Judith Freund

A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving Hiv protease inhibitors

Objective:To describe a syndrome of peripheral lipodystrophy (fat wasting of the face, limbs and upper trunk), hyperlipidaemia and insulin resistance in patients receiving potent HIV protease inhibitor therapy. Design:Cross-sectional study. Setting:Outpatient clinic of a university teaching hospital. Patients:HIV-infected patients either receiving at least one protease inhibitor (n = 116) or protease inhibitor-naive (n = 32), and healthy men (n = 47). Interventions and main outcome measures:Lipodystrophy was assessed by physical examination and questionnaire and body composition by dual-energy X-ray absorptiometry. Fasting triglyceride, cholesterol, free fatty acid, glucose, insulin, C-peptide and fructosamine levels, other metabolic parameters, CD4 lymphocyte counts, and HIV RNA load were also assessed. Results:HIV protease inhibitor-naive patients had similar body composition to healthy men. HIV protease inhibitor therapy was associated with substantially lower total body fat (13.2 versus 18.7 kg in protease inhibitor-naive patients; P = 0.005), and significantly higher total cholesterol and triglyceride levels. Lipodystrophy was observed clinically in 74 (64%) protease inhibitor recipients after a mean 13.9 months and 1(3%) protease inhibitor-naive patient (P = 0.0001). Fat loss occurred in all regions except the abdomen after a median 10 months. Patients with lipodystrophy experienced a relative weight loss of 0.5 kg per month and had significantly higher triglyceride, cholesterol, insulin and C-peptide levels and were more insulin-resistant than protease inhibitor recipients without lipodystrophy. Patients receiving ritonavir and saquinavir in combination had significantly lower body fat, higher lipids and shorter time to lipodystrophy than patients receiving indinavir. Three (2%) patients developed new or worsening diabetes mellitus. Conclusion:A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance is a common complication of HIV protease inhibitors. Diabetes mellitus is relatively uncommon.

Abdominal Fat and Insulin Resistance in Normal and Overweight Women: Direct Measurements Reveal a Strong Relationship in Subjects at Both Low and High Risk of NIDDM

Insulin resistance appears to be central to obesity, NIDDM, hyperlipidemia, and cardiovascular disease. While obese women with abdominal (android) fat distribution are more insulin resistant than those with peripheral (gynecoid) obesity, in nonobese women, the relationship between abdominal fat and insulin resistance is unknown. By measuring regional adiposity with dual-energy X-ray absorptiometry and insulin sensitivity by euglycemic-hyperinsulinemic clamp in 22 healthy women, with a mean ± SE body BMI of 26.7 ± 0.9 kg/m2 and differing risk factors for NIDDM, we found a strong negative relationship between central abdominal (intra-abdominal plus abdominal subcutaneous) fat and whole-body insulin sensitivity (r = −0.89, P < 0.0001) and nonoxidative glucose disposal (r = −0.77, P < 0.001), independent of total adiposity, family history of NIDDM, and past gestational diabetes. There was a large variation in insulin sensitivity, with a similar variation in central fat, even in those whose BMI was <25 kg/m2. Abdominal fat had a significantly stronger relationship with insulin sensitivity than peripheral nonabdominal fat (r2 = 0.79 vs. 0.44), and higher levels were associated with increased fasting nonesterified fatty acids, lipid oxidation, and hepatic glucose output. Because 79% of the variance in insulin sensitivity in this heterogeneous population was accounted for by central fat, abdominal adiposity appears to be a strong marker and may be a major determinant of insulin resistance in women.

The effects of high-intensity intermittent exercise training on fat loss and fasting insulin levels of young women

Objective:To determine the effects of a 15-week high-intensity intermittent exercise (HIIE) program on subcutaneous and trunk fat and insulin resistance of young women.Design and procedures:Subjects were randomly assigned to one of the three groups: HIIE (n=15), steady-state exercise (SSE; n=15) or control (CONT; n=15). HIIE and SSE groups underwent a 15-week exercise intervention.Subjects:Forty-five women with a mean BMI of 23.2±2.0 kg m−2 and age of 20.2±2.0 years.Results:Both exercise groups demonstrated a significant improvement (P<0.05) in cardiovascular fitness. However, only the HIIE group had a significant reduction in total body mass (TBM), fat mass (FM), trunk fat and fasting plasma insulin levels. There was significant fat loss (P<0.05) in legs compared to arms in the HIIE group only. Lean compared to overweight women lost less fat after HIIE. Decreases in leptin concentrations were negatively correlated with increases in VO2peak (r=−0.57, P<0.05) and positively correlated with decreases in TBM (r=0.47; P<0.0001). There was no significant change in adiponectin levels after training.Conclusions:HIIE three times per week for 15 weeks compared to the same frequency of SSE exercise was associated with significant reductions in total body fat, subcutaneous leg and trunk fat, and insulin resistance in young women.

The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.

The route of estrogen replacement therapy has a major impact on the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. Estrogen administration by the oral, but not the transdermal route, reduces IGF-I and increases GH levels in postmenopausal women. To investigate whether these perturbations have metabolic consequences, we compared the effects of 24 wk each of oral (Premarin 1.25 mg) and transdermal (Estraderm 100TTS) estrogen on energy metabolism and body composition in 18 postmenopausal women in an open-label randomized crossover study. Energy expenditure, lipid oxidation (lipid(ox)), and carbohydrate oxidation (CHOox) were measured by indirect calorimetry in the fasted and fed state before and after 2 and 6 mon treatment. Lean body mass, fat mass, and total body bone mineral density were measured by dual X-ray absorptiometry before and after 6 mon treatment. Mean (+/-SE) Luteinizing hormone levels fell to comparable levels during oral and transdermal estrogen, and bone mineral density was significantly increased by both treatments. Mean IGF-I was significantly lower during oral estrogen (77+/-7 versus 97+/-7 microg/liter, P < 0.05) treatment. Lipid(ox) 30-60 min after a standardized meal was significantly lower (36+/-5 versus 54+/-5 mg/min, P < 0.01) and CHOox higher (147+/-13 versus 109+/-12 mg/min, P < 0.05) with oral compared with transdermal estrogen. Oral estrogen resulted in a 1.2+/-0.5 kg (P < 0.05) increase in fat mass and a 1.2+/-0.4 kg (P < 0.01) decrease in lean mass compared with transdermal estrogen. Lean body mass (0.4+/-0.2 kg) and fat mass (0. 1+/-0.4 kg) did not change significantly during transdermal estrogen. In summary, when compared with the transdermal route, oral estrogen reduces lipid(ox), increases fat mass, and reduces lean body mass. The route of estrogen therapy confers distinct and divergent effects on substrate oxidation and body composition. The suppression of lipidox during oral estrogen therapy may increase fat mass although the fall in IGF-I may lead to a loss of lean body mass. The route-dependent changes in body composition observed during estrogen replacement therapy may have important implications for postmenopausal health.

The Effect of High-Intensity Intermittent Exercise on Body Composition of Overweight Young Males

To determine the effect of a 12-week high intensity intermittent exercise (HIIE) intervention on total body, abdominal, trunk, visceral fat mass, and fat free mass of young overweight males. Participants were randomly assigned to either exercise or control group. The intervention group received HIIE three times per week, 20 min per session, for 12 weeks. Aerobic power improved significantly (P < 0.001) by 15% for the exercising group. Exercisers compared to controls experienced significant weight loss of 1.5 kg (P < 0.005) and a significant reduction in total fat mass of 2 kg (P < 0.001). Abdominal and trunk adiposity was also significantly reduced in the exercising group by 0.1 kg (P < 0.05) and 1.5 kg (P < 0.001). Also the exercise group had a significant (P < 0.01) 17% reduction in visceral fat after 12 weeks of HIIE, whereas waist circumference was significantly decreased by week six (P < 0.001). Fat free mass was significantly increased (P < 0.05) in the exercising group by 0.4 kg for the leg and 0.7 kg for the trunk. No significant change (P > 0.05) occurred in levels of insulin, HOMA-IR, and blood lipids. Twelve weeks of HIIE resulted in significant reductions in total, abdominal, trunk, and visceral fat and significant increases in fat free mass and aerobic power.

High prevalence of brown adipose tissue in adult humans

CONTEXT Positron emission tomography (PET)-computed tomography (CT) has identified metabolically active supraclavicular fat in adult humans based on uptake of labeled glucose and confirmed to be brown adipose tissue (BAT) histologically. However, PET-CT has estimated a prevalence of BAT as low as 5% in adult humans, casting doubt on its significance. The true prevalence of BAT is unknown because of the suboptimal sensitivity of standard PET-CT. OBJECTIVE The objective of the study was to determine whether BAT is present in PET-negative supraclavicular fat. DESIGN This was a prospective cohort study. SETTING The study was conducted at a tertiary referral hospital. PATIENTS Seventeen patients who underwent preoperative PET-CT for staging of head and neck malignancy participated in the study. MAIN OUTCOME The main outcome was signature BAT gene transcripts and protein in biopsies of supraclavicular fat with sc fat as negative control. RESULTS PET-CT was positive in three and negative in 14 patients. PET-positive fat harbored multilobulated lipid droplets and stained strongly for uncoupling protein 1 (UCP1). These features are absent in sc fat. By contrast, PET-negative fat contained a predominance of cells with unilobulated lipid droplets, with scattered cells containing multilobulated lipid droplets and variable UCP1 staining. Molecular analyses of fat biopsies showed lower but clear expression of UCP1, NDUFS3 (NADH dehydrogenase (ubiquinone) iron-sulfur protein 3), β₃-adrenoceptor, and PRDM16 (PR domain containing 16) transcripts. CONCLUSIONS BAT is present in supraclavicular fat, regardless of PET status. BAT is highly prevalent in adult humans, and its abundance determines PET status.

Mechanisms of rapid bone loss following cardiac transplantation

Rapid bone loss after orthoptic cardiac transplantation (OHTX) is a major problem; however, the mechanisms are poorly understood. To investigate these mechanisms we measured biochemical and hormonal indices of bone turnover serially in 25 patients (21 men, 4 women) after OHTX. Serum osteocalcin was reduced immediately post-OHTX (2.2±0.5 ng/ml) but rose significantly by 6 and 12 months (14.1±2.5 and 15.7±2.2 respectively). Bone resorption indices (urinary hydroxyproline/creatinine and calcium/creatinine ratios) were increased immediately post-OHTX but fell by 6 months. Serum testosterone was reduced in males but recovered towards normal values by 6–12 months. Regression analysis showed lumbar bone loss was predicted independently by the change in both serum osteocalcin and testosterone. The data suggest that bone loss post-OHTX is due to a combination of accelerated turnover and hypogonadism.

Timing of cardiac transplantation in idiopathic dilated cardiomyopathy

Seventy-nine patients with idiopathic dilated cardiomyopathy were assessed and followed up to evaluate 9 variables that might predict duration of survival after assessment for cardiac transplantation. Patients with ischemic heart disease, alcoholic and peripartum cardiomyopathy were excluded. There were 38 deaths (48%) during the 18-month (mean) follow-up. Patients underwent determination of left ventricular ejection fraction by radionuclide scan, echocardiography, cardiac catheterization and myocardial biopsy. Only left ventricular ejection fraction determined by radionuclide study correlated significantly with time to death in nonsurvivors (r = 0.38, p less than 0.05). Multivariant analysis and Cox multivariate regression analysis revealed that the single consistent determinant of prognosis was radionuclide-determined ejection fraction. It was an excellent predictor of survival to 3 months (p less than 0.0001) and a reasonable predictor of survival to 6 months (p less than 0.05). There was no variable that efficiently predicted survival for any period greater than 6 months. In 15 of 70 patients (21% of the entire group), clinical status and radionuclide ejection fraction improved after assessment but only one of these had an ejection fraction less than or equal to 0.10. No patient with a radionuclide ejection fraction greater than or equal to 0.20 died within 6 months of assessment. For those with ejection fraction between 0.11 and 0.19, survival after cardiac transplantation exceeded that of the natural history of their disease; this suggests that transplantation should be undertaken within 6 to 12 months of assessment. Left ventricular ejection fraction less than or equal to 0.10 predicts an extremely poor prognosis (6-month survival was 17%) and such patients should be transplanted with minimal delay.

A Comparison of Longitudinal Measurements in the Spine and Proximal Femur Using Lunar and Hologic Instruments

Absolute values of bone mineral density (BMD), using dual‐energy X‐ray absorptiometry (DXA), differ between instruments from different manufacturers. Despite these differences, the rates of change calculated from serial measurements on different densitometers have been assumed to be comparable. We compared the change in BMD in 34 subjects in the lumbar spine and at the standard sites in the proximal femur, from measurements performed using a Lunar DPX‐L and a Hologic QDR–1000. Measurements were obtained on the same day, and repeated on the same day, on both machines after a mean interval of 4.8 years (range 4.1–6.3 years). There were strong positive correlations between the percentage change in BMD calculated using the two machines in the lumbar spine, trochanteric region, and total proximal femur: r = 0.82, 0.84, and 0.73, respectively (p < 0.0001 at all sites). In the femoral neck and in Wards triangle, the correlations were not as high: r = 0.55 (p = 0.003) and 0.43 (p = 0.028), respectively. At all sites, despite the significant correlations, the agreement between the two densitometers was not high and there may be significant errors in individual subjects if one uses measurements from one densitometer to predict the change in BMD using the scanner of the other manufacturer. There is less of a problem comparing group data in the lumbar spine and trochanteric region, although errors are still likely to occur in comparing group data of bone loss, calculated using different densitometers, in the other proximal femur sites. In conclusion, the study suggests that caution is necessary in combining bone loss data derived using densitometers from different manufacturers, particularly in the proximal femur. This has important implications for multicenter studies.

Discordance in Lumbar Spine T-Scores and Nonstandardization of Standard Deviations

Previous studies have demonstrated differences in proximal femur bone mineral density T-scores depending on the reference range used. This subsequently was addressed by the recommended adoption of the National Health and Nutrition Examination Survey III reference range. There is, however, no accepted reference range for interpretation of lumbar spine bone mineral density (BMD), and the use of different reference populations by different manufacturers could result in inconsistencies in diagnosis of osteopenia or osteoporosis. We compared lumbar spine BMD, as well as T- and Z-scores, in 59 women measured using Lunar DPXL and Norland Excel densitometers. BMD measured by the instruments was highly correlated (r = 0.98, p < 0.0001). The instruments however assigned significantly different values when BMD was expressed as T-scores. There were also significant differences in BMD assignments between instruments, when expressed as Z-scores. The observed differences relate to the different young normal mean, and SD employed in calculating the T- and Z scores. To conclude, in the lumbar spine, two commonly used DXA instruments provide comparable absolute values but there are significant differences in derived T-scores due to differences in manufacturer- specific reference ranges. There is a need for standardization of the reference ranges used in the lumbar spine.