Myocardial fatty acid oxidation in patients with impaired glucose tolerance.

AIMS/HYPOTHESIS: Fatty acids are an important source of energy in the myocardium. Abnormal myocardial fatty acid metabolism could contribute to the deterioration of cardiac function frequently observed in patients with Type II (non-insulin-dependent) diabetes mellitus. In our previous study, myocardial total uptake of non-esterified fatty acid (NEFA) was measured in patients with impaired glucose tolerance and found to be normal. This study aimed to investigate the subsequent metabolic steps and beta-oxidation of NEFA. METHODS: A total of 6 men with impaired fasting glucose (age 50 +/- 2 years, BMI 29 +/- 1 kg/m2, means +/- SEM) and 6 healthy men (50 +/- 1 years, 25 +/- 1 kg/ m2) were studied in the fasting state. Myocardial blood flow was measured with [15O]H2O and positron emission tomography and myocardial NEFA metabolism with [11C]palmitic acid. RESULTS: Myocardial blood flow was normal and not different between the impaired glucose tolerance and the control group (78 +/- 6 vs 73 +/- 13 ml/100 g/ min, NS). The [11C]palmitic acid uptake indices were similar between the groups (10.4 +/- 0.5 vs 11.2 +/- 0.8 ml/100 g/min, respectively, NS). The clearance of [11C]-palmitate from the myocardium, an index of NEFA beta-oxidation, was similar between the groups (half-times of activity 17.6 +/- 1.6 vs 19.5 +/- 2.3 min, respectively, NS) CONCLUSION/INTERPRETATION: The results indicate that myocardial NEFA uptake and beta-oxidation are not altered in patients with IGT. Thus, it is not likely that altered NEFA metabolism contributes to the deterioration of the cardiac function in patients with IGT or Type II diabetes.

Insulin sensitivity after a reduced-fat diet and a monoene-enriched diet in subjects with elevated serum cholesterol and triglyceride concentrations.

BACKGROUND AND AIMS: To investigate the effect of a reduced-fat diet and a monoene-enriched diet (MUFA diet) on serum lipids, glucose and insulin metabolism in subjects with elevated cholesterol and triglyceride concentrations. METHODS AND RESULTS: Eighteen subjects with elevated serum cholesterol and triglyceride concentrations consumed the MUFA diet (39% of energy (E%) as fat and 21 E% monoenes) and the reduced-fat diet (34 E% fat, 16 E% monoenes) for 4 weeks according to a randomized cross-over design. Both periods were preceded by consumption of a standardized baseline diet for 2 weeks. Serum lipid and lipoprotein concentrations were determined at the beginning and end of each diet period. A frequently sampled intravenous glucose tolerance test was performed after the MUFA diet and the reduced-fat diet. Insulin sensitivity index (SI) was 40% higher after the reduced-fat diet than after the MUFA diet (2.42 +/- 0.42 vs 1.73 +/- 0.24 10(-4) min-1 U-1 ml-1, p = 0.018). This change in insulin sensitivity was seen in 13 subjects and was most evident in those who began with the MUFA diet. Compared to the baseline diet (high in saturated fat), both experimental diets lowered serum total and LDL cholesterol concentrations (6.6-6.9%, p < 0.05 and 7.4-8.0%, p < 0.05 respectively). CONCLUSIONS: Both diets were equally effective in lowering serum lipid concentrations, but the reduced-fat diet resulted in better insulin sensitivity.

Long-term effect of acetyl-L-carnitine on myocardial 123I-MIBG uptake in patients with diabetes.

Carnitine derivatives may have beneficial effects on cardiac and nerve function in patients with diabetes. The aim of this study was to investigate the effect of acetyl-L-carnitine (ALC) on myocardial sympathetic nervous function as measured with 123I-meta-iodobenzyl guanidine (MIBG) and single-photon emission tomography (SPET) in 19 patients with diabetes (placebo group, n = 6; ALC group, n = 13) at the beginning and at the end of a 1-year randomized, placebo-controlled, double-blind trial. The coefficient of variation for the MIBG analysis was 4%. In patients who were given a placebo, global myocardial MIBG uptake deteriorated during the study (MIBG uptake 1-year follow-up/baseline, 0.86 +/- 0.05, mean +/- standard error of mean), whereas in patients treated with ALC, MIBG uptake did not change significantly (1-year follow-up/baseline, 1.07 +/- 0.08; p = 0.03 between the groups). On the basis of these preliminary data, we conclude that long-term treatment with ALC may be of potential value in preventing the progressive loss of myocardial sympathetic nervous function in patients with diabetes. MIBG-SPET is a sensitive and thus valuable method in assessing the development of myocardial sympathetic nervous dysfunction.

A high-trans fatty acid diet and insulin sensitivity in young healthy women.

Epidemiological and experimental studies suggest that a diet rich in saturated fat affects insulin sensitivity. Monoenes and dienes that have an usaturated bond with the trans configuration (trans fatty acids) resemble saturated fatty acids with respect to structure, but no published data are available on the effect of trans fatty acids on insulin sensitivity. Therefore, the effects of diets high in trans fatty acids (TFA diet) and oleic acid (monounsaturated fat [MUFA] diet) on glucose and lipid metabolism were studied in 14 healthy women. Subjects consumed both experimental diets for 4 weeks according to a randomized crossover study design. Both experimental diet periods were preceded by consumption of a standardized baseline diet for 2 weeks. The diets provided 36.6% to 37.9% of energy (E%) as fat. In the TFA diet, there was 5.1 E% trans fatty acids, and in the MUFA diet, 5.2 E% oleic acid, substituted for saturated fatty acids in the baseline diet. A frequently sampled intravenous glucose tolerance test (FSIGT) was performed at the end of the experimental diet periods. Glucose effectiveness (S(G)) and the insulin sensitivity index (S(I)) did not differ after the two experimental diet periods. There was also no difference in the acute insulin response between the diets. The total cholesterol to high-density lipoprotein (HDL) cholesterol ratio and serum total triglyceride, HDL, and low-density lipoprotein (LDL) triglyceride and apolipoprotein B (apoB) concentrations were higher (P < .05) after the TFA diet. In conclusion, in young healthy women, the TFA diet resulted in a higher total/HDL cholesterol ratio and an elevation in triglyceride and apo B concentrations but had no effect on glucose and insulin metabolism compared with the MUFA diet.

Impaired free fatty acid uptake in skeletal muscle but not in myocardium in patients with impaired glucose tolerance: studies with PET and 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid.

Free fatty acids (FFAs) are an important substrate for myocardial and skeletal muscle metabolism, and increased availability and oxidation of FFA are suggested to be associated with insulin resistance. This study was undertaken to assess whether myocardial or muscle uptake of FFA is altered in patients with impaired glucose tolerance (IGT). Eight healthy men (control group; age 48+/-1 years, BMI 25+/-1 kg/m2, mean +/- SE) and eight men with IGT (glucose-intolerant group; age 49+/-1 years, BMI 29+/-1 kg/m2) were studied in the fasting state. Myocardial oxygen consumption and blood flow and myocardial and femoral muscle FFA uptake rates were measured with positron emission tomography (PET) and [15O]O2, [15O]H2O, [15O]CO, and 14(R, S)-[18F]fluoro-6-thia-heptadecanoic acid ([18F]FTHA), a fatty acid tracer trapped into the cell after undergoing initial steps of beta-oxidation. Serum glucose and insulin concentrations were higher in the glucose-intolerant group during the PET study, but FFA concentrations were comparable between the groups. No differences between the groups were observed in the myocardial blood flow, oxygen consumption, fractional FTHA uptake rates, or FFA uptake indices (5.6+/-0.4 vs. 5.2+/-0.4 pmol x 100 g(-1) x min(-1), glucose-intolerant versus control, NS). In the femoral muscle, fractional FTHA uptake (0.0062+/-0.0003 vs. 0.0072+/-0.0003 min(-1), P = 0.044) and FFA uptake indices (0.30+/-0.02 vs. 0.43+/-0.04 min(-1), P = 0.020) were significantly lower in the glucose-intolerant group than in the control group. In conclusion, when studied at the fasting state and normal serum FFA concentrations, subjects with IGT have similar myocardial but lowered femoral muscle FFA uptake. This finding argues against the hypothesis that an increased oxidation of serum FFA, via the competition of glucose and FFA as fuel sources, is the primary cause for impaired peripheral glucose utilization and insulin resistance commonly observed in IGT.

A high-stearic acid diet does not impair glucose tolerance and insulin sensitivity in healthy women.

Results in epidemiological and experimental studies suggest that a diet rich in saturated fat may affect insulin sensitivity. However, no published data are available on the effect of stearic acid in this respect. Therefore, we examined the effects of a high-stearic acid diet and a high-oleic acid diet on glucose metabolism, serum lipids and lipoproteins, and blood coagulation factors in 15 healthy female subjects. Subjects followed the two experimental diets for 4 weeks according to a randomized crossover design. Both experimental diet periods were preceded by consumption of a baseline diet for 2 weeks. The diets provided 36% of energy (E%) as fat. In the experimental diets, 5 E% stearic or oleic acid was substituted for 5 E% of saturated fatty acids in the baseline diet. After the experimental diets, no differences were found in the insulin sensitivity index (mean+/-SEM, 5.4+/-1.9 v 5.2+/-1.6 x 10(-4) min(-1) x microU(-1) x mL(-1), nonsignificant [NS]), glucose effectiveness (0.026+/-0.006 v 0.026+/-0.003 min(-1), NS), or first-phase insulin reaction ([FPIR] 368+/-57 v 374+/-66 mU/L x min, NS). The concentration of serum lipids and lipoproteins and blood coagulation factors did not differ after the diet periods. In conclusion, a diet rich in stearic acid did not deteriorate glucose tolerance or insulin action in young healthy female subjects as compared with a diet rich in oleic acid.

Serum leptin in obesity is related to gender and body fat topography but does not predict successful weight loss.

OBJECTIVE: Leptin is the product of the ob gene shown to regulate body fat and appetite in mice. It is produced by human adipose tissue also, but its physiological functions in man are poorly known. STUDY DESIGN AND METHODS: We studied serum leptin concentrations in ten obese men and 35 obese women (age and body mass index 42 +/- 7 years and 35.1 +/- 3.6 kg/m2 respectively) before (baseline) and at 17 and 57 weeks during weight loss of 10.9% of the initial weight. RESULTS: Serum leptin concentrations at baseline were 55% higher in women than in men (after adjustment for age and body fat mass, P = 0.002) and remained so during the follow-up. At baseline, serum leptin correlated with fat mass (r = 0.60, P < 0.001) estimated by bioelectrical impedance, and the changes in leptin concentrations from baseline to week 17 correlated with the changes in fat mass (r = 0.73, P < 0.001), but baseline leptin levels were not predictive of the successful weight loss. Leptin concentrations correlated with hip circumference (r = 0.49, P < 0.001 at baseline adjusted for age and sex), but the correlation with waist circumference became evident only during the weight loss (at week 57, r = 0.63, P < 0.001). CONCLUSIONS: Serum leptin concentrations are higher in obese women than in obese men before and during weight loss, but the topography of fat tissue influences serum leptin concentrations. Serum leptin concentrations do not predict the response to weight reduction.

Abnormal myocardial kinetics of 123I-heptadecanoic acid in subjects with impaired glucose tolerance.

Increased triglyceride accumulation has been observed in the diabetic heart, but it is not known whether the abnormalities in myocardial fatty acid metabolism differ between insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetic patients or whether they are present even prior to overt diabetes. Therefore, we studied myocardial fatty acid kinetics with single-photon emission tomography using 123I-heptadecanoic acid (HDA) in four groups of men: impaired glucose tolerance (IGT) (n = 13, age 53 +/- 2 years, mean +/- SEM), IDDM (n = 8, age 43 +/- 3 years), NIDDM (n = 10, age 51 +/- 2 years) and control subjects (n = 8, age 45 +/- 4 years). Echocardiography and myocardial perfusion scintigraphy (IGT and NIDDM groups) were performed to study cardiac function and flow. In the IGT subjects, myocardial HDA beta-oxidation index was reduced by 53% (4.6 +/- 0.4 vs 9.7 +/- 1.0 mumol .min-1.100 g-1, p < 0.01) and HDA uptake by 34% (3.7 +/- 0.2 vs 5.6 +/- 0.3% of injected dose 100g, p < 0.01) compared with the control subjects. The fractional HDA amount used for beta-oxidation was lower in the IGT compared with the control subjects (43 +/- 4 vs 61 +/- 4%, p < 0.05). NIDDM patients also tended to have a lowered HDA beta-oxidation index, whereas IDDM patients had similar myocardial HDA kinetics compared to the control subjects. Myocardial perfusion imaging during the dipyridamole-handgrip stress was normal both in the IGT and NIDDM groups, indicating that abnormal myocardial perfusion could not explain abnormal fatty acid kinetics. In conclusion, even before clinical diabetes, IGT subjects show abnormalities in myocardial fatty acid uptake and kinetics. These abnormalities may be related to disturbed plasma and cellular lipid metabolism.

Subjective and physiological cephalic phase responses to food in obese binge-eating women.

OBJECTIVE: The subjective and physiological cephalic phase reactivity to food was investigated in obese binge-eating women. METHOD: Eleven obese binge-eating women and 10 obese nonbinge-eating women participated in a cephalic phase response test consisting of baseline, anticipation, food exposure, and free eating periods. Serum insulin, free fatty acids, and plasma glucose concentrations as well as salivation, feeling of hunger, and desire to eat were repeatedly measured during the test. RESULTS: During the food exposure, the binge eaters reported more desire to eat than did the nonbinge eaters. No differences were found between the groups in the physiological cephalic phase responses except for the lower salivation in the binge eaters during the food exposure. The amount of food eaten after the food exposure was similar in both groups. DISCUSSION: Binge-eating women are characterized by stronger subjective but not stronger physiological cephalic phase reactivity to food.

Serum leptin in subjects with impaired glucose tolerance in relation to insulin sensitivity and first-phase insulin response.

OBJECTIVE: It has been suggested that insulin could regulate the secretion of leptin, the ob gene product, but the findings have been contradictory. Therefore, we studied the association between leptin and insulin secretion and insulin sensitivity in impaired glucose tolerance (IGT). SUBJECTS: 39 obese subjects (17 men, 22 women, body mass index (BMI) 30.6 +/- 0.6 kg/m2, age 54 +/- 1 y, mean +/- s.e.m.) with IGT. MEASUREMENTS: Leptin, insulin sensitivity and first-phase insulin response (frequently sampled intravenous glucose tolerance test), anthropometry, infrared densitometric assay. RESULTS: Leptin correlated with BMI (r = 0.36, P = 0.022), fat percent (r = 0.74, P < 0.001) and fat mass (r = 0.53, P < 0.001). After adjustment for sex and fat mass, leptin showed no significant linear correlation with fasting insulin, insulin sensitivity or first-phase insulin response. CONCLUSION: In obese IGT subjects fat mass is the main correlate of serum leptin concentration. First-phase insulin response or the degree of insulin resistance are not associated with leptin in IGT.

Serum leptin in relation to resting energy expenditure and fuel metabolism in obese subjects.

OBJECTIVE: Leptin is the product of ob gene shown to regulate body fat in mice. It is produced by human adipose tissue as well, but its physiological functions in man are not known. We explored if there is a relationship in obese humans with serum leptin and energy and fuel metabolism. DESIGN: Cross-sectional study including 45 obese (10 men, 35 women; age and body mass index: 42 +/- 7 y and 35.1 +/- 3.6 kg/m2, respectively). MEASUREMENTS: Food intake by a four-day-food record, blood samples for serum leptin concentrations and resting energy expenditure by indirect calorimetry. RESULTS: Leptin concentrations showed an inverse association (adjusted for fat mass, age and sex) with resting energy expenditure, respiratory quotient and carbohydrate oxidation rate (r = -0.324, P < 0.05; r = -0.420, P < 0.01; r = 0.478, P = < 0.01, respectively), and interestingly, also with dietary fat intake (unadjusted r = -0.30, P < 0.05). Especially, leptin concentrations were elevated in those with low resting energy expenditure and respiratory quotient (below the median). CONCLUSION: Serum leptin concentrations in obese subjects showed an inverse association with resting energy expenditure, respiratory quotient and carbohydrate oxidation rate. The physiological significance of these associations is unclear at the moment but could indicate that obese subjects show resistance to the actions of leptin also outside the brain in terms of regulating metabolic rate and fuel metabolism.

Demonstration of regional sympathetic denervation of the heart in diabetes. Comparison between patients with NIDDM and IDDM.

OBJECTIVE: Global myocardial uptake of 123I-metaiodobenzylguanidine (MIBG) has been shown to be decreased in diabetic patients with autonomic neuropathy, indicating cardiac sympathetic dysfunction. However, possible differences in myocardial MIBG distribution between NIDDM and IDDM diabetic patients are not known. RESEARCH DESIGN AND METHODS: Regional myocardial distribution of 123I-MIBG was studied in seven male IDDM patients (age 45 +/- 2 years, duration of diabetes 30 +/- 3 years, means +/- SE) and 13 NIDDM patients (8 men, 5 women, age 59 +/- 2 years, duration of diabetes 10 +/- 1 years). A dual-tracer single-photon emission tomography was carried out with 123I-MIBG and 99mTc-methoxyisobutylisonitrrile to asses simultaneously myocardial sympathetic innervation and perfusion at rest. Conventional autonomic nervous function tests, power spectral analysis of heart rate variability, and echocardiography were performed for assessments of autonomic function and cardiac dimensions and function. RESULTS: Autonomic nervous function tests and echocardiography showed similar results in IDDM and NIDDM patients. Despite this, global myocardial MIBG uptake (0.43 +/- 0.04 vs. 0.59 +/- 0.06, P = 0.03) and MIBG heart-to-liver ratio (0.59 +/- 0.03 vs. 0.68 = 0.03, P = 0.05) were lower in NIDDM compared with IDDM patients. Regional distribution of MIBG uptake and regional MIBG/perfusion ratio revealed significantly reduced uptake in NIDDM patients especially in the inferoposterior segments of the left ventricle compared with IDDM patients. Difference in age between NIDDM and IDDM patients did not explain the results. CONCLUSIONS: Reduced myocardial MIBG uptake was found in NIDDM patients compared with the uptake in IDDM patients, particularly involving inferoposterior segments. Regional sympathetic damage not detectable with conventional autonomic function tests is relatively common in NIDDM.

Determinants of the cephalic-phase insulin response in obese nondiabetic subjects.

Large interindividual variation is characteristic of the cephalic-phase insulin response (CPIR). Our aim was to examine the largely unknown determinants of CPIR in obese nondiabetic subjects before and after weight reduction. After a 12-hour overnight fast, 20 healthy, obese (body mass index, 31.1 to 41.4 kg/m2) subjects were individually exposed to food without being allowed to eat it. Levels of insulin, glucose, C-peptide, free fatty acids, and salivation, together with assessments of feeling of hunger and desire to eat, were measured during the experiment. Subjects were divided into three groups according to CPIR before the weight reduction: positive (PR), intermediate (IR), and negative (NR) responders. CPIR measurements before and after weight reduction correlated significantly with each other (r = .61, P < . 01,n=18). At the beginning of the study, NR had higher fasting plasma glucose and insulin values, as well as higher postload plasma glucose values, as compared with PR and IR. These differences disappeared after weight reduction. In an intravenous glucose tolerance test (IVGTT) performed 9 to 12 months afterward, first-phase insulin secretion was significantly lower in NR. Thus, the negative CPIR during visual and olfactory exposure to food-related stimuli may be related to the attenuated first-phase insulin secretion and mildly impaired glucose metabolism, possibly related to insulin resistance.

Athletic heart: a metabolic, anatomical, and functional study.

Previous studies have suggested a reduced glucose uptake by the athlete's heart at rest. To examine whether there is a compensatory increase in the myocardial fatty acid utilization, we studied nine male endurance-trained athletes (age 26 +/- 2 yr, VO2max 60 +/- 1 ml.kg-1.min-1, mean +/- SEM) and eight sedentary subjects (age 26 +/- 1 yr, VO2max 38 +/- 2 ml.kg-1.min-1) by single photon emission tomography using 123I-heptadecanoic acid (HDA) and mathematical modeling. Magnetic resonance imaging (MRI) and echocardiography were performed for the measurements of cardiac dimensions and left ventricular (LV) mass. No significant differences were found in the myocardial HDA beta-oxidation index (5.2 +/- 2.0 vs 7.4 +/- 1.6 mumol.min-1.100 g-1, P = NS) between endurance-trained and sedentary subjects. Fractional amounts of HDA beta-oxidation, backdiffusion, and esterification were also similar. In MRI study, LV mass was greater in the trained subjects (213 +/- 9 vs 179 +/- 10 g, P < 0.01) and in particular, LV long-axis diameter measured from the mitral valve level to the apex was increased (102 +/- 2 vs 88 +/- 2 mm, P < 0.001, trained vs sedentary subjects). VO2max correlated with LV long-axis diameter (r = 0.77, P < 0.001). In contrast to our hypothesis, myocardial HDA utilization was not enhanced in endurance-trained athletes at rest. Increases in LV mass and especially in LV long-axis diameter were observed in the athletes, indicating LV longitudinal remodeling.