Physiologic growth hormone replacement improves fasting lipid kinetics in patients with HIV lipodystrophy syndrome.

BACKGROUND: HIV lipodystrophy syndrome (HLS) is characterized by accelerated lipolysis, inadequate fat oxidation, increased hepatic reesterification, and a high frequency of growth hormone deficiency (GHD). The effect of growth hormone (GH) replacement on these lipid kinetic abnormalities is unknown. OBJECTIVE: We aimed to measure the effects of physiologic GH replacement on lipid kinetics in men with HLS and GHD. DESIGN: Seven men with HLS and GHD were studied with the use of infusions of [13C1]palmitate, [2H5]glycerol, and [2H3]leucine to quantify total and net lipolysis, palmitate and free fatty acid (FFA) oxidation, and VLDL apolipoprotein B-100 synthesis before and after 6 mo of GH replacement (maximum: 5 microg x kg(-1) x d(-1)). RESULTS: GH replacement decreased the rates of total lipolysis [FFA(total) rate of appearance (x +/- SE): from 4.80 +/- 1.24 to 3.32 +/- 0.76 mmol FFA x kg fat(-1) x h(-1); P < 0.05] and net lipolysis (FFA(net) rate of appearance: from 1.87 +/- 0.34 to 1.20 +/- 0.25 mmol FFA x kg fat(-1) x h(-1); P < 0.05). Fat oxidation decreased (from 0.28 +/- 0.02 to 0.20 +/- 0.02 mmol FFA x kg lean body mass(-1) x h(-1); P < 0.002), as did the rate of appearance of FFAs available for intrahepatic reesterification (from 0.50 +/- 0.13 to 0.29 +/- 0.09 mmol FFA x kg fat(-1) x h(-1); P < 0.03). Fractional and absolute synthetic rates of VLDL apolipoprotein B-100 were unaltered. These kinetic changes were associated with a decrease in the waist-to-hip ratio but no significant change in fasting plasma lipid concentrations. Fasting plasma glucose concentrations increased after treatment (from 5.2 +/- 0.2 to 5.8 +/- 0.3 mmol/L; P < 0.01). CONCLUSIONS: Physiologic GH replacement has salutary effects on abnormal lipid kinetics in HLS. The effects are mediated by diminished lipolysis and hepatic reesterification rather than by increased fat oxidation.

Ketosis-prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and beta-cell functional classification, prospective analysis, and clinical outcomes.

Ketosis-prone diabetes is heterogeneous. Its causes could include novel beta-cell functional defects. To characterize such defects, 103 patients with diabetic ketoacidosis were evaluated for beta-cell autoimmunity and human leukocyte antigen (HLA) class II alleles, with longitudinal measurements of beta-cell function and biochemical and clinical parameters. They were classified into four A beta groups, based on the presence of glutamic acid decarboxylase (GAD)65, GAD67, or IA-2 autoantibodies (A+ or A-) and beta-cell functional reserve (beta+ or beta-). The group distribution was: 18 A+beta-, 23 A-beta-, 11 A+beta+, and 51 A-beta+. Collectively, the two beta- groups differed from the two beta+ groups in earlier onset and longer duration of diabetes, lower body mass index, less glycemic improvement, and persistent insulin requirement. HLA class II genotyping showed that the A-beta- group differed from the A+beta- group in having lower frequencies of two alleles strongly associated with autoimmune type 1 diabetes susceptibility: DQA*03 and DQB1*02. Similarly, the A-beta+ group differed from the A+beta+ group in having a lower frequency of DQB1*02. Ketosis-prone diabetes comprises at least four etiologically distinct syndromes separable by autoantibody status, HLA genotype, and beta-cell functional reserve. Novel, nonautoimmune causes of beta-cell dysfunction are likely to underlie the A-beta+ and A-beta- syndromes.

Improved outcomes in indigent patients with ketosis-prone diabetes: effect of a dedicated diabetes treatment unit.

OBJECTIVE: To investigate whether a specialized intervention program could improve diabetes-related health outcomes in indigent patients with type 1 diabetes who were prone to occurrence of diabetic ketoacidosis (DKA). METHODS: Patients with type 1 diabetes mellitus admitted because of DKA during a 24-month period were invited to receive outpatient care in a diabetes treatment unit (DTU). We compared DKA-related readmission rates, change in hemoglobin A1c (HbA1c) values, and diabetes-related medical costs in patients who participated in the DTU program (+DTU) and in those who did not (-DTU). RESULTS: During the study period, 115 patients underwent assessment. Of this overall group, 57 patients (49.6%) consented to participate in the DTU program, and 58 (50.4%) did not. After the follow-up period (median duration, 657 days), the following significant improvements were observed in the +DTU group (in comparison with the -DTU group): lower frequency of readmission for DKA (16% versus 43%; P = 0.001), lower number of readmissions for DKA per patient (0.22 +/- 0.6 versus 1.17 +/- 2.2 [mean +/- standard deviation]; P = 0.003), lower HbA1c level (10.4 +/- 2.3% versus 13.5 +/- 2.3%; P<0.0001), and lower cost of diabetes-related medical care (3,427.20 US dollars +/- 6,275.60 versus 10,119.10 US dollars +/- 19,688.10; P = 0.01). Multivariate analysis revealed that participation in the DTU program was the only factor associated with a significantly decreased risk of DKA-related readmission. CONCLUSION: Low-cost intervention by a dedicated outpatient DTU resulted in significant decreases in DKA-associated readmissions, in HbA1c values, and in costs of diabetes care in a multiethnic, indigent, ketosis-prone patient population.

Fenofibrate is effective in treating hypertriglyceridemia associated with HIV lipodystrophy.

OBJECTIVE: To determine the effectiveness of fenofibrate in treating hypertriglyceridemia associated with highly active antiretroviral therapy-associated HIV lipodystrophy syndrome (HLS). METHODS: The authors recruited from their HIV metabolic clinic 55 adult patients with anthropomorphic changes consistent with HLS together with hypertriglyceridemia. The patients had no prior history of taking lipid-lowering medications and were free of liver and renal disease. They were on various highly active antiretroviral therapy regimens, and these regimens were not altered during the course of the study. Fenofibrate was started at 54 mg a day and the dose increased every 2 weeks to a maximum of 162 mg/day. Fasting lipid concentrations were measured at baseline and 6 months after the intervention. RESULTS: At baseline, the fasting plasma concentrations of total cholesterol, triglyceride, and high-density lipoprotein (HDL) cholesterol were 259 +/- 11, 886 +/- 172, and 35.7 +/- 2.3 (mean +/- SEM) mg/dL, respectively. After 6 months of fenofibrate treatment, the fasting plasma concentrations were as follows: total cholesterol, 243 +/- 13; triglycerides, 552 +/- 104, and HDL cholesterol, 35.7 +/- 1.8 mg/dL. The decrease in fasting plasma triglyceride concentration was statistically significant (P < 0.05). Fenofibrate was well tolerated, and no subjects dropped out of the study. CONCLUSION: Fenofibrate is an effective, well-tolerated treatment for hypertriglyceridemia associated with HLS.

Effects of rosiglitazone on abnormal lipid kinetics in HIV-associated dyslipidemic lipodystrophy: a stable isotope study.

HIV-associated dyslipemic lipodystrophy (HADL) is a heterogeneous syndrome of fat redistribution, hypertriglyceridemia, and insulin resistance, associated with markedly accelerated rates of lipolysis, intraadipocyte and intrahepatic reesterification, and very low-density lipoprotein-triglyceride synthesis and release. The objective of the study was to determine if rosiglitazone can ameliorate these lipid kinetic defects in patients with HADL. Infusions of [(13)C(1)]palmitate and [(2)H(5)]glycerol were used to measure total and net lipolysis, adipocyte and hepatic reesterification, and plasma free fatty acid (FFA) oxidation in 9 men with HADL, before and after 3 months of treatment with rosiglitazone (8 mg/d). Rosiglitazone treatment significantly increased both total lipolysis (R(a) FFA(total) from 3.37 ± 0.40 to 4.57 ± 0.68 mmol FFA per kilogram fat per hour, P < .05) and adipocyte reesterification (1.25 ± 0.35 to 2.43 ± 0.65 mmol FFA per kilogram fat per hour, P < .05). However, there was no change in net lipolysis (R(a) FFA(net) 2.47 ± 0.43 to 2.42 ± 0.37 mmol FFA per kilogram fat per hour), plasma FFA oxidation (0.30 ± 0.046 to 0.32 ± 0.04 mmol FFA per kilogram lean body mass per hour), or FFA flux available for hepatic reesterification (0.59 ± 0.07 to 0.56 ± 0.10 mmol FFA per kilogram fat per hour). There were significant decreases in fasting plasma insulin concentrations and insulin resistance, but not in fasting plasma lipid or glucose concentrations. There was a significant decrease in waist to hip ratio (0.98 ± 0.02 to 0.95 ± 0.02, P < .05) consistent with a significant increase in hip circumference (0.93 ± 0.02 to 0.95 ± 0.02 m, P < .05), without change in waist circumference. Rosiglitazone significantly increased adipocyte reesterification and improved insulin sensitivity, but the potential benefit of these changes was compromised by increase in total lipolysis. Combining rosiglitazone with agents designed to blunt lipolysis could expand depleted peripheral adipose depots in patients with HIV lipodystrophy.