FTO predicts weight regain in the Look AHEAD clinical trial.

BACKGROUND: Genome-wide association studies have provided new insights into the genetic factors that contribute to the development of obesity. We hypothesized that these genetic markers would also predict magnitude of weight loss and weight regain after initial weight loss. METHODS: Established obesity risk alleles available on the Illumina CARe iSelect (IBC) chip were characterized in 3899 overweight or obese participants with type 2 diabetes from the Look AHEAD (Action for Health in Diabetes), a randomized trial to determine the effects of intensive lifestyle intervention (ILI) and diabetes support and education (DSE) on cardiovascular morbidity and mortality. Primary analyses examined the interaction between 13 obesity risk polymorphisms in eight genes and randomized treatment arm in predicting weight change at year 1, and weight regain at year 4 among individuals who lost 3% or more of their baseline weight by year 1. RESULTS: No single-nucleotide polymorphisms (SNPs) were significantly associated with magnitude of weight loss or interacted with treatment arm at year 1. However, fat mass and obesity associated gene (FTO) rs3751812 predicted weight regain within DSE (1.56 kg per risk allele, P=0.005), but not ILI (P=0.761), resulting in SNP × treatment arm interaction (P=0.009). In a partial replication of prior research, the obesity risk (G) allele at BDNF rs6265 was associated with greater weight regain across treatment arms (0.773 kg per risk allele), although results were of borderline statistical significance (P=0.051). CONCLUSIONS: Variations in the FTO and BDNF loci may contribute risk of weight regain after weight loss.

The combination oral and nutritional treatment of late-onset diabetes mellitus (CONTROL DM) trial results.

OBJECTIVE: To examine the effect of short-term improvements in glycaemic control on brachial artery endothelial function as a marker of cardiovascular health. METHODS: Persons with Type 2 diabetes who were poorly controlled on oral therapy were randomly assigned to monotherapy with repaglinide or combination therapy with repaglinide plus metformin. Brachial artery flow-mediated vasodilation was assessed by ultrasonography at randomization and following 16 weeks of therapy. The primary outcome was change in brachial artery endothelial function from baseline. Comparison of randomized groups was a secondary aim. RESULTS: Eighty-six participants were randomized, and 83 were followed to study completion. Post occlusion brachial artery vasodilation was 3.74% at baseline and 3.82% following 16 weeks of therapy (P = 0.77). The treatment effect was 0.08% (95% CI: -0.48%, 0.64%). No difference was seen between treatment groups (P = 0.69). Overall, A1C was reduced from 8.3% to 7.0%, with a greater reduction in the combination therapy group (from 8.4% to 6.7%) than in the monotherapy group (from 8.3% to 7.3%, p for difference between groups = 0.01). Statistically significant reductions were observed in fasting glucose, and plasminogen activator inhibitor-1. Statistically significant increases were observed for fasting insulin, uric acid, weight and BMI. CONCLUSIONS: Brachial artery endothelial function was not influenced by short-term improvements in glycaemic control. The CONTROL DM group was successful in lowering A1C. Future research should explore more intensive and longer-lasting improvements in glycaemic control on endothelial function. Some data previously published in abstract form (Diabetes 2001; 50 (Suppl. 2): A217).

Evidence for common controls over inheritance of bone quantity and body size from segregation analysis in a pedigreed colony of nonhuman primates (Macaca nemestrina).

The genetic determinants of bone mineral quantity and body size and their postulated interaction are just beginning to be elucidated. The heritability of bone quantity and its relationship to components of body size were therefore investigated using segregation analysis applied to a large pedigreed nonhuman primate (Macaca nemestrina) breeding colony. The colony consisted of 216 females and 16 males with uniform dietary histories, environmental conditions, and rearing of offspring apart from the mother to minimize familial aggregation. Bone quantity (bone mineral content and spinal areal density) was measured by dual-energy X-ray absorptiometry (DXA). Size included measures of body mass, length, breadth, and a composite index. Body mass was determined from both body weight and lean body mass by DXA. Length was assessed by measuring trunk and thigh lengths, and breadth by measuring chest circumference and bitrochanteric width. A composite index of size was also calculated from a linear function of trunk and thigh lengths, chest circumference and bitrochanteric width, and lean body mass. Traits of bone quantity and size were highly correlated (r = 0.56-0.96, p < 0.001). Significant (p < or = 0.03) univariate heritabilities were found for spine bone mineral density (SPBMD; h(2) = 0.66) and whole body bone mineral content (WBBMC; h(2) = 0.40) and size measures of length (trunk h(2) = 0.71, thigh h(2) = 0.65), breadth (bitrochanteric width h(2) = 0.31), lean body mass (LEAN; h(2) = 0.37), and the composite index of size (SIZE-PC, h(2) = 0.49) adjusted for demographic variables. The data were also subjected to an analysis of bivariate genetic correlations and factor analysis, both of which suggested a robust interaction between body size and bone quantity. Bivariate genetic correlations between body size and the bone quantities WBBMC, SBMD, and spine bone mineral content (SPBMC) were high (e.g., using LEAN as a measure of size, r = 0.57, 0.41, and 0.57, respectively). Factor analysis showed that 80% of the phenotypic and 72% of the genetic variances of all traits were accounted for by a single factor, suggesting common genetic controls operative over bone quantity and size.

Bone physiology during pregnancy and lactation in young macaques.

We used a nonhuman primate model (Macaca nemestrina) of adolescent human pregnancy to characterize bone remodeling at midpregnancy and at weaning and the associated changes in bone mass. In this longitudinal study, 125 nulliparous females were followed through pregnancy, 6 months of lactation, and 3 months postweaning; 13 nonpregnant females served as controls. Between early pregnancy and midpregnancy, the whole body bone mineral increased. There was no significant change between midpregnancy and parturition. Between parturition and 3 months lactation, the animals lost 3.0% of their bone mineral (p < 0.01), which was regained by 3 months after weaning. The vertebral bone mineral apparent density decreased during pregnancy and 6 months of lactation, followed by an increase during the 3 months after weaning. Calcium, phosphate, 25-hydroxyvitamin D, and osteocalcin increased significantly from midpregnancy to weaning whereas 1,25-dihydroxyvitamin D values showed significant decreases. Histomorphometric measurements from bone biopsies showed significant increases in most parameters of bone formation between pregnancy and weaning. These results are consistent with the hypothesis that at midpregnancy bone formation is decreased and cancellous bone resorption may have increased. During lactation, losses occur in both cortical and cancellous bone, partially depleting the maternal reservoir of calcium, but a subsequent increase in bone formation enables restoration of bone mineral after weaning to values similar to those in the control group.

Metabolic bone disease in gut diseases.

A wide spectrum of gastrointestinal illnesses impairs bone health and can result in bone pain, demineralization, and fracture. This article summarizes current knowledge of the skeletal pathology exhibited in patients with diseases of the liver, biliary tree, pancreas, and bowel. Mechanisms responsible for these syndromes and treatment options are discussed. This article enhances the practicing gastroenterologist's knowledge of the implications of gastrointestinal illness for bone.

A longitudinal study of calcium regulation in a nonhuman primate model of parenteral nutrition.

The question of whether parenteral nutrition adversely affects calcium regulation remains unclear. Human studies of this question have been confounded by uncontrolled variables including the degree to which food is ingested orally; gut absorption; underlying disease; medication adversely affecting bone, including steroids; and aluminum contamination of parenteral nutrients. The present study was undertaken to examine whether parenteral nutrition adversely affects calcium regulation in a nonhuman primate model that allows for control of underlying clinical variables and mobility. With use of this model, it was possible to show weight maintenance and positive nitrogen and calcium balances with parenteral nutrition. There was no demonstrable effect of the animals' wearing a jacket and tether system or of catheterization on calcium regulation. Calciuria in response to parenteral nutrition was elevated initially but diminished by 2 wk of therapy. The calciuria observed resulted from an increased urine-filtered calcium load. Calcium balance with parenteral nutrition was preserved by a diminished fraction of calcium filtered by the kidney being excreted in the urine. The present study suggests that negative calcium balance produced by parenteral nutrition may result from abnormal renal tubular function or disruption of normal parathyroid hormone regulation.

Evaluation of vertebral volumetric vs. areal bone mineral density during growth.

Bone mineral "density" (BMD) measured by dual-energy X-ray absorptiometry (DEXA) does not represent the volumetric density (grams per cubic centimeter), but rather the areal density (grams per square centimeter). This distinction is important during growth. The purpose of this study was to measure vertebral dimensions in cadavers of young pigtail macaques (Macaca nemestrina), and to derive equations to predict the volumetric bone density from noninvasive measurements. We measured the areal bone density by DEXA, vertebral volume by underwater weighing, mineral content by ashing, dimensions of lumbar vertebrae by calipers, and dimensions of vertebrae by radiography. Somatometric measurements of the female lumbar vertebral bodies showed that the shape changed during growth. The bone mineral content from the densitometer correlated significantly with the ash weight (r = 0.99, error 8.7%). The correlation coefficient between the volumetric bone mineral density and areal BMD measurement was significant (r = 0.68, p < 0.0001) with a 9.5% error; this improved significantly to 0.82 (7.2% error) when the BMD was divided by the vertebral depth from the radiograph. A real BMD showed a strong correlation with age (r = 0.82, p < 0.0001), with an average increase of 7.4%/year. In contrast, volumetric mineral density showed a weak relationship with age (r = 0.43, p < 0.01), for an average increase of 1.5%/year. When studying bone mineral density during growth, the differences between volumetric and areal bone mineral density should be taken into consideration.

Osteopenia in rats supported by intravenous nutrition.

The etiology of bone disease seen in long-term total parenteral nutrition patients is poorly defined. This study examined the question of whether abnormal bone could be induced in otherwise normal weanling rats fed a balanced nutrient solution intravenously. Young adult, male Wag/Rij rats were divided into three groups. One group was fed a commercial liquid research diet, one group received an indwelling jugular catheter and was fed an intravenous elemental solution formulated to be nutritionally complete, and one group received an indwelling catheter but was fed the commercial liquid diet orally. Significant differences were seen between groups in percent bone, femur length, growth-plate width, endosteal label area, periosteal mineral apposition rate, and periosteal and endosteal bone-formation rates. This study suggests that intravenous administration of otherwise adequate nutrients to rats results in altered bone remodeling compared to orally fed cohorts.

Nutrition support of a pregnant comatose patient via percutaneous endoscopic gastrostomy.

A pregnant woman was comatose after a motor vehicle accident at 13 weeks' gestation. The nutritional needs of the patient were supported by tube feedings after percutaneous endoscopic gastrostomy. Clinical management was required for nutrition support, infection, and fetal development. At 37 weeks' gestation, a normal 3640-g male infant was delivered by cesarean section. This represents the first case report of a successful pregnancy outcome after percutaneous endoscopic gastrostomy for enteral nutrition support of a pregnant comatose patient.

Assessment of nutritional status. The clinician's perspective.

The prevalence of malnourished patients in the hospital continues to hover around 50%. As more ambulatory and day care medical and surgical facilities open, those actually admitted to the nation's acute care hospitals will be sicker, and thus a higher percentage will be malnourished. There is currently a plethora of tools designed to assess nutritional status within the spectrum of a broad range of costs and sensitivity. At the very least, upon admission to an acute care hospital, patients should undergo a nutritional screening consisting of weight history, recent dietary habits, and serum albumin concentration. An accurate assessment of the degree of malnutrition should rely on the expertise of a dietician trained to use the techniques of global nutritional assessment in conjunction with anthropometries. Clinical laboratories need to enlarge their services to encompass more direct measures of body composition (e.g., BIA) and dynamic assessment of muscle function (e.g., WOB). Subsequent serial measurements of nutritional status have limited sensitivity and specificity but may be useful in selected patients with a high severity of illness score (i.e., APACHE) and prolonged LOS. Attention should be directed to ensuring that nutrient intakes correspond to estimated needs.

Metabolic bone disease in adults receiving long-term parenteral nutrition: longitudinal study with regional densitometry and bone biopsy.

A syndrome of bone pain and fractures has been described in patients receiving long-term support from parenteral nutrition containing large quantities of aluminium or vitamin D2. Whether this same syndrome occurs in patients supported by current therapeutic regimens is controversial. In this study, bone health was longitudinally evaluated over 7 to 61 months in 14 subjects maintained on long-term parenteral nutrition. The parameters of bone health evaluated included bone mass as measured by single and dual photon absorptiometry and quantitative histomorphometry of bone biopsies. There was a striking heterogeneity in baseline measures of bone health. Mean bone density of parenteral nutrition patients was significantly below expected values on entry into the study at both the distal radius (z score = -0.76 +/- 0.27) and the lumbar spine (z score = -1.17 +/- 0.27). Mean areal density at the forearm was less severely depressed (z score = -0.62 +/- 0.34). The longitudinal changes in bone density and morphology were heterogeneous, with some subjects showing deterioration, others improvement, and still others no change. We conclude that patients already established on parenteral nutrition frequently have osteopenia. The group as a whole did not demonstrate normalization of the osteopenia, but our results also suggest that current parenteral nutrition formulations low in aluminum and vitamin D2 do not necessarily cause worsening of bone health. The etiology of this clinical syndrome merits additional study.

A histomorphometric comparison of bone in young growing rats fed an elemental diet versus a chemically defined polymeric diet.

This study was designed to examine whether a synthetic elemental diet, which could be adapted for total parenteral nutrition, is capable of promoting bone growth comparable to a commercially available liquid polymeric diet. The orally fed young rat was chosen as a model of rapid bone growth. Sixteen male, Wag/Rij rats weighing 120 +/- 3 g were divided into two groups of eight rats each. One group was fed an elemental diet formulated to approximate the nutritional requirements of the rat as recommended by the National Research Council. The comparison group received a liquid polymeric diet. After 14 days there were no significant differences between groups in femur and tibia weights, cortical and medullary area, periosteal and endosteal label area, growth plate width, percent cancellous bone, bone apposition rates and osteoblasts and osteoclasts per millimeter. Both groups maintained a positive calcium and nitrogen balance. These data indicate that bone growth, structure and remodeling comparable to that seen in a polymeric-fed comparison group can be achieved in young rats when fed an oral dextrose/amino acid-based elemental solution for 2 weeks.

Serum markers of bone formation in parenteral nutrition patients.

Bone gamma-carboxyglutamic acid containing protein (BGP) has been utilized effectively as a serum marker of bone turnover in healthy normals and in individuals with a variety of metabolic bone disorders including postmenopausal osteoporosis and Paget's disease. The utility of this serum marker in other bone disorders, including that associated with the maintenance of patients on long-term parenteral nutrition, still requires definition. Because of our interest in this clinical syndrome and the availability of serum and of bone formation rates (BFR) measured directly from double tetracycline labeling in 11 long-term parenteral nutrition patients, we measured BGP levels in these patients and attempted to correlate this measure with BFR. Serum vitamin D metabolites, immunoreactive parathyroid hormone (PTH), and alkaline phosphatase (alk phos) were also measured. Serum BGP was only weakly and not significantly correlated (r = 0.24, p = NS) with bone formation rate for the group as a whole. However, in a subgroup of 10 patients without hyperparathyroidism, there was strong and significant correlation (r = 0.81, P less than 0.01) between BGP and BFR. There was also a strong correlation between bone formation rate and serum 1,25 dihydroxyvitamin D [1,25(OH)2D] levels (r = 0.89, P less than 0.01, n = 11). The mechanism of this association could not be established. A correlation of borderline significance was observed between bone formation rate and serum alk phos (r = 0.60, P = 0.05, n = 11). The current data suggest that additional studies may help to more fully define the utility of serum measurements in quantifying bone dynamics in parenteral nutrition patients, and that measures of vitamin D metabolites, BGP, and alk phos may prove useful.

Long-term parenteral nutrition in unrestrained nonhuman primates: an experimental model.

A freely mobile jacket and tether system was developed for the investigation of total parenteral nutrition (TPN)-induced metabolic bone disease and complications of prolonged TPN in 12 Macaca fascicularis nonhuman primates. The animals received TPN for 49 +/- 7 d (means +/- SEM), providing 82 +/- 2 kcal.kg-1.d-1. Serum glucose increased from 3.6 +/- 0.2 mmol/L at baseline to 8.3 +/- 1.9 mmol/L (p less than 0.01) during TPN, and serum albumin decreased from 38 +/- 1 g/L at baseline to 29 +/- 1 g/L (p less than 0.001) during 2.75% amino acid TPN and 30 +/- 2 g/L (p less than 0.01) during 5% amino acid TPN infusion. No significant changes were seen in serum prealbumin, total protein, bilirubin, alanine aminotransferase, and 5'-nucleotidase during TPN infusion. Major complications included catheter sepsis, hyperglycemia, diarrhea, and premature death in six animals. Thus, metabolic complications of prolonged TPN support may be investigated in a freely mobile nonhuman primate.

Acetate inhibition of chick bone cell proliferation and bone growth in vitro.

A hypothesis has been advanced that parenteral solutions as commonly formulated for use in clinical practice have a toxic effect on cell metabolism. A specific component of these solutions, sodium acetate, has been suggested to disrupt normal bone turnover and therefore to contribute to the osteopenia observed in patients receiving hemodialysis and parenteral nutrition (PN). We developed an in vitro model to test the hypothesis that sodium acetate at concentrations that are infused in PN solutions has a deleterious effect on bone metabolism. Osteoblasts and preosteoblasts from 16- to 17-day-old embryonic chick calvaria, and tibiae and femora from 10-day-old embryonic chicks were grown in BGJb medium (control) or in BGJb medium plus sodium acetate (5, 10, or 20 mM). Calvarial cell proliferation was quantified by direct cell counts as well as by incorporation of [3H]TdR into DNA as an index of cell proliferation. Calvarial cell alkaline phosphatase activity was quantified by the ability of extracts of the cultured cells to hydrolyze p-nitrophenyl phosphate to p-nitrophenol, and bone growth was determined by measuring final dry weight. Calvarial cell counts as well as DNA synthesis showed a dose-dependent decrease in the presence of sodium acetate (5-20 mM) compared with controls. [3H]TdR incorporation was decreased a mean 19% with 5 mM, 38% with 10 mM, and 63% with 20 mM acetate. Alkaline phosphatase activity per cell increased 48% with 5 mM, 140% with 10 mM, and 355% with 20 mM acetate. Cell viability as assessed by trypan blue exclusion was identical for test and control media (greater than 95%).(ABSTRACT TRUNCATED AT 250 WORDS)

D-lactate and metabolic bone disease in patients receiving long-term parenteral nutrition.

D-lactate accumulates in some patients with malabsorption who continue oral intake of carbohydrate leading to a clinical syndrome of acidosis and encephalopathy. To assess the possibility that D-lactate contributes to acidosis and/or metabolic bone disease in patients with malabsorption receiving long-term parenteral nutrition yet maintaining oral intake, D-lactate levels in serum and urine were measured in 14 long-term parenteral nutrition subjects (average duration of support 74 months) and 27 control subjects. Significant elevations in both serum and urine D-lactate were found in only two parenteral nutrition subjects. Both subjects with elevated D-lactate levels had bone pain, x-ray evidence of fractures, and biopsy evidence of osteomalacia. These studies suggest that D-lactate accumulation may be a heretofore unappreciated metabolic abnormality associated with metabolic bone disease and acidosis in patients with malabsorption who are supported by long-term parenteral nutrition.

Sedimentation equilibrium analysis of five lipocortin-related phospholipase A2 inhibitors from human placenta. Evidence against a mechanistically relevant association between enzyme and inhibitor.

Five proteins from human placenta capable of inhibiting pancreatic phospholipase A2 were purified. Two of these proteins were identified as lipocortins I and II. The other three proteins were immunologically distinct from lipocortins I and II and had apparent subunit molecular masses of 32, 33, and 73 kDa as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Amino acid sequence analysis of peptides produced by cyanogen bromide digestion indicated sequence homology of these proteins with lipocortin I and the heavy chain subunit of lipocortin II. Two of these proteins were identified as endonexin II and 67-kDa calelectrin. The third protein appears to be the human form of bovine endonexin I, also characterized as porcine protein II. Sedimentation equilibrium analysis of lipocortin I, endonexin I and II, and the 67-kDa calelectrin suggested monomer-dimer equilibria with dissociation constants in the range of 0.33-1.3 X 10(-3) M and monomer molecular masses of 38,050, 36,400, 36,850, and 73,610 Da, respectively. Self-association of lipocortin II was described by dimerization of a protomer (K12 = 5.3 x 10(-7) M), followed by an indefinite self-association of the dimer (isodesmic dissociation constant, Kiso = 3.6 x 10(-6) M). The protomer molecular mass was 48,800 Da, consistent with a heterodimeric structure composed of one heavy (38,600 Da) and one light (10,944 Da) chain as previously characterized for lipocortin II. Sedimentation equilibrium analysis of mixtures of individual protein inhibitors and purified pancreatic phospholipase A2 indicated weak association between enzyme and inhibitor (Kd greater than or equal to 3 x 10(-5) M), insufficient to account for the observed inhibition of enzyme activity.