The insulin gene variable number of tandem repeat: associations and interactions with childhood body fat mass and insulin secretion in normal children

CONTEXT: Polymorphism at the insulin gene (INS) variable number of tandem repeat (VNTR) shows variable associations with childhood body mass index (BMI) in different populations. OBJECTIVE: The objective of this study was to observe INS VNTR associations with body composition and insulin secretion in children. DESIGN: The study was designed as a prospective birth cohort study. PARTICIPANTS: A total of 947 children genotyped for the INS VNTR participated. MAIN OUTCOME MEASURES: Main outcome measures were whole body dual x-ray emission absorptiometry at 9 yr to estimate height-corrected fat mass index (FMI), truncal FMI, and fat-free mass, and insulin secretion after oral glucose at 8 yr. RESULTS: Homozygous III/III children had higher BMI (P = 0.020), FMI (P = 0.015), and truncal FMI (P = 0.022) at 9 yr than class I bearers, but no difference in fat-free mass (P = 0.23). Gain in weight sd score between birth and 3 yr was associated positively with BMI, FMI, and truncal FMI in class I bearers, but not in III/III children (p-interaction with genotype = 0.009-0.066). INS VNTR genotype was not associated overall with insulin secretion at 8 yr (P = 0.64), but class I bearers showed a stronger positive correlation between insulin secretion and BMI at 8 yr (regression coefficient +/- se, 0.26 +/- 0.05; P < 0.0001) than III/III children (-0.10 +/- 0.07; P = 0.48) (p-interaction = 0.003). CONCLUSION: We clarified that the overall association between INS VNTR class III/III genotype and larger BMI in this population relates to fat mass, but not fat-free mass. In contrast, among the subgroup of children who showed rapid infancy weight gain, class I bearers tended to have larger BMI and fat mass than III/III children. This genetic interaction could relate to insulin secretion, which, in class I bearers, increased more rapidly with overweight and obesity.     

Loss of bone mineral density in Chinese pre-menopausal women with systemic lupus erythematosus treated with corticosteroids

The adverse effect of disease and chronic corticosteroid therapy on bone mineral density (BMD) in patients with systemic lupus erythematosus (SLE) has been reported in several studies of Caucasian populations. As the factors controlling bone homeostasis may be different in Asian populations, we measured BMD in 52 pre-menopausal Chinese women (mean age 34.1 +/- 8.0 yr) with SLE (mean disease duration 6.4 +/- 4.5 yr) treated with prednisone (mean daily dose 11.4 +/- 10.8 mg/day). Lumbar spine, hip (total and subregions) and total body BMDs were measured in the SLE patients using dual-energy X-ray absorptiometry (DEXA), and compared with those from healthy controls matched for age, sex and body mass index. Compared to controls, SLE patients were found to have lower BMD (g/cm2) at several sites: the lumbar spine (0.98 vs 0.90, P = 0.001), Ward's triangle (0.72 vs 0.67, P = 0.03), total body (1.04 vs 1.01, P = 0.04) and total hip (0.87 vs 0.82, P = 0.05). There was no correlation between BMD at any region and duration of disease, activity of disease or prednisone therapy (mean daily dose, cumulative dose or treatment duration). When BMDs were compared between controls and SLE patients, subgrouped according to those not on calcium and those arbitrarily receiving calcium supplements (1 g/day), significantly lower BMDs were found in those not on calcium compared to both controls and SLE patients on calcium. BMDs in SLE patients on calcium were not different from those in controls. The low prevalence of osteoporosis in our SLE patients (4-6%) suggests significant loss of BMD in Chinese SLE patients on corticosteroid therapy is less than that reported in Caucasians (12-18%).      

Changes in body composition after glucocorticoid therapy in patients with systemic lupus erythematosus

The aim of this study was to evaluate the changes in body composition after glucocorticoid treatment in patients with systemic lupus erythematosus (SLE). Consecutive SLE patients were recruited for serial measurements (baseline, months 2 and 6) of bone mineral density (BMD) and body composition [bone mineral content (BMC), fat and lean mass] by dual energy X-ray absorptiometry scan after high-dose oral glucocorticoid therapy. Factors correlated with changes in body composition were evaluated. 29 SLE patients were studied (age 39.7 +/- 11.5 years; 83% women with 29% postmenopausal; SLE duration 80.1 +/- 80 months). Fourteen patients (48%) were glucocorticoid-naive. The mean maximum daily dosage of prednisolone was 32.9 +/- 6.5 mg and the cumulative prednisolone dosage in 6 months was 2.7 +/- 0.7 g. At 6 months, a significant drop in BMC of the trunk (-5.0 +/- 2.2%; P = 0.04) and whole body (-1.2 +/- 0.4%; P = 0.002) compared with baseline was observed, and so was the BMD of the hip (-1.7 +/- 0.6%; P = 0.006) and whole body (-0.7 +/- 0.3%; P = 0.01). A significant increase in the fat mass of the trunk (+14.5 +/- 4.1%; P = 0.001) and limbs (+10.0 +/- 3.2%; P = 0.004), but a non-significant drop in lean mass of the trunk (-3.3 +/- 1.8%; P = 0.08) and limbs (-0.8 +/- 2.4%; P = 0.75) also occurred. The changes in whole body BMC correlated significantly with age (rho = -0.51; P = 0.02) and changes in total fat mass (rho = 0.44; P = 0.02) but not with lean mass (rho = -0.21; P = 0.27), gender, body mass index, smoking, prednisolone dosages or changes in BMD. In SLE patients, high-dose glucocorticoids lead to an early and rapid drop in bone mass, which is more serious in older patients and correlates with an increase in body fat.     

The effect of tibolone on fat mass, fat-free mass, and total body water in postmenopausal women

Changes in body composition occur around the menopausal transition. The major characteristics are a decline in fat-free mass and an increase in body fat as a percentage of body weight. These alterations might be affected by age only or by menopause-related changes in hormone concentration. In this study the effects of tibolone, a tissue-specific compound with favorable effects on bone, vagina, and climacteric symptoms, were determined on body composition using bioelectrical impedance analysis. The focus was especially on fat mass, fat-free mass, and total body water in a group of 85 healthy women (mean +/- SD age, 54.2 +/- 4.7 yr), between 1-15 yr postmenopausal. Participants were randomly assigned to either tibolone (2.5 mg; n = 42) or identically appearing placebo tablets (n = 43) daily for 12 months. All analyses were based on the intent to treat group and last visit. Compared with placebo, tibolone significantly increased fat-free mass by 0.85 kg (P = 0.003) and total body water by 0.78 liter (P = 0.001). No significant difference was observed on the fat mass parameter (P = 0.16). From these results it can be concluded that tibolone may counteract the postmenopausal changes in body composition.     

Body composition,bone mineral density,and circulating leptin levels in postmenopausal Turkish women

OBJECTIVE: We analyzed the relationship between serum leptin levels and bone mineral density (BMD) values as well as the relationship between serum leptin levels and whole body composition, whether or not they were associated. In addition, we also investigated whether lean mass or fat mass is a better predictor of BMD in postmenopausal Turkish women. DESIGN AND MEASUREMENTS: One hundred consecutive postmenopausal women with a mean age of 55.1 +/- 6.3 years who visited our outpatient clinic for the evaluation of osteoporosis were recruited. Skin fold thickness at four sites and waist:hip ratio were measured. Body mass index (BMI) was calculated in kg/m(2). Serum concentrations of leptin, insulin, and estradiol were evaluated. Bone formation and resorption markers were also determined. The BMD values were measured by dual energy X-ray absorptiometry (DEXA) at the lumbar spine and femoral neck. Whole body composition (lean mass, fat mass, and percentage of fat), total bone mineral content (BMC) in g, and total BMD were also measured by DEXA. RESULTS: Serum leptin levels did not correlate with BMD values at all skeleton sites measured. Leptin correlated positively with fat mass, percentage of fat, and BMI (r = 0.738 and P = 0.00, r = 0.536 and P = 0.00, r = 0.356 and P = 0.00, respectively). Lean mass correlated with BMD at all sites measured (r = 0.339 and P = 0.00, r = 0.312 and P = 0.01, r = 0.523 and P = 0.00, r = 0.636 and P = 0.00). Lean mass correlated with BMI (r = 0.636, P = 0.00) but not with serum leptin (r = -0.021, P = 0.881), and it was an independent determinant of BMD at all skeleton sites measured. CONCLUSION: Our study showed that lean mass is a better predictor than fat mass of bone mineral density and that serum leptin levels are not associated with BMD.     

Body composition in systemic lupus erythematosus

The objectives were to determine the body composition, and the effects of disease and corticosteroid therapy on body composition, in a population of female patients with systemic lupus erythematosus (SLE). All female SLE patients managed through a single centre were invited to participate in a cross-sectional study of body composition. Data were collected by standardized interview and examination, and review of medical records. Body composition was assessed by dual-energy X-ray absorptiometry (DXA). Eighty-two subjects were evaluated, 30 of whom were post-menopausal. Univariate linear regression analysis revealed a significant association of reduced fat-free mass with SLE severity [as measured by the Systemic Lupus International Collaborative Clinics (SLICC)] (P = 0.020), a history of corticosteroid exposure (P = 0.043) and age (P = 0.048). Reduced total body bone mineral density (BMD) was also significantly associated with SLICC (P < 0.001) and corticosteroid exposure (P = 0.017), and with age (P < 0.001), post-menopausal status (P = 0.003) and the duration of menopause (P < 0.001). Stepwise multiple linear regression analysis revealed a significant association between fat-free mass and total body, lumbar spine and femoral neck BMD (P = 0.007, P = 0.025, P = 0.003, respectively). Fat mass was significantly associated only with lumbar spine BMD (P = 0.008). In this SLE population, disease severity and corticosteroid exposure were independently associated with a negative effect both on total body BMD and on fat-free mass. Fat-free mass was a significant predictor of lumbar spine, femoral neck and total body BMD.      

肥胖男性体成分与骨密度的相关性

目的探讨成年肥胖男性体成分与骨密度（BMD）的关系。方法选取89名20～50岁男性为研究对象,根据体重指数分为体重正常组（25名）、超重组（31名）和肥胖组（33名）。应用双能X线骨密度仪进行BMD及体成分测定。结果肥胖组受试者总体脂肪质量、总体肌肉质量和BMD均高于对照绀（P〈0．05）。BMD与总体脂肪质量（r=0．296）、总体肌肉质量（r=0．392）、上肢脂肪质节（r=0．355）、人腿脂肪质量（r=0．334）和躯干脂肪质量（r=0．256）均呈正相关（P〈0．05）。BMD与躯干／总体脂肪（r=-0．197,P=0．068）呈负相关趋势。以BMD为因变量,行多元线性回归分析结果显爪,总体肌肉质量（B=0．005,P=0．000）和躯干／总体脂肪（β=-0．399,P=0．010）被引入办程。结论成年肥胖男性BMD高于非肥胖男性。肥胖者BMD增加与肌肉质量关系更为密切。建议成年肥胖男性加强体育锻炼,减少脂肪禽硅,增加肌肉含量,以预防骨质疏松症。     

Leptin and bone mineral density: a cross-sectional study in obese and nonobese men

Leptin has been suggested to decrease bone mineral density (BMD). This observational analysis explored the relationship between serum leptin and BMD in 327 nonobese men (controls) (body mass index 26.1 +/- 3.7 kg/m(2), age 49.9 +/- 6.0 yr) and 285 juvenile obese men (body mass index 35.9 +/- 5.9 kg/m(2), age 47.5 +/- 5.1 yr). Whole-body dual-energy x-ray absorptiometry scan measured BMD, fat mass, and lean mass. Fasting serum leptin (nanograms per milliliter) was strongly associated with fat mass (kilograms) in both controls (r = 0.876; P < 0.01) and juvenile obese (r = 0.838; P < 0.001). An inverse relation between BMD adjusted for body weight and serum leptin emerged in both the control group (r = -0.186; P < 0.01) and the juvenile obese group (r = -0.135; P < 0.05). In a multiple linear regression, fat mass, lean body mass, and occupational physical activity were positively associated with BMD in the control group, whereas in the juvenile obese, only lean body mass was positively associated with BMD and smoking negatively associated with BMD. Our study supports that leptin is inversely associated with BMD and may play a direct role in the bone metabolism in nonobese and obese Danish males, but it also stresses the fact that the strong covariation between the examined variables is a shortcoming of the cross-sectional design.     

Effects of DHEA replacement on bone mineral density and body composition in elderly women and men

OBJECTIVE: Dehydroepiandrosterone (DHEA) is a precursor for both oestrogens and androgens. Its marked decline with ageing may influence age-related changes in tissues influenced by sex hormones. The aim of this study was to determine the effects of DHEA replacement on bone mineral density (BMD) and body composition in elderly women and men with low serum DHEA sulphate (DHEAS) levels. DESIGN: Prospective 6 month trial of oral DHEA replacement, 50 mg/day. PATIENTS: Experimental subjects were 10 women and eight men, aged 73 +/- 1 years. Control subjects were 10 women and eight men, aged 74 +/- 1 years. MEASUREMENTS: BMD, body composition, serum markers of bone turnover, serum lipids and lipoproteins, oral glucose tolerance, serum IGF-I, total serum oestrogens and testosterone. RESULTS: BMD of the total body and lumbar spine increased (mean +/- SEM; 1.6 +/- 0.6% and 2.5 +/- 0.8%, respectively; both P < or = 0.05), fat mass decreased (- 1.3 +/- 0.4 kg; P < 0.01) and fat-free mass increased (0.9 +/- 0.4 kg; P < or = 0. 05) in response to DHEA replacement. DHEA replacement also resulted in increases in serum IGF-I (from 108 +/- 8 to 143 +/- 7 microg/l; P < 0.01) and total serum testosterone concentrations (from 10.7 +/- 1.2 to 15.6 +/- 1.8 nmol/l in the men and from 2.1 +/- 0.2 to 4.5 +/- 0.4 nmol/l in the women; both P < or = 0.05). CONCLUSIONS: The results provide preliminary evidence that DHEA replacement in those elderly women and men who have very low serum DHEAS levels can partially reverse age-related changes in fat mass, fat-free mass, and BMD, and raise the possibility that increases in IGF-I and/or testosterone play a role in mediating these effects of DHEA.     

Low relative resting metabolic rate and body weight gain in adult Caucasian Italians

OBJECTIVE: To investigate the relationship between resting metabolic rate (RMR) and subsequent changes in body size and degree of fatness in a group of adult Caucasian Italians. DESIGN: Prospective, longitudinal, observational study. SUBJECTS: In total, 155 subjects (72 males and 83 females, age range: 18-55 y; BMI: 17.5-63.4 kg/m2) were evaluated. In total, 43 (26 m and 17 f; BMI: 28.9+/-1.1 kg/m2, mean+/-s.e.m.) of them were reassessed 10-12 y later. MEASUREMENTS: Anthropometric and body composition (bioimpedance analysis) parameters and RMR (indirect calorimetry) were taken at baseline and after 10-12 y. RESULTS: Subjects (15 m, 8 f) who gained body weight (arbitrarily defined as a change in body weight > or = 5 kg) had baseline BMI (29.9+/-1.8 vs 28.0+/-1.4; P = NS) and body composition in terms of fat mass (FM%) and fat-free mass (FFM kg) comparable to those of the subjects (11 m, 9 f) whose body weight remained stable. Baseline RMR was significantly lower in subjects who gained weight than in those who did not (108+/-2.1 vs 122+/-3.1 kJ/kg-FFM 24 h; P < 0.001), although it did not differ significantly between the two groups (119+/-2 vs 121+/-2 kJ/kg-FFM 24 h; P = NS) 10-12 y later. Baseline RMR was inversely correlated to both change in body weight (r = -0.57; P < 0.001) and FM (r = -0.50; P < 0.001). CONCLUSION: A low RMR normalized for FFM appears to be associated with body weight gain in the long run in adult Caucasian Italians.     

Menopausal status influences the relationship between serum ghrelin levels and fat mass in healthy women

OBJECTIVE: To examine the relationships of fasting serum ghrelin levels to bone mass index (BMI) and body fat mass, focusing on the effects of menopausal status and changes in fat distribution in women after menopause. DESIGN: An observational study. PATIENTS: Fifty-nine pre-menopausal and 31 post-menopausal healthy Japanese women volunteers were enrolled in the present study. MEASUREMENTS: Total and regional body fat mass weight was measured by dual energy x-ray absorptiometry. Serum ghrelin was measured. Relationships of serum ghrelin levels to weight, BMI, total body and regional fat mass weight were separately examined in post-menopausal and pre-menopausal women. RESULTS: Serum ghrelin levels were significantly inversely correlated with weight (r = -0.377, p < 0.05, Pearson's correlation test), right arm fat mass (r = -0.408, p < 0.05), left arm fat mass (r = -0.386, p < 0.05), trunk fat mass (r = -0.361, p < 0.05) and total body fat mass (r = -0.383, p < 0.05) in the post-menopausal women but not in pre-menopausal women. CONCLUSIONS: Menopausal status may influence the relationship between serum ghrelin levels and fat mass in healthy women.     

以生物电阻法检测的身体组成成分与女性骨量的关系

目的 探讨体内的体脂和非体脂对绝经前和绝经后妇女骨密度(BMD)的作用。方法 282例绝经前和205例绝经后妇女参加本研究,用双能X线骨密度仪测定腰椎和股骨颈BMD,用生物电阻法测定体脂和非体脂,同时测量身高、体重、腰围、臀围,并计算体重指数(BMI)和腰臀围比(WHR)。结果 体脂和非体脂与绝经前、绝经后妇女腰椎和股骨颈BMD均呈显著正相关(P＜0．01),多元逐步回归分析显示,在绝经前妇女中,非体脂和年龄是腰椎BMD的独立影响因素(R^2=0．077,P=0．000),非体脂、年龄和BMI是影响股骨颈BMD的决定因素(R^2=0．130,P=0．000),在绝经后妇女中,体脂和年龄是影响腰椎和股骨颈BMD的决定因素(R^2分别为0．153和0．184,P=0．000)。结论 体脂和非体脂对绝经前和绝经后妇女BMD的作用不同,非体脂是决定绝经前妇女骨量的重要因素,而体脂是影响绝经后妇女骨量的重要因素。     

Androgenicity and obesity are independently associated with insulin sensitivity in postmenopausal women

An increase in androgenicity may contribute to the development of insulin resistance in postmenopausal women. Increased androgenicity in women has been found to be associated with the development of type 2 diabetes. In addition, obesity and central obesity are associated with greater androgenicity. Insulin sensitivity, androgenicity, and body composition were characterized in 34 nondiabetic postmenopausal women age 72 +/- 1 years (mean +/- SEM) to test the hypothesis that androgenicity is a predictor of insulin sensitivity independent of measures of obesity. Androgenicity was measured using levels of sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and free androgen index (FAI). Insulin sensitivity (S(I)) was determined from a frequently sampled intravenous glucose tolerance test. Body composition measures included body mass index (BMI) and dual energy x-ray absorptiometry measurements of total and central fat mass. S(I) was found to be associated with total fat mass (r = -.51, P =.002), central fat mass (r = -.62, P =.0001), BMI (r = -.55, P =.0008), SHBG levels (r =.65, P =.0001), and FAI (r = -.41, P =.01). SHBG levels were inversely correlated with central fat mass (r = -.59, P =.0002). Using multiple regression, SHBG and central fat mass were the only significant independent predictors of S(I), accounting for 50% of its variance (r =.71, P =.0001); total fat mass, BMI, total and free testosterone, DHEA-S, androstenedione, and FAI did not enter the model. We conclude that there is a significant association between insulin sensitivity and androgenicity in postmenopausal women that is independent of obesity. Interventions to decrease androgenicity may therefore be useful in improving insulin sensitivity in postmenopausal women.     

Relation of BMI to fat and fat-free mass among children and adolescents

OBJECTIVE: Although the body mass index (BMI, kg/m2) is widely used as a surrogate measure of adiposity, it is a measure of excess weight, rather than excess body fat, relative to height. We examined the relation of BMI to levels of fat mass and fat-free mass among healthy 5- to 18-y-olds. METHODS AND PROCEDURES: Dual-energy X-ray absorptiometry was used to measure fat and fat-free mass among 1196 subjects. These measures were standardized for height by calculating the fat mass index (FMI, fat mass/ht2) and the fat-free mass index (FFMI, fat-free mass/ht2). RESULTS: The variability in FFMI was about 50% of that in FMI, and the accuracy of BMI as a measure of adiposity varied greatly according to the degree of fatness. Among children with a BMI-for-age > or =85th P, BMI levels were strongly associated with FMI (r=0.85-0.96 across sex-age categories). In contrast, among children with a BMI-for-age <50th P, levels of BMI were more strongly associated with FFMI (r=0.56-0.83) than with FMI (r=0.22-0.65). The relation of BMI to fat mass was markedly nonlinear, and substantial differences in fat mass were seen only at BMI levels > or =85th P. DISCUSSION: BMI levels among children should be interpreted with caution. Although a high BMI-for-age is a good indicator of excess fat mass, BMI differences among thinner children can be largely due to fat-free mass.     

Leptin levels in relation to body composition and insulin concentration in patients with endogenous Cushing's syndrome compared to controls matched for body mass index

Cushing's syndrome (CS) is associated with weight gain and visceral obesity. We examined the relationship between regional fat distribution and serum levels of leptin, cortisol and insulin. Twenty-three consecutive patients with recently diagnosed CS (18 with pituitary adenoma, 5 with adrenal tumor), where compared to obese controls, matched for age, sex and Body Mass Index (BMI). Serum insulin, leptin, cortisol, C-peptide and body composition determined by DEXA were measured. Serum leptin levels were significantly increased in patients with CS (36.9+/-3.8 vs 18.9+/-2.4 ng/ml, p<0.001; women: 40.1+/-4.6 vs 21.7+/-2.9 ng/ml, p<0.01; men: 27.9+/-5.7 vs 10.9+/-2.3 ng/ml; p<0.05), the same were fasting insulin levels (178+/-30 vs 81+/-10 pmol/l; p<0.01) and C-peptide (1.51+/-0.12 vs 0.77+/-0.07 nmol/l; p<0.001). In a subgroup of 12 patients, truncal fat mass was significantly elevated when compared to obese controls (19.2 kg vs 14.7 kg, p<0.01, and 42% vs 36% in percentage of truncal body tissue, p<0.05), whereas total fat mass was insignificantly increased. Serum leptin correlated positively to total body fat (%) as in patients with CS (r=0.94, p<0.001) as in controls (r=0.68, p<0.01). The correlation to truncal body fat (%) was also significant in both groups (CS: r=0.84, p<0.001; controls: r=0.63, p<0.01). Multiple regression showed that percent total body fat was the predictor of leptin concentrations among patients with CS (r2=0.88, p<0.001) whereas insulin did not contribute significantly to the variance in leptin concentrations. In controls, both leptin and insulin (r2=0.65, p<0.001) contributed significantly to the variations in leptin levels. Controlled for the differences in total body fat, patients with endogenous CS have significantly increased serum leptin levels, compared to BMI-matched obese controls. This suggests that hyperleptinemia in CS not primarily reflects changes in body composition, but is the result of different hormonal influences on adipose tissue.     

Longitudinal analysis of bone mineral density in pre-menopausal female systemic lupus erythematosus patients: deleterious role of glucocorticoid therapy at the lumbar spine

OBJECTIVE: To evaluate whether bone loss occurs over time in pre-menopausal systemic lupus erythematosus (SLE) patients. METHODS: We performed a longitudinal bone mineral density (BMD) analysis in a group of 35 pre-menopausal female SLE patients. Lumbar spine and hip (total and sub-regions) BMDs were measured twice 21 +/- 11 (mean +/- S.D.) months apart by dual-energy X-ray absorptiometry. RESULTS: In the whole cohort of SLE patients, significant bone loss was observed at the lumbar spine (-1.22%/yr) but not at the total hip. Further analyses indicated that lumbar spine bone loss (-2.12%/yr) occurred exclusively in the subgroup of patients who had taken a mean prednisolone daily dose >7.5 mg between the two BMD measurements. Moreover, bone loss was more important in patients who had previously received a cumulative prednisolone dose 7.5 mg.     

Determinants of total body and regional bone mineral density in normal postmenopausal women--a key role for fat mass.

In order to determine which clinical, anthropometric, dietary, and biochemical variables are independent predictors of total and regional bone mineral density (BMD) in normal postmenopausal women, a cross-sectional study of 140 normal postmenopausal women has been carried out. Subjects were white, aged 45-71 yr (mean 58 yr), and had no history of disorders or medication use likely to influence bone or calcium metabolism. Multiple regression analysis was used to derive models for total and regional BMD in terms of the other variables measured. The analysis indicated that total body BMD was positively related to fat mass (P less than 0.0001), serum estrone (P = 0.0095) and age at menopause (P = 0.0165), and negatively related to age (P less than 0.0001), 24-h urine calcium (P = 0.0002), sex hormone-binding globulin (P = 0.0003), and serum alkaline phosphatase activity (P = 0.0029) (R2 = 0.61). Similar relationships were found in the subregions of the total body scans and in the lumbar spine and proximal femur, with insulin-like growth factor-1, parity, and age at menarche also being related to BMD at at least two of these sites. Lean body mass was not an independent correlate of BMD at any site once fat mass was taken into account. Muscle strength, physical activity, alcohol intake, and dietary intakes of calcium, sodium and protein did not emerge as significant predictors of BMD in this homogeneous group of postmenopausal women. We conclude that total body fat is the most significant predictor of BMD throughout the skeleton and this relationship is not explicable in terms of either estrone production in fat tissue or the dependence of skeletal load-bearing on fat mass. The mechanism underlying this relationship is an important question to be addressed in bone biology.     

Beta-adrenergically stimulated fat oxidation is diminished in middle-aged compared to young subjects.

The effect of aging on beta-adrenergically mediated substrate utilization was investigated in nine young (25.2 +/- 1.7 yr old) and eight older males (52.9 +/- 2.1 yr old), matched for body weight and body composition. In a first experiment, the nonselective beta-agonist isoprenaline (ISO) was infused in increasing standardized doses, and during each infusion period energy expenditure and substrate utilization were determined by indirect calorimetry. In a second experiment, forearm skeletal muscle metabolism was studied during a standardized infusion dose of ISO (19 ng/kg fat-free mass x min). During beta-adrenergic stimulation there was an increased carbohydrate oxidation (at an ISO infusion dose of 24 ng/kg fat-free mass x min, 31% vs. 21% of total energy expenditure; P < 0.05) and a decreased fat oxidation (51 vs. 62 of total energy expenditure; P < 0.05) in older compared to young subjects. Skeletal muscle lactate release significantly increased in the older subjects (from -175 +/- 32 to -366 +/- 66 nmol/100 mL forearm tissue x min), whereas there was no change in young subjects (from -32 +/- 21 to 23 +/- 57 nmol/100 mL forearm tissue x min; interaction group x ISO, P < 0.01). Additionally, there was a tendency toward a blunted ISO-induced increase in nonesterified fatty acid uptake in the older subjects (interaction group x ISO, P = 0.062). Thus, middle-aged subjects have a blunted ability to oxidize fat during beta-adrenergic stimulation compared to young subjects. This diminished fat oxidation may be an important etiological factor in the age-related increase in body fatness and obesity by favoring fat storage above oxidation.     

Withdrawal of long-term physiological growth hormone (GH) administration: differential effects on bone density and body composition in men with adult-onset GH deficiency

Adults with acquired GH deficiency (GHD) have been shown to have osteopenia associated with a 3-fold increase in fracture risk and exhibit increased body fat and decreased lean mass. Replacement of GH results in decreased fat mass, increased lean mass, and increased bone mineral density (BMD). The possible differential effect of withdrawal of GH replacement on body composition compartments and regional bone mass is not known. We performed a randomized, single blind, placebo-controlled 36-month cross-over study of GH vs. placebo (PL) in adults with GHD and now report the effect of withdrawal of GH on percent body fat, lean mass, and bone density, as measured by dual energy x-ray absorptiometry. Forty men (median age, 51 yr; range, 24-64 yr) with pituitary disease and peak serum GH levels under 5 microg/L in response to two pharmacological stimuli were randomized to GH therapy (starting dose, 10 microg/kg x day, final dose 4 microg/kg x day) vs. PL for 18 months. Replacement was provided in a physiological range by adjusting GH doses according to serum insulin-like growth factor I levels. After discontinuation of GH, body fat increased significantly (mean +/- SEM, 3.18 +/- 0.44%; P = 0.0001) and returned to baseline. Lean mass decreased significantly (mean loss, 2133 +/- 539 g; P = 0.0016), but remained slightly higher (1276 +/- 502 g above baseline; P = 0.0258) than at study initiation. In contrast to the effect on body composition, BMD did not reverse toward pretreatment baseline after discontinuation of GH. Bone density at the hip continued to rise during PL administration, showing a significant increase (0.0014 +/- 0.00042, g/cm2 x month; P = 0.005) between months 18-36. Every bone site except two (radial BMD and total bone mineral content), including those without a significant increase in BMD during the 18 months of GH administration, showed a net increase over the entire 36 months. Therefore, there is a critical differential response of the duration of GH action on different body composition compartments. Physiological GH administration has a persistent effect on bone mass 18 months after discontinuation of GH.