Hyperandrogenemia in human immunodeficiency virus-infected women with the lipodystrophy syndrome

A novel lipodystrophy syndrome characterized by insulin resistance, hypertriglyceridemia, and fat redistribution has recently been described in human immunodeficiency virus (HIV)-infected men and women. Women with the HIV lipodystrophy syndrome exhibit a marked increase in waist-to-hip ratio and truncal adiposity; however, it is unknown whether androgen levels are increased in these patients. In this study, we assessed androgen levels in female patients with clinical lipodystrophy based on evidence of significant fat redistribution in the trunk, extremities, neck and/or face (LIPO: n = 9; age, 35.7+/-1.7 yr; BMI, 24.7+/-0.8 kg/m2) in comparison with age- and BMI-matched nonlipodystrophic HIV-infected females (NONLIPO: n = 14; age, 37.6+/-1.1 yr; BMI, 23.4+/-0.6 kg/m2) and healthy non-HIV-infected control subjects (C: n = 16; age, 35.8+/-0.9 yr; BMI, 23.1+/-0.4 kg/m2). Fasting insulin, lipid levels, virologic parameters, and regional body composition using dual energy x-ray absorptiometry were also assessed. Total testosterone [ LIPO, 33+/-6 ng/dL (1.1+/-0.2 nmol/L); NONLIPO, 17+/-2 ng/dL (0.6+/-0.1 nmol/L); C, 23+/-2 ng/dL (0.8+/-0.1 nmol/L); P < 0.05 LIPO vs. C and LIPO vs. NONLIPO] and free testosterone determined by equilibrium dialysis [LIPO, 4.5+/-0.9 pg/mL (16+/-3 pmol/L); NONLIPO, 1.7+/-0.2 pg/mL (6+/-1 pmol/L); C, 2.4+/-0.2 pg/mL (8+/-1 pmol/L); P < 0.05 LIPO vs. C and LIPO vs. NONLIPO] were increased in the lipodystrophic patients. Sex hormone-binding globulin levels were not significantly different between LIPO and C, but were significantly lower in the LIPO vs. NONLIPO patients (LIPO 84+/-7 vs. NONLIPO 149+/-17 nmol/L, P < 0.05). The LH/FSH ratio was significantly increased in the LIPO group compared with the NONLIPO and C subjects (LIPO, 2.0+/-0.6; NONLIPO, 1.1+/-0.1; C, 0.8+/-0.1; P < 0.05 LIPO vs. NONLIPO and LIPO vs. C). Body fat distribution was significantly different between LIPO and C subjects. Trunk to extremity fat ratio (1.46+/-0.17 vs. 0.75+/-0.05, LIPO vs. C, P < 0.05) was increased and extremity to total fat ratio decreased (0.40+/-0.03 vs. 0.55+/-0.01, LIPO vs. C, P < 0.05). In contrast, fat distribution was not different in the NONLIPO group vs. control subjects. Among the HIV-infected patients, free testosterone correlated with percent truncal fat (trunk fat/trunk mass) (r = 0.43, P = 0.04). These data suggest that hyperandrogenemia is another potentially important feature of the HIV-lipodystrophy syndrome in women. Additional studies are necessary to determine the clinical significance of increased androgen levels and the relationship of hyperandrogenism to fat redistribution and insulin resistance in this population of patients.     

Different growth hormone sensitivity of target tissues and growth hormone response to glucose in HIV-infected patients with and without lipodystrophy

Growth hormone (GH)-secretion in HIV-lipodystrophy is impaired; however, GH-sensitivity of GH-target tissues remains to be evaluated. We measured overnight fasting concentrations of GH-sensitive insulin-like growth-factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) including GH binding protein (GHBP), a marker of GH-receptor sensitivity, in antiretroviral treated HIV-infected patients with (LIPO) and without lipodystrophy (NONLIPO) and antiretroviral naive HIV-infected patients (NAIVE). Three h GH-suppression tests using oral glucose were undertaken to determine dynamics of GH-secretion. IGF-I and IGFBP-3 were increased in LIPO compared with NONLIPO (p <0.05), but did not differ significantly between NONLIPO and NAIVE. Area under the curve of GH (AUC-GH) during the GH-suppression test was decreased in LIPO compared with NONLIPO (p <0.05). Ratio of limb to trunk fat, which was decreased in LIPO compared to NONLIPO and NAIVE (p <0.001), correlated positively with AUC-GH and rebound-GH (p <0.05). All groups displayed suppression of GH during the suppression test (p <0.05) and all groups, except LIPO, displayed a rebound of GH (p <0.05), which probably is explained by persistently increased plasma glucose in LIPO compared with NONLIPO and NAIVE (p <0.01). GHBP was inversely correlated with AUC-GH (p <0.01). Our data suggest that GH-target tissues in LIPO are at least as GH-sensitive as in HIV-infected patients without lipodystrophy.     

Elevated concentrations of free fatty acids are associated with increased insulin response to standard glucose challenge in human immunodeficiency virus-infected subjects with fat redistribution

Fat redistribution, defined by both increased abdominal visceral fat and/or decreased abdominal, extremity, and facial subcutaneous fat, is increasingly recognized among human immunodeficiency virus (HIV)-infected patients treated with combination antiretroviral therapy. Fat redistribution in this population is associated with insulin resistance and dyslipidemia and is often referred to as the HIV lipodystrophy syndrome (LIPO). Fatty acids are known to modulate insulin resistance in other disease states, but a comprehensive evaluation of fatty acids has not been undertaken among HIV-infected patients with fat redistribution. In this study, we investigated fatty acid concentrations in 64 HIV-infected individuals (45 men and 19 women) with evidence of fat redistribution (LIPO) in comparison to 30 HIV-infected individuals (20 men and 10 women) without evidence of fat redistribution (NONLIPO) and 32 HIV-negative healthy control subjects (C) (21 males and 11 females) of similar age and body mass index (BMI). Glucose, insulin, and free fatty acid (FFA) levels were measured in response to a 75-g oral glucose tolerance test (OGTT) in the LIPO, NONLIPO, and C subjects. In addition, fasting lipids were obtained, and body composition was determined by anthropometric measurements and dual-energy x-ray absorptiometry (DXA). Fasting FFA concentrations were significantly increased in the LIPO group as compared with NONLIPO and C subjects (0.74 +/- 0.03 v 0.60 +/- 0.04 [mean +/- SEM] mmol/L, P =.002, LIPO v NONLIPO; 0.74 +/- 0.03 v 0.59 +/- 0.03 mmol/L, P =.001, LIPO v C). In contrast, fasting FFA concentrations were not increased in the NONLIPO group (0.60 +/- 0.04 v 0.59 +/- 0.03, P =.909, NONLIPO v C). Similarly, fasting triglycerides and 120-minute OGTT FFA were significantly increased in the LIPO group as compared with the NONLIPO and C group. FFA decreased in HIV-infected LIPO, NONLIPO, and C subjects in response to OGTT, but the 120-minute FFA concentrations remained significantly elevated in LIPO patients compared with NONLIPO and C subjects. In a multivariate regression model of LIPO patients, fasting FFA (P =.027) was a strong independent predictor of insulin area under the curve (AUC), controlling for age, BMI, gender, and body composition (r(2) for model =.31). No differences were observed in FFA concentrations in the LIPO group in an analysis based on current protease inhibitor (PI) use. These data suggest that FFA concentrations are increased in HIV-infected patients with fat redistribution. Increased fasting concentrations of fatty acids are associated with abnormal insulin responses to standard glucose challenge in HIV-infected patients with fat redistribution. Further studies are necessary to determine the mechanism of increased fatty acid concentrations and the role played by increased FFA in mediating insulin resistance in this population.     

Growth hormone (GH) responses to GH-releasing hormone-arginine testing in human immunodeficiency virus lipodystrophy

Prior studies suggest reduced overnight GH secretion in association with excess visceral adiposity among patients with HIV lipodystrophy (LIPO, i.e. with fat redistribution). We now investigate GH responses to standardized GHRH-arginine in LIPO patients (n = 39) in comparison with body mass index- and age-matched control groups [HIV patients without fat distribution (NONLIPO, n = 17)] and healthy subjects (C, n = 16). IGF-I [242 +/- 17; 345 +/- 38; 291 +/- 27 ng/ml (P < 0.05 vs. NONLIPO)] was lowest in the LIPO group. Our data demonstrate failure rates of 18% for the LIPO group vs. 5.9% for the NONLIPO group and 0% for the C group, using a stringent criterion of 3.3 ng/ml for peak GH response to GHRH-arginine (P < 0.05 LIPO vs. C). Using less stringent cutoffs, the failure rate in the LIPO group rises to 38.5% at 7.5 ng/ml. Among the LIPO patients, the peak GH response to GHRH-arginine was significantly predicted by visceral adipose tissue (P = 0.008), free fatty acid (P = 0.04), and insulin level (P = 0.007) in regression modeling controlling for age, body mass index, sc fat area, and triglyceride level. These data demonstrate increased failure rates to standardized stimulation testing with GHRH-arginine in LIPO patients, in association with increased visceral adiposity. The effects of low-dose GH should be assessed in the large subset of LIPO patients with abnormal GH stimulation testing.     

Assessment of growth hormone dynamics in human immunodeficiency virus-related lipodystrophy

Human immunodeficiency virus (HIV) lipodystrophy (LIPO) is characterized by increased visceral adiposity, peripheral fat atrophy, dyslipidemia, and insulin resistance. GH concentrations are known to vary inversely with excess weight and body fat but have not been investigated in HIV lipodystrophy. Twenty-one subjects with HIV LIPO, 20 HIV-infected nonlipodystrophy subjects (NONLIPO), and 20 control (C) subjects were prospectively recruited for this study and compared. Subjects in the three groups were all male, age-matched [median, 47 yr old (interquartile range, 37-50) LIPO; 41 (37-44) NONLIPO; and 43 (37-49) C], and body mass index-matched [median, 24.3 kg/m(2) (interquartile range, 22.2-26.6) LIPO; 24.4 (23.3-25.9) NONLIPO; and 24.8 (22.7-26.1) C] (P: > 0.05 for all comparisons). Visceral abdominal fat [16,124 mm(2) (11,246-19,790) LIPO; 7,559 (5,134-11,201) NONLIPO; and 8,803 (6,165-11,623) C; P < 0.01 LIPO vs. NONLIPO and LIPO vs. C] and the ratio of visceral abdominal fat to sc abdominal fat [1.37 (0.71-2.44) LIPO vs. 0.57 (0.47-0.78) NONLIPO vs. 0.55 (0.41-0.71) C, P < 0.01 LIPO vs. NONLIPO and LIPO vs. C] were significantly increased in the LIPO subjects but were not significantly different between NONLIPO and C. The mean overnight GH concentration, determined from frequent sampling every 20 min (from 2000 h to 0800 h) was decreased in the LIPO subjects [0.38 microg/L (0.13-0.67) LIPO vs. 0.96 (0.53-1.30) NONLIPO vs. 0.81 (0.49-1.03) C, P < 0.05 LIPO vs. NONLIPO and LIPO vs. C] and not significantly different between NONLIPO and C. Pulse analysis demonstrated decreased baseline GH [0.08 microg/L (0.06-0.21) LIPO vs. 0.19 (0.10-0.32) NONLIPO vs. 0.17 (0.12-0.57) C, P < 0.05 LIPO vs. NONLIPO and LIPO vs. C] and GH peak amplitude [1.06 microg/L (0.46-1.94) LIPO vs. 2.47 (1.22-3.43) NONLIPO and 2.27 (1.36-4.25) C, P < 0.05 LIPO vs. NONLIPO and LIPO vs. C] in the LIPO subjects but no significant difference in pulse frequency. No significant differences were observed between NONLIPO and C for any GH parameter. Insulin-like growth factor-I was not different between the groups. Total body fat (r = -0.40, P = 0.01) and visceral fat (r = -0.58, P = 0.0001) correlated inversely with mean overnight GH concentrations in the HIV-infected patients. In a multivariate regression model, controlling for age, body mass index, body fat, and visceral fat, only visceral fat was a significant predictor of mean GH concentrations (P = 0.0036, r(2) for model = 0.40). These data demonstrate normal GH pulse frequency and insulin-like growth factor-I concentrations but reduced mean GH concentrations, basal GH concentrations, and GH pulse amplitude in patients with HIV lipodystrophy. Increased visceral adiposity is the strongest predictor of reduced GH concentrations in HIV lipodystrophy. Further studies are necessary to determine the clinical significance of reduced GH in patients with HIV lipodystrophy.     

Impaired proinsulin secretion before and during oral glucose stimulation in HIV-infected patients who display fat redistribution

The beta-cell function of HIV-infected patients on highly active antiretroviral therapy who display lipodystrophy may be impaired. An early defect in beta-cell function may be characterized by an increase in secretion of 32-33 split proinsulin (SP) and intact proinsulin (IP). To address this issue, the secretion patterns of SP and IP of 16 HIV-infected men with lipodystrophy (LIPO) and 15 HIV-infected men without lipodystrophy (NONLIPO) were studied during an oral glucose tolerance test (OGTT). All patients received highly active antiretroviral therapy. Insulin secretion rates were determined by deconvolution of plasma C-peptide concentrations. More LIPO than NONLIPO patients displayed diabetes mellitus and impaired glucose tolerance than normal glucose tolerance (LIPO 2/8/6 vs NONLIPO 1/2/12, P = .05). LIPO patients had increased fasting levels of SP and IP, ratio of SP/IP, and area under the curve of SP and IP during the early phase (0, 10, and 20 minutes) and during the late phase (45, 75, and 105 minutes) of the OGTT compared with NONLIPO patients (Ps < .05). LIPO patients exhibited significantly increased fasting SP/IP ratio, fasting SP/insulin ratio, and total proinsulin to C-peptide ratio during the OGTT. LIPO patients displayed increased incremental secretion of IP during the first 10 minutes of the OGTT (P < .05), although the incremental insulin secretion during this period did not differ between LIPO and NONLIPO patients. These data suggest that HIV-infected patients with lipodystrophy display major perturbations of proinsulin secretion in the fasting state and during an OGTT, which is compatible with the notion of a beta-cell dysfunction of such patients.     

Insulin-like growth factors, insulin-like growth factor-binding proteins, insulin-like growth factor-binding protein-3 protease, and growth hormone-binding protein in lipodystrophic human immunodeficiency virus-infected patients

Human immunodeficiency virus (HIV)-lipodystrophy is associated with impaired growth hormone (GH) secretion. It remains to be elucidated whether insulin-like growth factors (IGFs), IGF-binding proteins (IGFBPs), IGFBP-3 protease, and GH-binding protein (GHBP) are abnormal in HIV-lipodystrophy. These parameters were measured in overnight fasting serum samples from 16 Caucasian males with HIV-lipodystrophy (LIPO) and 15 Caucasian HIV-infected males without lipodystrophy (NONLIPO) matched for age, weight, duration of HIV infection, and antiretroviral therapy. In LIPO, abdominal fat mass and insulin concentration were increased (>90%, P < .01) and insulin sensitivity (Log10ISI(composite)) was decreased (-50%, P < .001). Total and free IGF-I, IGF-II, IGFBP-3, and IGFBP-3 protease were similar between groups (all P > .5), whereas, in LIPO, IGFBP-1 and IGFBP-2 were reduced (-36%, P < .05 and -50%, P < .01). In pooled groups, total IGF-I, free IGF-I, total IGF-II, and IGFBP-3, respectively, correlated inversely with age (all P < .01). In pooled groups, IGFBP-1 and IGFBP-2 correlated positively with insulin sensitivity (age-adjusted all P < .05). IGFBP-3 protease correlated with free IGF-I in pooled groups (r(p) = 0.47, P < .02), and in LIPO (r(p) = 0.71, P < .007) controlling for age, total IGF-I, and IGFBP-3. GHBP was increased, whereas GH was decreased in LIPO (all P < .05). GH correlated inversely with GHBP in pooled groups (P < .05). Taken together the similar IGFs and IGFBP-3 concentrations between study groups, including suppressed GH, and increased GHBP in LIPO, argue against GH resistance of GH-sensitive tissues in LIPO compared with NONLIPO; however, this notion awaits examination in dose-response studies. Furthermore, our data suggest that IGFBP-3 protease is a significant regulator of bioactive IGF-I in HIV-lipodystrophy.     

Tumor necrosis factor alpha is associated with insulin-mediated suppression of free fatty acids and net lipid oxidation in HIV-infected patients with lipodystrophy

Tumor necrosis factor alpha (TNF-alpha) stimulates lipolysis in man. We examined whether plasma TNF-alpha is associated with the degree by which insulin suppresses markers of lipolysis, for example, plasma free fatty acid (FFA) and net lipid oxidation (LIPOX) rate in HIV-infected patients with lipodystrophy (LIPO) and those without (controls). LIPOX was estimated by indirect calorimetry during fasting and steady state of a hyperinsulinemic euglycemic clamp in 36 (18 LIPO and 18 controls) normoglycemic HIV-infected men on highly active antiretroviral therapy. In LIPO, TNF-alpha correlated with clamp FFA (r = 0.67, P < .01), clamp LIPOX (r = 0.47, P < .05), incremental FFA (r = 0.69, P < .01), and incremental LIPOX (r = 0.64, P < .01), all of which, but not the clamp LIPOX correlation (r = 0.29, P > .05), remained significant after correction for insulin sensitivity. None of these correlations were significant in controls. In all patients, TNF-alpha correlated with clamp FFA (r = 0.61, P < .001), clamp LIPOX (r = 0.43, P < .01), and incremental FFA (r = 0.43, P < .01), with the 2 former correlations remaining significant after correction for insulin sensitivity. LIPOX and FFA (fasting and clamp values combined) correlated strongly and positively in both LIPO (R2 = 0.43, P < .001) and controls (R2 = 0.60, P < .0001). Fasting FFA and LIPOX did not differ between study groups; however, the insulin-mediated suppression of FFA and LIPOX was attenuated in LIPO (P's < .05). Our data indicate that higher TNF-alpha, independently of insulin sensitivity, is associated with attenuated insulin-mediated suppression of FFA and LIPOX in HIV-LIPO, suggesting in turn that TNF-alpha stimulates lipolysis in this syndrome. Furthermore, FFA may be a major determinant of LIPOX in HIV-infected patients on highly active antiretroviral therapy.     

In nondiabetic, human immunodeficiency virus-infected patients with lipodystrophy, hepatic insulin extraction and posthepatic insulin clearance rate are decreased in proportion to insulin resistance

In healthy, nondiabetic individuals with insulin resistance, fasting insulin is inversely correlated to the posthepatic insulin clearance rate (MCRi) and the hepatic insulin extraction (HEXi). We investigated whether similar early mechanisms to facilitate glucose homeostasis exist in nondiabetic, human immunodeficiency virus (HIV)-infected patients with and without lipodystrophy. We studied 18 HIV-infected patients with lipodystrophy (LIPO) on antiretroviral therapy and 25 HIV-infected patients without lipodystrophy (controls) of whom 18 were on antiretroviral therapy and 7 were not. Posthepatic insulin clearance rate was estimated as the ratio of posthepatic insulin appearance rate to steady-state plasma insulin concentration during a euglycemic hyperinsulinemic clamp (40 mU.m-2 .min-1). Posthepatic insulin appearance rate during the clamp was calculated, taking into account the remnant endogenous insulin secretion, which was estimated by deconvolution of C-peptide concentrations. Hepatic extraction of insulin was calculated as 1 minus the ratio of fasting posthepatic insulin delivery rate to fasting endogenous insulin secretion rate. Compared with controls, LIPO displayed increased fasting insulin (130%, P < .001), impaired insulin sensitivity index (M value, -29%, P < .001), and reduced MCRi (-17%, P < .01). Hepatic extraction of insulin was similar between groups (LIPO, 55%; controls, 57%; P > .8). In LIPO, HEXi and MCRi correlated inversely with fasting insulin (r = -0.56, P < .02 and r = -0.68, P < .002) and positively with M value (r = 0.63, P < .01 and r = 0.65, P < .004). In controls, MCRi correlated inversely with fasting insulin (r = -0.47, P < .02) and positively with M value (r = 0.57, P < .004); however, the correlations between HEXi and these parameters were insignificant (P > .1). Our data suggest that HEXi and MCRi are decreased in proportion to the degree of insulin resistance in nondiabetic HIV-infected patients with lipodystrophy.     

Relationship of fat distribution with adipokines in human immunodeficiency virus infection

BACKGROUND AND METHODS: HIV-infected patients receiving antiretroviral therapy often develop changes in body fat distribution; the dominant change is reduction in sc adipose tissue (SAT). Because adipose tissue makes important hormones involved in whole-body energy metabolism, including leptin and adiponectin, we examined plasma concentrations and their relationship to regional adiposity measured by magnetic resonance imaging in 1143 HIV-infected persons (803 men and 340 women) and 286 controls (151 men and 135 women) in a cross-sectional analysis of the FRAM study. RESULTS: Total and regional adiposity correlated positively with leptin levels in HIV-infected subjects and controls (P < 0.0001). In controls, total and regional adiposity correlated negatively with adiponectin. In HIV-infected subjects, adiponectin was not significantly correlated with total adiposity, but the normal negative correlation with visceral adipose tissue and upper trunk SAT was maintained. However, leg SAT was positively associated with adiponectin in HIV-infected subjects. Within the lower decile of leg SAT for controls, HIV-infected subjects had paradoxically lower adiponectin concentrations compared with controls (men: HIV 4.1 microg/ml vs. control 7.5 microg/ml, P = 0.009; women: HIV 7.8 microg/ml vs. control 11.6 microg/ml, P = 0.037). Even after controlling for leg SAT, exposure to stavudine was associated with lower adiponectin, predominantly in those with lipoatrophy. CONCLUSION: The normal relationships between adiponectin levels and total and leg adiposity are lost in HIV-infected subjects, possibly due to changes in adipocyte function associated with HIV lipodystrophy, whereas the inverse association of adiponectin and visceral adipose tissue is maintained. In contrast, the relationship between adiposity and leptin levels appears similar to controls and unaffected by HIV lipodystrophy.     

Hepatic fat content is a determinant of postprandial triglyceride levels in type 2 diabetes mellitus patients with normal fasting triglyceride

Postprandial hypertriglyceridemia is common in type 2 diabetes mellitus (T2D). Significant numbers of T2D patients who have normal fasting triglyceride (TG) have postprandial hypertriglyceridemia. The role of regional adipose tissue and adiponectin on postprandial TG responses in this group of T2D patients is unclear. This study aimed to examine the contribution of regional adipose tissue and adiponectin to the variation of postprandial TG responses in T2D patients who have normal fasting TG levels. Thirty-one Thai T2D patients who had fasting TG<1.7 mmol/L were studied. All were treated with diet control or sulphonylurea and/or metformin. None was treated with lipid-lowering agents. Mixed-meal test was performed after overnight fast. Plasma glucose, insulin, and TG were measured before and 1, 2, 3, and 4 hours after the test. Adiponectin was measured in fasting state. Visceral as well as superficial and deep subcutaneous abdominal adipose tissues were determined by magnetic resonance imaging, and hepatic fat content (HFC) was determined by magnetic resonance spectroscopy. Univariate and multivariate regression analyses of postprandial TG and regional adipose tissue and metabolic parameters were performed. The TG levels before and 1, 2, 3, and 4 hours after the mixed meal were 1.32+/-0.40 (SD), 1.40+/-0.41, 1.59+/-0.40, 1.77+/-0.57, and 1.80+/-0.66 mmol/L, respectively (P<.0001). The area under the curve (AUC) of postprandial TG was positively and significantly correlated with fasting TG (r=0.84, P<.0001) and log.HFC (r=0.456, P=.033) and was inclined to be correlated with log.deep subcutaneous adipose tissue (r=0.38, P=.05) and sex (r=0.326, P=.073). The AUC of postprandial TG was not correlated with age, body mass index, waist circumference, log.superficial subcutaneous adipose tissue, log.visceral adipose tissue, hemoglobin A1c, fasting glucose, AUC.glucose, log.fasting insulin, log.AUC.insulin, log.homeostasis model assessment%B, log.homeostasis model assessment of insulin resistance, and adiponectin. Only fasting TG (beta=.815, P<.0001) and log.HFC (beta=.249, P=.035) predicted AUC of postprandial TG in regression model (adjusted R2=0.84, P<.0001). In conclusion, in T2D patients with normal fasting TG, the increase of postprandial TG levels is directly determined by fasting TG level and the amount of hepatic fat.     

Acarbose lowers serum triglyceride and postprandial chylomicron levels in type 2 diabetes

AIM: This study was designed to examine the therapeutic effect of acarbose on serum triglyceride (TG), free fatty acid (FFA), very low-density lipoprotein (VLDL) and chylomicron (CM) in the meal tolerance test (MTT) before and after acarbose treatment in type 2 diabetes mellitus (DM2). METHODS: Effects of acarbose on postprandial lipid metabolism were examined in DM2 patients. The subjects with normotriglyceridaemia (TG > or = 1.7 mmol/l, n = 60) were divided to three groups (A, B and C), and DM2 patients with hypertriglyceridaemia (TG > 1.7 mmol/l, n = 20) were designated group D. Group A was a control, and group B was designed to examine the one-dose effect of acarbose (100 mg) on lipid levels in MTT using the balanced food of 400 kcal. In groups C and D, acarbose 300 mg/day was administered for 8 weeks, and MTT with the one-dose acarbose administration was performed. We determined the levels of fasting and postprandial levels of glucose, insulin, FFA and TG-rich lipoproteins such as CM and VLDL. RESULTS: Acarbose treatment lowered plasma glucose levels and insulin secretion. In comparison among study groups A, B and C, acarbose significantly lowered serum TG levels in postprandial state. In group D, after the 8-week acarbose administration, fasting or postprandial FFA, TG and VLDL levels were also lowered. Interestingly, postprandial increase in CM was suppressed by acarbose administration in group B, C or D. CONCLUSIONS: Acarbose lowers postprandial TG and CM levels in DM2 with either normotriglyceridaemia or hypertriglyceridaemia. Improvement of insulin resistance with acarbose may also reduce fasting TG levels in DM2 with hypertriglyceridaemia. Acarbose is a beneficial therapeutic agent to reduce TG levels in DM2 patients, thereby leading to suppression of cardiovascular events.     

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.     

Glucose-stimulated prehepatic insulin secretion is associated with circulating alanine, triglyceride, glucagon, lactate and TNF-alpha in patients with HIV-lipodystrophy

OBJECTIVES: We examined whether insulin-resistant lipodystrophic HIV-infected patients with known high fasting prehepatic insulin secretion rates (FISRs) displayed alterations in first-phase prehepatic insulin response to intravenous glucose (ISREG0-10 min). METHODS: Eighteen normoglycaemic lipodystrophic HIV-infected (LIPO) patients and 25 normoglycaemic nonlipodystrophic HIV-infected patients (controls) were included in the study. The prehepatic insulin secretion rate was estimated by deconvolution of C-peptide concentrations, and insulin sensitivity (SIRd) was estimated by the glucose clamp technique. The disposition index (Di=ISREG0-10 min x SIRd) was calculated to estimate the beta-cell response relative to insulin sensitivity. RESULTS: FISR was increased by 69% (P<0.001), whereas median Di was decreased by 75% (P<0.01), primarily as a result of a reduction of SI(Rd) by 60% (P<0.001) in LIPO patients compared with controls. Three LIPO groups were identified arbitrarily according to their FISR and ISREG0-10 min values relative to those of controls. Four LIPO patients displayed high FISR [+3 standard deviations (SD), P<0.001], high ISREG0-10 min (+3 SD, P<0.001) and low SIRd (P<0.01), suggesting an intact B-cell capacity to compensate insulin resistance; six LIPO patients exhibited high FISR (+3SD, P<0.001), low ISREG0-10min (-1 SD, P=0.01), and low SIRd (P<0.01), suggesting depletion of readily releasable insulin stores; the remaining eight LIPO patients and controls displayed identical FISR and ISREG0-10 min. Increased concentrations of the nonglucose insulin secretagogues triglyceride (+124%), alanine (+35%) and glucagon (+88%), and also lactate (+96%) and tumour necrosis factor (TNF)-alpha (+62%) were observed in the 10 LIPO patients with aberrations in FISR and ISREG0-10 min compared with the remaining HIV-infected patients (all P<0.05). CONCLUSION: Plasma triglyceride, alanine, glucagon, lactate and TNF-alpha may be associated with alterations in the first-phase prehepatic insulin secretion response to intravenous glucose in normoglycaemic lipodystrophic HIV-infected patients.     

Short-term energy restriction reduces resting energy expenditure in patients with HIV lipodystrophy and hypermetabolism

We have previously shown that resting energy expenditure (REE) is increased in patients with HIV lipodystrophy. This hypermetabolism could be the result of an inadequate storage capacity for lipid fuel secondary to atrophy of the subcutaneous adipose tissue depot. Therefore, energy restriction may be able to alleviate this hypermetabolism. To test this hypothesis, we measured REE in HIV-infected patients with lipodystrophy and hypermetabolism and in HIV-infected and healthy controls. Measurements were taken during the overnight fasted state after 3 days on a eu-energetic diet and again after 3 days on a diet of similar composition but reduced in energy by 50%. After 3 days of eu-energetic feeding, REE was significantly higher in HIV-infected patients with lipodystrophy compared with healthy controls (139.5 +/- 1.3 vs 117.2 +/- 1.3 kJ/kg lean body mass, P < .001) and tended to be higher compared with HIV-infected subjects without lipodystrophy (139.5 +/- 13 vs 127.3 +/- 1.4 kJ/kg lean body mass, P = .06). Furthermore, energy restriction caused a significant decline in REE in patients with HIV lipodystrophy (P < .001). This dietary manipulation did not lead to a significant reduction in REE in either HIV-infected or healthy controls. This suggests that energy intake and REE may be uniquely coupled in patients with lipodystrophy as a means to dissipate energy that cannot be stored in a normal manner. A better understanding of this coupling would have important implications for weight regulation in general.     

Role of insulin resistance in adipose tissue and liver in the pathogenesis of endogenous hypertriglyceridaemia in man

Studies were performed to evaluate the relative importance of enhanced adipose tissue lipolysis and increased insulin levels in modulating hepatic VLDL production in patients with endogenous hypertriglyceridaemia. Eight control subjects and nine patients with hypertriglyceridaemia were investigated. The latter group comprised four patients with idiopathic hypertriglyceridaemia, three maturity onset diabetics, and two siblings with diabetic lipodystrophy. Each individual's plasma VLDL was selectively labelled with I131 in the apoprotein moiety and then reinjected to assess the turnover of these molecules. This was correlated with the insulin response to an oral glucose load and with the plasma FFA flux measured by a continuous infusion of 14C palmitate. In the patients with idiopathic hypertriglyceridaemia and in the adult onset diabetics, plasma VLDL-appoprotein turnover was increased suggesting enhanced hepatic production of these molecules. Although the insulin levels in these patients were higher than normal, no significant correlation was demonstrable between the plasma insulin and the turnover of VLDL-B-apoprotein. Furthermore, in the two patients with lipo-dystrophy the turnover of plasma VLDL was within the normal range, whereas the plasma insulin responses were the highest among all the patients. These results suggest that hyperinsulinaemia alone is not sufficient to account for the increased VLDL production seen in some of our patients. The plasma FFA flux was raised in the patients with idiopathic hypertriglyceridaemia and in the maturity onset diabetics, and was within the normal range in the two patients with lipodystrophy. Indded, in all the subjects studied a significant correlation was observed between the turnover of plasma VLDL-B-apoprotein and the plasma FFA flux. The results thus indicate that the rate of FFA release to plasma constitutes the predominant factor in determining hepatic output of VLDL and that in the majority of patients with endogenous hypertriglyceridaemia the increased FFA flux resulting from insulin resistance in adipose tissue could effectively increase VLDL production. This process appears to be independent of the prevailing insulin levels, and could occur in the presence of insulin resistance in the liver. The latter, however, could be responsible for the impaired glucose tolerance observed in some patients.     

Delayed and exaggerated postprandial complement component 3 response in familial combined hyperlipidemia

Very low density lipoprotein overproduction is the major metabolic characteristic in familial combined hyperlipidemia (FCHL). Peripheral handling of free fatty acids (FFAs) in vitro may be impaired in FCHL by decreased action of acylation-stimulating protein (ASP), which is identical to the immunologically inactive complement component 3a (C3adesArg). Because decreased FFA uptake by impaired complement component 3 (C3) response (as the precursor for ASP) may result in enhanced FFA flux to the liver in FCHL, we have evaluated postprandial C3 changes in vivo in FCHL patients. Accordingly, 10 untreated FCHL patients and 10 matched control subjects underwent an oral fat loading test. Fasting plasma C3 and ASP levels were higher in FCHL patients (1.33+/-0.09 g/L and 70.53+/-4.37 mmol/L, respectively) than in control subjects (0.91+/-0.03 g/L and 43.21+/-8.96 mmol/L, respectively; P=0.01 and P<0.05). In control subjects, C3 concentrations increased significantly after 4 hours (to 1.03+/-0.04 g/L). In FCHL, plasma C3 was unchanged after 4 hours. The earliest postprandial C3 rise in FCHL patients occurred after 8 hours (1.64+/-0.12 g/L). The maximal apolipoprotein B-48 concentration was reached after 6 hours in FCHL patients and control subjects. Postprandial FFA and hydroxybutyric acid (as a marker of hepatic FFA oxidation) were significantly higher in FCHL patients than in control subjects, and the early postprandial C3 rise was negatively correlated with the postprandial FFA and hydroxybutyric acid concentrations. The present data suggest an impaired postprandial plasma C3 response in FCHL patients, most likely as a result of a delayed response by C3, as the precursor for the biologically active ASP, acting on FFA metabolism. Therefore, an impaired postprandial C3 response may be associated with impaired peripheral postprandial FFA uptake and, consequently, lead to increased hepatic FFA flux and very low density lipoprotein overproduction.