Pharmacodynamic Effects of Low-Dose Pioglitazone in Patients with the Metabolic Syndrome without Diabetes Mellitus.

STUDY OBJECTIVE: To determine the effects of low-dose pioglitazone on plasma adipocyte-derived cytokines, high-sensitivity C-reactive protein (hs-CRP), and components of the metabolic syndrome in adults with the metabolic syndrome without diabetes mellitus. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: University of Colorado Clinical and Translational Research Center. PATIENTS: Thirty-two men and women, aged 30-60 years, without diabetes who had a clinical diagnosis of the metabolic syndrome, as defined by the American Heart Association/National Heart, Lung, and Blood Institute criteria. INTERVENTION: Patients were randomly assigned to receive oral pioglitazone 7.5 mg daily or matching placebo for 8 weeks. MEASUREMENTS AND MAIN RESULTS: The primary end point was the change in plasma high-molecular-weight (HMW) adiponectin level from baseline to week 8. Other end points were changes in plasma total adiponectin, omentin, and hs-CRP levels, and changes in components of the metabolic syndrome (e.g., insulin sensitivity) from baseline to week 8. Pioglitazone was associated with a significant increase in plasma HMW adiponectin from baseline to week 8 compared with placebo (+47% vs -10%, p<0.001). Insulin sensitivity increased significantly from baseline to week 8 in the pioglitazone group (+88%, p=0.02) but not in the placebo group (+15%, p=0.14). Change in HMW adiponectin was significantly correlated with the change in insulin sensitivity in the pioglitazone group (r = 0.784, p=0.003). No significant differences in mean percentage changes in plasma total adiponectin, omentin, and hs-CRP levels were observed between the pioglitazone and placebo groups. Likewise, changes in body weight, insulin sensitivity, glucose, lipids, and blood pressure did not differ significantly between the groups. CONCLUSION: Low-dose pioglitazone favorably modulates plasma HMW adiponectin, which was associated with an improvement in insulin sensitivity, in patients with the metabolic syndrome without diabetes.

Evaluation of the relationship between circulating omentin-1 concentrations and components of the metabolic syndrome in adults without type 2 diabetes or cardiovascular disease.

BACKGROUND: Dysregulation of omentin-1, a beneficial adipokine, is thought to play a role in the development of type 2 diabetes and cardiovascular disease. The objective of this study was to evaluate the relationship between circulating omentin-1 concentrations and components of the metabolic syndrome in adults without type 2 diabetes or cardiovascular disease, and to determine if sex differences influenced the observed relationships. METHODS: Fasting blood samples were obtained from 93 adults, ages 30-60 years, without type 2 diabetes and/or cardiovascular disease. Participants were classified as having the metabolic syndrome according to American Heart Association/National Heart, Lung and Blood Institute criteria. Plasma omentin-1 concentrations were measured using a commercially-available enzyme-linked immunosorbent assay, and relationships between plasma omentin-1 and components of the metabolic syndrome were assessed in the entire study cohort, by metabolic syndrome status, and by sex. RESULTS: On average, participants were 48 ± 8 years of age, 50.5% were women, 54.8% were Caucasian, and 70% had the metabolic syndrome. Plasma omentin-1 concentrations did not differ significantly between individuals with versus without the metabolic syndrome (145.7 ± 70 versus 157.4 ± 79.3 ng/ml, p = 0.50). However, men with the metabolic syndrome had significantly lower omentin-1 levels than men without the metabolic syndrome (129.9 ± 66 versus 186.3 ± 84.3 ng/ml, p = 0.03). Plasma omentin-1 concentrations were significantly correlated with HDL cholesterol in the entire study cohort (r = 0.26; p = 0.01), which was primarily driven by a correlation in men (r = 0.451, p = 0.002) and participants with the metabolic syndrome (r = 0.36; p = 0.003). Plasma omentin-1 concentrations did not differ significantly between men and women; however men with the metabolic syndrome had 20% lower plasma omentin-1 levels than women with the metabolic syndrome (p = 0.06). CONCLUSION: These data demonstrate that circulating omentin-1 levels are associated with HDL cholesterol, primarily in men and in the presence of the metabolic syndrome. In addition, sex appears to influence the relationship between plasma omentin-1 concentrations and components of the metabolic syndrome. Additional studies are needed to explore sexual dimorphism in circulating omentin-1 levels, and the role of omentin-1 in the metabolic syndrome.

Influence of CYP2C8*2 on the pharmacokinetics of pioglitazone in healthy African-American volunteers.

STUDY OBJECTIVES: To determine the influence of the Cytochrome P450 (CYP) 2C8*2 polymorphism on pioglitazone pharmacokinetics in healthy African-American volunteers. DESIGN: Prospective, open-label, single-dose pharmacokinetic study. SETTING: University of Colorado Hospital Clinical and Translational Research Center. PARTICIPANTS: Healthy African-American volunteers between 21 and 60 years of age were enrolled in the study based on CYP2C8 genotype: CYP2C8*1/*1 (9 participants), CYP2C8*1/*2 (7 participants), and CYP2C8*2/*2 (1 participant). INTERVENTION: Participants received a single 15-mg dose of pioglitazone in the fasted state, followed by a 48-hour pharmacokinetic study. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of pioglitazone and its M-III (keto) and M-IV (hydroxy) metabolites were compared between participants with the CYP2C8*1/*1 genotype and CYP2C8*2 carriers. Pioglitazone area under the plasma concentration-time curve (AUC)0-∞ and half-life (t1/2 ) did not differ significantly between CYP2C8*1/*1 and CYP2C8*2 carriers (AUC0-∞ 7331 ± 2846 vs 10431 ± 5090 ng*h/ml, p=0.15, t1/2 7.4 ± 2.7 vs 10.5 ± 4.0 h, p=0.07). M-III and M-IV AUC0-48 also did not differ significantly between genotype groups. However, the M-III:pioglitazone AUC0-48 ratio was significantly lower in CYP2C8*2 carriers than CYP2C8*1 homozygotes (0.70 ± 0.15 vs 1.2 ± 0.37, p=0.006). Similarly, CYP2C8*2 carriers had a significantly lower M-III:M-IV AUC0-48 ratio than participants with the CYP2C8*1/*1 genotype (0.82 ± 0.26 vs 1.22 ± 0.26, p=0.006). CONCLUSION: These data suggest that CYP2C8*2 influences pioglitazone pharmacokinetics in vivo, particularly the AUC0-48 ratio of M-III:parent drug, and the AUC0-48 ratio of M-III:M-IV. Larger studies are needed to further investigate the impact of CYP2C8*2 on the pharmacokinetics of CYP2C8 substrates in individuals of African descent.

Effect of ABCB1 polymorphisms and atorvastatin on sitagliptin pharmacokinetics in healthy volunteers.

OBJECTIVES: The objectives of this study were to determine if ABCB1 polymorphisms are associated with interindividual variability in sitagliptin pharmacokinetics and if atorvastatin alters the pharmacokinetic disposition of sitagliptin in healthy volunteers. METHODS: In this open-label, randomized, two-phase crossover study, healthy volunteers were prospectively stratified according to ABCB1 1236/2677/3435 diplotype (n = 9, CGC/CGC; n = 10, CGC/TTT; n = 10, TTT/TTT). In one phase, participants received a single 100 mg dose of sitagliptin; in the other phase, participants received 40 mg of atorvastatin for 5 days, with a single 100 mg dose of sitagliptin administered on day 5. A 24-h pharmacokinetic study followed each sitagliptin dose, and the study phases were separated by a 14-day washout period. RESULTS: Sitagliptin pharmacokinetic parameters did not differ significantly between ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotype groups during the monotherapy phase. Atorvastatin administration did not significantly affect sitagliptin pharmacokinetics, with geometric mean ratios (90 % confidence intervals) for sitagliptin maximum plasma concentration, plasma concentration-time curve from zero to infinity, renal clearance, and fraction of sitagliptin excreted unchanged in the urine of 0.93 (0.86-1.01), 0.96 (0.91-1.01), 1.02 (0.93-1.12), and 0.98 (0.90-1.06), respectively. CONCLUSIONS: ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotypes did not influence sitagliptin pharmacokinetics in healthy volunteers. Furthermore, atorvastatin had no effect on the pharmacokinetics of sitagliptin in the setting of ABCB1 CGC/CGC, CGC/TTT, and TTT/TTT diplotypes.

Impact of the CYP2C8 *3 polymorphism on the drug-drug interaction between gemfibrozil and pioglitazone.

AIM: The objective of this study was to determine the extent to which the CYP2C8*3 allele influences pharmacokinetic variability in the drug-drug interaction between gemfibrozil (CYP2C8 inhibitor) and pioglitazone (CYP2C8 substrate). METHODS: In this randomized, two phase crossover study, 30 healthy Caucasian subjects were enrolled based on CYP2C8*3 genotype (n = 15, CYP2C8*1/*1; n = 15, CYP2C8*3 carriers). Subjects received a single 15 mg dose of pioglitazone or gemfibrozil 600 mg every 12 h for 4 days with a single 15 mg dose of pioglitazone administered on the morning of day 3. A 48 h pharmacokinetic study followed each pioglitazone dose and the study phases were separated by a 14 day washout period. RESULTS: Gemfibrozil significantly increased mean pioglitazone AUC(0,∞) by 4.3-fold (P < 0.001) and there was interindividual variability in the magnitude of this interaction (range, 1.8- to 12.1-fold). When pioglitazone was administered alone, the mean AUC(0,∞) was 29.7% lower (P = 0.01) in CYP2C8*3 carriers compared with CYP2C8*1 homozygotes. The relative change in pioglitazone plasma exposure following gemfibrozil administration was significantly influenced by CYP2C8 genotype. Specifically, CYP2C8*3 carriers had a 5.2-fold mean increase in pioglitazone AUC(0,∞) compared with a 3.3-fold mean increase in CYP2C8*1 homozygotes (P = 0.02). CONCLUSION: CYP2C8*3 is associated with decreased pioglitazone plasma exposure in vivo and significantly influences the pharmacokinetic magnitude of the gemfibrozil-pioglitazone drug-drug interaction. Additional studies are needed to evaluate the impact of CYP2C8 genetics on the pharmacokinetics of other CYP2C8-mediated drug-drug interactions.

Influence of SLCO1B1 polymorphisms on the drug-drug interaction between darunavir/ritonavir and pravastatin.

The authors investigated whether SLCO1B1 polymorphisms contribute to variability in pravastatin pharmacokinetics when pravastatin is administered alone versus with darunavir/ritonavir. HIV-negative healthy participants were prospectively enrolled on the basis of SLCO1B1 diplotype: group 1 (*1A/*1A, n = 9); group 2 (*1A/*1B, n = 10; or *1B/*1B, n = 2); and group 3 (*1A/*15, n = 1; *1B/*15, n = 5; or *1B/*17, n = 1). Participants received pravastatin (40 mg) daily on days 1 through 4, washout on days 5 through 11, darunavir/ritonavir (600/100 mg) twice daily on days 12 through 18, with pravastatin 40 mg added back on days 15 through 18. Pharmacokinetic studies were conducted on day 4 (pravastatin alone) and day 18 (pravastatin + darunavir/ritonavir). Pravastatin area under the plasma concentration-time curve (AUC(tau)) was 21% higher during administration with darunavir/ritonavir compared with pravastatin alone; however, this difference was not statistically significant (P = .11). Group 3 variants had 96% higher pravastatin AUC(tau) on day 4 and 113% higher pravastatin AUC(tau) on day 18 compared with group 1. The relative change in pravastatin pharmacokinetics was largest in group 3 but did not differ significantly between diplotype groups. In sum, the influence of SLCO1B1*15 and *17 haplotypes on pravastatin pharmacokinetics was maintained in the presence of darunavir/ritonavir. Because OATP1B1 inhibition would be expected to be greater in carriers of normal or high-functioning SLCO1B1 haplotypes, these findings suggest that darunavir/ritonavir is not a potent inhibitor of OATP1B1-mediated pravastatin transport in vivo.

Association of increased upper trunk and decreased leg fat with 2-h glucose in control and HIV-infected persons.

OBJECTIVE: Changes in body fat distribution and abnormal glucose metabolism are common in HIV-infected patients. We hypothesized that HIV-infected participants would have a higher prevalence of impaired glucose tolerance (IGT) compared with control subjects. RESEARCH DESIGN AND METHODS: A total of 491 HIV-infected and 187 control participants from the second examination of the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM) underwent glucose tolerance testing (GTT). Multivariable regression was used to identify factors associated with GTT parameters. RESULTS: The prevalence of impaired fasting glucose (IFG) (>110 mg/dL) was similar in HIV-infected and control participants (21 vs. 25%, P = 0.23). In those without IFG, the prevalence of IGT was slightly higher in HIV-infected participants compared with control subjects (13.1 vs. 8.2%, P = 0.14) and in HIV+ participants with lipoatrophy versus without (18.1 vs. 11.5%, P = 0.084). Diabetes detected by GTT was rare (HIV subjects 1.3% and control subjects 0%, P = 0.65). Mean 2-h glucose levels were 7.6 mg/dL higher in the HIV-infected participants (P = 0.012). Increased upper trunk subcutaneous adipose tissue (SAT) and decreased leg SAT were associated with 2-h glucose and IGT in both HIV-infected and control participants. Adjusting for adipose tissue reduced the estimated effects of HIV. Exercise, alcohol use, and current tenofovir use were associated with lower 2-h glucose levels in HIV-infected participants. CONCLUSIONS: In HIV infection, increased upper trunk SAT and decreased leg SAT are associated with higher 2-h glucose. These body fat characteristics may identify HIV-infected patients with normal fasting glucose but nonetheless at increased risk for diabetes.

Brown fat activity is not apparent in subjects with HIV lipodystrophy and increased resting energy expenditure.

The HIV lipodystrophy (LD) syndrome is associated with increased resting energy expenditure (REE), but the basis of this hypermetabolism has not been determined. The objective of this pilot study was to determine if brown fat is activated in subjects with HIV LD and increased REE. In this descriptive study of four subjects with HIV LD and marked hypermetabolism, REE was measured by indirect calorimetry and brown fat activity was determined by (18)F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) combined with anatomic computed tomography (CT). Brown fat activity was not apparent in any subject with HIV LD and resting hypermetabolism. Therefore, brown fat activation is unlikely to be the principal cause of the increased REE associated with the HIV LD syndrome. Evidence of adaptive thermogenesis has been demonstrated in this syndrome, but this study suggests that tissues other than brown adipose tissue (BAT) are responsible. Further understanding of the chronic hypermetabolism associated with HIV LD could provide new insights into the regulation of energy balance.

Pharmacodynamic effects of rosiglitazone in nondiabetic patients with metabolic syndrome.

STUDY OBJECTIVES: To determine the effects of the thiazolidinedione rosiglitazone on the adipocyte-derived cytokines adiponectin (an antiinflammatory and insulin-sensitizing cytokine; low levels have been associated with metabolic syndrome) and resistin (an inflammation mediator; high levels have been associated with metabolic syndrome) in nondiabetic patients with metabolic syndrome, and to characterize the effects of rosiglitazone on other components of the metabolic syndrome phenotype in this population. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: Outpatient general clinical research center. PATIENTS: Thirty-two nondiabetic men and women with a clinical diagnosis of metabolic syndrome (as defined in the American Heart Association-National Heart, Lung, and Blood Institute scientific statement). INTERVENTION: Patients were randomly assigned to receive either oral rosiglitazone 4 mg/day or matching placebo for 12 weeks. MEASUREMENTS AND MAIN RESULTS: The primary end point was change in serum adiponectin concentrations from baseline to week 12. Secondary end points were changes in serum resistin concentrations, insulin resistance, fasting glucose level, fasting insulin level, body weight, lipid levels, systolic and diastolic blood pressure, and waist circumference from baseline to week 12. Also, changes from baseline in adiponectin and resistin concentrations and insulin resistance were assessed over time at weeks 2, 4, 8, and 12. Rosiglitazone was associated with a significant increase in serum adiponectin concentration after 12 weeks compared with placebo (45.8% vs 2.6%, p=0.002). The increase in adiponectin concentration occurred quickly, with a significant difference observed after 2 weeks of therapy. Compared with placebo, rosiglitazone was not associated with significant 12-week changes in serum resistin concentrations, insulin resistance, fasting glucose level, fasting insulin level, body weight, lipid levels, systolic or diastolic blood pressure, or waist circumference. CONCLUSION: Rosiglitazone had beneficial effects on adiponectin concentrations without significantly affecting other components of the metabolic syndrome phenotype. Additional studies that further elucidate the time course of thiazolidinedione pharmacodynamic effects, along with their effects on cardiovascular end points, are warranted in nondiabetic patients with metabolic syndrome.

Dual-energy X-ray absorptiometry modeling to explain the increased resting energy expenditure associated with the HIV lipoatrophy syndrome.

BACKGROUND: The HIV lipoatrophy syndrome is characterized by loss of subcutaneous fat and is associated with increased resting energy expenditure (REE). Recently, dual-energy X-ray absorptiometry (DXA) modeling of organ-tissue mass combined with specific organ-tissue metabolic rates has been used to gain further insight into the relation of the lean body mass to REE and to better understand differences in REE between groups. OBJECTIVE: This study examined the organ-tissue basis of the increased REE shown in HIV lipoatrophy. DESIGN: REE was measured in 29 HIV-infected patients with lipoatrophy and in 29 HIV-infected and 19 healthy control subjects. Five organ-tissue mass components (brain, bone, skeletal muscle, adipose tissue, and residual mass) were calculated with the use of DXA modeling and body weight. RESULTS: DXA modeling showed no significant differences in predicted REE between the 3 groups. However, measured REE was significantly greater in subjects with lipoatrophy than in control subjects. Measured REE remained significantly greater in lipoatrophy subjects after routine adjustment for lean body mass and after adjustment for each organ-tissue mass component. Finally, DXA and regression modeling of REE suggests that increased energy expenditure in skeletal muscle may account for the resting hypermetabolism of patients with HIV lipoatrophy. CONCLUSIONS: Increased REE in subjects with HIV lipoatrophy cannot be explained by differences in organ-tissue mass as modeled by DXA. Instead, DXA and regression modeling of REE suggests that skeletal muscle is hypermetabolic in patients with HIV lipoatrophy. This may be a form of adaptive thermogenesis in response to an inability to store triglyceride fuel in a normal manner.

Relationship between plasma resistin concentrations, inflammatory chemokines, and components of the metabolic syndrome in adults.

Recent data suggest that resistin, an adipocyte-derived cytokine, has a putative role in inflammatory processes and metabolic derangements. In vitro data suggest that resistin stimulates the production of inflammatory chemokines, yet the relationship in vivo is largely unknown. The purpose of this study was to determine if a relationship exists between plasma resistin concentrations, plasma inflammatory chemokine aged concentrations (ie, monocyte chemoattractant protein 1 [MCP-1] and epithelial neutrophil activator 78 [ENA-78]), and components of the metabolic syndrome in nondiabetic subjects without known cardiovascular disease (CVD). Plasma samples were obtained from nondiabetic subjects (N = 123) aged 18 to 55 years without known CVD or CVD risk equivalents. The presence of the metabolic syndrome was assessed using consensus guidelines. Fasting plasma resistin, MCP-1, ENA-78, and high-sensitivity C-reactive protein (hs-CRP) concentrations were analyzed. The study population consisted of 67.5% women and 68.3% Caucasians (mean age = 44 +/- 7 years and mean body mass index = 33.3 +/- 6 kg/m(2)). The metabolic syndrome was present in 46.3% of study participants. Resistin concentrations were significantly correlated with white blood cell count (r = 0.326, P < .001), hs-CRP concentrations (r = 0.293, P = .005), MCP-1 concentrations (r = 0.251, P = .005), body mass index (r = 0.193, P = .033), and high-density lipoprotein cholesterol (r = -0.182, P = .044). Resistin concentrations were 1.21 times higher in subjects with the metabolic syndrome compared with those without the metabolic syndrome (P = .003). In stepwise regression analysis, white blood cell count (P < .001) and MCP-1 concentrations (P = .002) were significantly associated with resistin concentrations, independent of hs-CRP, sex, body mass index, presence of the metabolic syndrome, and high-density lipoprotein cholesterol. Data from our cross-sectional study demonstrate that plasma resistin concentrations are associated with circulating chemokine markers of inflammation, namely, MCP-1, and white blood cell count in nondiabetic adults without CVD. Future studies examining the causal relationship between plasma resistin concentrations, chemokine markers of inflammation, CVD, and diabetes are warranted.

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.

Influence of SLCO1B1 and CYP2C8 gene polymorphisms on rosiglitazone pharmacokinetics in healthy volunteers.

Polymorphisms in drug transporter genes and/or drug-metabolising enzyme genes may contribute to inter-individual variability in rosiglitazone pharmacokinetics in humans. We sought to determine the joint effects of polymorphisms in the SLCO1B1 drug transporter gene and the cytochrome P450 ( CYP ) 2C8-metabolising enzyme gene on rosiglitazone pharmacokinetics in healthy volunteers. Healthy Caucasian subjects were prospectively enrolled on the basis of SLCO1B1 521 T > C genotype. Additionally, subjects were genotyped for SLCO1B1 -11187 G > A, -10499 A > C and 388 A > G polymorphisms, and the CYP2C8*3 polymorphism. SLCO1B1 haplotypes and diplotypes were computationally assigned. Rosiglitazone plasma concentrations were determined by high-performance liquid chromatography and analysed using non-compartmental methods. The study population consisted of 26 subjects, with a mean age of 33 +/- 9 years, and a mean weight of 66.6 +/- 11.7 kg. There were no significant differences in rosiglitazone pharmacokinetic parameters between SLCO1B1 diplotype groups. Subjects with the CYP2C8*1/*3 genotype ( n = 7), however, had significantly lower rosiglitazone area under the plasma concentration-time curve (AUC) and significantly higher rosiglitazone oral clearance, compared with CYP2C8 wild-type homozygotes ( n = 19). Stepwise linear regression analysis revealed that CYP2C8 genotype ( p = 0.006) and weight ( p = 0.022) were significant predictors of rosiglitazone AUC (overall p = 0.002; R 2 = 41.6 per cent). We concluded that polymorphisms in the CYP2C8 drug-metabolising enzyme gene, but not the SLCO1B1 drug transporter gene, significantly influence rosiglitazone disposition in humans. Future studies examining the influence of CYP2C8 genotypes and haplotypes on thiazolidinedione disposition and response in patients with type 2 diabetes are warranted.

Short-term overfeeding increases resting energy expenditure in patients with HIV lipodystrophy.

BACKGROUND: HIV lipodystrophy and other lipodystrophy syndromes are characterized by extensive loss of subcutaneous adipose tissue. Lipodystrophy syndromes are also associated with increased resting energy expenditure (REE). This hypermetabolism may be an adaptive response to an inability to store triacylglycerol fuel in a normal manner. OBJECTIVE: This study was done to determine whether REE increases significantly after short-term overfeeding in patients with HIV lipodystrophy. DESIGN: REE was measured in HIV-infected patients with lipodystrophy (n = 9) and in HIV-infected (n = 10) and healthy (n = 9) controls after 3 d on a eucaloric diet and again after 3 d on a diet of similar composition but increased in calories by 50%. RESULTS: After 3 d of eucaloric feeding, REE was significantly higher in patients with HIV lipodystrophy [33.2 +/- 0.27 kcal/kg lean body mass (LBM)] than for both HIV-infected and healthy controls (29.9 +/- 0.26 and 29.6 +/- 0.27 kcal/kg LBM, respectively; P < 0.01). Furthermore, after 3 d of overfeeding, REE increased significantly in patients with HIV lipodystrophy but not in the control groups (33.2 +/- 0.27 vs 34.7 +/- 0.27 kcal/kg LBM; P < 0.01). Finally, postprandial thermogenesis did not differ among the groups after a "normal" test meal but tended to be higher in patients with HIV lipodystrophy than in healthy controls after a large test meal. CONCLUSIONS: Adaptive thermogenesis in the resting component of total daily energy expenditure and in the postprandial period may be a feature of the HIV lipodystrophy syndrome and may be due to an inability to store triacylglycerol fuel in a normal manner.

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.

In combination, nucleoside reverse transcriptase inhibitors have significant effects on 3T3-L1 adipocyte lipid accumulation and survival.

The use of nucleoside reverse transcriptase inhibitors (NRTIs) for the treatment of HIV infection is clearly linked to the development of subcutaneous fat atrophy. Until recently, however, in vitro studies of adipocytes have shown no or only modest and inconsistent effects of these agents on adipocyte biology. This is in contrast to the protease inhibitors (PIs), which are also linked to the development of HIV lipodystrophy. These agents have relatively consistent inhibitory effects on the differentiation of cultured adipocytes, and have occasionally been found to have other effects on adipocyte biology as well. We aimed to explore more thoroughly the effects of NRTIs and combinations of antiretroviral agents commonly used in clinical practice on multiple aspects of adipocyte biology using the 3T3-L1 adipocyte cell line. We found that when used individually, NRTIs decrease cell survival but only lamivudine significantly alters lipid accumulation. However, NRTI and dual NRTI-PI combinations do significantly decrease lipid accumulation in 3T3-L1 adipocytes, have a much greater detrimental impact on cell survival and decrease adipocyte differentiation.

Acute pancreatitis in HIV-infected patients: are etiologies changing since the introduction of protease inhibitor therapy?

INTRODUCTION: Hypertriglyceridemia is a well-established cause of acute pancreatitis in the general population. Protease inhibitor (PI) therapy, introduced in 1996 for HIV infection, is associated with moderate to severe hypertriglyceridemia. AIMS: To determine whether the prevalence of hyperlipidemic pancreatitis in HIV-infected patients has increased since the introduction of PIs. METHODOLOGY: This was a retrospective study of patients with acute pancreatitis and HIV infection admitted to three local hospitals between 1990 and 2001. RESULTS: Before PIs became available (1990-1995), 30 index cases of acute pancreatitis in the setting of HIV infection were identified, and one of these cases (3.3%) was attributed to hypertriglyceridemia. After the introduction of PIs (1996-2001), 54 cases of acute pancreatitis in HIV-infected patients were identified, and two of these cases were attributed to hypertriglyceridemia (3.7%; p = 0.6). In both time periods, medication-induced pancreatitis was the most common cause of pancreatitis in HIV-infected patients. CONCLUSION: Despite the well-established association between PIs and hypertriglyceridemia, there was no significant increase in the prevalence of hyperlipidemic pancreatitis in this HIV-infected population after the introduction of PIs. Medication-associated pancreatitis remains the most common cause of acute pancreatitis in the era of potent antiretroviral therapy.

Total energy expenditure and carbohydrate oxidation are increased in the human immunodeficiency virus lipodystrophy syndrome.

To determine whether total energy expenditure (TEE) is increased in the human immunodeficiency virus (HIV) lipodystrophy syndrome, we compared energy expenditure (EE) and substrate oxidation rates in 12 HIV-infected men with lipodystrophy, 7 HIV-infected men without lipodystrophy, and 14 healthy controls. TEE and nutrient oxidation rates were assessed by whole-room indirect calorimetry. Resting energy expenditure (REE) was measured by indirect calorimetry using the open-circuit technique. Body composition was assessed by dual-energy x-ray absorptiometry (DEXA). Insulin sensitivity was measured using the insulin-modified frequently sampled intravenous glucose tolerance test. TEE adjusted for lean body mass (LBM) was significantly higher in the HIV-infected group with lipodystrophy compared to HIV-infected patients without lipodystrophy (2,873.3 +/- 69 v 2,573.9 +/- 92 kcal/d, P =.02) and compared to healthy controls (2,873.3 +/- 69 v 2,404.0 +/- 64 kcal/d, P <.001). REE and sleeping metabolic rate (SMR) adjusted for LBM were also significantly higher in the HIV-infected group with lipodystrophy compared to both HIV-infected and healthy controls. Carbohydrate oxidation rates adjusted for LBM were higher in men with HIV lipodystrophy as compared to healthy controls (362.5 +/- 23 v 250.0 +/- 22 g/d, P = <.01) and tended to be higher as compared to HIV-infected controls (362.5 +/- 23.6 v 297.3 +/- 31 g/d, P =.1). In conclusion, TEE and carbohydrate oxidation are increased in the HIV lipodystrophy syndrome. The increase in TEE appears to be due to increases in REE. The pathogenesis of elevated EE in HIV lipodystrophy and other forms of lipodystrophy remains to be determined.