acipimox and Diabetes-Mellitus

Mitogen-activated protein kinase (MAPK) pathways are activated in skeletal muscle during endurance exercise, but the upstream molecular events are incompletely resolved. As an increase in plasma nonesterified fatty acids (NEFA) is a common feature of long-lasting exercise, the authors tested the hypothesis that NEFA contribute to the activation of MAPK during endurance exercise. Acipimox was used before and during endurance exercise to prevent the elevation of plasma NEFA levels in healthy subjects and patients with diabetes. In 2 separate studies, healthy subjects cycled for 2 hr and patients with diabetes for 1 hr at 50% Wmax. In control conditions, plasma NEFA concentrations increased from 0.35 to 0.90 mM during exercise in healthy subjects and from 0.55 to 0.70 mM in patients with diabetes (p < .05). Phosphorylation states of extracellularly regulated kinase 1 and 2 (ERK1/2), p38, and c-Jun NH2-terminal kinases (JNK) were significantly increased after exercise in the vastus lateralis in both groups. Acipimox blocked the increase in plasma NEFA concentrations and almost completely repressed any rise in ERK1/2 and p38 but not in JNK. In conclusion, the data support a role for plasma NEFA in the activation of p38 and ERK1/2 in skeletal-muscle tissue of healthy and diabetic subjects during endurance exercise. Further investigation will be required to determine the molecular link between NEFA and MAPK activation during exercise in human skeletal muscle.

Topics: Diabetes Mellitus; Exercise; Fatty Acids, Nonesterified; Humans; Hypolipidemic Agents; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Signaling System; Middle Aged; Muscle, Skeletal; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Physical Endurance; Pyrazines; Sedentary Behavior; Young Adult

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

Obesity is commonly associated with elevated plasma free fatty acid (FFA) levels, as well as with insulin resistance and hyperinsulinemia, two important cardiovascular risk factors. What causes insulin resistance and hyperinsulinemia in obesity remains uncertain. Here, we have tested the hypothesis that FFAs are the link between obesity and insulin resistance/hyperinsulinemia and that, therefore, lowering of chronically elevated plasma FFA levels would improve insulin resistance/hyperinsulinemia and glucose tolerance in obese nondiabetic and diabetic subjects. Acipimox (250 mg), a long-acting antilipolytic drug, or placebo was given overnight (at 7:00 P.M., 1:00 A.M., 7:00 A.M.) to 9 lean control subjects, 13 obese nondiabetic subjects, 10 obese subjects with impaired glucose tolerance, and 11 patients with type 2 diabetes. Euglycemic-hyperinsulinemic clamps and oral glucose tolerance tests (75 g) were performed on separate mornings after overnight Acipimox or placebo treatment. In the three obese study groups, Acipimox lowered fasting levels of plasma FFAs (by 60-70%) and plasma insulin (by approximately 50%). Insulin-stimulated glucose uptake during euglycemic-hyperinsulinemic clamping was more than twofold higher after Acipimox than after placebo. Areas under the glucose and insulin curves during oral glucose tolerance testing were both approximately 30% lower after Acipimox administration than after placebo. We conclude that lowering of elevated plasma FFA levels can reduce insulin resistance/hyperinsulinemia and improve oral glucose tolerance in lean and obese nondiabetic subjects and in obese patients with type 2 diabetes.

Topics: Adult; Basal Metabolism; Diabetes Mellitus; Fatty Acids, Nonesterified; Female; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hypolipidemic Agents; Insulin Resistance; Male; Obesity; Oxidation-Reduction; Pyrazines

Pharmacological suppression of lipolysis is being increasingly used in the treatment of diabetic hyperlipidaemia. Although theoretical hazard of such treatment is that recovery from hypoglycaemia might be impaired. Seven normal subjects were therefore studied on two occasions, following treatment with a single dose of either acipimox 250 mg or placebo. Hypoglycaemic recovery was unaffected, despite effective suppression of plasma non-esterified fatty acid levels with acipimox. The results suggest that under these conditions activation of lipolysis may not be essential to recovery from hypoglycaemia.

Topics: Acetoacetates; Adult; Blood Glucose; Diabetes Complications; Diabetes Mellitus; Fatty Acids, Nonesterified; Female; Glycerol; Humans; Hyperlipidemias; Hypoglycemia; Hypolipidemic Agents; Insulin; Lipolysis; Male; 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

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