c-peptide and acipimox

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

Concentrations of the orexigenic peptide ghrelin is affected by a number of hormones, which also affect circulating levels of free fatty acids (FFAs). The present study was therefore designed to determine the direct effect of FFAs on circulating ghrelin.. Eight lean, healthy men were examined for 8 h on four occasions using variable infusion rates (0, 3, 6 and 12 microl/kg per min) of intralipid to create different plasma FFA concentrations. Constant levels of insulin and GH were obtained by administration of acipimox (250 mg) and somatostatin (300 microg/h). At the end of each study day a hyperinsulinaemic-euglycaemic clamp was performed.. Four distinct levels of FFAs were obtained at the end of the lipid infusion period (FFA(LIPID): 0.03 +/- 0.00 vs: 0.49 +/- 0.04, 0.92 +/- 0.08 and 2.09 +/- 0.38 mmol/l; ANOVA P < 0.0001) and during hyperinsulinaemia (FFA(LIPID+INSULIN): 0.02 +/- 0.00 vs: 0.34 +/- 0.03, 0.68 +/- 0.09 and 1.78 +/- 0.32 mmol/l; ANOVA P < 0.0001). Whereas, somatostatin infusion alone reduced ghrelin concentration by approximately 67%, concomitant administration of increasing amounts of intralipid reduced circulating ghrelin by a further 14, 19 and 19% respectively (change in ghrelin: 0.52 +/- 0.05 vs: 0.62 +/- 0.06, 0.72 +/- 0.09 and 0.71 +/- 0.05 microg/l; ANOVA P = 0.04). No further reduction in ghrelin concentration was observed during hyperinsulinaemia.. FFA exposure between 0 and 1 mmol/l significantly suppresses ghrelin levels independent of ambient GH and insulin levels.

Topics: Adult; Anticoagulants; Blood Glucose; C-Peptide; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Ghrelin; Glucose Clamp Technique; Heparin; Human Growth Hormone; Humans; Hydrocortisone; Hyperinsulinism; Hypolipidemic Agents; Insulin; Male; Peptide Hormones; Pyrazines; Somatostatin

Obesity is associated with increased hepatic glycogen content. In vivo and in vitro data suggest that plasma free fatty acids (FFA) may cause this increase. In this study we investigated the effect of physiological plasma FFA levels on hepatic glycogen metabolism by studying intrahepatic glucose pathways in lean and obese subjects. Six lean and 6 obese males were studied twice during a 16- to 22-hour fast, once with and once without acipimox, an inhibitor of lipolysis. Intrahepatic glucose fluxes were measured by infusion of [2-(13C1)]glycerol, [1-(2H1)]galactose, and [U-(13C6)]glucose. Acetaminophen was administered as a glucuronate probe. In both lean and obese control studies, plasma FFA levels increased progressively, whereas acipimox completely suppressed plasma FFA levels for the whole study period. In lean males glycogenolysis did not change in the acipimox study, but decreased in the control study (P < .01). In lean males, neither glycogen synthesis, glycogen synthesis retained as glycogen, nor glycogen balance differed between control and acipimox studies. In obese males glycogenolysis did not change in the acipimox study, but decreased in the control study (P < .01). Glycogen synthesis did not change in either study. Glycogen synthesis retained as glycogen did not change in acipimox study, but increased in the control study (P = .03). Glycogen balance did not change in the acipimox study, but increased in the control study (P < .01). This study demonstrates that in obese males physiological levels of FFA contribute to the retention of hepatic glycogen during short-term fasting by inhibiting breakdown of glycogen and increasing glycogen synthesis retained as glycogen, whereas in lean males this effect was absent due to unaltered glycogen synthesis retained as glycogen.

Topics: Adult; C-Peptide; Fasting; Fatty Acids, Nonesterified; Gas Chromatography-Mass Spectrometry; Gluconeogenesis; Glucose; Hormones; Humans; Hypolipidemic Agents; Insulin; Liver Glycogen; Male; Middle Aged; Obesity; Pyrazines; Stimulation, Chemical

To evaluate the effects of long-term acipimox administration on glucose-induced insulin secretion and peripheral insulin sensitivity in polycystic ovarian syndrome (PCOS), 20 PCOS subjects (eight lean and 12 obese) and 14 body mass index-matched controls (seven lean and seven obese) were investigated.. Fasting blood samples were collected for basal hormone and lipoprotein assays, after which patients underwent an oral glucose tolerance test (OGTT). The following day a euglycaemic-hyperinsulinaemic clamp was performed. After 4-6 weeks of treatment with acipimox at a dose of 250 mg given orally three times a day, the patients repeated the study protocol.. No significant differences were found in the glucose, insulin or C-peptide responses to OGTT before and after anti-lipolytic drug administration in any group, nor was there any effect on insulin sensitivity. Concerning the lipid profile, acipimox administration led to a significant decrease of cholesterol and low-density lipoprotein levels in obese PCOS patients as well as in obese and lean controls. Lower triglycerides were found after the drug administration in both obese groups. Post-treatment free fatty acid levels were not significantly different when compared with basal values.. Acipimox does not appear to be an effective insulin-lowering drug in PCOS, even if it can be used in obese women with PCOS as an additional therapeutic agent to ameliorate the atherogenic lipid profile of the syndrome.

Topics: Adult; Blood Glucose; C-Peptide; Female; Glucose Tolerance Test; Humans; Hypolipidemic Agents; Insulin; Obesity; Pilot Projects; Polycystic Ovary Syndrome; Pyrazines; Thinness; Time Factors; Triglycerides

To evaluate the effects of acute lowering of FFAs on glucose-induced insulin secretion and GH response to GHRH in polycystic ovary syndrome (PCOS), 27 PCOS subjects (11 lean and 16 obese) and 17 body mass index-matched controls (8 lean and 9 obese) were investigated. Patients underwent an oral glucose tolerance test and a GHRH test before and after administration of the antilipolytic drug acipimox (250 mg orally 3 h and 1 h before the starting of the tests). Blood samples were collected for 2 h after GHRH bolus and for 4 h after the oral glucose tolerance test. Serum concentrations of GH, insulin, glucose, and c-peptide were assayed in each sample, and the results were expressed as area under the curve (AUC). No significant differences were found as to glucose, insulin, and c-peptide AUC before and after acute FFA plasma reduction in any of the investigated groups. Basally, lower GH-AUC was found in lean PCOS compared with body mass index-matched controls and in obese vs. lean controls; no significant differences were found as to the same variable between the two obese groups. The acipimox induced FFA suppression elicited in the four groups a sustained increase in the GH response to its trophic hormone; indeed, the GH-AUC nearly doubled with respect to basal evaluation in all the studied groups. However, the antilipolytic drug was not able to abolish the differences found between lean groups in basal conditions. In conclusion, the presented data confirm that FFAs have a main role in regulating GH secretion at the pituitary level; however, it does not seem that they could explain the GH as well as insulin dysfunction of PCOS.

Topics: Adult; Area Under Curve; Body Mass Index; C-Peptide; Fatty Acids, Nonesterified; Female; Glucose Tolerance Test; Growth Hormone-Releasing Hormone; Hormones; Human Growth Hormone; Humans; Hypolipidemic Agents; Insulin; Insulin Resistance; Lipids; Obesity; Polycystic Ovary Syndrome; Pyrazines

This study investigated the percentage of carbohydrate utilization than can be accounted for by glucose ingested during exercise performed after the ingestion of the potent lipolysis inhibitor Acipimox. Six healthy male volunteers exercised for 3 h on a treadmill at about 45% of their maximal oxygen uptake, 75 min after having ingested 250 mg of Acipimox. After 15-min adaptation to exercise, they ingested either glucose dissolved in water, 50 g at time 0 min and 25 g at time 60 and 120 min (glucose, G) or sweetened water (control, C). Naturally labelled [13C]glucose was used to follow the conversion of the ingested glucose to expired-air CO2. Acipimox inhibited lipolysis in a similar manner in both experimental conditions. This was reflected by an almost complete suppression of the exercise-induced increase in plasma free fatty acid and glycerol and by an almost constant rate of lipid oxidation. Total carbohydrate oxidation evaluated by indirect calorimetry, was similar in both experimental conditions [C, 182, (SEM 21); G, 194 (SEM 16) g.3 h-1], as was lipid oxidation [C, 57 (SEM 6); G, 61 (SEM 3) g.3 h-1]. Exogenous glucose oxidation during exercise G, calculated by the changes in 13C:12C ratio of expired air CO2, averaged 66 (SEM 5) g.3 h-1 (19% of the total energy requirement). Consequently, endogenous carbohydrate utilization was significantly smaller after glucose than after placebo ingestion: 128 (SEM 18) versus 182 (SEM 21) g.3 h-1, respectively (P < 0.05). Symptoms of intense fatigue and leg cramps observed with intake of sweet placebo were absent with glucose ingestion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Blood Glucose; C-Peptide; Calorimetry, Indirect; Carbohydrate Metabolism; Energy Metabolism; Glucagon; Glucose; Glycerol; Humans; Hypolipidemic Agents; Insulin; Lipid Metabolism; Lipolysis; Male; Oxidation-Reduction; Physical Exertion; Pyrazines

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

To test the hypothesis that intrahepatic availability of fatty acid could modify the rate of suppression of endogenous glucose production (EGP), acipimox or placebo was administered before and during a test meal. We used a modified isotopic methodology to measure EGP in 11 healthy subjects, and (1)H magnetic resonance spectroscopic measurement of hepatic triglyceride stores was also undertaken. Acipimox suppressed plasma free fatty acids markedly before the meal (0.05 +/- 0.01 mmol/l at -10 min, P = 0) and throughout the postprandial period (0.03 +/- 0.01 mmol/l at 150 min). Mean peak plasma glucose was significantly lower after the meal on acipimox days (8.9 +/- 0.4 vs. 10.1 +/- 0.5 mmol/l, P < 0.01), as was mean peak serum insulin (653.1 +/- 99.9 vs. 909 +/- 118 pmol/l, P < 0.01). Fasting EGP was similar (11.15 +/- 0.58 micromol.kg(-1).min(-1) placebo vs. 11.17 +/- 0.89 mg.kg(-1).min(-1) acipimox). The rate of suppression of EGP after the meal was almost identical on the 2 test days (4.36 +/- 1.52 vs. 3.69 +/- 1.21 micromol.kg(-1).min(-1) at 40 min). There was a significant negative correlation between the acipimox-induced decrease in peak plasma glucose and liver triglyceride content (r = -0.827, P = 0.002), suggesting that, when levels of liver fat were low, inhibition of lipolysis was able to affect glucose homeostasis. Acute pharmacological sequestration of fatty acids in triglyceride stores improves postprandial glucose homeostasis without effect on the immediate postprandial suppression of EGP.

Topics: Adult; Blood Glucose; C-Peptide; Fatty Acids, Nonesterified; Female; Food; Glucagon; Glucose; Glycerol; Humans; Hypolipidemic Agents; Insulin; Kinetics; Lipolysis; Liver; Magnetic Resonance Spectroscopy; Male; Middle Aged; Oxidation-Reduction; Placebos; Pyrazines; 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