Effects of exercise and lifestyle modification on fitness, insulin resistance, skeletal muscle oxidative phosphorylation and intramyocellular lipid content in obese children and adolescents.

BACKGROUND: Obesity is associated with poor fitness and adverse metabolic consequences in children. OBJECTIVE: To investigate how exercise and lifestyle modification may improve fitness and insulin sensitivity in this population. DESIGN AND SUBJECTS: Randomized controlled trial, 21 obese (body mass index ≥ 95% percentile) subjects, ages 10 to 17 years. METHODS: Subjects were given standardized healthful lifestyle advice for 8 weeks. In addition, they were randomized to an in-home supervised exercise intervention (n = 10) or control group (n = 11). MEASUREMENTS: Fasting laboratory studies (insulin, glucose, lipid profile) and assessments of fitness, body composition, skeletal muscle oxidative phosphorylation and intramyocellular lipid content (IMCL), were performed at baseline and study completion. RESULTS: Subjects were 13.0 ± 1.9 (standard deviation) years old, 72% female and 44% non-white. Exercise improved fitness (P = 0.03) and power (P = 0.01), and increased IMCL (P = 0.02). HOMA-IR decreased among all subjects in response to lifestyle modification advice (P = 0.01), regardless of exercise training assignment. In univariate analysis in all subjects, change in cardiovascular fitness was associated with change in HOMA-IR. In exploratory analyses, increased IMCL was associated with greater resting energy expenditure (r = 0.78, P = 0.005) and a decrease in fasting respiratory quotient (r = -0.70, P = 0.02) (n = 11). CONCLUSIONS: Change in fitness was found to be related to change in insulin resistance in response to lifestyle modification and exercise in obese children. IMCL increased with exercise in these obese children, which may reflect greater muscle lipid oxidative capacity.

Circulating branched-chain amino acid concentrations are associated with obesity and future insulin resistance in children and adolescents.

UNLABELLED: What is already known about this subject Circulating concentrations of branched-chain amino acids (BCAAs) can affect carbohydrate metabolism in skeletal muscle, and therefore may alter insulin sensitivity. BCAAs are elevated in adults with diet-induced obesity, and are associated with their future risk of type 2 diabetes even after accounting for baseline clinical risk factors. What this study adds Increased concentrations of BCAAs are already present in young obese children and their metabolomic profiles are consistent with increased BCAA catabolism. Elevations in BCAAs in children are positively associated with insulin resistance measured 18 months later, independent of their initial body mass index. BACKGROUND: Branched-chain amino acid (BCAA) concentrations are elevated in response to overnutrition, and can affect both insulin sensitivity and secretion. Alterations in their metabolism may therefore play a role in the early pathogenesis of type 2 diabetes in overweight children. OBJECTIVE: To determine whether paediatric obesity is associated with elevations in fasting circulating concentrations of BCAAs (isoleucine, leucine and valine), and whether these elevations predict future insulin resistance. METHODS: Sixty-nine healthy subjects, ages 8-18 years, were enrolled as a cross-sectional cohort. A subset of subjects who were pre- or early-pubertal, ages 8-13 years, were enrolled in a prospective longitudinal cohort for 18 months (n = 17 with complete data). RESULTS: Elevations in the concentrations of BCAAs were significantly associated with body mass index (BMI) Z-score (Spearman's Rho 0.27, P = 0.03) in the cross-sectional cohort. In the subset of subjects that followed longitudinally, baseline BCAA concentrations were positively associated with homeostasis model assessment for insulin resistance measured 18 months later after controlling for baseline clinical factors including BMI Z-score, sex and pubertal stage (P = 0.046). CONCLUSIONS: Elevations in the concentrations of circulating BCAAs are significantly associated with obesity in children and adolescents, and may independently predict future insulin resistance.

The association of macro- and micronutrient intake with growth hormone secretion.

CONTEXT: Growth hormone (GH) is known to be nutritionally regulated, but the effect of dietary composition on detailed GH secretion parameters has not previously been comprehensively evaluated. OBJECTIVE: The objective of the study was to determine whether specific macro- and micronutrients are associated with discrete parameters of GH secretion among subjects with wide ranges of body mass index. DESIGN: Detailed macro- and micronutrient intake was assessed by 4-day food records while GH secretion was assessed by standard stimulation testing in 108 men and women in one study (Study 1), and by overnight frequent blood sampling in 12 men in another study (Study 2). RESULTS: Peak stimulated GH was positively associated with vitamin C (r=+0.29; P=0.003), dietary fiber (r=+0.27; P=0.004), arachidic acid (r=+0.25; P=0.008), and behenic acid (r=+0.30; P=0.002) intake in univariate analysis. Controlling for age, gender, race/ethnicity, visceral fat, HOMA-IR, total caloric intake and these four dietary factors in step-wise multivariate modeling, peak GH remained significantly associated with vitamin C and visceral fat (both P<0.05). In addition, vitamin C intake was associated with various parameters of endogenous GH secretion including basal GH secretion (r=+0.95; P<0.0001), GH half-life (r=+.75; P=0.005), total GH production (r=+0.76; P=0.004), GH area-under-the-curve (r=+0.89; P=0.0001), mean log(10) GH pulse area (r=+0.67; P=0.02), and overnight maximum (r=+0.62; P=0.03), nadir (r=+0.97; P<0.0001), and mean GH secretion (r=+0.89; P=0.0001). CONCLUSIONS: These results suggest that certain micronutrients such as vitamin C intake are strongly and uniquely associated with stimulated and endogenous spontaneous GH secretion.

Relationship of adiponectin to endogenous GH pulse secretion parameters in response to stimulation with a growth hormone releasing factor.

OBJECTIVE: Obesity is associated with both reduced growth hormone (GH) and adiponectin. However, the relationship between adiponectin and parameters of endogenous GH secretion remains unknown. The aim of this study was to determine the relationship between total and high molecular weight (HMW) adiponectin and parameters of endogenous pulsatile GH secretion and the effects of tesamorelin, a synthetic GH releasing hormone (GHRH(1-44)), on total and HMW adiponectin. DESIGN: A 2-week interventional study with tesamorelin was conducted at an academic medical center in 13 men with BMI 20-35 kg/m(2). Overnight frequent blood sampling and measurement of total and HMW adiponectin at baseline and after treatment were performed to assess the effects of augmenting endogenous pulsatile GH secretion. RESULTS: Total, but not HMW, adiponectin was positively associated with log(10)Peak GH area (r=+0.73; P=0.005), basal GH secretion (r=+0.67; P=0.01), and total GH production (r=+0.57; P=0.04), but was not associated with the number of secretion events (P=0.85). Two-week treatment with tesamorelin increased endogenous GH release and IGF-1, but neither total (change -0.16±0.64; P=0.40), nor HMW (change +0.03±0.70; P=0.87) adiponectin changed significantly with treatment. Sub-analyses in overweight and obese men yielded similar results. CONCLUSIONS: Our study demonstrates a strong relationship between specific parameters of endogenous GH pulsatility and adiponectin. However, short-term augmentation of GH pulsatility over 2-weeks does not change adiponectin. Therefore, the relationship between GH and adiponectin is most likely mediated by specific covariates related to adiposity or other factors.

Regulation of adiponectin in adipocytes upon exposure to HIV-1.

OBJECTIVES: Adipose dysregulation, dyslipidemia, and insulin resistance are hallmarks of HIV-related lipodystrophy. The precise mechanisms behind these disturbances are unknown. In HIV-infected patients, we previously demonstrated a strong relationship between lipodystrophy and levels of adiponectin, an adipose peptide implicated in regulation of glucose and lipid metabolisms. In this study we investigated the effect of HIV on adipocytes, to determine whether HIV can directly infect adipocytes and/or alter the regulation and secretion of the adipocyte-derived hormone adiponectin. METHODS: Human subcutaneous preadipocytes and adipocytes were exposed to HIV-1 under various conditions. Adiponectin was measured in supernatants and cell lysates. RESULTS: Although adipocytes expressed CD4, the major HIV receptor, they could not be infected in vitro. However, exposure to HIV dramatically increased the secretion of adiponectin from human adipocytes, in the absence of infection. This was exacerbated with sustained exposure to HIV in a transwell assay. Further, human peripheral mononuclear cells also produced adiponectin, but this was largely dependent upon T-cell activation. CONCLUSIONS: We propose that the stimulation of adiponectin production by HIV can perturb adiponectin regulation, leading to substantially decreased levels upon viral suppression by antiretroviral therapy. These data suggest a potential molecular mechanism of adiponectin regulation in HIV-infected patients.

Effects of an oral contraceptive (norgestimate/ethinyl estradiol) on bone mineral density in women with hypothalamic amenorrhea and osteopenia: an open-label extension of a double-blind, placebo-controlled study.

OBJECTIVE: The effects of long-term triphasic oral contraceptive administration on bone mineral density (BMD) were investigated in premenopausal women with hypothalamic amenorrhea (HA) and osteopenia. METHODS: After completing three 28-day cycles in the double-blind phase of a placebo-controlled trial, women (mean age, 26.7 years) who received norgestimate 180-250 microg/ethinyl estradiol 35 microg (NGM/EE, n = 15) or placebo (n = 12) in the double-blind phase were to receive open-label NGM/EE for 10 additional cycles. RESULTS: For subjects completing > or =10 NGM/EE treatment cycles, mean posteroanterior total lumbar spine BMD (L1-L4) increased from 0.881+/-0.0624 g/cm2 at baseline (last visit prior to NGM/EE) to 0.894+/-0.0654 g/cm2 at final visit (p = .043); no significant changes in hip BMD occurred. Decreases in N-telopeptide, osteocalcin, procollagen type I propeptide and bone-specific alkaline phosphatase levels indicated effects on bone metabolism. CONCLUSIONS: Long-term administration of triphasic NGM/EE to osteopenic women with HA may increase total lumbar spine BMD.

Effects of a triphasic combination oral contraceptive containing norgestimate/ethinyl estradiol on biochemical markers of bone metabolism in young women with osteopenia secondary to hypothalamic amenorrhea.

This multicenter, double-blind, placebo-controlled, randomized study of 45 patients evaluated the short-term effects of an oral contraceptive [Ortho Tri-Cyclen, 180-250 micro g of norgestimate (NGM) and 35 microg of ethinyl estradiol (EE)] on biochemical markers of bone resorption, formation, and osteoprotegerin in young women (mean age +/- SD, 26.5 +/- 6.3 yr) with hypothalamic amenorrhea and osteopenia. Body fat, endocrine, and cognitive function were evaluated as secondary endpoints. Biomarkers of bone metabolism were measured at baseline and after three cycles of NGM/EE or placebo. There were significant decreases in mean values of N-telopeptide [mean (SD), -13.4 (13.4) vs. 1.2 (23.8) nmol bone collagen equivalents (BCE)/mmol creatinine (Cr); P = 0.001] and deoxypyridinoline [-1.2 (2.9) vs. -0.5 (1.5) nmol deoxypyridinoline/mmol Cr; P = 0.021] as well as significant decreases in bone specific alkaline phosphatase [-5.1 (3.5) vs. 0.4 (3.1) ng/ml; P < 0.001], osteocalcin [-5.9 (3.6) vs. -2.9 (3.7); P = 0.016], and procollagen of type I propeptide [-35.2 (44.6) vs. -0.2 (30.0) ng/ml; P = 0.025], but not osteoprotegerin [0.39 (1.46) vs. -0.2 (0.49) pmol/liter; P = 0.397] in the NGM/EE vs. placebo group. There were no significant differences between groups with respect to changes in cognitive function, mood, body weight, body mass index, body fat, percentage of body fat, and all endocrine levels except FSH, [-3.7 (3.8) vs. -0.6 (2.1) IU/liter; P < 0.001, NGM/EE vs. placebo]. No serious adverse events were reported in either group. These results suggest that NGM/EE decreases bone turnover in osteopenic premenopausal women with hypothalamic amenorrhea. Further studies are needed to determine whether estrogen will increase bone density in this population.

Osteopenia in eugonadal men with acquired immune deficiency syndrome wasting syndrome.

Multiple endocrine and metabolic consequences of human immunodeficiency virus (HIV) infection exist that may contribute to bone loss in men with the acquired immune deficiency syndrome (AIDS) wasting syndrome. Recent studies suggest that anabolic strategies can increase lean body mass in men with AIDS wasting. Prior studies have not examined the effects of anabolic agents on bone mineral density (BMD) or bone turnover in these men. To determine the effects of testosterone and progressive resistance training on BMD and bone turnover in eugonadal men with AIDS wasting, we randomly assigned 54 eugonadal men with AIDS wasting (weight < 90% IBW or weight loss >10% from preillness baseline) to receive either testosterone enanthate (200 mg/week, im) or placebo and to progressive resistance training (3 times/week) or no training in a 2 x 2 factorial study design for 3 months. The BMD of the lumbar spine, proximal femur, and total body; lean body mass; and fat mass were measured by dual energy x-ray absorptiometry. Total body scans were repeated after 12 weeks of therapy. Baseline bone turnover and BMD were compared with those in 35 age-matched healthy non-HIV-infected control subjects. Compared with controls, lumbar spine BMD (1.021 +/- 0.018 vs. 1.084 +/- 0.025 g/cm(2); P = 0.04) and total hip BMD (0.951 +/- 0.017 vs. 1.070 +/- 0.019 g/cm(2); P < 0.0001) were reduced in men with AIDS wasting. T-scores were lower in men with AIDS wasting at the lumbar spine (-0.62 +/- 0.17 vs. -0.07 +/- 0.23, P = 0.05) and total hip (-0.65 +/- 0.11 vs. +0.20 +/- 0.014, P < 0.0001). Total hip T scores were less than -1.0 in 33% of men with AIDS wasting. Neither the use of protease inhibitors nor the duration of protease inhibitors use correlated with BMD. Serum osteocalcin levels were lower (3.63 +/- 0.29 vs. 4.54 +/- 0.31 nmol/L; P < 0.04) and urinary N-telopeptide excretion was higher (45.4 +/- 4.5 vs. 26.8 +/- 3.0 nmol BCE/mmol creatinine; P = 0.004) in men with AIDS wasting than in controls. Lumbar spine BMD, as assessed on regional total body dual energy x-ray absorptiometry scan, increased over the 12-week treatment period in response to testosterone (+2.4 +/- 1.3 vs. -1.3 +/- 1.0%, testosterone vs. placebo, respectively; P = 0.02), but not in response to training (+0.8 +/- 1.0 vs. +0.4 +/- 1.3%, training vs. no training; P = 0.70). Lumbar spine and total hip BMD are reduced in eugonadal men with AIDS wasting. Biochemical markers of bone turnover suggest that bone formation and bone resorption are uncoupled in these men. Testosterone administration, but not resistance training, over 3 months increases lumbar spine BMD in eugonadal men with AIDS wasting.

Assessment of macronutrient and micronutrient intake in women with anorexia nervosa.

OBJECTIVE: The purpose of this study is to evaluate the accuracy of diet history compared to observed food intake in the nutritional assessment of women with anorexia nervosa (AN) and healthy age-matched controls. METHOD: One-month diet history was compared to 1-day observed food intake in 30 women with AN and 28 control subjects. RESULTS: Reported intake by diet history was similar to observed intake for macronutrient composition and fat intake for patients with AN. Reported energy intake was higher than observed intake (1,602 +/- 200 kcal vs. 1,289 +/- 150 kcal, p <.05), but was in agreement with predicted energy expenditure by the Harris-Benedict equation (1,594 +/- 18 kcal, p =.97) in patients with AN. Micronutrient intake by diet history was highly correlated with observed intake in patients with AN. More than one half of the patients with AN failed to meet the recommended dietary allowance (RDA) for vitamin D, calcium, folate, vitamin B12, zinc, magnesium, and copper when assessed by diet history. In contrast to patients with AN, diet history did not correlate with observed intake of energy, macronutrients, or most micronutrients among the controls. DISCUSSION: Diet history is an accurate tool to assess fat intake and macronutrient composition in patients with AN and demonstrates significant micronutrient deficiencies in this population. The agreement between total energy intake and predicted energy expenditure supports the overall utility of the diet history in the nutritional assessment of patients with AN.

Eating disorders.

Eating disorders are common among adolescent girls and young women and are associated with potentially serious medical complications, yet they often go undetected and untreated. All patients with eating disorders should be evaluated and treated for medical complications of the disease at the same time that psychotherapy and nutritional counseling are undertaken. Pharmacologic agents are often useful as adjuncts to psychotherapy for bulimia nervosa or binge-eating disorder; in the case of anorexia nervosa, psychotropic medication is generally reserved for patients with a concurrent psychiatric illness or those who have recovered some weight.

Decreased leptin levels in normal weight women with hypothalamic amenorrhea: the effects of body composition and nutritional intake.

Leptin is a protein encoded by the ob gene and expressed in adipocytes. A sensitive marker of nutritional status, leptin is known to correlate with fat mass and to respond to changes in caloric intake. Leptin may also be an important mediator of reproductive function, as suggested by the effects of leptin infusions to restore ovulatory function in an animal model of starvation. We hypothesized that leptin levels are decreased in women with hypothalamic amenorrhea and that leptin may be a sensitive marker of overall nutritional status in this population. We, therefore, measured leptin levels and caloric intake in 21 women with hypothalamic amenorrhea (HA) and 30 age-, weight-, and body fat-matched eumenorrheic controls. Age (24 +/- 5 vs. 24 +/- 3 yr), body mass index (20.6 +/- 1.3 vs. 21.1 +/- 1.5 kg/m2), percent ideal body weight (94.9 +/- 5% vs. 96.3 +/- 6.3%), and fat mass (14.2 +/- 3.6 vs. 15.5 +/- 2.9 kg, determined by dual energy x-ray absortiometry) did not differ between the groups. Leptin levels were significantly lower in the HA subjects compared with those in the controls (7.1 +/- 3.0 vs. 10.6 +/- 4.9 micrograms/L; P = 0.005). Total caloric intake (1768 +/- 335 vs. 2215 +/- 571 cal/day; P = 0.003), fat intake (333 +/- 144 vs. 639 +/- 261 cal/day; P < 0.0001), and insulin levels (5.6 +/- 1.2 vs. 7.4 +/- 3.2 microU/mL; P = 0.015) were lower in the women with HA than in the eumenorrheic controls. The difference in leptin levels remained significant after controlling for insulin (P = 0.023). These data are the first to demonstrate hypoleptinemia, independent of fat mass, in women with HA. The hypoleptinemia may reflect inadequate calorie intake, fat intake, and/or other subclinical nutritional disturbances in women with HA. The mechanism and reproductive consequences of low leptin in this large population of women remain unknown.

Pseudo-Cushing's syndrome in human immunodeficiency virus-infected patients.

To our knowledge, an association between human immunodeficiency virus infection and pseudo-Cushing's syndrome has not previously been described. We describe four HIV-infected patients with pseudo-Cushing's syndrome, characterized by striking dorsocervical and submandibular fat accumulation and central obesity. In each case, cortisol levels were either normal or suppressed adequately with administration of dexamethasone, excluding the diagnosis of true Cushing's syndrome. Immune function and weight improved significantly preceding the development of pseudo-Cushing's syndrome. Three of the four patients were taking a common protease inhibitor at the onset of symptoms, and the fourth reported the exacerbation of his symptoms with the addition of a protease inhibitor. The observed characteristic pattern of fat deposition may be attributable to a specific effect of new antiretroviral therapies or may relate to recovery independent of medication usage. Distinguishing between pseudo-Cushing's syndrome and true Cushing's syndrome is critical for preventing the unnecessary and potentially harmful treatment of such patients. Further research into the mechanisms of this novel phenomenon is needed.

Effects of fasting and glucose infusion on basal and overnight leptin concentrations in normal-weight women.

The plasma concentration of leptin is reduced in association with chronic energy restriction and weight loss in humans, but little is known about the acute effects of fasting and glucose infusion on leptin. In this study, plasma leptin, insulin, glucose, and fatty acid concentrations were measured daily in 14 healthy, normal-weight, female volunteers aged 24 +/- 4 y with a body mass index (kg/m2) of 24.2 +/- 3.6 during a 4-d fast. The mean plasma leptin concentration decreased by 54 +/- 8% with fasting (P = 0.0006, ANOVA). In a stepwise-regression model, the change in leptin concentration with fasting correlated most significantly with the change in insulin (R2 = 0.48, P = 0.0057) and to a lesser extent with the change in body fat by bioimpedance analysis (R2 = 0.19, P = 0.03). Plasma leptin concentrations measured every 20 min from 2000 to 0800 on the fourth night of the fast did not show a time-dependent rise. A continuous intravenous infusion of 5% glucose providing 1414 +/- 323 kJ/d (338 +/- 78 kcal/d) was begun after 4 d of fasting in seven subjects who continued to fast for an additional 6 d. Within 24 h of the glucose infusion, leptin concentrations increased significantly by 80 +/- 52% (P < 0.05). These data show the sensitivity of plasma leptin concentrations to small changes in energy supply and suggest a basic role of substrate metabolism in the short-term regulation of leptin.

Decreased bone formation and increased mineral dissolution during acute fasting in young women.

Severe chronic undernutrition is associated with decreased bone turnover and significant bone loss. However, little is known about the short-term effects of nutritional deprivation on bone turnover. To investigate the effects of short-term fasting on bone metabolism and the contribution of acidosis to these changes, 14 healthy women ages 18-26 (mean, 21 +/- 2 (SD years) were randomized to potassium bicarbonate (KHCO3, 2 meq/kg/day in divided doses) to prevent acidosis or control (potassium chloride, 25 meq/day) during a complete 4-day fast. Bone turnover was assessed using specific markers of formation [osteocalcin (OC) and Type I procollagen carboxyl-terminal propeptide (PICP)] and resorption [pyridinoline (PYRX) and deoxypyridinoline (DPYRX)]. Serum bicarbonate levels fell significantly from 27.0 +/- 3.2 to 17.3 +/- 2.6 mmol/L (P < 0.01) in the control group and were decreased compared to patients receiving KHCO3 [17.3 +/- 2.6 vs. 23.4 +/- 2.4 mmol/L, (P < 0.001)]. Serum total and ionized calcium increased significantly in the control group [9.1 +/- 0.1 to 9.4 +/- 0.2 mg/dL (P < 0.01) and 1.20 +/- 0.03 to 1.23 +/- 0.03 mmol/L (P < 0.05), respectively], but not in patients receiving KHCO3. In addition, serum parathyroid hormone (PTH) levels decreased from 32 +/- 17 to 16 +/- 10 pg/mL (P < 0.05) and urinary calcium excretion increased [86 +/- 51 to 182 +/- 103 mg/day (P = 0.01)] in the control group, but not in patients receiving KHCO3. Serum osteocalcin (OC) and procollagen carboxyl-terminal propeptide (PICP) levels decreased significantly after 4 days of fasting from 9.1 +/- 3.4 to 5.5 +/- 4.2 ng/mL (P < 0.01) and 121 +/- 21 to 46 +/- 13 ng/mL (P = 0.0001) respectively in the patients receiving bicarbonate, and from 10.1 +/- 3.3 to 4.0 +/- 2.9 ng/mL (P < 0.01) and from 133 +/- 22 to 47 +/- 19 ng/mL (P < 0.001) respectively in the control group. The decrease in osteocalcin and PICP during fasting was comparable in both treatment groups. By contrast, urinary excretion of PYRX and DPYRX did not change significantly in either group with 4 days of fasting. These data are the first to demonstrate that markers of bone formation decline significantly with short-term fasting, independent of changes in acid-base status. By contrast, these data demonstrate a direct effect of acidosis in stimulating calcium release from bone during short-term fasting and suggest that acidosis may increase mineral dissolution independent of osteoclast activation and PTH in this experimental model of acute starvation.

Effects of rhIGF-I administration on bone turnover during short-term fasting.

Insulin-like growth factor-I (IGF-I) is a nutritionally dependent bone trophic hormone which stimulates osteoblast function and collagen synthesis in vivo and in vitro. We hypothesized that in the fasting state, IGF-I levels would decline significantly and would establish a model in which we could investigate the effects of IGF-I administration on bone turnover. We therefore studied 14 normal women ages 19-33 (mean, 24 +/- 4 [SD] years) during a complete 10-d fast. After 4 d of fasting, subjects were randomized to receive rhIGF-I or placebo subcutaneously twice a day for 6 d. Bone turnover was assessed using specific markers of formation (osteocalcin and type I procollagen carboxyl-terminal propeptide [PICP]) and resorption (pyridinoline, deoxypyridinoline, type I collagen crosslinked N-telopeptide [N-telopeptide] and hydroxyproline). Serum levels of PICP and osteocalcin decreased from 143 +/- 52 to 60 +/- 28 ng/ml (P = 0.001) and from 7.6 +/- 5.4 to 4.2 +/- 3.1 ng/ml (P = 0.001) respectively with 4 d of fasting. Urinary excretion of pyridinoline and deoxypyridinoline decreased from 96 +/- 63 to 47 +/- 38 nmol/mmol creatinine (P < 0.05) and from 28 +/- 17 to 14 +/- 11 nmol/mmol creatinine (P < 0.05) respectively. Mean IGF-I levels decreased from 310 +/- 81 to 186 +/- 78 ng/ml (P = 0.001). In the second part of the experimental protocol, serum osteocalcin and PICP levels increased 5- and 3-fold, respectively with rhIGF-I administration and were significantly elevated compared with the placebo group at the end of treatment (20.9 +/- 17.3 vs. 5.9 +/- 6.4 ng/ml for osteocalcin [P < 0.05] and 188 +/- 45 vs. 110 +/- 37 ng/ml for PICP [P < 0.05]). In contrast, all four markers of bone resorption, including urinary pyridinoline, deoxypyridinoline, N-telopeptide and hydroxyproline were unchanged with rhIGF-I administration. This report is the first to demonstrate that bone turnover falls rapidly with acute caloric deprivation in normal women. RhIGF-I administration uncouples bone formation in this setting by significantly increasing bone formation, but not resorption. These data suggest a novel use of rhIGF-I to selectively stimulate bone formation in states of undernutrition and low bone turnover.

Case report: increased levothyroxine requirement in a patient with cryptic celiac-sprue disease.

An increased requirement for levothyroxine may be due to poor patient compliance, pregnancy, low potency levothyroxine preparations, interfering drugs and small intestinal disease. Data on thyroid hormone absorption in celiac sprue disease is limited to a single study involving four patients without thyroid disease, in which malabsorption of a single dose of radiolabeled levothyroxine was noted in three of the four subjects. Increased levothyroxine requirements have not been reported in hypothyroid patients with celiac sprue. Furthermore, cryptic celiac sprue has never been described to cause levothyroxine malabsorption. We report such a patient in whom cryptic celiac sprue was an important cause of levothyroxine malabsorption with increased thyroid hormone requirement.

Aetiology and pathogenesis of hormonal and metabolic disorders in HIV infection.

Many hormonal and metabolic disturbances are documented in HIV infection, the most important of which is the wasting syndrome associated with progressive HIV infection. We are only now beginning to understand the pathogenesis of these disturbances. In rare cases, infiltration of endocrine tissue by secondary infectious or malignant processes is the underlying cause of hormonal insufficiency. In most instances, however, hypofunction is secondary to the well-known effects of severe illness. Similarly, hyperfunction of the adrenal axis along with many of the derangements in substrate metabolism are also likely to be secondary to severe illness, perhaps through activation of cytokines and other molecules. Specific disturbances in asymptomatic patients are more difficult to document and may represent unique and as yet unexplained manifestations of HIV disease. Hypermetabolism and depletion of lean body mass are most profound in the acutely ill patient with active secondary infection. At this stage, the HIV-infected patient is in a catabolic state and adaptive mechanisms which normally decrease energy expenditure and preserve lean body mass are either overridden or not operative. Strategies to reverse the catabolic state and diminish wasting are only now being developed.

Sepsis and adrenal function.

In the setting of sepsis, adrenal function can be difficult to evaluate. Cortisol levels, normally elevated by the stress of sepsis, are occasionally reduced, signifying possible adrenal dysfunction. Even elevated cortisol levels do not assure that adrenal reserve is adequate and may in fact portend a preterminal state. Bilateral adrenal hemorrhage leading to adrenal insufficiency is one complication of the sepsis syndrome. This endocrine rounds illustrates the importance in considering adrenal insufficiency and adrenal hemorrhage in patients with overwhelming sepsis while discussing the pathophysiology, clinical presentation, and therapeutic implications of this dire complication.

Endocrine manifestations of AIDS.

The endocrine manifestations of AIDS are now appreciated to involve virtually any of the endocrine organs. Some of these manifestations are subtle and clinically not apparent. Others, like adrenal involvement, can eventuate, although rarely, into frank glandular insufficiency. This Endocrine Rounds case illustrates a number of endocrine manifestations of AIDS and discusses their involvement from clinical and pathophysiologic aspects.