and second-phase (+31 +/- 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 +/- 7 (P < 0.05) and 41 +/- 8% (P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR (r2 = 0.31, P < 0.02) and acute (2-4 min) glucose-induced insulin release after acipimox (r2 =0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM.

Topics: Adult; Blood Glucose; C-Peptide; Circadian Rhythm; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Genetic Predisposition to Disease; Glucose Clamp Technique; Hormones; Humans; Hyperglycemia; Hypolipidemic Agents; Insulin; Insulin Secretion; Male; Osmolar Concentration; Pyrazines; Time Factors

In the present study, we investigated the consequences of adipose tissue lipolytic inhibition on skeletal muscle substrate use in type 2 diabetic patients.. We studied ten type 2 diabetic patients under the following conditions: (1) at rest; (2) during 60 min of cycling exercise at 50% of maximal workload capacity and subsequent recovery. Studies were done under normal, fasting conditions (control trial: CON) and following administration of a nicotinic acid analogue (low plasma non-esterified fatty acid trial: LFA). Continuous [U-13C]palmitate and [6,6 -2H2]glucose infusions were applied to quantify plasma NEFA and glucose oxidation rates, and to estimate intramuscular triacylglycerol (IMTG) and glycogen use. Muscle biopsies were collected before and after exercise to determine net changes in lipid and glycogen content specific to muscle fibre type.. Following administration of the nicotinic acid analogue (Acipimox), the plasma NEFA rate of appearance was effectively reduced, resulting in lower NEFA concentrations in the LFA trial (p<0.001). Plasma NEFA oxidation rates were substantially reduced at rest, during exercise and subsequent recovery in the LFA trial. The lower plasma NEFA oxidation rates were compensated by an increase in IMTG and endogenous carbohydrate use (p<0.05). Plasma glucose disposal rates did not differ between trials. In accordance with the tracer data, a greater net decline in type I muscle fibre lipid content was observed following exercise in the LFA trial (p<0.05).. This study shows that plasma NEFA availability regulates IMTG use, and that adipose tissue lipolytic inhibition, in combination with exercise, could be an effective means of augmenting intramuscular lipid and glycogen use in type 2 diabetic patients in an overnight fasted state.

Topics: Adipose Tissue; Aged; Algorithms; Body Composition; Body Mass Index; Breath Tests; Diabetes Mellitus, Type 2; Diet; Energy Metabolism; Exercise Test; Fatty Acids, Nonesterified; Female; Glycogen; Humans; Hypolipidemic Agents; Insulin; Kinetics; Lipolysis; Male; Middle Aged; Muscle, Skeletal; Oxidation-Reduction; Palmitates; Pyrazines

To investigate the effect of a sustained (7-day) decrease in plasma free fatty acid (FFA) concentrations on insulin action and intramyocellular long-chain fatty acyl-CoAs (LCFA-CoAs), we studied the effect of acipimox, a potent inhibitor of lipolysis, in seven type 2 diabetic patients (age 53 +/- 3 years, BMI 30.2 +/- 2.0 kg/m2, fasting plasma glucose 8.5 +/- 0.8 mmol/l, HbA 1c 7.5 +/- 0.4%). Subjects received an oral glucose tolerance test (OGTT) and 120-min euglycemic insulin (80 mU/m2 per min) clamp with 3-[3H]glucose/vastus lateralis muscle biopsies to quantitate rates of insulin-mediated whole-body glucose disposal (Rd) and intramyocellular LCFA-CoAs before and after acipimox (250 mg every 6 h for 7 days). Acipimox significantly reduced fasting plasma FFAs (from 563 +/- 74 to 230 +/- 33 micromol/l; P < 0.01) and mean plasma FFAs during the OGTT (from 409 +/- 44 to 184 +/- 22 micromol/l; P < 0.01). After acipimox, decreases were seen in fasting plasma insulin (from 78 +/- 18 to 42 +/- 6 pmol/l; P < 0.05), fasting plasma glucose (from 8.5 +/- 0.8 to 7.0 +/- 0.5 mmol/l; P < 0.02), and mean plasma glucose during the OGTT (from 14.5 +/- 0.8 to 13.0 +/- 0.8 mmol/l; P < 0.05). After acipimox, insulin-stimulated Rd increased from 3.3 +/- 0.4 to 4.4 +/- 0.4 mg x kg(-1) x min(-1) (P < 0.03), whereas suppression of endogenous glucose production (EGP) was similar and virtually complete during both insulin clamp studies (0.16 +/- 0.10 vs. 0.14 +/- 0.10 mg x kg(-1) x min(-1); P > 0.05). Basal EGP did not change after acipimox (1.9 +/- 0.2 vs. 1.9 +/- 0.2 mg x kg(-1) x min(-1)). Total muscle LCFA-CoA content decreased after acipimox treatment (from 7.26 +/- 0.58 to 5.64 +/- 0.79 nmol/g; P < 0.05). Decreases were also seen in muscle palmityl CoA (16:0; from 1.06 +/- 0.10 to 0.75 +/- 0.11 nmol/g; P < 0.05), palmitoleate CoA (16:1; from 0.48 +/- 0.05 to 0.33 +/- 0.05 nmol/g; P = 0.07), oleate CoA (18:1; from 2.60 +/- 0.11 to 1.95 +/- 0.31 nmol/g; P < 0.05), linoleate CoA (18:2; from 1.81 +/- 0.26 to 1.38 +/- 0.18 nmol/g; P = 0.13), and linolenate CoA (18:3; from 0.27 +/- 0.03 to 0.19 +/- 0.02 nmol/g; P < 0.03) levels after acipimox treatment. Muscle stearate CoA (18:0) did not decrease after acipimox treatment. The increase in R(d) correlated strongly with the decrease in muscle palmityl CoA (r = 0.75, P < 0.05), oleate CoA (r = 0.76, P < 0.05), and total muscle LCFA-CoA (r = 0.74, P < 0.05) levels. Plasma adiponectin did not change significantly after acipimox treatm

Topics: Acyl Coenzyme A; Adiponectin; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Humans; Hyperlipidemias; Hypolipidemic Agents; Insulin; Male; Middle Aged; Muscle, Skeletal; Pyrazines

During the noninvasive assessment of myocardial viability with (18)F-FDG metabolic imaging, adequate regulation of metabolic conditions is needed to ensure optimal image quality. The aim of this study was to compare the feasibility and image quality of cardiac (18)F-FDG SPECT imaging using acipimox in patients with diabetes and patients without diabetes.. Seventy patients with ischemic cardiomyopathy underwent (18)F-FDG SPECT using acipimox for the assessment of myocardial viability, followed by resting 2-dimensional echocardiography to identify dysfunctional myocardial tissue. The image quality was scored visually and quantitatively; the myocardium-to-background ratio was determined by region-of-interest analysis. The plasma concentrations of glucose and free fatty acids were determined to evaluate the metabolic conditions before and during (18)F-FDG imaging.. Thirty-four patients had diabetes mellitus; of these, 12 had insulin-dependent diabetes mellitus and 22 had non-insulin-dependent diabetes mellitus. The remaining 36 patients had no diabetes. During (18)F-FDG SPECT, no severe side effects occurred. Acipimox significantly lowered plasma levels of free fatty acids in both groups. Fifteen of 34 patients with diabetes had a plasma glucose level > 9 mmol/L, which was lowered successfully in all patients with additional insulin. Visual evaluation of the (18)F-FDG images showed good, moderate, and poor image quality in 27, 5, and 2 patients, respectively, with diabetes mellitus and in 32, 4, and 0 patients, respectively, without diabetes (P = not statistically significant). The myocardium-to-background ratio of (18)F-FDG SPECT images was comparable in patients with and without diabetes mellitus (3.1 +/- 1.0 vs. 3.5 +/- 0.9, P = not statistically significant). The type of diabetes had no influence on (18)F-FDG image quality.. (18)F-FDG SPECT metabolic imaging after acipimox is safe and practical for routine assessment of viability in patients with ischemic cardiomyopathy. Image quality is good, even in patients with diabetes, although additional insulin is sometimes needed.

Topics: Blood Glucose; Coronary Artery Disease; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Feasibility Studies; Female; Fluorodeoxyglucose F18; Heart Ventricles; Humans; Male; Middle Aged; Pyrazines; Radionuclide Imaging; Radiopharmaceuticals; Ventricular Dysfunction, Left

Topics: Cross-Over Studies; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Acids, Nonesterified; Food Deprivation; Gluconeogenesis; Glucose; Glycogen; Humans; Hypolipidemic Agents; Insulin Resistance; Liver; Male; Pyrazines

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.

Topics: Area Under Curve; Blood Glucose; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Fatty Acids, Nonesterified; Female; Humans; Hypolipidemic Agents; Insulin; Leptin; Male; Middle Aged; Niacin; Pyrazines; Triglycerides

To assess the feasibility of an intensive lipid-lowering strategy in diabetic subjects pursuing target plasma lipid levels.. Patients with diabetes mellitus (DM), Type 1 or 2, with plasma lipid levels exceeding target values (LDL-cholesterol <2.6 mmol/l, triglycerides < 1.7 mmol/l, HDL-cholesterol > 0.9 mmol/l for men and > 1.1 mmol/l for women) were eligible. After 6-12 weeks of diet and glycaemic control, lipid-lowering medication (simvastatin/gemfibrozil/acipimox) was prescribed in steps of incremental dosages and combinations for 30 weeks.. Of all eligible clinic patients, 25% initially responded and finally 12% were entered. Thirty-six patients with Type 1 and 59 with Type 2 DM were studied. Mean baseline lipid levels in Type 1 and Type 2 diabetic subjects were: LDL-cholesterol 3.6 and 3.7 mmol/l, triglycerides 1.7 and 2.2 mmol/l, HDL-cholesterol for men 1.1 and 1.0 mmol/l, and for women 1.4 and 1.2 mmol/l, respectively. All three target values were reached in 66% of the patients. LDL-cholesterol was reduced by 1.2 mmol/l in Type 1 and 1.3 mmol/l in Type 2 diabetic patients and triglycerides by 0.7 mmol/l and 1.1 mmol/l, respectively. HDL-cholesterol increased by 0.15 mmol/l and 0.34 mmol/l in men and women with Type 1 diabetes mellitus, respectively. The cholesterol-triglyceride ratio decreased significantly in VLDL in Type 1 diabetes and in IDL in Type 2 diabetes and increased significantly in HDL in Type 2 DM.. A minority of subjects eligible for intensive lipid lowering agreed to participate in a feasibility study, suggesting a potentially large compliance problem for a general lipid-lowering programme in a diabetes clinic. Nevertheless, intensive lipid lowering with drug combinations can attain the recommended target lipid levels in 66% of subjects with diabetes. With this strategy the plasma lipoprotein composition shifts towards a less atherogenic profile. Subjects with diabetes should therefore receive lipid-lowering therapy tailored to reach target levels, rather than standard dosages, in order to reduce atherogenic risk.

Topics: Adult; Aged; Blood Glucose; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diet; Female; Gemfibrozil; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipoproteins; Male; Middle Aged; Pyrazines; Simvastatin; Triglycerides

Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from HDL to VLDL and LDL. Phospholipid transfer protein (PLTP) transfers phospholipids between lipoproteins, converts HDL3 into larger and smaller particles, and is involved in pre-beta-HDL generation. We examined the effects of 24-h hyperinsulinemia (30 mU x kg(-1) x h(-1)) and 24-h Acipimox (250 mg/4 h) on plasma lipids as well as CETP and PLTP activities (measured with exogenous substrate assays) in eight healthy and eight type 2 diabetic subjects. After 24 h of insulin, plasma free fatty acids (FFAs), HDL cholesterol, and plasma apolipoprotein AI decreased in healthy subjects and type 2 diabetic patients (P < 0.05). Plasma triglycerides did not significantly change in either group. After 24 h of Acipimox, all parameters, including plasma triglycerides, decreased in both groups (P < 0.05). Insulin decreased plasma PLTP activity by 17.6% after 24 h in healthy subjects (P < 0.05) and 10.2% in diabetic patients (P < 0.05 vs. baseline; P < 0.05 vs. healthy subjects). Acipimox lowered PLTP activity by 10.3% in healthy subjects (P < 0.05) and 11.3% in diabetic patients (P < 0.05). When insulin was infused for 3 h after Acipimox, a further decrease was found only in healthy subjects. Plasma CETP activity decreased by 9.5% after 24 h of insulin in healthy subjects (P < 0.05), but not in diabetic patients. Acipimox did not decrease plasma CETP activity in either group. In healthy subjects, the PLTP responses with insulin and Acipimox were larger than the changes in CETP activity (P < 0.05). These findings suggest that there is a metabolic link between the regulation of plasma FFA and PLTP, but not CETP. The PLTP response to insulin is blunted in type 2 diabetes.

Topics: Adult; Carrier Proteins; Cholesterol Ester Transfer Proteins; Diabetes Mellitus, Type 2; Glycoproteins; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Lipids; Male; Membrane Proteins; Middle Aged; Phospholipid Transfer Proteins; Pyrazines; Reference Values; Time Factors

Elevated circulating plasma nonesterified fatty acids (NEFA) may contribute to the insulin resistance and hyperglycemia of non-insulin-dependent diabetes mellitus (NIDDM), and decreasing plasma NEFA could provide a therapeutic benefit. A sustained-release preparation of acipimox, a lipolysis inhibitor, was used in an attempt to decrease circulating plasma NEFA levels long-term, and the effects on glycemic control, insulin resistance, and serum lipids were measured. Sixty NIDDM patients (43 males and 17 females) took part in a randomized controlled trial of acipimox or placebo for 12 weeks. Fasting plasma NEFA levels did not change in acipimox-treated patients (baseline v 12 weeks, 0.84 +/- 0.35 v 0.88 +/- 0.55 mmol x L(-1), mean +/- SD). Fasting blood glucose was unchanged (mean difference v placebo, -0.5 mmol x L(-1); 95% confidence interval [CI], -1.4 to 0.3 mmol x L[-1]), but serum fructosamine decreased (mean difference v placebo, -26 micromol x L(-1); 95% CI, -51 to 0 mmol x L[-1]), as did the standardized hemoglobin A1 ([HbA1] mean difference v placebo, -1.4%; 95% CI, -3.0% to -0.1%). Insulin resistance measured as steady-state plasma glucose during an insulin-dextrose infusion test was unchanged (mean difference v placebo, -1.4 mmol x L(-1); 95% CI, -3.2 to 0.5 mmol x L[-1]). Serum total cholesterol (mean difference v placebo, -0.4 mmol x L(-1); 95% CI, -0.6 to -0.1 mmol x L[-1]), serum apolipoprotein B ([apo B] mean difference v placebo, -0.19 g x L(-1); 95% CI, -0.3 to -0.1 g x L[-1]), and serum triglycerides (mean difference v placebo for pretreatment v posttreatment ratio, 0.59; 95% CI, 0.40 to 0.88) were all lower with acipimox. Serum high-density lipoprotein (HDL) cholesterol (mean difference v placebo, 0.10 mmol x L(-1); 95% CI, -0.05 to 0.3 mmol x L[-1]), serum apo A1 (mean difference v placebo, 0.03 g x L(-1); 95% CI, -0.04 to 0.1 g x L[-1]), and serum lipoprotein(a) ([Lp(a)] acipimox v placebo, 154 (0 to 1,574) v 71 (0 to 1,009), median and range) were unchanged. Despite the lack of change in fasting plasma NEFA levels, acipimox caused a modest beneficial improvement in overall glycemic control and plasma lipids in NIDDM patients and could be a useful agent in the treatment of dyslipidemic NIDDM patients.

Topics: Apolipoprotein A-I; Apolipoproteins B; Blood Glucose; Cholesterol; Delayed-Action Preparations; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Fatty Acids, Nonesterified; Female; Humans; Hyperlipidemias; Hypolipidemic Agents; Insulin; Male; Placebos; Pyrazines; Triglycerides

Studies have shown that a high plasma non-esterified fatty acid concentration may inhibit glucose induced insulin secretion in vitro and in vivo. The effect of lowering the fatty acid concentration on the acute insulin response was investigated in first degree relatives of people with Type II diabetes in a double-blind, randomised, placebo-controlled trial. Fifty first degree relatives of people with Type II diabetes volunteered for the study. Twenty five were given acipimox (250 mg/day, four times daily) and 25 placebo. The group treated with acipimox had a lower 2-h plasma glucose concentration (6.1 +/- 0.2 vs 7.7 +/- 0.3 vs mmol/l, p < 0.01); better insulin-mediated glucose uptake (35.4 +/- 0.5 vs 28.3 +/- 0.4 mumol/kg fat free mass per min, p < 0.01), acute insulin response (68 +/- 4.4 vs 46 +/- 7.3 mU/l, p < 0.01) and respiratory quotient (0.81 +/- 0.02 vs 0.77 +/- 0.03, p < 0.05); and a rise in the plasma glucagon (164 +/- 63 vs 134 +/- 72 ng/1, p < 0.05), growth hormone (1.31 +/- 0.13 vs 0.97 +/- 0.21 microgram/l, p < 0.03) and cortisol (325 +/- 41 vs 284 +/- 139 nmol/l, p < 0.05) concentrations. The difference in the acute insulin response persisted, even after adjustment for the 2-h plasma glucose concentration, insulin-mediated glucose uptake, the fasting plasma glucagon concentration and the growth hormone concentration (p < 0.05). In a subgroup of eight patients acipimox was compared with acipimox plus intralipid. The acute insulin response (44 +/- 5.1 vs 71 +/- 5.3 mU/l, p < 0.01) and the insulin-mediated glucose uptake (27.4 +/- 0.4 vs 36.7 +/- 0.5 mumol/kg fat free mass per min, p < 0.003) were lower with acipimox plus intralipid treatment than with acipimox alone. It is concluded that long term acipimox treatment lowers the plasma fasting free fatty acid concentration and improves the acute insulin response and the insulin mediated glucose uptake.

Topics: Adult; Blood Glucose; Body Composition; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Human Growth Hormone; Humans; Hydrocortisone; Hypolipidemic Agents; Insulin; Insulin Secretion; Male; Middle Aged; Oxygen Consumption; Placebos; Pyrazines

In type 2 diabetes, it is not uncommon to find an elevated serum triglyceride and/or reduced high-density lipoprotein (HDL) cholesterol levels; elevated total cholesterol levels often occur as well. To evaluate the short-term efficacy and tolerability of combination therapy with lovastatin and acipimox in Chinese patients with type 2 diabetes who have mixed dyslipidemia, an open-label 6-month trial was conducted. All patients had type 2 diabetes (n = 33) with total cholesterol > or = 6.2 mmol/L and fasting triglyceride > or = 2.8 mmol/L, which had been confirmed twice and persisted for at least 12 weeks after introduction of diet control. After a 4-week run-in period, they were given lovastatin 40 mg daily at night for 12 weeks. Acipimox 250 mg three times a day was then added for a further 12 weeks. After 12 weeks of treatment with lovastatin alone, improvement was observed in total cholesterol (21% reduction), triglyceride (32% reduction), low-density lipoprotein (LDL) cholesterol (5.5% reduction), HDL cholesterol (11.6% elevation), apolipoprotein A-I (4.6% elevation), and apolipoprotein B (20.5% reduction). The addition of acipimox to lovastatin for an additional 12 weeks further reduced serum total cholesterol, triglyceride, LDL cholesterol, and apolipoprotein B, but this additional decrease was not statistically significant. However, HDL cholesterol and apolipoprotein A-I levels were significantly increased by the addition of acipimox (a 14.2% and 9.0% elevation, respectively). Serum creatine phosphokinase increased slightly after 12 weeks of lovastatin but decreased to a concentration similar to baseline after 12 weeks of combination treatment. No patients reported muscle pain or weakness or other side effects. Combination treatment with lovastatin and acipimox appears to be a safe and effective therapy in patients with type 2 diabetes and mixed dyslipidemia, and has particular benefit in elevating serum HDL cholesterol and apolipoprotein A-I levels.

Topics: Adult; Aged; Anticholesteremic Agents; China; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Humans; Hyperlipidemias; Hypolipidemic Agents; Lovastatin; Male; Middle Aged; Pyrazines

To obtain optimal image quality in myocardial viability studies, it is recommended that 18F-fluordeoxyglucose (18F-FDG) studies be performed with hyperinsulinaemic glucose clamping. 18F-FDG imaging after oral administration of acipimox, a nicotinic acid derivative, results in comparable image quality to clamping. Twenty consecutive patients (7 with diabetes mellitus) with angiographically confirmed coronary artery disease and similar demographic/clinical profiles were randomly allocated to gated cardiac 18F-FDG-PET with a standard euglycaemic hyperinsulinaemic clamp protocol or using a combination of oral administration of acipimox and the insulin clamp technique. The image quality, expressed as the myocardial-to-blood pool activity ratio, was superior in the combined protocol compared with the insulin clamping technique alone (3.37 +/- 1.46 vs 2.27 +/- 0.62, P = 0.037). Although there were no significant differences in plasma insulin and free fatty acids concentrations between the two protocols, plasma glucose concentrations obtained with the standard protocol were elevated compared with the combined protocol (11.1 +/- 3.7 vs 6.3 +/- 3.0 mM during clamping; 10.2 +/- 3.3 vs 5.5 +/- 3.0 mM during acquisition). We conclude that gated 18F-FDG-PET imaging after oral administration of acipimox plus insulin clamping yields image quality superior to that obtained with clamping alone.

Topics: Administration, Oral; Coronary Disease; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Fluorodeoxyglucose F18; Glucose Clamp Technique; Heart; Humans; Hyperinsulinism; Hypolipidemic Agents; Infusions, Intravenous; Insulin; Male; Middle Aged; Pyrazines; Radiopharmaceuticals; Reproducibility of Results; Tomography, Emission-Computed

Hyperlipidemia, hypertriglyceridemia in particular, is a common feature in patients with noninsulin dependent diabetes mellitus (NIDDM) and may associate with insulin insensitivity. Acipimox, being widely prescribed for treating hypertriglyceridemia, is also used in NIDDM patients for their dyslipidemia. In the present study, we evaluated the effect of acipimox in Chinese NIDDM patients with hypertriglyceridemia. A total of 16 patients enrolled in a double-blind, randomized, placebo-controlled and two-period crossover study. After an 8 week run-in period, patients were randomly assigned into two groups receiving either acipimox (250 mg, twice daily) or placebo treatment. A total of 12 weeks later, these two groups switched their treatment for an additional 12 weeks. Blood samples were collected at the end of the run-in period and then at 4-week intervals in the whole study for lipid profile. A modified insulin suppression test was performed at the ends of the run-in period, 12-week and 24-week treatment to assess changes in insulin sensitivity. Our results showed that acipimox significantly lowered serum total triglyceride while compared to those by placebo. However, no difference was observed in serum non-esterified fatty acid, low-density lipoprotein cholesterol, total cholesterol (TC), high density lipoprotein-cholesterol (HDL-C) and HDL-C/ TC ratio between the two groups. Furthermore, glycemic indices and insulin sensitivity were similar during the base-line, placebo or acipimox periods. Taken together, our data suggest that acipimox significantly lowered TG without perturbation of insulin sensitivity in hypertriglyceridemic NIDDM patients.

Topics: Adult; Aged; Apolipoprotein A-I; Apolipoproteins B; Diabetes Mellitus, Type 2; Female; Glycated Hemoglobin; Humans; Hyperlipidemias; Hypertriglyceridemia; Hypolipidemic Agents; Insulin; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Pyrazines; Triglycerides

The aim of the study was to evaluate an acute decrease in NEFA levels during an oral glucose tolerance test and its effects on glucose tolerance, muscle glucose uptake and muscle indirect calorimetry in ten lean non-insulin-dependent diabetic subjects. Two 75-g oral glucose tolerance tests were performed in random order. Placebo or 250 mg acipimox (to inhibit lipolysis) were administered orally 2 h before the start of the oral glucose tolerance test. Two hours after acipimox administration (time 0), non-esterified fatty acid, glycerol and 3-hydroxybutyrate levels decreased by 84, 68 and 77% respectively, compared to basal levels. Concomitantly, muscle lipid oxidation and non-oxidative glycolysis also decreased significantly. After placebo administration, non-esterified fatty acids, glycerol and 3-hydroxybutyrate and lipid oxidation increased by 29, 28, 106 and 33%, respectively (NS vs basal levels; p < 0.001 vs acipimox). There was a negative rate of net glucose storage (interpreted as glycogenolysis) during post-absorptive conditions and at time 0 after administration of both drugs. After oral glucose tolerance test, the incremental areas of blood glucose and insulin were significantly decreased by 18 and 19% after acipimox compared to placebo. In addition, the ratio between the incremental area of forearm muscle glucose uptake and the insulin levels was significantly increased by 45% during acipimox compared to placebo administration. Glucose oxidation and non-oxidative glycolysis were significantly higher while lipid oxidation was significantly lower after acipimox than after placebo. In conclusion, our study found that in lean non-insulin-dependent diabetic subjects, an acute decrease in non-esterified fatty acid levels improves glucose tolerance, muscle glucose uptake, glucose oxidation and non-oxidative glycolysis, but is unable to normalize glucose storage.

Topics: 3-Hydroxybutyric Acid; Blood Glucose; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Forearm; Glucose; Glucose Tolerance Test; Glycerol; Glycogen; Humans; Hydroxybutyrates; Hypolipidemic Agents; Kinetics; Middle Aged; Muscle, Skeletal; Pyrazines; Regional Blood Flow; Thinness; Time Factors

Patients with Type 2 diabetes are at increased risk from macrovascular disease whether or not they are hyperlipidaemic. Several factors may contribute to this increased risk including abnormalities of lipoprotein composition. The aim of our study was to determine the effects of lipid lowering drugs on lipoprotein composition (lipoprotein fractions were separated by sequential flotation ultracentrifugation) and insulin sensitivity (measured by a modified Harano technique) in 44 patients with mild hyperlipidaemia. All patients had total cholesterol concentrations between 5.2 and 6.5 mmol l-1 and total triglyceride concentrations < 3.0 mmol l-1, and were randomized by minimization to receive treatment for 12 weeks with bezafibrate, acipimox, simvastatin or placebo. Total cholesterol concentrations were decreased by simvastatin, 5.7 +/- 0.4 to 3.7 +/- 0.6 mmol l-1 (p < 0.05), due mainly to reduced LDL-cholesterol levels (-1.25 mmol l-1; p < 0.05), and bezafibrate 5.7 +/- 0.6 to 4.6 +/- 0.4 mmol l-1 (p < 0.05). The LDL:HDL-cholesterol ratio was reduced in the simvastatin group 2.0 +/- 0.5 to 1.2 +/- 0.3 (p < 0.005). There was no effect of the drugs on glycated haemoglobin or insulin sensitivity. In conclusion bezafibrate and simvastatin improve the lipid profile in Type 2 diabetic patients without adversely affecting diabetic control.

Topics: Apolipoproteins B; Bezafibrate; Blood Glucose; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Humans; Hyperlipidemias; Hypolipidemic Agents; Lovastatin; Middle Aged; Phospholipids; Placebos; Pyrazines; Simvastatin; Triglycerides

Acute administration of the antilipolytic nicotinic acid analog acipimox to patients with noninsulin-dependent diabetes mellitus (NIDDM) is associated with increased peripheral and hepatic insulin sensitivity. However, long term acipimox treatment (250 mg, 3 times/24 h) of NIDDM patients does not improve blood glucose control, possibly due to rebound lipolysis. The current study assessed the influence of intensified acipimox administration (125 mg, 12 times/24 h) on diurnal plasma profiles of glucose, insulin, nonesterified FFA (NEFA), and triglycerides during a 3-day period. Eight NIDDM patients [mean age, 58.9 yr (range, 46-68); mean body mass index, 31.4 kg/m2 (range, 24.9-39.6)] were included in a randomized, double blind, placebo-controlled, cross-over study. Blood samples were collected every second hour during the study. The acipimox and placebo treatments were separated by a 2-week washout period. Acipimox treatment was associated with reduced diurnal mean plasma concentrations of NEFA [0.26 +/- 0.03 (+/- SEM) vs. 0.63 +/- 0.06 mmol/L; P < 0.001], triglycerides (1.74 +/- 0.21 vs. 2.10 +/- 0.18 mmol/L; P < 0.03), glucose (12.7 +/- 1.0 vs. 15.8 +/- 1.2 mmol/L; P < 0.002), and insulin (157 +/- 21 vs. 207 +/- 27 pmol/L; P < 0.05). However, despite the overall reduction in mean NEFA, during acipimox treatment NEFA increased from days 1-3 (0.18 +/- 0.03 vs. 0.34 +/- 0.04 mmol/L; P < 0.001), whereas plasma glucose (13.4 +/- 1.2 vs. 12.3 +/- 0.9 mmol/L; P < 0.03) and plasma insulin (168 +/- 23 vs. 148 +/- 17 pmol/L; P < 0.04) decreased steadily from days 1-3 during active treatment. In conclusion, inhibition of lipolysis using the intensified acipimox treatment regiment was associated with a pronounced blood glucose- and plasma insulin-lowering effect. However, minor rebound effects of lipolysis occurred in some patients despite the presence of allegedly effective acipimox levels. This suggests that caution should be employed concerning long term use of acipimox as a hypoglycemic agent in NIDDM patients.

Topics: Blood Glucose; Blood Pressure; Cholesterol; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypolipidemic Agents; Insulin; Lactates; Lactic Acid; Male; Middle Aged; Osmolar Concentration; Placebos; Pyrazines; Time Factors

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)

Topics: Analysis of Variance; Blood Glucose; Carbon Radioisotopes; Diabetes Mellitus, Type 2; Double-Blind Method; Fatty Acids, Nonesterified; Glucagon; Gluconeogenesis; Growth Hormone; Humans; Hydrocortisone; Hypolipidemic Agents; Lactates; Lipolysis; Liver; Male; Middle Aged; Oxygen Consumption; Pyrazines; Tritium

To study the tolerability and efficacy of acipimox on hyperlipidemia and diabetes compensation in patients with NIDDM under conditions of a routine clinical practice.. We recruited 121 patients (60 men and 61 women) from 10 participating clinical centers. They were randomly divided into two groups and treated for 3 mo either with acipimox (250 mg three times a day) or placebo, using an open study design.. Acipimox treatment led to a significant drop in fasting serum total triglyceride levels (by 28%) after 1 mo of drug administration. This decrease prevailed up to the end of the 3-mo study. Serum total cholesterol levels declined by 14%, and high-density lipoprotein tended to rise in acipimox-treated patients. These changes in lipid metabolism were not accompanied by any adverse effects of acipimox on glucose metabolism as judged by HbA1c measurements and the oral glucose tolerance test. Eight patients (out of 82 treated with acipimox) reported moderate adverse events of transient character, such as skin reactions and gastric disturbances.. Acipimox seems to be a useful agent for treatment of diabetic dyslipidemia and does not deteriorate glycemic control.

Topics: Blood Glucose; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glycated Hemoglobin; Humans; Hyperlipoproteinemias; Hypolipidemic Agents; Insulin; Lipids; Lipoproteins; Male; Middle Aged; Pyrazines; Triglycerides

To examine whether overnight suppression of free fatty acid levels reduces hepatic glucose production, 20 NIDDM patients were given a slow-release formulation of the antilipolytic agent acipimox, in a double-blind crossover manner at bedtime for 4 wk. During acipimox treatment, serum free fatty acid concentrations were suppressed between 2400 and 0600 by 64% (P < 0.001), but no reduction in hepatic glucose production was observed (2.16 +/- 0.16 vs. 2.23 +/- 0.16 mg.kg-1 x min-1, acipimox vs. placebo). In contrast, from 0800 to 2000 a sustained 50% rise occurred in serum free fatty acids (P < 0.001). As a consequence, the 24-h area under the free fatty acid curve was similar during both treatment periods. In the morning, the rise in free fatty acid concentration occurred despite identical serum acipimox concentrations as those measured at midnight, when free fatty acid levels were suppressed. Although energy expenditure was higher (P < 0.05) during periods of elevated free fatty acid levels, the sums of energy expenditure measured in the morning and in the evening were similar during the acipimox and placebo periods. To exclude that the free fatty acid rise was caused by administration of acipimox only once at bedtime, additional experiments were performed administering acipimox every 2 h for 4 days. Despite similar acipimox concentration on day 1 and day 4 of this frequent dosing regimen, the free fatty acid concentrations were significantly higher on day 4 compared with day 1 (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; Calorimetry; Chromatography, High Pressure Liquid; Circadian Rhythm; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Fatty Acids, Nonesterified; Female; Glucagon; Glucose; Glycerol; Growth Hormone; Humans; Hydrocortisone; Hypolipidemic Agents; Insulin; Liver; Male; Middle Aged; Pyrazines; Time Factors

Elevated fasting plasma non-esterified fatty acid (NEFA) levels have been reported in Type 2 diabetes. We examined whether such changes persist during low-grade exercise and influence carbohydrate metabolism. Eight Type 2 diabetic patients with moderate glycaemic control and eight healthy controls received the anti-lipolytic agent, acipimox, or placebo on separate occasions before exercising for 45 min at 35% pre-determined VO2max. Fasting plasma NEFA levels were similar (0.40 +/- 0.06 (SEM) and 0.45 +/- 0.05 mmol l-1; healthy and Type 2 diabetic subjects) following placebo, and increased to comparable levels with exercise (0.73 +/- 0.07 and 0.73 +/- 0.10 mmol l-1). Acipimox lowered basal NEFA levels (0.14 +/- 0.03 and 0.28 +/- 0.04 mmol l-1; both p < 0.05 vs placebo), and prevented the rise with exercise. Blood glucose (p < 0.001) and serum insulin (p < 0.01) levels were higher in the Type 2 diabetic patients (vs controls) for both treatments. Whole body lipid oxidation increased from baseline to a comparable degree with exercise following placebo (3.2 +/- 0.3 and 2.8 +/- 0.3 mg kg-1 min-1; healthy and Type 2 diabetic subjects, both p < 0.02). Although less marked, the same was also observed following acipimox (2.0 +/- 0.4 and 2.1 +/- 0.5 mg kg-1 min-1; both p < 0.05). Carbohydrate oxidation increased with exercise in both subject groups, but with no significant difference between the treatments. Thus, the metabolic response to low-grade exercise was normal in Type 2 diabetic patients with moderate glycaemic control, but occurred against a background of hyperinsulinaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3-Hydroxybutyric Acid; Blood Glucose; C-Peptide; Calorimetry; Carbon Dioxide; Diabetes Mellitus, Type 2; Energy Metabolism; Exercise; Fatty Acids, Nonesterified; Female; Glucagon; Glycerol; Growth Hormone; Humans; Hydroxybutyrates; Hypolipidemic Agents; Insulin; Lactates; Male; Middle Aged; Nitrogen; Oxygen Consumption; Pyrazines; Reference Values

The short-term administration of a nicotinic acid analogue (acipimox) increases insulin sensitivity and consequently glucose disposal, both in patients with non-insulin-dependent diabetes mellitus (NIDDM) and in patients with cirrhosis. This effect has been attributed to a decrease in plasma nonesterified fatty acid (NEFA) levels and fatty acid oxidation rates, and a corresponding increase in carbohydrate oxidation. The aim of the present study was to determine whether acipimox influenced glucose disposal independent of changes in lipid metabolism. Seven normal men (age, 31 +/- 4 years; body mass index, 23.2 +/- 1.8 kg.m-2; fat-free mass [FFM], 66.8 +/- 4.2 kg) were studied on two separate occasions with hyperinsulinemic (0.06 U.kg FFM-1.h-1) euglycemic clamps (duration, 150 minutes). A primed (150 U), continuous (0.4 U.kg-1.min-1) infusion of heparin together with 10% intralipid (25 mL.h-1) was infused in both studies from -90 to 150 minutes to maintain comparable levels of plasma NEFA and lipid oxidation rates. Acipimox (500-mg capsules) or placebo were administered orally in a double-blind random fashion at t = -90 and t = 0 minutes. Whole-body lipid and carbohydrate oxidation were measured in the last 30 minutes of both the basal (preclamp) period (-30 to 0 minutes) and the clamp period (120 to 150 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Alanine; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Fatty Acids, Nonesterified; Glucagon; Glucose; Glycerol; Growth Hormone; Humans; Hydroxybutyrates; Hypolipidemic Agents; Insulin; Lactates; Lipid Metabolism; Male; Oxidation-Reduction; Pyrazines; Pyruvates; Radioimmunoassay; Time Factors

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)

Topics: 3-Hydroxybutyric Acid; Acetoacetates; Blood Glucose; Calorimetry, Indirect; Diabetes Mellitus, Type 2; Exercise; Fatty Acids, Nonesterified; Glycerol; Growth Hormone; Heparin; Humans; Hydroxybutyrates; Hypolipidemic Agents; Insulin; Ketone Bodies; Male; Middle Aged; Norepinephrine; Pyrazines; Triglycerides

Plasma nonesterified fatty acid (NEFA) levels are increased in the insulin-stimulated state in non-insulin-dependent diabetes mellitus (NIDDM) and may contribute to the decrease in peripheral and hepatic insulin sensitivity. To test this hypothesis and to avoid the confounding effect of obesity, we examined the effect of decreasing plasma NEFA levels on peripheral and total glucose metabolism in eight non-obese, NIDDM patients. Each received 250 mg Acipimox (a nicotinic acid analogue) or placebo at 0 and 120 minutes on separate occasions. [6,6-2H2]-glucose (0 to 300 minutes) and insulin (120 to 300 minutes) were infused in each study, and isoglycemia was maintained. Plasma NEFA levels (140 +/- 30 v 600 +/- 70 mumol/L [SEM]; P < .001) and forearm NEFA uptake measured with [1-14C]-palmitate (+93 +/- 21 v +313 +/- 42 nmol x 100 mL forearm-1; P < .001) were decreased with acipimox during the basal period (90 to 120 minutes), with no change in forearm glucose uptake (+334 +/- 80 and +330 +/- 60 nmol x 100 mL forearm-1 x min-1) and hepatic glucose output ([HGO] 13.6 +/- 0.9 and 13.4 +/- 0.7 mumol.kg-1 x min-1). Serum insulin (256 +/- 12 and 266 +/- 18 pmol/L) and plasma glucose (9.5 +/- 0.6 and 9.4 +/- 0.5 mmol/L) levels were comparable during the clamp period (270 to 300 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Forearm; Glucose; Hormones; Humans; Hypolipidemic Agents; Insulin; Liver; Male; Middle Aged; Osmolar Concentration; Pyrazines

1. Increased rates of fatty acid oxidation are frequently observed in patients with non-insulin-dependent diabetes mellitus and may contribute to hyperglycaemia by both decreasing peripheral glucose disposal and, more importantly, by increasing the rate of gluconeogenesis and therefore hepatic glucose output. Despite this relationship between lipid and carbohydrate metabolism, fasting glucose concentrations do not fall acutely in patients with non-insulin-dependent diabetes mellitus when plasma non-esterified fatty acid concentrations and lipid oxidation rates are decreased, questioning the importance of this interaction to glycaemic control. We have therefore measured the acute changes that occur 120-150 min after administration of 500 mg of the antilipolytic agent acipimox in eight non-obese male patients with non-insulin-dependent diabetes mellitus. 2. After administration of acipimox, lipolysis was inhibited as reflected by lower plasma non-esterified fatty acid (0.05 +/- 0.02 versus 0.55 +/- 0.05 mmol/l, P less than 0.001) and blood glycerol (8 +/- 1 versus 56 +/- 8 mumol/l, P less than 0.001) concentrations. The lipid oxidation rate was decreased (0.63 +/- 0.05 versus 1.02 +/- 0.08 mg min-1 kg-1, P less than 0.001), whereas there was a significant increase in the carbohydrate oxidation rate (1.93 +/- 0.17 versus 1.22 +/- 0.18 mg min-1 kg-1, P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 3-Hydroxybutyric Acid; Blood Glucose; Diabetes Mellitus, Type 2; Epinephrine; Fatty Acids, Nonesterified; Glucagon; Glycerol; Humans; Hydrocortisone; Hydroxybutyrates; Hypolipidemic Agents; Lipolysis; Male; Middle Aged; Norepinephrine; Pyrazines

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)

Topics: 3-Hydroxybutyric Acid; Alanine; Blood Glucose; Cholesterol; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Glycerol; Humans; Hydroxybutyrates; Hypolipidemic Agents; Insulin; Lactates; Male; Middle Aged; Obesity; Pyrazines; Pyruvates; Triglycerides

The effect of prolonged treatment with Acipimox on in vivo peripheral insulin sensitivity, and on glucose and lipid metabolism, was investigated in patients with NIDDM in a double-blind study. Twelve NIDDM patients were randomized to treatment with either placebo or Acipimox in pharmacological doses (250 mg x 3) for three months. Fasting plasma glucose, insulin, C-peptide and HbA1c concentrations were unaffected after three months of acipimox treatment. However, fasting plasma non-esterified fatty acid (NEFA) concentrations were twofold elevated after Acipimox treatment (1.34 +/- 0.09 vs 0.66 +/- 0.09 mmol/l; p < 0.05). Despite this, repeated acute Acipimox administration after the three months' treatment period enhanced total insulin-stimulated glucose disposal to the same extent as acute Acipimox administration before the treatment period (367 +/- 59 vs 392 +/- 66 mg.m-2.min-1, NS; both p < 0.05 vs placebo glucose disposal) (267 +/- 44 mg.m-2.min-1). In conclusion, insulin resistance or tachyphylaxis towards the effects of Acipimox on insulin stimulated glucose disposal was not induced during prolonged Acipimox treatment. The lack of improvement of blood glucose control in the patients with NIDDM may be due to the demonstrated rebound effect of lipolysis.

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Energy Metabolism; Female; Glucose; Glucose Clamp Technique; Humans; Hypolipidemic Agents; Insulin; Insulin Resistance; Lipid Metabolism; Male; Middle Aged; Pyrazines; Time Factors

Hyperlipidaemia, in particular raised concentrations of serum triglycerides, together with raised plasma non-esterified fatty acid concentrations, is common in patients with Type 2 (non-insulin-dependent) diabetes mellitus and may be associated with insulin insensitivity. Thirty non-obese Type 2 diabetic patients (15 controlled with diet alone and 15 with diet plus oral sulphonylurea therapy) were therefore recruited to take part in a double-blind, randomized, crossover comparison of acipimox (250 mg three times daily for 3 months) and placebo. Serum lipids, blood glucose control, insulin sensitivity, and glucose tolerance were measured before and after each treatment period. There was a significant decrease in serum triglycerides (2.05 +/- 1.08 vs 2.91 +/- 1.75: p < 0.005), cholesterol (5.66 +/- 1.02 vs 6.26 +/- 1.17: p = 0.0005), and apoprotein B (1.32 +/- 0.23 vs 1.44 +/- 0.25: p < 0.05) while HDL cholesterol and apoprotein A-1 concentrations were unchanged. There was no change in blood glucose control measured by fasting glucose, insulin, and HBA, concentrations, but there was a significant improvement in insulin action assessed by glucose-insulin infusion. Although plasma non-esterified fatty acid concentrations were lower during the oral glucose tolerance test after acipimox, there was no difference in either the peak or 2-h plasma glucose concentrations and the total area under the glucose curve did not change. Acipimox was well tolerated and no patients withdrew from the study for drug-related symptoms. Thus, acipimox effectively lowers serum cholesterol and triglycerides in patients with Type 2 diabetes without adversely altering blood glucose control, and appears to improve insulin sensitivity.

Topics: Analysis of Variance; Apolipoprotein A-I; Apolipoproteins B; Blood Glucose; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 2; Diet, Diabetic; Double-Blind Method; Female; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Insulin; Lipids; Male; Middle Aged; Pyrazines; Triglycerides

The objective of this work was to test in type II diabetics with hyperlipoproteinaemia the action of a new analogue of nicotinic acid--Acipimox (Olbetam, Farmitalia Carlo Erba). The investigation comprised 24 patients of whom 16 took for three months Olbetam (250 mg 3 x per day by the oral route) and 8 patients were given placebo. The investigated biochemical parameters were examined before administration of the preparation was started and 4 and 12 weeks following its administration. Contrary to the group taking placebo, in the group taking Olbetam a significant decline of the triglyceride serum level occurred and a slight decline of total serum cholesterol levels and increase of HDL-cholesterol and the atherogenic risk indexes were thus more favourable. The results indicate that Olbetam is a satisfactory hypolipidemic agent for the treatment of diabetic hyperlipoproteinaemia.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Female; Humans; Hyperlipoproteinemias; Hypolipidemic Agents; Lipids; Male; Middle Aged; Pyrazines

Insulin resistance and dysregulation of free fatty acid (FFA) metabolism are core defects in type 2 diabetic (T2DM) and obese normal glucose tolerant (NGT) individuals. Impaired muscle mitochondrial function (reduced ATP synthesis) also has been described in insulin-resistant T2DM and obese subjects. We examined whether reduction in plasma FFA concentration with acipimox improved ATP synthesis rate and altered reactive oxygen species (ROS) production. Eleven NGT obese and 11 T2DM subjects received 1) OGTT, 2) euglycemic insulin clamp with muscle biopsy, and 3) (1)H-magnetic resonance spectroscopy of tibialis anterior muscle before and after acipimox (250 mg every 6 h for 12 days). ATP synthesis rate and ROS generation were measured in mitochondria isolated from muscle tissue ex vivo with chemoluminescence and fluorescence techniques, respectively. Acipimox 1) markedly reduced the fasting plasma FFA concentration and enhanced suppression of plasma FFA during oral glucose tolerance tests and insulin clamp in obese NGT and T2DM subjects and 2) enhanced insulin-mediated muscle glucose disposal and suppression of hepatic glucose production. The improvement in insulin sensitivity was closely correlated with the decrease in plasma FFA in obese NGT (r = 0.81) and T2DM (r = 0.76) subjects (both P < 0.001). Mitochondrial ATP synthesis rate increased by >50% in both obese NGT and T2DM subjects and was strongly correlated with the decrease in plasma FFA and increase in insulin-mediated glucose disposal (both r > 0.70, P < 0.001). Production of ROS did not change after acipimox. Reduction in plasma FFA in obese NGT and T2DM individuals improves mitochondrial ATP synthesis rate, indicating that the mitochondrial defect in insulin-resistant individuals is, at least in part, reversible.

Topics: Adult; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose; Humans; Hypolipidemic Agents; Insulin Resistance; Liver; Male; Middle Aged; Mitochondria; Obesity; Pyrazines; Reactive Oxygen Species

Topics: Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Humans; Insulin Resistance; Male; Mitochondria; Obesity; Pyrazines

Free fatty acids (FFAs) have been implicated in the pathogenesis of insulin resistance. Reducing plasma FFA concentration in obese and type 2 diabetic (T2DM) subjects improves insulin sensitivity. However, the molecular mechanism by which FFA reduction improves insulin sensitivity in human subjects is not fully understood. In the present study, we tested the hypothesis that pharmacological FFA reduction enhances insulin action by reducing local (muscle) inflammation, leading to improved insulin signalling. Insulin-stimulated total glucose disposal (TGD), plasma FFA species, muscle insulin signalling, IBα protein, c-Jun phosphorylation, inflammatory gene (toll-like receptor 4 and monocyte chemotactic protein 1) expression, and ceramide and diacylglycerol (DAG) content were measured in muscle from a group of obese and T2DM subjects before and after administration of the antilipolytic drug acipimox for 7 days, and the results were compared to lean individuals. We found that obese and T2DM subjects had elevated saturated and unsaturated FFAs in plasma, and acipimox reduced all FFA species. Acipimox-induced reductions in plasma FFAs improved TGD and insulin signalling in obese and T2DM subjects. Acipimox increased IBα protein (an indication of decreased IB kinase-nuclear factor B signalling) in both obese and T2DM subjects, but did not affect c-Jun phosphorylation in any group. Acipimox also decreased inflammatory gene expression, although this reduction only occurred in T2DM subjects. Ceramide and DAG content did not change. To summarize, pharmacological FFA reduction improves insulin signalling in muscle from insulin-resistant subjects. This beneficial effect on insulin action could be related to a decrease in local inflammation. Notably, the improvements in insulin action were more pronounced in T2DM, indicating that these subjects are more susceptible to the toxic effect of FFAs.

Topics: Administration, Oral; Adult; Case-Control Studies; Ceramides; Chemokine CCL2; Diabetes Mellitus, Type 2; Diglycerides; Fatty Acids, Nonesterified; Female; Glucose; Humans; Hypolipidemic Agents; I-kappa B Kinase; Insulin; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Male; Middle Aged; Muscle, Skeletal; Obesity; Pyrazines; Signal Transduction; Toll-Like Receptor 4

Suppression of lipolysis by acipimox is known to improve insulin-stimulated glucose disposal, and this is an important phenomenon. The mechanism has been assumed to be an enhancement of glucose storage as glycogen, but no direct measurement has tested this concept or its possible relationship to the reported impairment in insulin-stimulated muscle ATP production. Isoglycaemic-hyperinsulinaemic clamps with [13C]glucose infusion were performed on Type 2 diabetic subjects and matched controls with measurement of glycogen synthesis by 13C MRS (magnetic resonance spectroscopy) of muscle. 31P saturation transfer MRS was used to quantify muscle ATP turnover rates. Glucose disposal rates were restored to near normal in diabetic subjects after acipimox (6.2 ± 0.8 compared with 4.8 ± 0.6 mg·kgffm⁻¹·min⁻¹; P<0.01; control 6.6 ± 0.5 mg·kgffm⁻¹·min⁻¹; where ffm, is fat-free mass). The increment in muscle glycogen concentration was 2-fold higher in controls compared with the diabetic group, and acipimox administration to the diabetic group did not increase this (2.0 ± 0.8 compared with 1.9 ± 1.1 mmol/l; P<0.05; control, 4.0 ± 0.8 mmol/l). ATP turnover rates did not increase during insulin stimulation in any group, but a modest decrease in the diabetes group was prevented by lowering plasma NEFAs (non-esterified fatty acids; 8.4 ± 0.7 compared with 7.1 ± 0.5 μmol·g⁻¹·min⁻¹; P<0.05; controls 8.6 ± 0.8 μmol·g⁻¹·min⁻¹). Suppression of lipolysis increases whole-body glucose uptake with no increase in the rate of glucose storage as glycogen but with increase in whole-body glucose oxidation rate. ATP turnover rate in muscle exhibits no relationship to the acute metabolic effect of insulin.

Topics: Adenosine Triphosphate; Blood Glucose; Breath Tests; Diabetes Mellitus, Type 2; Double-Blind Method; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Glycogen; Humans; Hypolipidemic Agents; Insulin; Lipolysis; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Pyrazines

Short-term caloric restriction increases plasma levels of nonesterified fatty acids (NEFAs) and is associated with increased myocardial triglyceride (TG) content and decreased myocardial function in healthy subjects. Whether this flexibility of myocardial TG stores and myocardial function is also present in patients with type 2 diabetes mellitus (T2DM) is yet unknown. Myocardial TG content and left ventricular (LV) ratio between the early (E) and atrial (A) diastolic filling phase (E/A) were determined using magnetic resonance (MR) spectroscopy and MR imaging, respectively, before and after a 3-day very low-calorie diet (VLCD) in 11 patients with T2DM. In addition, we studied patients after a 3-day VLCD combined with the antilipolytic drug acipimox. The VLCD induced myocardial TG accumulation [from 0.66 +/- 0.09% (mean +/- SE, baseline) to 0.98 +/- 0.16%, P = 0.028] and a decrease in E/A ratio [from 1.00 +/- 0.05 (baseline) to 0.90 +/- 0.06, P = 0.002]. This was associated with increased plasma NEFA levels (from 0.57 +/- 0.08 mmol/l at baseline to 0.92 +/- 0.12, P = 0.019). After the VLCD with acipimox, myocardial TG content, diastolic function, and plasma NEFA levels were similar to baseline values. In conclusion, in patients with T2DM, a VLCD increases myocardial TG content and is associated with a decrease in LV diastolic function. These effects were not observed when a VLCD was combined with acipimox, illustrating the physiological flexibility of myocardial TG stores and myocardial function in patients with T2DM.

Topics: Adipose Tissue; Blood Glucose; Blood Pressure; Caloric Restriction; Cholesterol; Diabetes Mellitus, Type 2; Diastole; Fatty Acids, Nonesterified; Glycated Hemoglobin; Heart Rate; Humans; Hypolipidemic Agents; Liver; Magnetic Resonance Imaging; Male; Middle Aged; Myocardium; Pyrazines; Triglycerides

Plasma adiponectin is associated with insulin resistance and atherosclerosis. Adiponectin expression in adipose tissue is up-regulated by peroxisome proliferator-activated receptor (PPAR)-gamma agonist treatment and its plasma level may be affected by insulin. We tested the hypothesis that prolonged exogenous insulin infusion decreases plasma adiponectin, and examined whether a possible effect of insulin on plasma adiponectin is attributable to inhibition of lipolysis.. The effect of insulin infusion on plasma adiponectin (Linco enzyme-linked immunosorbent assay) was evaluated during a 24-h moderately hyperinsulinemic clamp (8.3 microU kg(-1) s(-1)) in 8 male type 2 diabetic patients and in 8 healthy men. On a separate day, acipimox (250 mg/4 h for 24 h) was administered to inhibit lipolysis. Insulin and acipimox were administered in random order with 1 week between study days.. In type 2 diabetic patients, insulin infusion decreased plasma adiponectin from 7.74+/-2.53 mg/l to 6.76+/-2.41 mg/l after 24 h (p<0.05). In healthy subjects, the change in plasma adiponectin after 24 h of insulin was not significant (8.10+/-2.76 and 7.55+/-2.41 mg/l at baseline and after 24 h of insulin, respectively). The change in plasma adiponectin after 24 h insulin in healthy subjects was not different from the change in diabetic patients. Plasma adiponectin did not decrease after 24 h acipimox administration in either group (type 2 diabetic patients: 6.84+/-2.19 and 6.54+/-2.93 mg/l at baseline and after 24 h, respectively (NS); healthy subjects; 7.35+/-2.52 and 8.31+/-3.37 mg/l, at baseline and after 24 h, respectively (NS)). When the results from diabetic and healthy subjects were combined, the decrease in plasma adiponectin after 24 h of insulin infusion (-0.76+/-1.08 mg/l, equivalent to a -9% change from baseline, p<0.05) was different (p = 0.05) from the change after 24 h acipimox (+0.33+/-1.74 mg/l, equivalent to a +4% change from baseline). Plasma free fatty acids decreased during insulin infusion (p<0.01 for both groups after 24 h) as well as in response to acipimox (p<0.05 for healthy subjects; p<0.01 type 2 diabetic patients after 24 h). After administration of acipimox, plasma insulin did not change in either group.. Plasma adiponectin is modestly decreased during 24 h of insulin infusion. It is unlikely that this response to exogenous insulin is attributable to inhibition of lipolysis, since plasma adiponectin did not decrease after acipimox.

Topics: Adiponectin; Adult; Aged; Depression, Chemical; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucose Clamp Technique; Half-Life; Humans; Insulin; Intercellular Signaling Peptides and Proteins; Lipolysis; Male; Middle Aged; Pyrazines; Time Factors

To investigate the effect of a sustained (7-d) decrease in plasma free fatty acid (FFA) concentration in individuals genetically predisposed to develop type 2 diabetes mellitus (T2DM), we studied the effect of acipimox, a potent inhibitor of lipolysis, on insulin action and adipocytokine concentrations in eight normal glucose-tolerant subjects (aged 40 +/- 4 yr, body mass index 26.5 +/- 0.8 kg/m(2)) with at least two first-degree relatives with T2DM. Subjects received an oral glucose tolerance test (OGTT) and 120 min euglycemic insulin clamp (80 mU/m(2).min) with 3-[(3)H] glucose to quantitate rates of insulin-mediated whole-body glucose disposal (Rd) and endogenous (primarily hepatic) glucose production (EGP) before and after acipimox, 250 mg every 6 h for 7 d. Acipimox significantly reduced fasting plasma FFA (515 +/- 64 to 285 +/- 58 microm, P < 0.05) and mean plasma FFA during the OGTT (263 +/- 32 to 151 +/- 25 microm, P < 0.05); insulin-mediated suppression of plasma FFA concentration during the insulin clamp also was enhanced (162 +/- 18 to 120 +/- 15 microm, P < 0.10). Following acipimox, fasting plasma glucose (5.1 +/- 0.1 vs. 5.2 +/- 0.1 mm) did not change, whereas mean plasma glucose during the OGTT decreased (7.6 +/- 0.5 to 6.9 +/- 0.5 mm, P < 0.01) without change in mean plasma insulin concentration (402 +/- 90 to 444 +/- 102 pmol/liter). After acipimox Rd increased from 5.6 +/- 0.5 to 6.8 +/- 0.5 mg/kg.min (P < 0.01) due to an increase in insulin-stimulated nonoxidative glucose disposal (2.5 +/- 0.4 to 3.5 +/- 0.4 mg/kg.min, P < 0.05). The increment in Rd correlated closely with the decrement in fasting plasma FFA concentration (r = -0.80, P < 0.02). Basal EGP did not change after acipimox (1.9 +/- 0.1 vs. 2.0 +/- 0.1 mg/kg.min), but insulin-mediated suppression of EGP improved (0.22 +/- 0.09 to 0.01 +/- 0.01 mg/kg.min, P < 0.05). EGP during the insulin clamp correlated positively with the fasting plasma FFA concentration (r = 0.49, P = 0.06) and the mean plasma FFA concentration during the insulin clamp (r = 0.52, P < 0.05). Plasma adiponectin (7.1 +/- 1.0 to 7.2 +/- 1.1 microg/ml), resistin (4.0 +/- 0.3 to 3.8 +/- 0.3 ng/ml), IL-6 (1.4 +/- 0.3 to 1.6 +/- 0.4 pg/ml), and TNFalpha (2.3 +/- 0.3 to 2.4 +/- 0.3 pg/ml) did not change after acipimox treatment. We concluded that sustained reduction in plasma FFA concentration in subjects with a strong family history of T2DM increases peripheral (muscle) and hepatic insulin sensitivity without incre

Topics: Adiponectin; Adult; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Female; Glucose; Glucose Tolerance Test; Humans; Insulin; Intercellular Signaling Peptides and Proteins; Interleukin-6; Male; Proteins; Pyrazines; Tumor Necrosis Factor-alpha

We tested the effects of acute perturbations of elevated fatty acids (FA) on insulin secretion in type 2 diabetes. Twenty-one type 2 diabetes subjects with hypertriglyceridemia (triacylglycerol >2.2 mmol/l) and 10 age-matched nondiabetic subjects participated. Glucose-stimulated insulin secretion was monitored during hyperglycemic clamps for 120 min. An infusion of Intralipid and heparin was added during minutes 60-120. In one of two tests, the subjects ingested 250 mg of Acipimox 60 min before the hyperglycemic clamp. A third test (also with Acipimox) was performed in 17 of the diabetic subjects after 3 days of a low-fat diet. Acipimox lowered FA levels and enhanced insulin sensitivity in nondiabetic and diabetic subjects alike. Acipimox administration failed to affect insulin secretion rates in nondiabetic subjects and in the group of diabetic subjects as a whole. However, in the diabetic subjects, Acipimox increased integrated insulin secretion rates during minutes 60-120 in the 50% having the lowest levels of hemoglobin A(1c) (379 +/- 34 vs. 326 +/- 30 pmol x kg(-1) x min(-1) without Acipimox, P < 0.05). A 3-day dietary intervention diminished energy from fat from 39 to 23% without affecting FA levels and without improving the insulin response during clamps. Elevated FA levels may tonically inhibit stimulated insulin secretion in a subset of type 2 diabetic subjects.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 2; Diet, Fat-Restricted; Dietary Proteins; Energy Intake; Exercise; Fasting; Fatty Acids; Female; Glucagon; Glucose Clamp Technique; Glycated Hemoglobin; Humans; Hyperglycemia; Hypertriglyceridemia; Insulin; Insulin Secretion; Male; Middle Aged; Obesity; Proinsulin; Pyrazines

To evaluate the effect of short-term administration of the anti-lipolytic agent, Acipimox, on the ability of plasma to stimulate cellular cholesterol removal, which represents one of the first steps in the anti-atherogenic process of reverse cholesterol transport.. Eight male Type 2 diabetic patients and eight healthy subjects were studied after a 12-h fast at baseline, after 24 h of Acipimox administration, 250 mg every 4 h, and again after 1 week (recovery). Plasma lipids, apolipoprotein AI, phospholipid transfer protein (PLTP) activity, pre-beta high-density lipoproteins (HDL) in incubated plasma and efflux of radiolabelled cholesterol from Fu5AH rat hepatoma cells to plasma were measured at each time point.. Acipimox lowered plasma triglycerides in diabetic patients (P = 0.001) and healthy subjects (P = 0.002), whereas plasma non-esterified fatty acids were decreased in diabetic patients (P = 0.001) compared with the averaged values at baseline and recovery. Acipimox decreased HDL cholesterol in healthy subjects (P = 0.007) and plasma apolipoprotein AI in both groups (P = 0.001 for diabetic patients; P = 0.008 for healthy subjects). Not only plasma PLTP activity (P = 0.001 for diabetic patients; P = 0.01 for healthy subjects), but also pre-beta HDL in incubated plasma (P = 0.001 for diabetic patients; P = 0.03 for healthy subjects) and cellular cholesterol efflux to plasma (P = 0.04 for diabetic patients; P = 0.005 for healthy subjects) were lowered by Acipimox in both groups.. Short-term Acipimox administration impairs the ability of plasma from Type 2 diabetic patients and healthy subjects to stimulate cellular cholesterol efflux, in conjunction with alterations in HDL parameters and in PLTP activity. If the impairment of cellular cholesterol efflux to plasma is sustained with long-term treatment, this potentially adverse effect should be considered when treating diabetic dyslipidaemia with Acipimox. Diabet. Med. 18, 509-513 (2001)

Topics: Animals; Apolipoprotein A-I; Body Mass Index; Carrier Proteins; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; High-Density Lipoproteins, Pre-beta; Humans; Hypolipidemic Agents; Lipoproteins, HDL; Liver Neoplasms, Experimental; Male; Membrane Proteins; Middle Aged; Phospholipid Transfer Proteins; Pyrazines; Rats; Reference Values; Tumor Cells, Cultured

We investigated the association between free fatty acid (FFA) concentration and ventricular premature complexes (VPCs) in nonischemic patients with non-insulin-dependent diabetes mellitus using 3 approaches: cross-sectional analysis (n = 142), intervention including induction of elevated FFA levels with Intralipid heparin (n = 15), and reduction in FFA levels with Acipimox (n = 34) and a longitudinal follow-up study (n = 59). Patients at the third tertile of fasting plasma FFA concentration had the strongest increase in VPCs. Independently of age, sex, body mass index (BMI), waist/hip ratio, left ventricular mass index, glycated hemoglobin, fasting plasma insulin and triglyceride concentration, and daily physical activity, FFA concentration and VPCs were significantly correlated (r = 0.21 p <0.01). At multiple logistic regression analysis independently of age, sex, BMI, waist/hip ratio, left ventricular mass index, mean arterial blood pressure, glycated hemoglobin, fasting plasma insulin, triglycerides and potassium concentration, fasting plasma low-density lipoprotein/high-density lipoprotein cholesterol ratio, and daily physical activity, plasma FFA concentration was a significant determinant of VPCs (odds ratio 1.2, 95% confidence interval 1.0 to 2.3). Intralipid infusion (10% in 24 hours) (n = 15) and acipimox administration (250 mg, 4 times/day) (n = 34) increased, and decreased fasting plasma FFA concentration, respectively. In those studies, change in VPCs paralleled the effects on plasma FFA. In the longitudinal study (n = 59), plasma FFA concentration predicted the development of VPCs (RR 1.4 95% confidence interval 1.0 to 1.9) independently of age, sex, BMI, waist/hip ratio, left ventricular mass index, mean arterial blood pressure, fasting plasma triglyceride concentration, fasting plasma low-density lipoprotein/high-density lipoprotein cholesterol ratio, and daily physical activity. In conclusion, in nonischemic patients with non-insulin-dependent diabetes mellitus, plasma FFA concentration is associated with the frequency of ventricular premature complexes.

Topics: Aged; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Female; Humans; Hypolipidemic Agents; Logistic Models; Longitudinal Studies; Male; Middle Aged; Pyrazines; Ventricular Premature Complexes

Thirty patients were investigated with hyperlipoproteinaemia, 15 patients with non-insulin dependent diabetes mellitus (NIDDM) and 15 with primary hyperlipoproteinaemia. The patients took 250 mg acipimox (5-metyl-pyrazine-carboxylic acid 4-oxide) 3 times per day for 2 months. Serum examinations were performed before and after 1 and 2 months of acipimox administration. After treatment the cholesterol and triglyceride levels decreased in both groups. Patients with NIDDM had 11% increase of high density lipoprotein-cholesterol (HDL-C) level at the end of the first, and 18% increase at the end of the second month, while patients with primary hyperlipoproteinaemia did not change significantly. The low density lipoprotein (LDL) level did not change significantly in either groups of patients. The apolipoprotein A 1 (apo A 1) levels increased significantly during the second month of acipimox administration. Uric acid levels decreased in both groups, but significant change could be detected mainly in the NIDDM group. Serum glucose level did not change in the non-diabetic patients, while it decreased significantly in the NIDDM group.

Topics: Apolipoprotein A-I; Blood Glucose; Cholesterol; Cholesterol, HDL; Diabetes Mellitus, Type 2; Female; Humans; Hypercholesterolemia; Hyperlipoproteinemias; Hypertriglyceridemia; Hypolipidemic Agents; Lipoproteins, LDL; Male; Middle Aged; Pyrazines; Time Factors; Triglycerides; Uric Acid

The effect of Olbetam on serum lipid and lipoproteins was studied in 30 diabetic patients with hyperlipidemia in four weeks trial. The dose of Olbetram was 500 mg/d. The results showed serum concentrations of TC, TG, and VLDL-C were decreased while HDL-C especially HDL2-C increased significantly after treatment. There were no significant changes in FBG, blood creatinine and urine acid. This result suggests Olbetam can improve dyslipidemia in NIDDM and was well tolerated by all patients.

Topics: Adult; Cholesterol; Cholesterol, HDL; Cholesterol, VLDL; Diabetes Mellitus, Type 2; Female; Humans; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Pyrazines; Triglycerides

Recently, the euglycemic hyperinsulinemic clamp technique was shown to give excellent image quality during metabolic steady-state conditions. Acipimox is a new potent nicotinic acid derivative that rapidly reduces serum free fatty acid (FFA) levels by inhibiting lipolysis in peripheral tissue.. To compare the effects of acipimox administration and insulin clamp on [18F]fluorodeoxyglucose ([18F]FDG) uptake and myocardial glucose utilization, five nondiabetic and seven type II diabetic patients who had had previous myocardial infarctions were studied twice: once during a clamp study and once after the administration of acipimox (2 x 250 mg orally). All patients also underwent resting SPECT perfusion imaging prior to PET scans.. The patients tolerated acipimox well. Although fasting plasma glucose levels were higher in diabetic patients (9.2 +/- 3.4 versus 5.5 +/- 0.3 mM, p = 0.03), they were decreased both during clamping and after acipimox; during imaging, no significant differences between the groups and approaches were detected. By visual analysis, the image quality and myocardial [18F]FDG uptake patterns were similar during clamping and after acipimox. Compared with the relative [18F]FDG uptake values obtained during clamping, acipimox yielded similar results in normal, mismatch and scar segments (r = 0.88, p = 0.0001). Similar rMGU values were also obtained during both approaches.. Thus, PET imaging with [18F]FDG after the administration of acipimox is a simple and feasible method for clinical viability studies both in nondiabetic and diabetic patients. It results in excellent image quality and gives rMGU levels similar to the insulin clamp technique.

Topics: Adult; Aged; Coronary Angiography; Deoxyglucose; Diabetes Mellitus, Type 2; Echocardiography; Female; Fluorodeoxyglucose F18; Glucose; Glucose Clamp Technique; Heart; Humans; Male; Middle Aged; Myocardial Infarction; Myocardium; Nicotinic Acids; Pyrazines; Radionuclide Ventriculography; Tomography, Emission-Computed

To study whether therapeutic reduction of non-esterified fatty acids (NEFA) can be used to improve glucose metabolism, we administered the antilipolytic agent, acipimox, 250 mg four times daily for 4 weeks in eight obese Type 2 diabetic patients. Glucose and NEFA metabolism were assessed before and after treatment with a two-step euglycaemic hyperinsulinaemic clamp (0.25 and 1 mU kg-1 min-1 insulin) combined with infusions of [3-3H] glucose and [1-14C] palmitate. Three days of acipimox treatment reduced 24-h serum NEFA levels by 10%, but the difference disappeared after 4 weeks of treatment mainly due to a two-fold rise in morning NEFA concentrations (p < 0.01). After 3 days of acipimox treatment, fasting and 24-h plasma glucose and serum triglyceride concentrations were significantly reduced (p < 0.05), but no longer after 4 weeks of treatment. Despite the rebound rise in NEFA, acute administration of acipimox still inhibited both oxidative and non-oxidative NEFA metabolism in the basal state (p < 0.01-0.001) and during insulin infusion (p < 0.05-0.001). Inhibition of NEFA metabolism was associated with increased insulin-stimulated glucose uptake (from 3.56 +/- 0.28 to 5.14 +/- 0.67 mumol kg-1 min-1, p < 0.05), mainly due to stimulation of non-oxidative glucose disposal (from 1.74 +/- 0.23 to 3.03 +/- 0.53 mumol kg-1 min-1, p < 0.05). In conclusion, acipimox administered acutely inhibits NEFA appearance (lipolysis), which is associated with improved glucose uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Glucose; Cholesterol; Cholesterol, HDL; Circadian Rhythm; Diabetes Mellitus, Type 2; Fasting; Fatty Acids, Nonesterified; Female; Glucose; Glucose Clamp Technique; Glycerol; Humans; Hypolipidemic Agents; Infusions, Intravenous; Insulin; Lipids; Liver; Male; Middle Aged; Pyrazines; Time Factors; Triglycerides

To study the effect of changes in plasma non-esterified fatty acid concentration on suppression of hepatic glucose production by insulin eight Type 2 (non-insulin-dependent) diabetic patients participated in three euglycaemic, hyperinsulinaemic (108pmol.m2-1.min-1) clamp studies combined with indirect calorimetry and infusion of [3-3H]-glucose and [1-14C]palmitate; (1) a control experiment with infusion of NaCl 154 mmol/l, (2) heparin was infused together with insulin, and (3) an antilipolytic agent, Acipimox, was administered at the beginning of the experiment. Six healthy volunteers participated in the control experiment. Plasma non-esterified fatty acid concentrations during the insulin clamp were in diabetic patients: (1) 151 +/- 36 mumol/l, (2) 949 +/- 178 mumol/l, and (3) 65 +/- 9 mumol/l; in healthy control subjects 93 +/- 13 mumol/l. Non-esterified fatty acid transport rate, oxidation and non-oxidative metabolism were significantly higher during the heparin than during the Acipimox experiment (p less than 0.001). Suppression of hepatic glucose production by insulin was impaired in the diabetic compared to control subjects (255 +/- 42 vs 51 +/- 29 mumol/min, p less than 0.01). Infusion of heparin did not affect the suppression of hepatic glucose production by insulin (231 +/- 49 mumol/min), whereas Acipimox significantly enhanced the suppression (21 +/- 53 mumol/min, p less than 0.001 vs 154 mmol/l NaCl experiment). We conclude that insulin-mediated suppression of hepatic glucose production is not affected by increased non-esterified fatty acid availability. In contrast, decreased non-esterified fatty acid availability enhances the suppression of hepatic glucose production by insulin.

Topics: Administration, Oral; Adult; Biological Transport; Calorimetry; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucose; Heparin; Humans; Hypolipidemic Agents; Infusions, Intravenous; Insulin; Lipid Metabolism; Liver; Middle Aged; Oxidation-Reduction; Palmitates; Pyrazines

Increased nonesterified fatty acid (NEFA) levels may be important in causing insulin resistance in skeletal muscles in patients with non-insulin-dependent diabetes mellitus (NIDDM). The acute effect of the antilipolytic nicotinic acid analogue Acipimox (2 X 250 mg) on basal and insulin-stimulated (3 h, 40 mU/m2 per min) glucose metabolism was therefore studied in 12 patients with NIDDM. Whole-body glucose metabolism was assessed using [3-3H]glucose and indirect calorimetry. Biopsies were taken from the vastus lateralis muscle during basal and insulin-stimulated steady-state periods. Acipimox reduced NEFA in the basal state and during insulin stimulation. Lipid oxidation was inhibited by Acipimox in all patients in the basal state (20 +/- 2 vs. 33 +/- 3 mg/m2 per min, P less than 0.01) and during insulin infusion (8 +/- 2 vs. 17 +/- 2 mg/m2 per min, P less than 0.01). Acipimox increased the insulin-stimulated glucose disposal rate (369 +/- 49 vs. 262 +/- 31 mg/m2 per min, P less than 0.01), whereas the glucose disposal rate was unaffected by Acipimox in the basal state. Acipimox increased glucose oxidation in the basal state (76 +/- 4 vs. 50 +/- 4 mg/m2 per min, P less than 0.01). During insulin infusion Acipimox increased both glucose oxidation (121 +/- 7 vs. 95 +/- 4 mg/m2 per min, P less than 0.01) and nonoxidative glucose disposal (248 +/- 47 vs. 167 +/- 29 mg/m2 per min, P less than 0.01). Acipimox enhanced basal and insulin-stimulated muscle fractional glycogen synthase activities (32 +/- 2 vs. 25 +/- 3%, P less than 0.05, and 50 +/- 5 vs. 41 +/- 4%, P less than 0.05). Activities of muscle pyruvate dehydrogenase and phosphofructokinase were unaffected by Acipimox. In conclusion, Acipimox acutely improved insulin action in patients with NIDDM by increasing both glucose oxidation and nonoxidative glucose disposal. This supports the hypothesis that elevated NEFA concentrations may be important for the insulin resistance in NIDDM. The mechanism responsible for the increased insulin-stimulated nonoxidative glucose disposal may be a stimulatory effect of Acipimox on glycogen synthase activity in skeletal muscles.

Topics: Biological Transport; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Glucose; Glycogen Synthase; Humans; Hypolipidemic Agents; Lactates; Lactic Acid; Lipid Metabolism; Middle Aged; Muscles; Oxidation-Reduction; Pyrazines; Pyruvate Dehydrogenase Complex

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Pyrazines