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Consumption of high-fructose diets promotes hepatic fatty acid synthesis (de novo lipogenesis [DNL]) and an atherogenic lipid profile. It is unclear whether these effects occur independent of positive energy balance and weight gain.We compared the effects of a high-fructose, (25% of energy content) weight-maintaining diet to those of an isocaloric diet with the same macronutrient distribution but in which complex carbohydrate (CCHO) was substituted for fructose.Eight healthy men were studied as inpatients for consecutive 9-day periods. Stable isotope tracers were used to measure fractional hepatic DNL and endogenous glucose production (EGP) and its suppression during a euglycemic-hyperinsulinemic clamp. Liver fat was measured by magnetic resonance spectroscopy.Weight remained stable. Regardless of the order in which the diets were fed, the high-fructose diet was associated with both higher DNL (average, 18.6 ± 1.4% vs 11.0 ± 1.4% for CCHO; P = .001) and higher liver fat (median, +137% of CCHO; P = .016) in all participants. Fasting EGP and insulin-mediated glucose disposal did not differ significantly, but EGP during hyperinsulinemia was greater (0.60 ± 0.07 vs 0.46 ± 0.06 mg/kg/min; P = .013) with the high-fructose diet, suggesting blunted suppression of EGP.Short-term high-fructose intake was associated with increased DNL and liver fat in healthy men fed weight-maintaining diets.

Background:Growth hormone (GH) is known to affect insulin and glucose metabolism. Blocking its effects in acromegalic patients improves diabetes and glucose metabolism. We aimed to determine the effect of pegvisomant, a GH receptor antagonist, on insulin resistance, endogenous glucose production (EGP) and lipolysis in insulin resistant non-diabetic men. Methods:Four men between the ages of 18-62 with a BMI of 18-35kg/m2, with insulin resistance as defined by a HOMA-IR > 2.77, were treated for four weeks with pegvisomant 20 mg daily. Inpatient metabolic assessments were performed before and after treatment. The main outcome measurements were: change after pegvisomant therapy in insulin sensitivity as measured by hyperinsulinemic euglycemic clamp; and EGP and lipolysis assessed by stable isotope tracer techniques.Results:Insulin like growth factor-1 (IGF-1) concentrations decreased from 134.0 ± 41.5 (mean ± SD) to 72.0 ± 11.7 ng/mL (p = 0.04) after 4 weeks of therapy. Whole body insulin sensitivity index (M/I 3.2 ± 1.3vs.3.4 ± 2.4;P= 0.82), as well as suppression of EGP (89.7 ± 26.9vs.83.5 ± 21.6%; p = 0.10) and Ra glycerol (59.4 ± 22.1%vs.61.2 ± 14.4%; p = 0.67) during the clamp were not changed significantly with pegvisomant treatment.Conclusions:Blockade of the GH receptor with pegvisomant for four weeks had no significant effect on insulin/glucose metabolism in a small phase II pilot study of non-diabetic insulin resistant participants without acromegaly.

Background Changes in the multiple mechanisms that regulate glucose metabolism after gastric bypass (RYGB) are still being unveiled. The objective of this study was to compare the changes of glucose and pancreatic hormones [C-peptide, glucagon, and pancreatic polypeptide (PP)] during a meal tolerance test (MTT) and steady-state insulin and free fatty acid (FFA) concentrations during euglycemic–hyperinsulinemic clamp 14 days and 6 months after RYGB in morbidly obese nondiabetic patients. Methods Two groups were studied at baseline and at 14 days: the RYGB followed by caloric restriction group (RYGB, n=12) and the equivalent caloric restriction alone group (Diet, n=10), to control for energy intake and weight loss. The RYGB group was studied again at 6 months to assess the changes after substantial weight loss. During MTT, the early and overall changes in glucose and pancreatic hormone concentrations were determined, and during the clamp, steady-state insulin and FFA concentrations were assessed. Results After 14 days, RYGB patients had enhanced postprandial glucose, C-peptide, and glucagon responses, and decreased postprandial PP concentrations. Steady-state insulin concentrations were decreased at 14 days only in RYGB patients, and FFA increased in both groups. Six months after RYGB and substantial weight loss, the decrease in insulin concentrations during clamp persisted, and there were further changes in postprandial glucose and glucagon responses. FFA concentrations during clamp were significantly lower at 6 months, relative to presurgical values. Conclusions In morbidly obese nondiabetic patients, RYGB produces early changes in postmeal glucose, C-peptide, glucagon, and PP responses, and it appears to enhance insulin clearance early after RYGB and improve insulin sensitivity in adipose tissue at 6 months postsurgery. The early changes cannot be explained by caloric restriction alone.

The role of host genetics in the development of subclinical atherosclerosis in the context of HIV-infected persons who are being treated with highly active antiretroviral therapy (HAART) is not well understood.The present genome-wide association study (GWAS) is based on 177 HIV-positive Caucasian males receiving HAART who participated in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM) Study. Common and internal carotid intima-media thicknesses (cIMT) measured by B-mode ultrasound were used as a subclinical measure of atherosclerosis. Single nucleotide polymorphisms (SNPs) were assayed using the Illumina HumanCNV370-quad beadchip. Copy Number Variants (CNV) were inferred using a hidden Markov Model (PennCNV). Regression analyses were used to assess the association of common and internal cIMT with individual SNPs and CNVs, adjusting for age, duration of antiretroviral treatment, and principal components to account for potential population stratification.Two SNPs in tight linkage disequilibrium, rs2229116 (a missense, nonsynonymous polymorphism (IIe to Val)) and rs7177922, located in the ryanodine receptor (RYR3) gene on chromosome 15 were significantly associated with common cIMT (P-value1.61 x 10). The RYR gene family has been known to play a role in the etiology of cardiovascular disease and has been shown to be regulated by HIV TAT protein.These results suggest that in the context of HIV infection and HAART, a functional SNP in a biologically plausible candidate gene, RYR3, is associated with increased common carotid IMT, which is a surrogate for atherosclerosis.

BACKGROUND HIV protease inhibitors have been shown to worsen glucose and lipid metabolism. Recent studies have suggested that protease inhibitors can impair insulin secretion in HIV-infected patients. We studied the effects of the protease inhibitor combination lopinavir and ritonavir on insulin secretion, insulin sensitivity, and lipid metabolism in HIV-negative persons. METHODS A combination dose of lopinavir 400 mg and ritonavir 100 mg was given twice daily to eight HIV-seronegative men for 4 weeks. Fasting glucose, insulin, lipid, and lipoprotein profiles; oral glucose tolerance; insulin secretion and insulin-mediated glucose disposal by hyperglycemic clamp; and body composition by dual energy X-ray absorptiometry were determined before and after lopinavir/ritonavir administration. RESULTS There was no change in first-phase insulin secretion (2.82 +/- 0.30 versus 2.71 +/- 0.31 nmol/l; P = 0.60), as well as fasting insulin and glucose levels, oral glucose tolerance, or insulin-mediated glucose disposal after 4 weeks administration of lopinavir/ritonavir. However, there were significant increases in fasting triglycerides (1.02 +/- 0.13 versus 2.20 +/- 0.31 mmol/l; P = 0.001), total cholesterol (4.42 +/- 0.30 versus 5.70 +/- 0.60 mmol/l; P = 0.007), and apo B-100 levels (0.86 +/- 0.07 versus 1.07 +/- 0.11 g/l; P = 0.0009). High-density lipoprotein cholesterol decreased (0.99 +/- 0.11 versus 0.82 +/- 0.10 mmol/l; P = 0.005). There were no changes in body composition, weight, or body fat. CONCLUSION Although administration of lopinavir/ritonavir to healthy, HIV-seronegative volunteers for 4 weeks resulted in increased triglyceride and decreased high-density lipoprotein cholesterol levels, there was no change in first-phase insulin secretion during the hyperglycemic clamp. The reported effects of protease inhibitor on insulin secretion in HIV-infected individuals may be due to changes in HIV-related factors and not a direct drug effect.

Reduced energy intake is a primary factor in HIV-associated wasting. Megestrol acetate (MA) stimulates appetite and weight gain. However, much of the weight gained is fat, possibly as a result of MA-induced hypogonadism.The objective of the study was to determine whether coadministration of testosterone with MA could enhance lean body mass (LBM) accrual and evaluate the effects of MA, alone or combined with testosterone, on sexual functioning and the hypothalamic-pituitary-adrenal axis.This was a randomized, double-blind, placebo-controlled, multicenter trial.Fourteen AIDS Clinical Trials Units in the United States participated in the study.Seventy-nine HIV-positive men with 5% or more weight loss or body mass index less than 20 kg/m2 took part in the study.Subjects were randomized to receive MA (800 mg daily) plus testosterone enanthate (200 mg; MA/TE; n = 41) or placebo (MA/PL; n = 38) biweekly for 12 wk.Weight, body composition (bioelectric impedance analysis), adrenal and gonadal hormones, and sexual functioning (questionnaire) were measured.Both groups experienced robust increases in weight (median 5.3 and 7.3 kg in MA/TE and MA/PL, respectively), LBM (3.3 and 3.3 kg), and fat (3.0 and 3.8 kg). There were no significant differences between groups in the magnitude or composition of weight gain (P = 0.44, 0.90, and 0.11 for weight, LBM, and fat, respectively). Trough testosterone concentrations decreased to a greater extent in MA/PL (-12.3 vs. -6.1 nmol/liter in MA/TE; P = 0.04). Cortisol levels became nearly undetectable in subjects with plasma MA levels greater than 150 ng/ml. Sexual functioning was preserved with MA/TE but worsened in MA/PL.MA produced robust weight gain. Coadministration of testosterone preserved sexual functioning but did not enhance LBM accrual.

Pharmacologic doses of growth hormone (GH) reduce HIV-associated fat accumulation but may worsen glucose metabolism. We investigated the effects of a low dose of GH (1 mg per day) in HIV-infected men with fat accumulation and found that such treatment reduced total fat and increased lean body mass without significant changes in glucose tolerance or insulin sensitivity. Visceral adipose tissue (VAT) levels did not change significantly for the group as a whole, although a reduction in the VAT level was seen in patients with a greater VAT level at baseline.

In light of current interest in recombinant human growth hormone (GH) as a treatment for fat distribution abnormalities, we retrospectively evaluated regional changes in fat and lean body mass in a subset of subjects who participated in randomized, double-blind, placebo-controlled trials of GH for treatment of wasting. Treatment with a pharmacologic dose of GH (0.1 mg/kg/day) resulted in significant and sustained increases in lean body mass and losses of fat in both the trunk and appendicular regions.

Wasting, and particularly loss of metabolically active lean tissue, contributes to increased mortality, accelerated disease progression, and impairment of strength and functional status in patients with HIV infection. A variety of protein anabolic agents, including growth hormone, insulin-like growth factor-I, testosterone, nandrolone decanoate, oxandrolone, and oxymetholone, have been studied in patients with HIV-associated wasting. Overall, these studies have demonstrated that treatment with protein anabolic agents can increase lean body mass (LBM) and in some cases provide functional benefits and improvements in quality of life. Further research is needed to determine whether such treatment prolongs survival or reduces the overall health care burden of HIV infection. The advances in identification of successful treatments for HIV-associated wasting can provide a model for using these therapies in other catabolic states, including end-stage renal disease, cancer, chronic obstructive pulmonary disease, and cardiac cachexia.

Objective To determine whether treatment with growth hormone (GH) enhances thymopoiesis in individuals infected with HIV-1. Methods Five HIV-1-infected adults were treated with GH for 6-12 months in a prospective open-label study. Immunological analyses were performed before GH treatment and repeated at 3 month intervals after GH initiation. Thymic mass was analysed using computed tomography with quantitative density and volume analysis. Analysis of circulating lymphocytes, including naive and memory T cell subsets, was performed using multiparameter flow cytometry. Results GH treatment was associated with a marked increase in thymic mass in all GH recipients. Circulating naive CD4 T cells also increased significantly in all patients during GH therapy, suggesting an enhancement of thymopoiesis. Conclusion GH has significant effects on the human immune system, including the reversal of thymic atrophy in HIV-1-infected adults. De-novo T cell production may thus be inducible in immunodeficient adults.

Therapy with HIV protease inhibitors (PI) causes insulin resistance even in the absence of HIV infection, hyperlipidemia or changes in body composition. The mechanism of the effects on insulin action is unknown. In vitro studies suggest that PI selectively and rapidly inhibit the activity of the insulin-responsive glucose transporter GLUT-4. We hypothesized that a single dose of the PI indinavir resulting in therapeutic plasma concentrations would acutely decrease insulin-stimulated glucose disposal in healthy human volunteers.Randomized, double-blind, cross-over study comparing the effect of 1200 mg of orally administered indinavir and placebo on insulin-stimulated glucose disposal during a 180-min euglycemic, hyperinsulinemic clamp. Six healthy HIV-seronegative adult male volunteers were studied twice with 7 to 10 days between studies.There were no significant differences in baseline fasting body weight, or plasma glucose, insulin, lipid and lipoprotein levels between placebo- and indinavir-treated subjects. During steady-state (t60-180 min) insulin reached comparable levels (394 +/- 13 versus 390 +/- 11 pmol/l) and glucose was clamped at approximately 4.4 mmol/l under both conditions. The average maximum concentration of indinavir was 9.4 +/- 2.2 microM and the 2-h area under the curve was 13.5 +/- 3.1 microM.h. Insulin-stimulated glucose disposal per unit of insulin (M/I) decreased in all subjects from 14.1 +/- 1.2 to 9.2 +/- 0.8 mg/kg.min per microUI/ml (95% confidence interval for change, 3.7-6.1; P0.001) on indinavir (average decrease, 34.1 +/- 9.2%). The non-oxidative component of total glucose disposal (storage) decreased from 3.9 +/- 1.8 to 1.9 +/- 0.9 mg/kg.min (P0.01). Free fatty acid levels were not significantly different at baseline and were suppressed equally with insulin administration during both studies.A single dose of indinavir acutely decreases total and non-oxidative insulin-stimulated glucose disposal during a euglycemic, hyperinsulinemic clamp. Our data are compatible with the hypothesis that an acute effect of indinavir on glucose disposal in humans is mediated by a direct blockade of GLUT-4 transporters.

We recently reported that treatment with a pharmacologic dose of recombinant human growth hormone (GH) resulted in a significant loss of body fat and gain in lean tissue in HIV-infected patients with syndromes of fat accumulation. However, insulin-mediated glucose disposal decreased transiently after one month of GH therapy. The present paper focuses on the changes of hepatic carbohydrate and fat metabolism associated with GH treatment in the same subjects. We assessed hepatic insulin sensitivity under both fasting and hyperinsulinemic-euglycemic clamp conditions prior to and after one and six months of GH treatment (3 mg/day) in five patients using stable isotope tracer techniques. Indirect calorimetry, and measurements of lipid concentrations. Fasting endogenous glucose production (EGP) increased significantly at one month (12.0 ± 0.7 to 14.9 ± 0.9 μmol/kg/min, P < 0.03), and the increase was sustained at six months of GH treatment (14.0 ± 1.1μ mol/kg/min, NS). This increase in EGP was driven in part by increased glucogenesis (GNG) (3.5 ± 0.9 to 5.2 ± 0.9 and 5.8 ±1.2 μmol/kg/min, n = 4, P < 0.01 and P < 0.01 at one and six months, respectively); small changes in hepatic glycogenolysis also contributed. Sustained increases in lipolysis and progressive decreases in hepatic fractional de novo lipogenesis (DNL) and triglyceride concentrations occurred with GH treatment. These changes were accompanied by an improved lipid profile with a significant increase in HDL cholesterol and significant decreases in total and LDL cholesterol and triglyceride levels, the latter consistent with the decrease in hepatic DNL. During a hyperinsulinemic-euglycemic glucose clamp, EGP and GNG were markedly suppressed compared to the corresponding time points under fasting conditions, albeit less so when measured after one month of GH treatment. Thus, in HIV-infected patients with abnormal fat distribution, pharmacologic doses of GH improved the overall lipid profile, but worsened glucose homeostasis under both fasting and hyperinsulinemic conditions. The combined implications of these positive and negative metabolic effects for cardiovascular disease risk remain unknown.

GH has been proposed as a therapy for patients with HIV-associated fat accumulation, but the pharmacological doses (6 mg/d) used have been associated with impaired fasting glucose and hyperglycemia. In contrast, physiologic doses of GH ( approximately 1 mg/d) in HIV-negative men reduced visceral adiposity and eventually improved insulin sensitivity, despite initially causing insulin resistance. We conducted an open-label study to evaluate the effects of a lower pharmacologic dose of GH (3 mg/d) in eight men with HIV-associated fat accumulation. Oral glucose tolerance, insulin sensitivity, and body composition were measured at baseline, and 1 and 6 months. Six patients completed 1 month and 5, 6 months of GH therapy. IGF-I levels increased 4-fold within 1 month of GH treatment. Over 6 months, GH reduced buffalo hump size and excess visceral adipose tissue. Total body fat decreased (17.9 +/- 10.9 to 13.5 +/- 8.4 kg, P = 0.05), primarily in the trunk region. Lean body mass increased (62.9 +/- 6.4 to 68.3 +/- 9.1 kg, P = 0.03). Insulin-mediated glucose disposal, measured by a euglycemic hyperinsulinemic clamp, declined at month 1 (49.7 +/- 27.5 to 25.6 +/- 6.6 nmol/kg(LBM).min/pmol(INSULIN)/liter, P = 0.04); values improved at month 6 (49.2 +/- 22.6, P = 0.03, compared with month 1) and did not differ significantly from baseline. Similarly, the integrated response to an oral glucose load worsened at month 1 (glucose area under the curve 20.1 +/- 2.3 to 24.6 +/- 3.7 mmol.h/liter, P0.01), whereas values improved at month 6 (22.1 +/- 1.5, P = 0.02, compared with month 1) and did not differ significantly from baseline. One patient developed symptomatic hyperglycemia within 2 wk of GH initiation; baseline oral glucose tolerance testing revealed preexisting diabetes despite normal fasting glucose. In conclusion, GH at 3 mg/d resulted in a decrease in total body fat and an increase in lean body mass in this open-label trial. While insulin sensitivity and glucose tolerance initially worsened, they subsequently improved toward baseline. However, the dose of GH used in this trial was supraphysiologic and led to an increase in IGF-I levels up to three times the upper normal range. Because there are known adverse effects of long-term GH excess, the effectiveness of lower doses of GH should be studied. We also recommend a screening oral glucose tolerance test be performed to exclude subjects at risk for GH-induced hyperglycemia.

Since the advent of highly active antiretroviral therapy (HAART), the resultant decline in mortality rate associated with human immunodeficiency virus (HIV) infection (1) has allowed patients and clinicians to consider other important health issues beyond short-term survival. Included among these issues is the maintenance of normal gonadal function, as well as ethical and practical considerations for those individuals who wish to conceive and have children. Here, we review the pathophysiology and treatment of abnormalities in gonadal and sexual function and consider some of the challenges surrounding reproductive health among HIVinfected men and women.

BACKGROUND Therapy with HIV protease inhibitors (PI) has been associated with hyperglycemia, hyperlipidemia and changes in body composition. It is unclear whether these adverse effects are drug related, involve an interaction with the host response to HIV or reflect changes in body composition. METHODS Indinavir 800 mg twice daily was given to 10 HIV-seronegative healthy men to distinguish direct metabolic effects of a PI from those related to HIV infection. Fasting glucose and insulin, lipid and lipoprotein profiles, oral glucose tolerance (OGTT), insulin sensitivity by hyperinsulinemic euglycemic clamp, and body composition were measured prior to and after 4 weeks of indinavir therapy. RESULTS Fasting glucose (4.9 +/- 0.1 versus 5.2 +/- 0.2 mmol/l; P = 0.05) insulin concentrations (61.7 +/- 12.2 versus 83.9 +/- 12.2 pmol/l; P < 0.05), insulin : glucose ratio (12.6 +/- 1.7 versus 15.9 +/- 1.9 pmol/mmol; P < 0.05) and insulin resistance index by homeostasis model assessment (1.9 +/- 0.3 versus 2.8 +/- 0.5;P < 0.05) all increased significantly. During OGTT, 2 h glucose (5.1 +/- 0.4 versus 6.5 +/- 0.6 mmol/l; P < 0.05) and insulin levels (223.1 +/- 48.8 versus 390.3 +/- 108.8 pmol/l;P =0.05) also increased significantly. Insulin-mediated glucose disposal decreased significantly (10.4 +/- 1.4 versus 8.6 +/- 1.2 mg/kg x min per microU/ml insulin; 95% confidence interval 0.6--.0;P < 0.01). There was no significant change in lipoprotein, triglycerides or free fatty acid levels. There was a small loss of total body fat (15.8 +/- 1.4 versus 15.2 +/- 1.4 kg;P = 0.01) by X-ray absorptiometry without significant changes in weight, waist : hip ratio, and visceral or subcutaneous adipose tissue by computed tomography. CONCLUSIONS In the absence of HIV infection, treatment with indinavir for 4 weeks causes insulin resistance independent of increases in visceral adipose tissue or lipid and lipoprotein levels.

To determine whether HIV infection, the wasting syndrome, or nucleoside analog reverse transcriptase inhibitor (NRTI) or protease inhibitor (PI) therapy uniquely affect fat distribution in men, we performed manual regional analysis of total, appendicular, trunk, and central abdominal fat measured by dual-energy X-ray absorptiometry (DEXA). Five groups of study subjects were identified for this cross-sectional analysis: HIV-negative controls (HIV-; N = 44) and four groups of HIV-positive subjects: antiretroviral (ARV)-naive or with limited prior use of NRTIs (ARV-; N = 23); on NRTIs for > or =6 months but PI-naive (NRTI; N = 30); on an NRTI/PI regimen for > or =6 months but with no complaints of abnormal fat distribution (NRTI/PI; N = 26); and those on NRTIs but PI-naive with the wasting syndrome (NRTI/WS; N = 40). Total, appendicular, trunk, and central abdominal fat was significantly lower in NRTI/WS. The ratio of trunk fat to appendicular fat was virtually identical in HIV- and ARV-. This ratio was significantly higher in the NRTI, NRTI/PI, and NRTI/WS groups, and values in these three groups were similar. These cross-sectional data suggest that HIV-infected men receiving NRTIs have an altered pattern of fat distribution, compared with HIV-negative men and HIV-positive men who are not receiving antiretroviral therapy. This effect was independent of the concomitant use of a PI or a diagnosis of the wasting syndrome. We saw no evidence of a unique effect of HIV infection per se on regional fat distribution. Although the fat ratio is increasingly employed, its physiologic significance is unclear. Our results, which have been obtained retrospectively, are intended to provide the impetus for prospective, controlled studies of the interactions among drug and host factors in the development of fat distribution abnormalities.

Although protease inhibitor (PI) therapy has improved the clinical status of patients with HIV infection, concerns have arisen that such treatment may have deleterious effects on glucose control, lipid metabolism, and body fat distribution. To determine whether initiation of PI therapy uniquely affects glucose and lipid metabolism, we analyzed paired data in HIV-infected patients before and after beginning antiretroviral therapy that included a PI (PI; N = 20) or lamivudine (3TC) but no PI (3TC; N = 9); and a control group on stable regimens that included neither of these agents (CONT: N = 12). Measurements included fasting glucose; insulin; triglycerides; total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol; HIV RNA; CD4+ lymphocytes; weight; and total and regional body composition. Neither weight nor total or regional fat content changed significantly in any group during the period of observation. Nonetheless, in patients beginning PI therapy, there were significant increases in glucose (+9+/-3 mg/dl; p = .0136), insulin (+12.2+/-4.9 U/ml; p = .023), triglycerides (+53+/-17 mg/dl; p = .0069), and total and LDL cholesterol (+32+/-11 and +18+/-5 mg/dl; p = .0082 and .0026, respectively). None of these parameters changed significantly in the 3TC or CONT groups. The PI and 3TC groups experienced comparable increases in CD4+ lymphocytes, suggesting that the observed metabolic effects may be associated with PIs uniquely, rather than improvement in clinical status. However, it is also possible that the metabolic effects of PIs are associated with more effective viral suppression, because a greater proportion of patients in the PI group achieved undetectable levels of virus. We conclude that changes in glucose and lipid metabolism are induced by PI therapy in the absence of significant changes in weight or fat distribution. Longer periods of follow-up will be required to determine the clinical significance of these changes. However, at the moment, the risks associated with these metabolic effects do not appear to outweigh improvements in survival seen with PI therapy.

Platelet-activating factor (PAF) acetylhydrolase (PAF-AH) catalyzes the hydrolysis of PAF, a mediator of inflammation, as well as other biologically active oxidized phospholipids. In humans, plasma PAF-AH activity is bound to low-density lipoprotein (LDL) and high-density lipoprotein (HDL). Higher levels of plasma PAF-AH activity have been found in a variety of diseases, and are thought to be a defense mechanism against the toxic effects of PAF and oxidized phospholipids. We studied plasma PAF-AH activity in patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS), a disease characterized by chronic HIV infection and a systemic host response. Plasma PAF-AH activity was significantly greater in AIDS patients compared with control subjects (25.2 +/- 2.0 v 17.0 +/- 0.8 nmol/min/mL, P < .001). The higher levels of plasma PAF-AH activity were found in LDL (28.2 +/- 2.2 v 18.3 +/- 1.0 nmol/min/mL for AIDS v controls, respectively, P = .0005), but not in HDL. Plasma PAF-AH activity in AIDS correlated with circulating interferon alfa (r = .575, P = .005) and plasma triglycerides (r = .556, P < .0025). The presence of secondary infection in AIDS did not significantly change plasma PAF-AH activity. The initiation of a new antiretroviral regimen with either a protease inhibitor or the nucleoside analog lamivudine did not significantly decrease plasma PAF-AH activity, despite successful suppression of HIV RNA levels. Plasma PAF-AH activity may be a sensitive marker of the host response to infection, and the higher levels of plasma and LDL-associated PAF-AH activity in patients with HIV infection and AIDS may be a physiological response to protect the host against oxidative injury from PAF and oxidized phospholipids.

Body wasting and loss of lean body mass (LBM) have been associated with increased mortality and disease progression, and reduced quality of life, in patients with human immunodeficiency virus (HIV) infection. The failure of nutritional therapies and, more recently, of effective viral suppression, to consistently restore LBM has prompted investigation of the pharmacologic use of a number of specific protein anabolic agents, including recombinant human growth hormone (rhGH), insulin-like growth factor I (rhIGF-I), and synthetic testosterone derivatives, such as nandrolone decanoate, oxandrolone, and oxymetholone. In a placebo-controlled trial, treatment with rhGH resulted in a significant and sustained increase in weight that was accompanied by an even greater increase in LBM and a decrease in fat, and improvement in treadmill work output. Preliminary data suggest that short-term rhGH treatment may be effective in mitigating weight loss in patients with secondary infections. Open-label studies of nandrolone decanoate suggest that this injectable agent also can increase weight and LBM. Two oral agents, oxandrolone and oxymetholone, can increase weight, but their effects on LBM in placebo-controlled trials have not been reported. Taken together, these studies demonstrate that HIV-infected individuals can regain weight and LBM under the proper therapeutic circumstances. The effects of reversal of wasting on survival and disease progression, long-term safety, and the potential value of these therapies in the treatment of fat redistribution remain to be determined.

In a previous study, we showed that dietary gamma-linolenic acid (GLA), an omega-6 polyunsaturated fatty acid found in borage oil (BOR), attenuates the development of hypertension in young spontaneously hypertensive rats (SHR). The purpose of this study was to determine the effects of dietary GLA on established hypertension in adult rats, as well as its effects on components of the renin-angiotensin-aldosterone axis. For 5 weeks, male SHR (14-15 weeks old) were fed a basal fat-free diet to which 11% by weight of sesame oil (SES) or BOR was added. Systolic blood pressure (SBP), determined by the tail cuff method, and weight were measured weekly. Plasma renin activity (PRA), aldosterone (PA), and corticosterone (PC) levels were measured at the end of the dietary treatments. The adrenal glands were homogenized, and angiotensin II (ANG II) binding was measured and plotted according to Scatchard. Systolic blood pressure was 12 mmHg lower at Week 5 in SHR fed the BOR diet compared to SES-fed rats (P < 0.005). Weight gains were similar in both dietary groups. Plasma aldosterone was lower, PRA was higher, and the PA/PRA ratio was significantly lower (P < 0.05) in BOR-fed rats. Levels of PC were the same in both groups. The BOR-enriched diet reduced adrenal ANG II receptor density and affinity compared to the SES diet. Results suggest that BOR inhibits adrenal responsiveness to ANG II by an action on adrenal receptors. Our findings demonstrated that dietary GLA lowers SBP in adult SHR. This effect may be mediated, at least in part, by interference with the renin-angiotensin-aldosterone system at the level of adrenal ANG II receptors.

A cross-sectional study was performed in a group of dialysis patients and control subjects to identify the determinants of serum levels of leptin, the protein product of the obese (ob) gene. Twenty-eight patients on dialysis (19 patients on hemodialysis [HD] and nine patients on peritoneal dialysis [PD]) and 41 healthy control subjects were studied. For each subject, blood was drawn for measurement of serum leptin levels and body composition was analyzed by dual-energy x-ray absorptiometry. Regression analyses were performed to determine the predictors of leptin levels, the independent contribution of HD and PD, and the relationship between leptin levels and markers of malnutrition and protein intake in the patients on dialysis. As expected, percentage of body fat was strongly correlated with leptin levels in the group as a whole and in each subgroup when analyzed separately. However, the slope of the relationship was significantly greater for dialysis patients than for control subjects (P < 0.05). Multivariate regression analysis showed that patients on HD and PD had higher leptin levels than control subjects even after adjustment for age, gender, and percentage of body fat. Univariate analyses were performed to assess the relationship between leptin levels and markers of nutritional status such as albumin, blood urea nitrogen, protein catabolic rate (PCR), transferrin, cholesterol, and lean body mass per height. There was a significant negative correlation between leptin levels and serum albumin (r = -0.598, P < 0.001) and between leptin and PCR (r = -0.433, P < 0.05) in the patients on dialysis. It is concluded that leptin levels adjusted for percentage of body fat are increased in dialysis patients compared with control subjects, particularly in those on PD. In addition, increased leptin levels are associated with low serum albumin levels and PCR in dialysis patients.

In previous studies, treatment with recombinant human GH (rhGH) produced sustained increases in weight and lean body mass (LBM) and decreases in fat mass in patients with human immunodeficiency virus (HIV)-associated wasting. To evaluate the effects of chronic rhGH treatment on components of energy balance, we recruited separate subgroups of HIV-positive patients with an involuntary weight loss of 10% or more to undergo paired measurements of resting energy metabolism (n = 6) or food intake (n = 11) before and during the final week of a 3-month rhGH (0.1 mg/kg·day) treatment period. In the energy metabolism subset, resting energy expenditure (REE) and substrate oxidation rates were measured by indirect calorimetry during brief admissions to a metabolic ward. Patients in the energy intake subset prepared written 4-day food intake diaries. Body composition was measured in both groups by bioelectrical impedance analysis. Changes in weight (+2.2 ± 0.9 and +2.2 ± 0.6 kg), LBM (+3.2 ± 0.6 and +3.8 ± 0.5 kg), an...

Previous studies have shown that CD4-positive T cells vary in a predictable manner over 24 h. This diurnal variance has significant clinical implications. Recently, viral RNA measurements have been increasingly used as a standard marker in the management of human immunodeficiency virus (HIV)-infected patients. Little detailed analysis of the variability of this marker has been conducted. To define the variance of plasma HIV-1 RNA levels within days, 11 clinically stable patients with established HIV infection and a baseline viral RNA level >40,000 copies/mL were studied. Following the patients' admission to an inpatient research unit, plasma samples were obtained frequently over 48 h and analyzed for HIV-1 RNA levels by use of a quantitative branched chain DNA assay (bDNA). No diurnal pattern was detected. In these clinically stable patients, viral RNA levels exhibited a variance of approximately 0.4 log.

Angiotensin II (Ang II) may act as an angiogenic and growth promoting factor in different tissues. To assess the role of Ang II in compensatory renal growth following unilateral nephrectomy (UNX), we measured renin, angiotensinogen, and Ang II type 1 (AT1) receptor mRNA levels, as well as Ang II receptor density, in two groups of Sprague-Dawley rats 7 days after either sham operation or UNX. Half of each group received either no treatment or an angiotensin-converting enzyme inhibitor (100 mg/dL captopril in the drinking water, initiated at the time of the intervention). Following UNX, the ratio of kidney weight to body weight (KW/BW) in untreated animals was greater than in rats undergoing sham UNX (0.46 ± 0.01 v 0.37 ± 0.01%, P < .01). Neither renal renin, nor renal or hepatic angiotensinogen mRNA levels, determined by slot blot hybridization, changed significantly after UNX. Ang II receptor density in glomeruli, determined using an 125I-Sar1-IIe8 Ang II in situ receptor binding assay on frozen kidney sections, did not change significantly after UNX, nor did renal AT1 receptor mRNA. In captopril-treated rats, KW/BW was greater in UNX than in sham operated rats (0.44 ± 0.01 v 0.37 ± 0.01%, P < .01), similar to results in untreated animals. Renal and hepatic angiotensinogen mRNA levels were not affected by captopril treatment and did not change further in response to UNX. Captopril treatment increased renin mRNA in both sham operated and UNX rats as compared with untreated controls, but had no significant effect on Ang II receptor density and AT1 receptor mRNA; and no change was observed in either variable as a consequence of UNX. Thus, compensatory renal hypertrophy following UNX occurred in the absence of measurable changes in components of the renin-angiotensin system, and despite functionally significant inhibition of this system by captopril. These data do not support a critical role for Ang II in compensatory renal hypertrophy.

Exposure to high glucose concentrations increases the mRNA levels of oxygen radical scavenging enzymes in cultured endothelial cells, suggesting a compensatory response to increased free radical production. To test the hypothesis that this response also occurs in vivo, Cu,Zn-superoxide dismutase (Cu,Zn-SOD) and catalase mRNA levels, were measured in the kidneys of Sprague-Dawley rats 17 days after intravenous injection of streptozotocin (60 mg/kg body weight) and compared with those of control rats. Diabetic rats were either left untreated or given differing insulin regimens (2, 3–8, 6–10 IU/day) in two different experiments that were designed to achieve varying degrees of metabolic control. Cu,Zn-SOD and catalase mRNA levels were measured by Northern blot hybridization and standardized by 28S ribosomal RNA determination. Renal Cu,Zn-SOD and catalase mRNA levels were significantly greater in untreated diabetic and in low-dose (2 IU/day) insulin-treated rats than in controls. Treatment with a moderate dose (3–8 IU/day) of insulin normalized catalase but not Cu,Zn-SOD mRNA levels. The highest insulin regimen (6–10 IU/day), in addition to achieving complete metabolic control as evidenced by normal growth and plasma glucose levels, normalized both catalase and Cu,Zn-SOD mRNA levels. Thus, in rats with streptozotocin-induced diabetes Cu,Zn-SOD and catalase renal mRNA levels are greater than in normal rats. This difference is prevented by sufficient insulin dosage to normalize plasma glucose and might be due to an increased production of free radicals. [Diabetologia (1997) 40: 23–29]

In addition to its well-characterized renal hemodynamic effects, angiotensin II (Ang II) promotes growth of cultured glomerular and tubular cells, suggesting a possible role in renal development. To better define potential developmental effects of Ang II, we examined the expression of Ang II receptors in embryonic (E19) and postnatal (1, 2, 3, 10 days, 6 weeks, 3 and 9 months) rat kidneys, using in situ autoradiography and the nonpeptide antagonists losartan and PD-123177 to identify receptor subtypes. At E19, 125I-[Sar1, Ile8]Ang II binding was equally reduced by losartan and PD-123177, indicating the presence of both AT1 and AT2 receptors. A progressive increase in Ang II receptor density occurred after birth, reaching a plateau at day 10. At that time, the AT1 subtype predominated and was virtually the sole subtype present thereafter. Ang II receptor density and AT1 mRNA levels decreased in aging rats. Total AT1 receptor mRNA levels in both kidney and liver were determined by Northern hybridization analysis using a radiolabeled AT1 anti-sense cRNA probe. In both tissues, AT1 mRNA levels increased rapidly following birth, reached a maximum on day 10 and decreased thereafter. To further characterize the ontogenic effects on AT1 gene expression, renal AT1A and AT1B receptor mRNA isoforms were determined by reverse transcription and the polymerase chain reaction. No significant differences were observed during maturation between the relative levels of AT1A and AT1B mRNAs, with the AT1A isoform accounting for approximately 78% at any time point. Thus, renal AT1 receptor density increases rapidly after birth, in association with an increase in both AT1A and AT1B receptor gene expression. As the predominant receptor isoform in the adult kidney, the AT1A receptor may account for the majority of the effects of Ang II on glomerular and tubular function.

Resume La denutrition, en particulier la perte de masse maigre (MM), est une complication frequente de l'infection par le virus de l'immunodeficience humaine (VIH). Elle est associee a une alteration de la qualite de vie, a une progression acceleree de la maladie ainsi qu'a une reduction de la survie. L'echec des traitements nutritionnels ou des stimulants de l'appetit pour restaurer de facon durable la MM a conduit a l'evaluation d'hormones stimulant specifiquement l'anabolisme proteique dans le cadre de la denutrition associee au VIH. Dans une etude metabolique a court terme, le traitement par des doses pharmacologiques d'hormone de croissance humaine recombinante (rhGH) a entraine un gain ponderal net et une augmentation de la retention azotee. De plus, dans une etude multicentrique controlee contre placebo, un apport de rhGH pendant 12 semaines entrainait un gain prolonge de poids et de MM. L'administration d' Insulin-like Growth Factor -I (IGF-I) recombinant humain, dont on pense qu'il est le mediateur des effets anabolisants proteiques de la rhGH, n'a eu qu'un effet benefique transitoire sur la balance azotee au cours d'une etude metabolique. Dans une etude multicentrique controlee contre placebo, l'association de rhIGF-I avec de faibles doses de rhGH a entraine, pour une duree d'etude comparable, une augmentation de MM representant moins de la moitie de celle obtenue avec les doses pharmacologiques de rhGH seule. Les resultats preliminaires de l'administration de testosterone et de ses derives mettent en evidence, chez les patients infectes par le VIH, une augmentation du poids et de la MM. En l'etat actuel, si on ne tient compte que des etudes controlees contre placebo et en double aveugle, seules des doses pharmacologiques de rhGH permettent d'obtenir une augmentation durable de la MM. Les etudes futures concernant l'utilisation des facteurs de croissance dans la denutrition associee au VIH devraient viser non seulement a evaluer le meilleur moyen d'administrer ces produits, mais aussi a determiner si des benefices fonctionnels significatifs sur le plan clinique vont de pair avec l'augmentation de poids et/ou de MM.

We report the occurrence of cutis verticis gyrata (CVG), a disfiguring dermatological condition, in four patients with HIV-related lipodystrophy (HIVLD). These four patients had abnormal metabolic and hormonal lab values which we compare with metabolic and hormonal perturbations cited in previous HIVLD cohorts. In addition, we describe the sole use of poly-L-lactic acid as a potential treatment for decreasing the appearance of CVG-associated ridges. © 2013 Keshav Khanijow et al.

We evaluated an African American woman referred in 1986 at age 33 years because of renal potassium and calcium wasting and chronic hip pain. She presented normotensive, hypokalemic, hypocalcemic, normophosphatemic, and hypercalciuric. Marked hyperparathyroidism was evident. Urinary cyclic adenosine monophosphate (cAMP) excretion did not increase in response to parathyroid hormone (PTH) infusion, indicating renal resistance to PTH. X-rays and bone biopsy revealed severe osteitis fibrosa cystica, confirming skeletal responsiveness to PTH. Renal potassium wasting, suppressed plasma renin activity, and elevated plasma and urinary aldosterone levels accompanied her hypokalemia, suggesting primary hyperaldosteronism. Hypokalemia resolved with spironolactone and, when combined with dietary sodium restriction, urinary calcium excretion fell and hypocalcemia improved, in accord with the known positive association between sodium intake and calcium excretion. Calcitriol and oral calcium supplements did not suppress the chronic hyperparathyroidism nor did they reduce aldosterone levels. Over time, hyperparathyroid bone disease progressed with pathologic fractures and persistent pain. In 2004, PTH levels increased further in association with worsening chronic kidney disease. Eventually hypercalcemia and hypertension developed. Localizing studies in 2005 suggested a left inferior parathyroid tumor. After having consistently declined, the patient finally agreed to neck exploration in January 2009. Four hyperplastic parathyroid glands were removed, followed immediately by severe hypocalcemia, attributed to "hungry bone syndrome" and hypoparathyroidism, which required prolonged hospitalization, calcium infusions, and oral calcitriol. Although her bone pain resolved, hyperaldosteronism persisted.

HIV-infected individuals are at risk for decreased bone mineral density (BMD). The known risk factors for bone loss do not fully explain the increased risk in this population. There is emerging evidence that leptin, a hormone secreted by adipocytes, plays an important role in bone metabolism. Several studies have assessed the relationship between leptin and bone density in healthy adults, but there are few such studies in HIV-infected individuals. Furthermore, HIV infected individuals on antiretroviral therapy are at increased risk for altered fat distribution, which may impact the relationship between leptin and BMD. In a cross-sectional analysis of data in 107 HIV-infected men, we determined whether serum leptin levels were associated with whole-body BMD and bone mineral content measured by dual-energy X-ray absorptiometry (DEXA), after adjusting for confounders including body fat distribution. We found an inverse association between leptin and bone density in those with peripheral lipoatrophy, defined objectively as 3 kg appendicular fat. This result suggests that fat distribution may modify the relationship between leptin and bone density.

Insulin has been postulated to play a role in the pathophysiology of essential hypertension via an antinatriuretic action. To further explain the sodium insulin interaction in the kidney, we studied effects of different salt intakes on insulin receptor binding and mRNA levels in tissues from rats maintained on 0.07%, 0.3%, or 7.5% NaCl for 14 days. Scatchard analysis of competition data from in situ autoradiography studies resulted in curvilinear profiles, indicating the presence of either two classes of receptors or a single class of receptors with a negative cooperative hormone-receptor interaction. When data were analyzed using the two-site model, binding capacity of the high-affinity receptor site was significantly less in high-salt-fed rats. No significant differences between dietary groups were observed in apparent dissociation constants of the two receptor sites or in maximal binding capacity of the low-affinity, high-capacity site. Analysis of insulin binding to glomeruli, cortex, outer medulla, and inner medulla indicated that the high-salt diet was associated with decreased receptor density in all regions studied. Insulin receptor mRNA, as quantified by Northern and slot blot analysis, was inversely related to salt intake in absence of a change in plasma glucose, insulin, and corticosterone levels. Both 7.2- and 9.4-kb transcripts were similarly affected by dietary sodium content. Plasma renin concentration and renal renin mRNA levels were decreased but blood pressure was not affected by high-salt diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Background Uridine is a therapy for hereditary orotic aciduria and is being investigated in other disorders caused by mitochondrial dysfunction, including toxicities resulting from treatment with nucleoside reverse transcriptase inhibitors in HIV. Historically, the use of uridine as a therapeutic agent has been limited by poor bioavailability. A food supplement containing nucleosides, NucleomaxX®, has been reported to raise plasma uridine to supraphysiologic levels. Methodology/Principal Findings Single- and multi-dose PK studies following NucleomaxX® were compared to single-dose PK studies of equimolar doses of pure uridine in healthy human volunteers. Product analysis documented that more than 90% of the nucleoside component of NucleomaxX® is in the form of triacetyluridine (TAU). Single and repeated dosing with NucleomaxX® resulted in peak plasma uridine concentrations 1–2 hours later of 150.9±39.3 µM and 161.4±31.5 µM, respectively, levels known to ameliorate mitochondrial toxicity in vitro. Cmax and AUC were four-fold higher after a single dose of NucleomaxX® than after uridine. No adverse effects of either treatment were observed. Conclusions/Significance NucleomaxX®, containing predominantly TAU, has significantly greater bioavailability than pure uridine in human subjects and may be useful in the management of mitochondrial toxicity.

A consensus conference convened by the Society of Sarcopenia, Cachexia and Wasting Disorders has concluded that “Sarcopenia, ie, reduced muscle mass, with limited mobility” should be considered an important clinical entity and that most older persons should be screened for this condition. “Sarcopenia with limited mobility” is defined as a person with muscle loss whose walking speed is equal to or less than 1 m/s or who walks less than 400 m during a 6-minute walk, and who has a lean appendicular mass corrected for height squared of 2 standard deviations or more below the mean of healthy persons between 20 and 30 years of age of the same ethnic group. The limitation in mobility should not clearly be a result of otherwise defined specific diseases of muscle, peripheral vascular disease with intermittent claudication, central and peripheral nervous system disorders, or cachexia. Clinically significant interventions are defined as an increase in the 6-minute walk of at least 50 meters or an increase of walking speed of at least 0.1 m/s. “A word is not a crystal, transparent and unchanged; it is the skin of a living thought and may vary greatly in color and content according to the circumstances and the time when it is used.”—Oliver Wendell Holmes

Body wasting, characterized by disproportionate loss of body cell mass, is a feature of many chronic diseases, including infection with the human immunodeficiency virus (HIV). Therapies that merely increase energy intake do not consistently restore body cell mass in patients with the wasting syndrome. Because treatment with GH has induced nitrogen (N) retention in catabolic patients after surgery, burns, cancer, and hypocaloric feeding, we designed this study to determine whether GH could also produce an anabolic response in persons with HIV-associated weight loss. Six HIV-positive (HIV+) men with an average weight loss of 19% and six healthy weight-stable controls (HIV-) were hospitalized on a metabolic ward, where they consumed a constant metabolic diet during successive 5-day precontrol, 7-day baseline, and 7-day treatment [recombinant human GH (rhGH), 0.1 mg/kg.day] periods. The effects of rhGH on body weight, N and electrolyte excretion, energy expenditure, substrate oxidation, and integrated lipid and carbohydrate metabolism were assessed. Body weight increased promptly and progressively during treatment (2.0 +/- 0.3 and 1.6 +/- 0.2 kg in HIV+ and HIV-, respectively). Urinary N excretion decreased by 288 +/- 17 and 287 +/- 42 mmol/day in HIV+ and HIV-, respectively. Resting energy expenditure increased by 7.5% in both groups. Protein oxidation decreased, whereas lipid oxidation increased significantly. Glucose flux increased, and modest increases in fasting plasma triglyceride, glucose, and insulin levels were observed. Thus, short term rhGH treatment increased both protein anabolism and protein-sparing lipid oxidation, effects that should increase body cell mass if sustained during chronic therapy.

Context: HIV-infected patients on antiretroviral therapy are at increased risk for excess visceral adiposity and insulin resistance. Treatment with GH decreases visceral adiposity but worsens glucose metabolism. IGF-I, which mediates many of the effects of GH, improves insulin sensitivity in HIV-negative individuals. Objective: Our objective was to determine whether IGF-I, complexed to its major binding protein, IGF-binding protein-3 (IGFBP-3), improves glucose metabolism and alters body fat distribution in HIV-infected patients with abdominal obesity and insulin resistance. Methods: We conducted a pilot, open-label study in 13 HIV-infected men with excess abdominal adiposity and insulin resistance to assess the effect of 3 months of treatment with IGF-I/IGFBP-3 on glucose metabolism and fat distribution. Glucose metabolism was assessed by oral glucose tolerance test and hyperinsulinemic-euglycemic clamp. Endogenous glucose production (EGP), gluconeogenesis, whole-body lipolysis, and de novo lipogenesis (DNL) were measured with stable isotope infusions. Body composition was assessed by dual-energy x-ray absorptiometry and abdominal computed tomography scan. Results: Glucose tolerance improved and insulin-mediated glucose uptake increased significantly during treatment. EGP increased under fasting conditions, and suppression of EGP by insulin was blunted. Fasting triglycerides decreased significantly in association with a decrease in hepatic DNL. Lean body mass increased and total body fat decreased, whereas visceral adipose tissue did not change. Conclusions: Treatment with IGF-I/IGFBP-3 improved whole-body glucose uptake and glucose tolerance, while increasing hepatic glucose production. Fasting triglycerides improved, reflecting decreased DNL, and visceral adiposity was unchanged.

Background: Some HIV protease inhibitors (PIs), including full-dose ritonavir (800 mg) and ritonavir-boosted lopinavir, acutely induce insulin resistance in the absence of HIV infection and changes in body composition. Boosting dose ritonavir (100-200 mg) is the most commonly prescribed PI, yet its effects on glucose metabolism have not been described in the absence of another PI. Methods: In this randomized, double-blind, cross-over study, a single dose of ritonavir 200 mg or placebo was given to healthy HIV-seronegative volunteers before assessment of insulin sensitivity by euglycemic hyperinsulinemic clamp. Results: Boosting dose ritonavir had no effect on insulin-mediated glucose disposal (M/I, placebo: 8.59 +/- 0.83 vs. ritonavir: 8.51 +/- 0.64 mg/kg per minute per mu U/mL insulin, P = 0.89). Conclusions: A single boosting dose of ritonavir does not alter insulin sensitivity, suggesting lopinavir is likely responsible for the induction of insulin resistance demonstrated in prior short-term studies of lopinavir/ritonavir. There is a dose-dependent effect of ritonavir on insulin sensitivity.

Introduction Altered gut and pancreatic hormone secretion may bolster resolution of insulin resistance after Roux-en-Y gastric bypass (RYGB), but the independent effects of weight loss and hormonal secretion on peripheral glucose disposal are unknown. Methods Two groups of nondiabetic morbidly obese patients were studied: RYGB followed by standardized caloric restriction (RYGB, n = 12) or caloric restriction alone (diet, n = 10). Metabolic evaluations (euglycemic–hyperinsulinemic clamp, meal tolerance test) were done at baseline and 14 days (both groups) and 6 months after RYGB. Results At baseline, body composition, fasting insulin, and glucose and peripheral glucose disposal did not differ between groups. At 14 days, excess weight loss (EWL) was similar (RYGB, 12.7% vs. diet, 10.9%; p = 0.12), fasting insulin and glucose decreased to a similar extent, and RYGB subjects had altered postmeal patterns of gut and pancreatic hormone secretion. However, peripheral glucose uptake (M value) was unchanged in both groups. Six months after RYGB, EWL was 49.7%. The changes in fasting glucose and insulin levels and gut hormone secretion persisted. M values improved significantly, and changes in M values correlated with the % EWL (r = 0.68, p = 0.02). Conclusions Improvement in peripheral glucose uptake following RYGB was observed only after substantial weight loss had occurred and correlated with the magnitude of weight lost.

In rats with STZ-induced diabetes mellitus, a reduction in insulin secretion is associated with increased insulin binding in the liver, muscle, fat, and kidney, but not in the brain. To test the hypothesis that tissue-specific modulation of insulin receptors (IRs) in STZ-induced diabetes occurs at the level of mRNA, IR mRNA levels were measured in the liver, kidney, and brain of Sprague-Dawley rats 15 days after intravenous administration of STZ (60 mg/kg body weight) and compared with those of control rats. Diabetic rats were either left untreated or given differing insulin regimens that were designed to achieve varying degrees of metabolic control. IR mRNA levels were measured by slot blot hybridization with a 32P-labeled rlR probe and standardized by 28S ribosomal RNA determination. Hepatic IR mRNA levels were increased significantly in both untreated diabetic rats and in those that received low-dose (2 U/day) insulin therapy. In contrast, hepatic IR mRNA levels did not differ significantly from controls in those that received moderate doses of insulin (3–8 U/day) and were significantly less than controls in those that received the highest doses (6–10 U/day). Renal IR mRNA levels also were increased significantly in the untreated diabetic rats but not in those that received low- or moderate-dose insulin therapy, and were significantly less than controls in those that received the highest doses. A highly significant negative correlation was observed between the level of hepatic (r = −0.84, P

Since the introduction of highly active antiretroviral therapy (HAART) more than a decade ago, there has been a dramatic improvement in the morbidity and mortality associated with human immunodeficiency virus (HIV) infection and AIDS. As survival has improved, a constellation of metabolic and morphologic abnormalities, often referred to as the HIV-associated lipodystrophy syndrome, has become increasingly evident. Features of this syndrome include abnormal glucose metabolism, dyslipidemia, and alterations in body fat distribution including peripheral lipoatrophy and central adiposity. In this chapter, we will focus primarily on the abnormalities of glucose metabolism in patients with HIV/AIDS, including insulin resistance, impaired glucose tolerance, and frank diabetes mellitus. After first considering the effects of HIV infection per se, we will examine the mechanisms by which antiretroviral (ARV) medications are purported to disrupt glucose metabolism.

Weight loss and low BMI due to an underlying illness have been associated with increased mortality, reduced functional capacity, and diminished quality of life. There is a need for well tolerated, long-term approaches to maintain body weight in patients with cachexia or wasting. The purpose of this review is to highlight the scientific and clinical evidence derived from the recent literature investigating the rationale for and potential medical use of creatine supplementation in patients with cachexia or wasting.Some studies have demonstrated that supplementation with creatine can increase creatine reserves in skeletal muscle and increase muscle mass and performance in various disease states that affect muscle size and function. The mechanisms underlying these effects are not clear. It has been suggested that creatine supplementation may increase intramuscular phosphocreatine stores and promote more rapid recovery of adenosine triphosphate levels following exercise, thus allowing users to exercise for longer periods or at higher intensity levels. Other hypothesized mechanisms include attenuation of proinflammatory cytokines, stimulation of satellite cell proliferation and upregulation of genes that promote protein synthesis and cell repair.Creatine is a generally well tolerated, low-cost, over-the-counter nutritional supplement that shows potential in improving lean body mass and functionality in patients with wasting diseases. However, placebo-controlled studies have shown variable effects, with improvements in some and not in others. Additional studies with longer follow-up are required to identify the populations that might benefit most from creatine supplementation.

Background The effects of different HIV protease inhibitors (PIs) on peripheral insulin resistance have been described, but less is known about their effects on insulin suppression of endogenous glucose production (EGP). Methods We tested the acute effects of 3 PIs, indinavir, ritonavir, and amprenavir, on EGP quantified by stable isotope techniques during the hyperinsulinemic, euglycemic clamp in 3 similar placebo-controlled protocols. Results EGP was higher with indinavir in the hyperinsulinemic state than with placebo (4.1 +/- 1.3 vs. 2.2 +/- 0.8 microg x kg(-1) x min(-1), P = 0.04). A trend toward higher EGP was seen with ritonavir (3.6 +/- 0.3 vs. 3.0 +/- 0.5 microg x kg(-1) x min(-1), P = 0.08). There was no evidence that amprenavir blunted insulin suppression of EGP compared with placebo (2.9 +/- 0.04 vs. 3.2 +/- 0.7 microg x kg(-1) x min(-1), P = 0.63). Conclusions Some PIs can acutely blunt the ability of insulin to suppress EGP, but, as with insulin resistance, the effects of PIs on EGP are drug-specific, not class-specific.

Context: Leptin deficiency is associated with dyslipidemia and insulin resistance in animals and humans with lipoatrophy; leptin replacement ameliorates these abnormalities. Objective: The objective of the study was to evaluate the effects of leptin therapy in lipoatrophic HIV-infected patients with dyslipidemia and hypoleptinemia. Design: This was a 6-month, open-label, proof-of-principle pilot study. Setting: Metabolic ward studies were performed before and 3 and 6 months after leptin treatment. Participants: Participants included eight HIV-infected men with lipoatrophy, fasting triglycerides greater than 300 mg/dl, and serum leptin less than 3 ng/ml. Intervention: Recombinant human leptin was given by sc injection (0.01 mg/kg and 0.03 mg/kg twice daily for successive 3 month periods). Outcome Measures: Measures included fat distribution by magnetic resonance imaging and dual-energy X-ray absorptiometry; fasting lipids; insulin sensitivity by euglycemic hyperinsulinemic clamp; endogenous glucose production, gluconeogenesis, glycogenolysis, and whole-body lipolysis by stable isotope tracer studies; oral glucose tolerance testing; liver fat by proton magnetic resonance spectroscopy; and safety. Results: Visceral fat decreased by 32% (P = 0.001) with no changes in peripheral fat. There were significant decreases in fasting total (15%, P = 0.012), direct low-density lipoprotein (20%, P = 0.002), and non-high-density lipoprotein (19%, P = 0.005) cholesterol. High-density lipoprotein cholesterol increased. Triglycerides, whole-body lipolysis, and free fatty acids decreased during fasting and hyperinsulinemia. Fasting insulin decreased. Endogenous glucose production decreased during fasting and hyperinsulinemia, providing evidence of improved hepatic insulin sensitivity. Leptin was well tolerated but decreased lean mass. Conclusions: Leptin treatment was associated with marked improvement in dyslipidemia. Hepatic insulin sensitivity improved and lipolysis decreased. Visceral fat decreased with no exacerbation of peripheral lipoatrophy. Results from this pilot study suggest that leptin warrants further study in patients with HIV-associated lipoatrophy.