Effects of hypoosmolality on whole-body lipolysis in man

Changes in extracellular osmolality, and thus in the cellular hydration state, appear to directly influence cell metabolism. The metabolic changes associated with cell swelling are inhibition of glycogenolysis, glycolysis, and proteolysis. Recent studies in our laboratory demonstrated diminished whole-body protein breakdown in humans during an acute hypoosmolar state. Because of the close interrelationship between carbohydrate and fat metabolism, we speculated that adipose tissue lipolysis and fatty acid oxidation are regulated by changes in extracellular osmolality. Therefore, we investigated the effect of artificially induced hypoosmolality on whole-body lipolysis and fat oxidation in seven healthy young men. Hypoosmolality was induced by intravenous administration of desmopressin, liberal ingestion of water, and infusion of hypotonic (0.45%) saline solution. Lipolysis was assessed by a stable-isotope method (2-[13C]-glycerol infusion). The glycerol rate of appearance (Ra), reflecting whole-body lipolysis, was higher under hypoosmolar compared with isoosmolar conditions (2.35+/-0.40 v 1.68+/-0.21 micromol/kg/min, P=.03). This was even more pronounced when lipolysis was suppressed during hyperinsulinemia and euglycemic clamping (0.90+/-0.08 v 0.61+/-0.03 micromol/kg/min, P=.002). However, plasma free fatty acid (FFA), glycerol, ketone body, insulin, and glucagon concentrations and carbohydrate and lipid oxidation measured by indirect calorimetry were not significantly altered by hypoosmolality. Plasma norepinephrine concentrations were lower under hypoosmolar conditions (P<.01 v control). In conclusion, hypoosmolality in vivo results in increased whole-body lipolysis, which is not due to changes in major lipolysis regulating hormones.     

Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active antiretroviral therapy

Human immunodeficiency virus (HIV) lipodystrophy is associated with fat redistribution, dyslipidemia, and insulin resistance; however, the mechanism of insulin resistance remains unknown. We hypothesized that HIV-infected subjects with fat redistribution have increased rates of lipolysis and increased circulating free fatty acid (FFA) levels that contribute to insulin resistance. Anthrompometric and body composition data were obtained and a standard 75-g oral glucose tolerance test (OGTT) was performed on day 1 of the study. Stable isotope infusions of glycerol and palmitate were completed following an overnight fast to assess rates of lipolysis and FFA flux in HIV-infected men (n = 19) with and without fat redistribution and healthy controls (n = 8) on day 2. Total FFA levels after standard glucose challenge were increased among HIV-infected subjects and positively associated with abdominal visceral adipose tissue area. In contrast, fasting total FFA levels were inversely associated with subcutaneous fat area. Rates of basal lipolysis were significantly increased among HIV-infected subjects (rate of appearance [Ra] glycerol, 4.1 +/- 0.2 v 3.3 +/- 0.2 micromol/kg/min in controls; P =.02). Among HIV-infected subjects, use of stavudine (P =.006) and the rate of lipolysis (ie, Ra glycerol, P =.02) were strong positive predictors of insulin resistance as measured by insulin response to glucose challenge, controlling for effects of age, body mass index (BMI), waist-to-hip ratio (WHR), and protease inhibitor (PI) exposure. These data demonstrate increased rates of lipolysis and increased total FFA levels in HIV-infected subjects and suggest that increased lipolysis may contribute to insulin resistance in this patient population.     

Physiological levels of glucagon do not influence lipolysis in abdominal adipose tissue as assessed by microdialysis

To determine whether glucagon stimulates lipolysis in adipose tissue, seven healthy young male volunteers were studied, with indwelling microdialysis catheters placed sc in abdominal adipose tissue. Subjects were studied three times: 1) during euglucagonemia (EG; glucagon infusion rate, 0.5 ng/kg.min); 2) during hyperglucagonemia (HG; (glucagon infusion rate, 1.5 ng/kg.min); and 3) during EG and a concomitant glucose infusion mimicking the glucose profile from the day of HG (EG+G). Somatostatin (450 microg/h) was infused to suppress hormonal secretion, and replacement doses of insulin and GH were administered. Sampling was done every 30 min for 420 min. Baseline circulating values of insulin, C-peptide, glucagon, GH, glycerol, and free fatty acids were comparable in all three conditions. During EG and EG+G, plasma glucagon was maintained at fasting level (20-40 ng/L); whereas, during HG, it increased (110-130 ng/L). Interstitial concentrations of glycerol were similar in the three conditions [30,870 +/- 5,946 (EG) vs. 31,074 +/- 7,092 (HG) vs. 29,451 +/- 6,217 (EG+G) micromol/L.120 min, P = 0.98]. Plasma glycerol (ANOVA, P = 0.5) and free fatty acids (ANOVA, P = 0.3) were comparable during the different glucagon challenges. We conclude that HG per se does not increase interstitial glycerol (and thus lipolysis) in abdominal sc adipose tissue; nor does modest hyperglycemia, during basal insulinemia and glucagonemia, influence indices of abdominal sc lipolysis.     

Lactate and glycerol release from subcutaneous adipose tissue in black and white lean men.

To measure interstitial glycerol and lactate production from the sc adipose tissue of two regions in nine black and nine white lean men, sc microdialysis was performed in combination with adipose tissue blood flow rates measured with 133Xe clearance. In the postabsorptive state, the plasma glucose and insulin levels of the black men and white men were similar. The black men had higher plasma free fatty acids (825+/-97 vs. 439+/-58 micromol/L; P < 0.005), glycerol (99.5+/-5.1 vs. 54.1+/-3.3 micromol/L; P < 0.0001), and lactate (1056+/-95 vs. 729+/-45 micromol/L; P < 0.01). Interstitial glycerol concentrations in the black and white men were 227 vs. 163 micromol/L (P < 0.01) and 230 vs. 162 micromol/L (P < 0.05) in the abdominal and femoral regions. The adipose tissue blood flow rate was higher in the black men in the abdominal (7.9+/-0.9 vs. 3.1+/-0.5 mL/100 g x min; P < 0.01) and femoral area (5.2+/-0.6 vs. 2.8+/-0.3; P < 0.01). Interstitial lactate concentrations in black and white men were 1976 vs. 1364 micromol/L (P < 0.004) and 1953 vs. 1321 micromol/L (P < 0.004) in the abdominal and femoral regions, respectively. Glycerol release was higher in black men vs. white men for abdominal (0.21+/-0.02 vs. 0.14+/-0.02 micromol/100 g x min; P < 0.02) and femoral (0.22+/-0.02 vs. 0.15+/-0.01; P < 0.05) areas. Postprandially, black men had higher plasma glucose levels [1 h, 9.6+/-0.4 vs. 8.2+/-0.5 mmol/L (P < 0.05); 2 h, 8.9+/-0.4 vs. 7.2+/-0.4 mmol/L (P < 0.01)], but lower plasma insulin levels [1 h, 173+/-13 vs. 264+/-48 pmol/L (P < 0.05); 2 h, 136+/-20 vs. 209+/-34 pmol/L (P < 0.05)]. Plasma free fatty acid, lactate, and glycerol levels remained higher in the black men. After 1 h, lactate release was higher in the black men vs. that in the white men for abdominal (20.5+/-1.6 vs. 14.7+/-2.5 micromol/100 g x min;P < 0.05) and femoral (15.6+/-1.1 vs. 12.1+/-1.8; P < 0.03) areas. We conclude that the black men, who are relatively insulinopenic postprandially, have a brisker lipolysis and also release more lactate from sc fat tissue than white men. These differences in adipose tissue metabolism may be related to differences in the lipid profiles and glucose metabolism previously documented in these ethnic groups.     

Inhibition of lipolysis during acute GH exposure increases insulin sensitivity in previously untreated GH-deficient adults

OBJECTIVE: Previous studies evaluating the lipolytic effect of GH have in general been performed in subjects on chronic GH therapy. In this study we assessed the lipolytic effect of GH in previously untreated patients and examined whether the negative effect of enhanced lipolysis on glucose metabolism could be counteracted by acute antilipolysis achieved with acipimox. METHODS: Ten GH-deficient (GHD) adults participated in four experiments each, during which they received in a double-blind manner: placebo (A); GH (0.88+/-0.13 mg) (B); GH+acipimox 250 mg b.i.d. (C); and acipimox b.i.d. (no GH) (D), where GH was given the night before a 2 h euglycemic, hyperinsulinemic clamp combined with infusion of [3-(3)H]glucose and indirect calorimetry. RESULTS: GH increased basal free fatty acid (FFA) levels by 74% (P=0.0051) and insulin levels by 93% (P=0.0051). This resulted in a non-significant decrease in insulin-stimulated glucose uptakes (16.61+/-8.03 vs 12.74+/-5.50 micromol/kg per min (s.d.), P=0.07 for A vs B). The rates of insulin-stimulated glucose uptake correlated negatively with the FFA concentrations (r=-0.638, P<0.0001). However, acipimox caused a significant improvement in insulin-stimulated glucose uptake in the GH-treated patients (17.35+/-5.65 vs 12.74+/-5.50 micromol/kg per min, P=0.012 for C vs B). The acipimox-induced enhancement of insulin-stimulated glucose uptake was mainly due to an enhanced rate of glucose oxidation (8.32+/-3.00 vs 5.88+/-2.39 micromol/kg per min, P=0.07 for C vs B). The enhanced rates of glucose oxidation induced by acipimox correlated negatively with the rate of lipid oxidation in GH-treated subjects both in basal (r=-0.867, P=0.0093) and during insulin-stimulated (r=-0.927, P=0.0054) conditions. GH did not significantly impair non-oxidative glucose metabolism (6.86+/-5.22 vs 8.67+/-6.65 micromol/kg per min, P=NS for B vs A). The fasting rate of endogenous glucose production was unaffected by GH and acipimox administration (10.99+/-1.98 vs 11.73+/-2.38 micromol/kg per min, P=NS for B vs A and 11.55+/-2.7 vs 10.99+/-1.98 micromol/kg per min, P=NS for C vs B). On the other hand, acipimox alone improved glucose uptake in the untreated GHD patients (24.14+/-8.74 vs 16.61+/-8.03 micromol/kg per min, P=0.0077 for D vs A) and this was again due to enhanced fasting (7.90+/-2.68 vs 5.16+/-2.28 micromol/kg per min, P=0.01 for D vs A) and insulin-stimulated (9.78+/-3.68 vs 7.95+/-2.64 micromol/kg per min, P=0.07 for D vs A) glucose oxidation. CONCLUSION: The study of acute administration of GH to previously untreated GHD patients provides compelling evidence that (i) GH-induced insulin resistance is mainly due to induction of lipolysis by GH; and (ii) inhibition of lipolysis can prevent the deterioration of insulin sensitivity. The question remains whether GH replacement therapy should, at least at the beginning of therapy, be combined with means to prevent an excessive stimulation of lipolysis by GH.     

Lipolysis and gluconeogenesis from glycerol are increased in patients with noninsulin-dependent diabetes mellitus.

The rate of lipolysis (glycerol Ra), gluconeogenesis from glycerol, and its contribution to overall hepatic glucose production (glucose Ra) were determined in 10 patients with noninsulin-dependent diabetes mellitus (NIDDM) [body mass index (BMI) 27.2 +/- 1.0 kg/m2, fasting plasma glucose 10.3 +/- 1.2 mmol/L], and in 6 matched control subjects (BMI 27.3 +/- 1.1 kg/m2, fasting plasma glucose 5.3 +/- 0.3 mmol/L) using infusions of [3-3H]glucose (0-600 min) and [U-14C]glycerol (360-600 min). Glycerol Ra was increased in the patients with NIDDM (120 +/- 16 mumol/m2.min) compared to the normal subjects (84 +/- 9 mumol/m2.min, P less than 0.05). Gluconeogenesis from glycerol was 1.7-fold higher in the patients (96 +/- 16 mumol/m2.min) than in the normal subjects (56 +/- 10 mumol/m2.min, P less than 0.05), and explained 9 +/- 1% and 7 +/- 1% (NS) of total glucose Ra in patients with NIDDM and normal subjects, respectively. To determine whether these abnormalities are more pronounced in overweight patients with NIDDM, glucose and glycerol Ra were also determined in 5 obese patients with NIDDM (BMI 36.4 +/- 1.0 kg/m2, fasting plasma glucose 11.3 +/- 1.3 mmol/L). Glycerol Ra (154 +/- 26 mumol/m2.min) was again higher than in the normal subjects (P less than 0.05) but not different from that in the less obese patients with NIDDM. The rate of gluconeogenesis from glycerol (159 +/- 20 mumol/m2.min) was significantly higher in the obese than in the less obese patients with NIDDM (P less than 0.05) but its contribution to total glucose Ra (10 +/- 1%) was similar to that in the less obese patients with NIDDM. When all data were analyzed together, gluconeogenesis from glycerol (r = 0.57, P less than 0.01) but not lipolysis (r = 0.02, NS) correlated with the percentage of lipolysis diverted toward gluconeogenesis suggesting that the rate of gluconeogenesis from glycerol is regulated by intrahepatic mechanisms rather than by glycerol availability. Neither the rate of lipolysis nor the rate of glycerol gluconeogenesis correlated with BMI, serum triglyceride, or insulin concentrations. We conclude that gluconeogenesis from glycerol is increased in patients with NIDDM. This increase appears to be the consequence of both accelerated lipolysis and increased intrahepatic conversion of glycerol to glucose.     

Sustained endogenous glucose production, diminished lipolysis and non-esterified fatty acid appearance and oxidation in non-obese women at high risk of type 2 diabetes

OBJECTIVE: To evaluate early defects in glucose production, lipolysis and fatty acid oxidation in non-obese, normally glucose tolerant women, who are nevertheless at risk of type 2 diabetes. METHODS: Ten women with previous gestational diabetes (pGDM) and ten controls were studied in two 4 h infusions of stable isotopes 6,6-(2)H(2)-glucose, 1-(13)C-palmitate, and 1,1,2,3,3-(2)H(5)-glycerol with and without infusion of adrenaline. Fatty acid oxidation was quantified using indirect calorimetry and (13)CO(2) measurements. Insulin sensitivity was evaluated using the short insulin tolerance test. RESULTS: The pGDM and control women were non-obese and carefully matched for body mass index and fat mass. Whole body insulin sensitivity and basal insulin concentrations did not differ significantly but basal glucose concentrations were increased in women with pGDM. During a 0.9% saline infusion, glucose appearance was not significantly different at the first (90-120 min) and second (210-240 min) steady states. However, glucose appearance decreased in controls but was maintained in the pGDM women (-0.33 +/- 0.02 vs -0.03 +/- 0.08 mg/kg per min; P = 0.004). Basal glycerol appearance (0.27 +/- 0.02 vs 0.38 +/- 0.03 mg/kg per min; P = 0.02), palmitate appearance (0.74 +/- 0.09 vs 1.05 +/- 0.09 mg/kg per min; P = 0.03) and palmitate oxidation (0.07 +/- 0.01 vs 0.10 +/- 0.01 mg/kg per min; P = 0.03) were lower in the pGDM women. During the adrenaline infusion, changes in glucose, glycerol and palmitate concentrations and kinetics were similar in both groups. CONCLUSIONS: Sustained glucose production during fasting is an early abnormality in non-obese subjects at risk of type 2 diabetes. Lipolysis and non-esterified fatty acid appearance and oxidation are diminished, suggesting an increased tendency to store fat. The observations are not readily attributable to differences in insulin or catecholamine sensitivity.     

Lipolysis and lipid oxidation in weight-losing cancer patients and healthy subjects

Increased lipolysis has been suggested as one of the possible mechanisms underlying cancer cachexia. The study aim was to assess whether lipolysis is increased in weight-losing cancer patients, considering their differences in food intake and body composition. Sixteen healthy subjects and 18 cancer patients with different tumor types and a weight loss of at least 5% in the previous 6 months were included in the study. Food intake was recorded for 4 days. After an overnight fast, [1,1,2,3,3-2H5]glycerol was infused to determine the rate of appearance (Ra) of glycerol as a measure of whole-body lipolysis, and [1-13C]palmitic acid was infused to determine the Ra of palmitate as a measure of adipocyte fatty acid release. Palmitate oxidation was determined by measuring 13CO2 enrichment in breath samples, and body composition was measured by bioelectrical impedance analysis. After adjustment for energy intake, whole-body lipolysis was significantly higher in cancer patients versus healthy subjects (6.46 +/- 0.63 and 4.67 +/- 0.46 micromol/kg +/- min, respectively, P < .05). The difference in adipocyte fatty acid release did not reach statistical significance. The rate of palmitate oxidation was also significantly higher in patients than in healthy subjects (1.15 +/- 0.10 and 0.93 +/- 0.07 )micromol/kg x min, respectively, P < .05). No differences in body composition were observed between groups. In conclusion, whole-body lipolysis (as measured by the Ra of glycerol) and palmitate oxidation were elevated in weight-losing cancer patients, but fatty acid release was not significantly different.     

The role of intramyocellular lipids during hypoglycemia in patients with intensively treated type 1 diabetes

CONTEXT: Endocrine defensive mechanisms provide for energy supply during hypoglycemia. Intramyocellular lipids (IMCL) were recently shown to contribute to energy supply during exercise. OBJECTIVE: The objective of this study was to assess the contribution of IMCL compared with lipolysis and endogenous glucose production (EGP) to insulin-mediated hypoglycemia counterregulation in patients with type 1 diabetes mellitus (T1DM). DESIGN AND SETTING: This was a prospective explorative study performed in a university research facility. PARTICIPANTS: Six well-controlled T1DM (age, 29 +/- 4 yr; body mass index, 23.4 +/- 1.0 kg/m2; hemoglobin A1c, 6.3 +/- 0.1%) and six nondiabetic humans (controls; age, 28 +/- 2 yr; body mass index, 23.4 +/- 1.0 kg/m2; hemoglobin A1c, 5.1 +/- 0.1%) were studied. INTERVENTIONS: We performed 240-min hypoglycemic (approximately 3 mM)-hyperinsulinemic (0.8 mU/kg x min) clamps on separate days to measure: 1) systemic lipolysis ([2H5]glycerol turnover), EGP ([6,6-(2)H2]glucose), and local lipolysis in abdominal s.c. adipose tissue and gastrocnemius muscle (microdialysis); and 2) IMCL (by 1H nuclear magnetic resonance spectroscopy) in soleus and tibialis anterior muscle. MAIN OUTCOME MEASURES: The main outcome measures were changes in IMCL during prolonged hypoglycemia. RESULTS: At baseline, EGP, glycerol turnover, and IMCL were not different between the groups. During hypoglycemia, hormonal counterregulation was blunted in T1DM (peak: glucagon, 68 +/- 4 vs. 170 +/- 37 pg/ml; cortisol, 16 +/- 2 vs. 24 +/- 2 microg/dl; epinephrine, 274 +/- 84 vs. 597 +/- 212 pg/ml; all P < 0.05 vs. control). T1DM had approximately 50% lower EGP (4.6 +/- 0.6 vs. 10.9 +/- 0.5 micromol/kg x min; P < 0.005), but approximately 40% higher glycerol turnover (374 +/- 21 vs. 272 +/- 19 micromol/kg x min; P < 0.01). Glycerol concentrations in muscle (T1DM, 302 +/- 22 control, 346 +/- 17 micromol/liter) and adipose tissue (264 +/- 25 vs. 318 +/- 25 micromol/liter) did not differ between groups. IMCL in soleus and tibialis anterior muscle did not change from baseline during hypoglycemia. CONCLUSIONS: In well-controlled T1DM, impaired hypoglycemia counterregulation is associated with decreased glucose production and augmented whole body lipolysis, which cannot be explained by either hydrolysis of muscle triglycerides or increased abdominal s.c. adipose tissue lipolysis.     

Effects of hypo- and hyperthyroidism on noradrenergic activity and glycerol concentrations in human subcutaneous abdominal adipose tissue assessed with microdialysis

Thyroid hormones play a major role in lipid metabolism. However, whether they directly affect lipolysis locally in the adipose tissue remains unknown. Therefore, we measured abdominal sc adipose tissue norepinephrine (NE), basal, and isoprenaline-stimulated lipolysis in 12 hypothyroid patients (HYPO), six hyperthyroid patients (HYPER), and 12 healthy controls by in vivo microdialysis. Adipose tissue NE was decreased in HYPO and increased in HYPER compared with controls (90.4 +/- 2.9 and 458.0 +/- 69.1 vs. 294.9 +/- 19.5 pmol/liter, P < 0.01). Similarly, basal lipolysis, assessed by glycerol assay, was lower in HYPO and higher in HYPER than in controls (88.2 +/- 9.9 and 566.0 +/- 42.0 vs. 214.3 +/- 5.1 micromol/liter P < 0.01). The relative magnitude of isoprenaline-induced glycerol increase was smaller in HYPO (39 +/- 19.4%, P < 0.05 vs. basal) and higher in HYPER (277 +/- 30.4%, P < 0.01) than in controls (117 +/- 5.6%, P < 0.01). The corresponding changes in NE after isoprenaline stimulation were as follows: 120 +/- 9.2% (P < 0.05), 503 +/- 113% (P < 0.01), and 267 +/- 17.2 (P < 0.01). In summary, by affecting local NE levels and adrenergic postreceptor signaling, thyroid hormones may influence the lipolysis rate in the abdominal sc adipose tissue.     

Effect of menopausal status on lipolysis: comparison of plasma glycerol levels in middle-aged, premenopausal and early, postmenopausal women

To determine whether menopausal status affects systemic lipolysis, we measured plasma glycerol concentrations following an overnight fast and during euglycemic hyperinsulinemic conditions (40 mU x m(-2) x min(-1)) in 43 middle-aged, premenopausal women (mean +/- SE; 47 +/- 0.4 years) and 26 early, postmenopausal (51 +/- 0.8 years) women. In addition, body composition was measured by dual-energy x-ray absorptiometry and abdominal fat distribution by computed tomography (CT). Postmenopausal women had greater amounts of whole body (fat mass, 22.8 +/- 1.4 v 17.4 +/- 1.2 kg; percent fat, 34.7 +/- 1.2 v 29.1 +/- 1.4; both P <.01) and intra-abdominal fat (89.0 +/- 6.5 v 55.9 +/- 4.4 cm2; P <.01) compared with premenopausal women. Despite greater adiposity, plasma glycerol concentrations were similar between pre- and postmenopausal women following an overnight fast (142.7 +/- 9.7 v 136.1 +/- 6.4 micromol/L) and at 30 minutes (112.7 +/- 5.5 v 108.4 +/- 4.5 micromol/L ) and 120 minutes (92.7 +/- 4.5 v 97.5 +/- 5.9 micromol/L ) into the euglycemic hyperinsulinemic clamp. Plasma glycerol levels remained similar after statistical adjustment for fat mass, percent fat, and intra-abdominal fat. Moreover, no differences in plasma glycerol were observed in pre- and postmenopausal women matched (+/- 5%) for fat mass (n = 22/group) or intra-abdominal fat (n = 15/group). In premenopausal women, plasma glycerol levels at 30 and 120 minutes of hyperinsulinemia were positively related to adiposity measures (range, r =.314 to r =.493; P <.05 to P <.01), although no relationships were found in postmenopausal women. Our results suggest no effect of menopausal status on plasma glycerol levels under postabsorptive or hyperinsulinemic conditions.     

Effects of massive obesity on insulin sensitivity and insulin clearance and the metabolic response to insulin as assessed by the euglycemic clamp technique

Insulin sensitivity was studied in nine nondiabetic massively obese patients (one male and eight females ages 39.0 +/- 2.7 years, body mass index 47.1 +/- 1) by the euglycemic clamp technique (40 microU/m2/min) and compared to seven lean control subjects (three males and three females, ages 34.8 +/- 2.5 years, body mass index 23 +/- 1.1). Fasting plasma glucose, immunoreactive insulin, and C-peptide concentrations were higher in the massively obese patients than in the controls (P less than 0.025). Following exogenous insulin infusion, immunoreactive glucagon and C-peptide concentrations decreased similarly in the massively obese patients and controls, indicating normal sensitivity of the alpha and beta cell to insulin. Glucose uptake (M) expressed either as mg X min-1 of fat free mass was significantly reduced in the massively obese patients compared to the controls (P less than 0.001). Similarly, the M/I ratio (glucose uptake per unit of insulin) was significantly reduced in the massively obese patients (P less than 0.001). Free fatty acids and glycerol concentrations measured in the fasting state were significantly elevated in the massively obese patients (free fatty acids 678 +/- 51 v 467 +/- 55 mumol/L, P less than 0.05; glycerol 97 +/- 9 v 59 +/- 11 mumol/L, P less than 0.02). The effects of insulin on antilipolysis was assessed by measuring the reductions in free fatty acids and glycerol concentration during the glucose clamp study. Although the absolute levels remained higher in the massively obese patients, inhibition of lipolysis was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lipolysis in African-American children: is it a metabolic risk factor predisposing to obesity?

Rates of obesity and type 2 diabetes are higher in African-American (AA), compared with American white (AW), adults and children. It is not known whether biologic and/or environmental differences are responsible for this racial disparity. We and others have demonstrated that AA children are hyperinsulinemic, compared with their AW peers. This investigation tested the hypothesis that hyperinsulinemia in AA children is associated with lower rates of lipolysis, which could be a risk factor for future obesity. Forty prepubertal children (20 AA and 20 AW) with comparable body composition (assessed by dual-energy x-ray absorptiometry) and visceral adiposity (evaluated with computed tomography scan) were studied. Total body lipolysis was measured with [(2)H(5)]glycerol after overnight fasting. Basal lipolysis was approximately 40% lower in AA vs. AW children, whether the data were expressed for total body (85.7 +/- 8.9 vs. 130.3 +/- 14.1 micromol/min, P = 0.011) or per-kilogram BW (2.4 +/- 0.2 vs. 3.8 +/- 0.4 micromol/min.kg, P = 0.002) or per kilogram fat free mass (FFM) (3.3 +/- 0.3 vs. 5.2 +/- 0.5 micromol/min.kg FFM, P = 0.004), or per kg fat mass (FM) (13.7 +/- 1.6 vs. 21.3 +/- 3.3 micromol/min.kg FM, P = 0.046). Fasting insulin levels were higher in AA children (99.6 +/- 7.8 vs. 77.4 +/- 5.9 pmol/L, P = 0.032). Lipolysis correlated positively with fat mass, percent body fat, and abdominal fat mass. However, in multiple-regression analysis models after controlling for insulin and body composition, race remained a significant contributor to the variance in lipolysis. In summary, the present study demonstrates that rates of lipolysis are significantly lower in AA children, compared with their white peers. This may constitute an early metabolic phenotype that may mediate fat trapping and susceptibility to obesity in a specific environmental context of energy excess conducive to fat accretion.     

Differences in adipose tissue metabolism between postmenopausal and perimenopausal women

Changes in adipose tissue metabolism may contribute to the changes in body fat distribution seen during the menopause transition. We compared in vitro abdominal and gluteal sc adipose tissue metabolism [basal and stimulated lipolysis and activity of adipose tissue lipoprotein lipase (AT-LPL)] in postmenopausal and perimenopausal women (n = 12/group), matched for race, body mass index (29.5 +/- 3.8 kg/m(2); mean +/- SD), and percentage body fat (42 +/- 6%). The postmenopausal women were older (54 +/- 3 vs. 48 +/- 3 yr; P < 0.01) and had higher FSH (55.5 +/- 26.4 vs. 16.6 +/- 22.5 IU/ml; P < 0.01) and lower estradiol (33.8 +/- 14.9 vs. 97.4 +/- 61.7 pmol/liter; P < 0.05) concentrations than the perimenopausal women. Despite similar fat cell size and beta-adrenergic receptor and postreceptor (dibutyryl-cAMP)-stimulated lipolysis, basal lipolysis was 77% lower in gluteal adipose cells from postmenopausal compared with perimenopausal women (P < 0.05). Within each group, AT-LPL activity in the gluteal region was significantly higher than in the abdominal region (P < 0.05). In addition, AT-LPL activity was significantly higher in the postmenopausal compared with perimenopausal women in both gluteal (4.9 +/- 3.6 vs. 2.0 +/- 1.4 nmol free fatty acid/g.min; P < 0.05) and abdominal (3.2 +/- 2.6 vs. 1.3 +/- 0.9 nmol free fatty acid/g.min; P < 0.05) adipose cells. The results of this study suggest that menopause status is associated with differences in adipose tissue metabolism in both the abdominal and gluteal fat depots. The lower lipolysis and higher AT-LPL activity in postmenopausal women may predispose them to gain body fat after menopause.     

Fat metabolism during high-intensity exercise in endurance-trained and untrained men

To determine whether trained individuals rely more on fat than untrained persons during high-intensity exercise, six endurance-trained men and six untrained men were studied during 30 minutes of exercise at 75% to 80% maximal oxygen consumption (VO2max). The rates of appearance (Ra) and disappearance (Rd) of glycerol and free fatty acids (FFAs) were determined using [1,1,2,3,3-2H]glycerol and [1-13C]palmitate, respectively, whereas the overall rate of fatty acid oxidation was determined using indirect calorimetry. During exercise, the whole-body rate of lipolysis (ie, glycerol Ra) was higher in the trained group (7.1 +/- 1.2 v 4.5 +/- 0.7 micromol x min(-1) x kg(-1), P < .05), as was the Ra (approximately Rd) of FFA (9.0 +/- 0.9 v 5.0 +/- 1.0 micromol x min(-1) x kg(-1), P < .001). FFA utilization was higher in trained subjects even when expressed as a percentage of total energy expenditure (10% +/- 1% v 7% +/- 1%, P < .05). However, this difference in plasma FFA flux could not account for all of the difference in fatty acid oxidation between trained and untrained subjects (20.8 +/- 3.3 v 7.9 +/- 1.6 micromol x min(-1) x kg(-1), or 23% +/- 3% v 13% +/- 2% of total energy expenditure, both P < .05). Thus, the oxidation of fatty acids derived from some other source also must have been greater in the trained men. We conclude that trained athletes use more fat than untrained individuals even during intense exercise performed at the same percentage of VO2max. The additional fatty acids appear to be derived from both adipose tissue and, presumably, intramuscular triglyceride stores.     

Amino acid, glucose, and lipid kinetics after palliative resection in a patient with glucagonoma syndrome

Glucagon excess causes catabolic changes, including enhanced glucose production, lipolysis, and amino acid oxidation. In this study, we evaluate the metabolic effects of debulking surgery on a patient with glucagon-producing tumor. Stable isotope tracer methods were used to measure glucose, glycerol, and alpha-ketoisocaproic acid (alpha KICA) rates of appearance (Ra) into plasma. Measurements were obtained 25 days after surgery in the basal state and during hormonal suppression of glucagon production by infusing somatostatin with insulin replacement. Basal plasma glucagon concentration (14,100 pg/mL) remained high after debulking surgery. Somatostatin infusion decreased plasma glucagon concentration to 6,735 pg/mL and basal substrate kinetics (alpha-KICA Ra from 1.97 to 1.48 micromol/kg/min; glucose Ra from 16.89 to 11.56 micromol/kg/min; and glycerol Ra from 3.33 to 2.74 micromol/kg/min). We conclude that debulking surgery fails to adequately suppress glucagon production and the alterations in substrate metabolism associated with excess glucagon. In these patients, somatostatin therapy can be an effective method to suppress secretion of glucagon and help attenuate its catabolic effects.     

Insulin action in adipose tissue and muscle in hypothyroidism

BACKGROUND: Although insulin resistance in thyroid hormone excess is well documented, information on insulin action in hypothyroidism is limited. METHODS: To investigate this, a meal was given to 11 hypothyroid (HO; aged 45 +/- 3 yr) and 10 euthyroid subjects (EU; aged 42 +/- 4 yr). Blood was withdrawn for 360 min from veins (V) draining the anterior abdominal sc adipose tissue and the forearm and from the radial artery (A). Blood flow (BF) in adipose tissue was measured with 133Xe and in forearm with strain-gauge plethysmography. Tissue glucose uptake was calculated as (A-V)glucose(BF), lipoprotein lipase as (A-V)Triglycerides(BF), and lipolysis as [(V-A)glycerol(BF)]-lipoprotein lipase. RESULTS: The HO group had higher glucose and insulin levels than the EU group (P < 0.05). In HO vs. EU after meal ingestion (area under curve 0-360 min): 1) BF (1290 +/- 79 vs. 1579 +/- 106 ml per 100 ml tissue in forearm and 706 +/- 105 vs. 1340 +/- 144 ml per 100 ml tissue in adipose tissue) and glucose uptake (464 +/- 74 vs. 850 +/- 155 micromol per 100 ml tissue in forearm and 208 +/- 42 vs. 406 +/- 47 micromol per 100 ml tissue in adipose tissue) were decreased (P < 0.05), but fractional glucose uptake was similar (28 +/- 6 vs. 33 +/- 6% per minute in forearm and 17 +/- 4 vs. 14 +/- 3% per minute in adipose tissue); 2) suppression of lipolysis by insulin was similar; and 3) plasma triglycerides were elevated (489 +/- 91 vs. 264 +/- 36 nmol/liter.min, P < 0.05), whereas adipose tissue lipoprotein lipase (42 +/- 11 vs. 80 +/- 21 micromol per 100 ml tissue) and triglyceride clearance (45 +/- 10 vs. 109 +/- 21 ml per 100 ml tissue) were decreased in HO (P < 0.05). CONCLUSIONS: In hypothyroidism: 1) glucose uptake in muscle and adipose tissue is resistant to insulin; 2) suppression of lipolysis by insulin is not impaired; and 3) hypertriglyceridemia is due to decreased clearance by the adipose tissue.     

Regulation of non-esterified fatty acid and glycerol concentration by insulin in normal individuals and patients with type 2 diabetes.

Plasma glycerol and non-esterified fatty acid (NEFA) concentrations were determined in the basal state and in response to physiological hyperinsulinaemia in 30 non-obese individuals, 15 with Type 2 diabetes and 15 with normal glucose tolerance. Patients with Type 2 diabetes had higher basal concentrations of both glycerol (81 +/- 7 (+/- SE) vs 61 +/- 7 mumol l-1, p less than 0.05) and NEFA (842 +/- 40 vs 630 +/- 46 mumol l-1, p less than 0.002). Plasma NEFA and glycerol concentrations fell in both groups when steady-state plasma insulin concentrations were raised to approximately 450 pmol l-1 by an infusion of exogenous insulin, but plasma concentrations of glycerol (28 +/- 3 vs 13 +/- 3 mumol l-1, p less than 0.002) and NEFA (186 +/- 15 vs 109 +/- 14 mumol l-1, p less than 0.001) were still higher in patients with Type 2 diabetes. Percentage decrease in glycerol from basal levels in response to insulin was significantly less in patients with Type 2 diabetes than in control subjects (64 +/- 3 vs 80 +/- 3%, p less than 0.005); percentage decrease in plasma NEFA concentration was similar in the two groups (78 +/- 3 vs 80 +/- 4%). These results suggest that both plasma glycerol and NEFA concentrations are higher than normal in patients with Type 2 diabetes when measured at the same insulin concentration, both under basal conditions and in response to physiological hyperinsulinaemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adipose tissue, hepatic, and skeletal muscle insulin sensitivity in extremely obese subjects with acanthosis nigricans

We evaluated insulin action in skeletal muscle (glucose disposal), liver (glucose production), and adipose tissue (lipolysis) in 5 extremely obese women with acanthosis nigricans (AN), who had normal oral glucose tolerance, and 5 healthy lean subjects, by using a 5-stage pancreatic clamp and stable isotopically labeled tracer infusion. Basal plasma insulin concentration was much greater in obese subjects with AN than lean subjects (54.8 +/- 4.5 vs 8.0 +/- 1.3 microU/mL, P < .001), but basal glucose and free fatty acid concentrations were similar in both groups. During stage 1 of the clamp, glucose rate of appearance (R(a)) (2.6 +/- 0.3 vs 3.7 +/- 0.3 micromol x kg FFM(-1) x min(-1), P = .02) and palmitate R(a) (2.4 +/- 0.6 vs 7.0 +/- 1.5 micromol x kg FFM(-1) x min(-1), P < .05) were greater in obese subjects with AN than lean subjects despite slightly greater plasma insulin concentration in subjects with AN (3.0 +/- 0.7 vs 1.1 +/- 0.4 microU/mL, P < .05). The area under the curve for palmitate R(a) (1867 +/- 501 vs 663 +/- 75 micromol x kg FFM(-1) x 600 min(-1), P = .03) and glucose R(a) (1920 +/- 374 vs 1032 +/- 88 micromol x kg FFM(-1) x 600 min(-1), P = .02) during the entire clamp procedure was greater in subjects with AN than lean subjects. During intermediate insulin conditions (plasma insulin, approximately 35 microU/mL), palmitate R(a) was 5-fold greater in subjects with AN than in lean subjects (2.6 +/- 1.1 vs 0.5 +/- 0.2 micromol x kg FFM(-1) x min(-1), P = .05). Maximal glucose disposal was markedly lower in obese subjects with AN than in lean subjects (13.0 +/- 0.8 vs 23.4 +/- 1.8 mg x kg FFM(-1) x min(-1), P = .01) despite greater peak plasma insulin concentration (1842 +/- 254 vs 598 +/- 38 microU/mL, P < .05). These data demonstrate obese young adults with AN have marked insulin resistance in multiple tissues. However, marked insulin hypersecretion can compensate for impaired insulin action, resulting in normal glucose and fatty acid metabolism during basal conditions.     

Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities

BACKGROUND AND AIMS: The pathogenesis of nonalcoholic steatohepatitis (NASH) is unknown. We tested the hypothesis that NASH is associated with 2 defects: (1) peripheral insulin resistance, which increases lipolysis, delivery of free fatty acids (FFA) to the liver, and hepatic fatty acid beta oxidation, thereby creating oxidative stress; and (2) an abnormality within the hepatocytes that might render them more susceptible to injury from oxidative stress. METHODS: The hypothesis was tested by evaluation of (1) insulin resistance by a 2-step hyperinsulinemic (10 and 40 mU. m(-2). min(-1)) euglycemic clamp; (2) insulin effects on lipolysis by enrichment of [U-(13)C]glycerol; (3) frequency and severity of structural defects in hepatocyte mitochondria in vivo; (4) fatty acid beta oxidation from serum [beta-OH butyrate], release of water-soluble radioactivity from (3)H-palmitate by cultured fibroblasts and urinary dicarboxylic acid excretion; and (5) hepatic lipid peroxidation by immunohistochemical staining for 3-nitrotyrosine (3-NT). Subjects with NASH (n = 6-10 for different studies) were compared with those with fatty liver (n = 6) or normal controls (n = 6). RESULTS: NASH and fatty liver were both associated with insulin resistance, with mean glucose infusion rates (normal/fatty liver/NASH) of step 1, 4.5/1.6/0.9; step 2, 9.5/7.7/4.5 (P < 0.03 for both steps). Although baseline rates of glycerol appearance were higher in those with NASH than in those with fatty liver (means, 14.6 vs. 21.6 micromol. kg(-1). min(-1); P < 0.05), neither group significantly suppressed glycerol appearance at insulin infusion rates of 10 mU. m(-2). min(-1). NASH was associated with loss of mitochondrial cristae and paracrystalline inclusions in 9 of 10 subjects, compared with 0 of 6 subjects with fatty liver. However, no evidence of a generalized defect in fatty acid beta oxidation was noted in any group. Also, mean [beta-OH butyrate] was highest in those with NASH (means, 90 vs. 110 vs. 160 micromol/L; P < 0.04). Increased staining for 3-NT was present in fatty liver, and even greater staining was seen in NASH. CONCLUSIONS: These data indicate that peripheral insulin resistance, increased fatty acid beta oxidation, and hepatic oxidative stress are present in both fatty liver and NASH, but NASH alone is associated with mitochondrial structural defects.