Calorically restricted diets decrease PCSK9 in overweight adolescents.

BACKGROUND AND AIMS: Nutritional therapy is the first line approach to treatment of hyperlipidemia in childhood. Proprotein convertase subtilisin kexin type 9 (PCSK9) is a key regulator of plasma cholesterol levels and a target of novel lipid-lowering pharmacotherapies. We examined the effects of an intensive nutritional intervention on PCSK9 levels in overweight adolescents with cardiovascular disease (CVD) risk factors. METHODS AND RESULTS: Twenty seven obese and overweight adolescents with CVD risk factors were assigned to either a low fat or low glycemic load diet. During an 8-week "Intensive Phase," assigned meals were delivered to the home, and all participants received weekly in-person home nutrition counseling and phone calls. The subjects then underwent a 4-month "Maintenance Phase" without food provision and with no in-person contact. Anthropometric measurements, laboratory data, and serum PCSK9 protein levels were measured at baseline, 8 weeks, and 6 months. PCSK9 decreased by 16.5% at 8 weeks (201.2 ± 56.3 vs 165.6 ± 58.4 ng/mL; p < 0.001); PCSK9 levels returned to baseline levels at 6 months, after the Maintenance Phase. Change in PCSK9 was associated with change in fasting insulin, HOMA-IR, and AUC insulin, independent of weight loss. CONCLUSIONS: PCSK9 decreased in youth participating in an intensive dietary intervention. Change in HOMA-IR was associated with change in PCSK9, independent of weight loss, suggesting an important relationship with insulin sensitivity. ClinicalTrials.gov Identifier: NCT01080339.

Estimated morbidity and mortality in adolescents and young adults diagnosed with Type 2 diabetes mellitus.

AIMS: To estimate remaining life expectancy (RLE), quality-adjusted life expectancy (QALE), causes of death and lifetime cumulative incidence of microvascular/macrovascular complications of diabetes for youths diagnosed with Type 2 diabetes. METHODS: A Markov-like computer model simulated the life course for a hypothetical cohort of adolescents/young adults in the USA, aged 15-24 years, newly diagnosed with Type 2 diabetes following either conventional or intensive treatment based on the UK Prospective Diabetes Study. Outcomes included RLE, discounted QALE in quality-adjusted life years (QALYs), cumulative incidence of microvascular/macrovascular complications and causes of death. RESULTS: Compared with a mean RLE of 58.6 years for a 20-year-old in the USA without diabetes, conventional treatment produced an average RLE of 43.09 years and 22.44 discounted QALYs. Intensive treatment afforded an incremental 0.98 years and 0.44 discounted QALYs. Intensive treatment led to lower lifetime cumulative incidence of all microvascular complications and lower mortality from microvascular complications (e.g. end-stage renal disease (ESRD) death 19.4% vs. 25.2%). Approximately 5% with both treatments had ESRD within 25 years. Lifetime cumulative incidence of coronary heart disease (CHD) increased with longer RLE and greater severity of CHD risk factors. Incorporating disutility (loss in health-related quality of life) of intensive treatment resulted in net loss of QALYs. CONCLUSIONS: Adolescents/young adults with Type 2 diabetes lose approximately 15 years from average RLE and may experience severe, chronic complications of Type 2 diabetes by their 40s. The net clinical benefit of intensive treatment may be sensitive to preferences for treatment. A comprehensive management plan that includes early and aggressive control of cardiovascular risk factors is likely needed to reduce lifetime risk of CHD.

Three-dimensional structure of cholera toxin penetrating a lipid membrane.

Two-dimensional crystals of cholera toxin bound to receptors in a lipid membrane give diffraction extending to 15 A resolution. Three-dimensional structure determination reveals a ring of five B subunits on the membrane surface, with one-third of the A subunit occupying the center of the ring. The remaining mass of the A subunit appears to penetrate the hydrophobic interior of the membrane. Cleavage of a disulfide bond in the A subunit, which activates the toxin, causes a major conformational change, with the A subunit mostly exiting from the B ring.

Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance.

Several lines of investigation suggest that the hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates body weight in mammals. Obese mice lacking functional leptin overexpress the MCH message in the fed or fasted state. Acute intracerebroventricular injection of MCH increases energy intake in rats. Mice lacking the MCH gene are lean. To test the hypothesis that chronic overexpression of MCH in mice causes obesity, we produced transgenic mice that overexpress MCH (MCH-OE) in the lateral hypothalamus at approximately twofold higher levels than normal mice. On the FVB genetic background, homozygous transgenic animals fed a high-fat diet ate 10% more and were 12% heavier at 13 weeks of age than wild-type animals, and they had higher systemic leptin levels. Blood glucose levels were higher both preprandially and after an intraperitoneal glucose injection. MCH-OE animals were insulin-resistant, as demonstrated by markedly higher plasma insulin levels and a blunted response to insulin; MCH-OE animals had only a 5% decrease in blood glucose after insulin administration, compared with a 31% decrease in wild-type animals. MCH-OE animals also exhibited a twofold increase in islet size. To evaluate the contribution of genetic background to the predisposition to obesity seen in MCH-OE mice, the transgene was bred onto the C57BL/6J background. Heterozygote C57BL/6J mice expressing the transgene showed increased body weight on a standard diet, confirming that MCH overexpression can lead to obesity.

A telephone intervention to achieve differentiation in dietary intake: a randomized trial in paediatric primary care.

BACKGROUND: Telehealth offers opportunities to extend clinical and research interventions for paediatric obesity. OBJECTIVES: To assess utility of a telephone intervention, implemented through a national primary care paediatric research network, for promoting differentiation in dietary intake, consistent with either a low-glycemic load (Low GL) or Low Fat prescription, among overweight/obese school-age children. METHODS: Five-week telephone dietary counselling intervention for parents of overweight/obese school-age children recruited through the Slone Center Office-based Research Network. Parent-child dyads were randomized to Low GL or Low Fat diet. Primary outcomes were dietary GL and dietary fat, adjusted for energy intake and assessed by 24-h dietary recall. RESULTS: Subjects were randomized to Low GL (n = 11, 8.1 ± 1.7 years, 45.5% male) or Low Fat (n = 11, 8.2 ± 2.0 years, 36.4% male), with no baseline differences. Overall, 86% of subjects attended at least four of five counselling sessions, and study completion rate was 91% (based on completion of the final dietary recalls). Reported satisfaction was high. In adjusted analyses limited to 'recall completers,' reduction in dietary GL (g/1000 kcal) achieved within the Low GL group was significant (p = 0.01) and greater than the change in dietary GL in the Low Fat group (mean ± SE; -12.9 ± 4.4 vs. 5.1 ± 4.9, p = 0.03). Similarly, reduction in dietary fat (% of total energy) within the Low Fat group was significant (-5.6 ± 2.5, p = 0.046) but with no difference between groups (p = 0.25). CONCLUSION: A telephone-based dietary intervention for overweight/obese children, implemented through a national paediatric research network, fostered prescribed dietary changes. ClinicalTrials.gov registration: NCT00620152.

Physical changes in the home environment to reduce television viewing and sugar-sweetened beverage consumption among 5- to 12-year-old children: a randomized pilot study.

This study evaluated the feasibility of a home-based intervention to reduce sugar-sweetened beverage intake and television viewing among children. Lower income parents of overweight children aged 5-12 years (n = 40) were randomized to a home environment intervention to reduce television viewing with locking devices and displace availability of sugar-sweetened beverages with home delivery of non-caloric beverages (n = 25), or to a no-intervention control group (n = 15) for 6 months. Data were collected at baseline and 6 months. After 6 months, television viewing hours per day was significantly lower in the intervention group compared with the control group (1.7 [SE = .02] vs. 2.6 [SE = .25] hours/day, respectively, P < .01). Sugar-sweetened beverage intake was marginally significantly lower among intervention group compared to control group children (0.21 [SE = .09] vs. 0.45 [SE = .10], respectively, P < .09). Body mass index (BMI) z-score was not significantly lower among intervention compared to control children. Among a lower income sample of children, a home-based intervention reduced television viewing, but not sugar-sweetened beverage intake or BMI z-score.

A randomized pilot study of dietary treatments for polycystic ovary syndrome in adolescents.

BACKGROUND: Evidence is lacking to recommend one diet over another when treating polycystic ovary syndrome (PCOS). OBJECTIVES: To obtain preliminary data, comparing the impact of a low-glycaemic load (LGL) vs. low-fat (LF) diet on biochemical hyperandrogenism in overweight and obese adolescents with PCOS. To ascertain feasibility of recruiting study participants, in partnership with an adolescent clinic, and implementing dietary interventions. METHODS: Randomized controlled trial of 19 overweight and obese adolescents with PCOS and not using hormonal contraceptives (HCs). Interventions comprised nutrition education, dietary counselling and cooking workshops to foster adherence to a LGL (45% carbohydrate, 35% fat, 20% protein) or LF (55% carbohydrate, 25% fat, 20% protein) diet over 6 months. Serum bioavailable testosterone was the primary outcome. RESULTS: Sixteen (LGL, n = 7; LF, n = 9) participants completed the study. Body fat percentage decreased (P < 0.05) in response to the interventions, with no difference between the LGL and LF groups (-1.2% vs. -2.2%; P = 0.16). Bioavailable testosterone did not change for either group (-0.4 vs. -1.8 ng dL(-1) ; P = 0.35). Regarding feasibility, recruiting adolescents posed a challenge, and use of HCs was a main reason for ineligibility. Participants attended 5.9 of 6 in-person visits and 2.6 of 3 cooking workshops, completed 4.9 of 6 telephone counselling calls, and reported high satisfaction with the diets and cooking workshops (≥8 on a 10-cm scale). CONCLUSIONS: Dietary interventions were beneficial for weight control but did not attenuate biochemical hyperandrogenism. Innovative strategies are needed to recruit adolescents for studies aimed at assessing independent effects of diet on features of PCOS.

Outcomes from an orientation model to reduce attrition in paediatric weight management.

We aimed to reduce attrition of newly referred patients in a paediatric weight management programme by implementing an orientation to address families' expectations and screen for and support behavioural and mental health problems and psychosocial stressors at programme outset. Orientation impact was monitored with run charts with percentages of scheduled encounters completed. Long-term impact was assessed by comparing patients in the initial 6 months of the orientation to a baseline group of referred patients during the same 6-month time interval in the prior year (Pre-Orientation Group). The outcome measure was programme attrition within 15 months. Groups were compared using Kaplan-Meier survival analysis and Cox proportional hazards regression modelling. Patients in the Orientation Group had a 23% increased odds of attrition compared to patients in the Pre-Orientation group (adjusted Hazard ratio, aHR 1.23; 95% confidence interval, CI: 1.01, 1.51) and shorter median duration of follow-up (2.0 vs. 2.9 months, P = 0.004). An increase in body mass index z-score of 1 unit resulted in a nearly fivefold increased odds of attrition (aHR 5.24; 95% CI: 2.95, 9.3). An orientation for new patients did not reduce attrition within 15 months. We suggest that ongoing retention strategies should be embedded into the treatment phase of the programme.

Creating an integrated care model for childhood obesity: a randomized pilot study utilizing telehealth in a community primary care setting.

In an integrated care model, involving primary care providers (PCPs) and obesity specialists, telehealth may be useful for overcoming barriers to treating childhood obesity. We conducted a pilot study comparing body mass index (BMI) changes between two arms (i) PCP in-person clinic visits plus obesity specialist tele-visits ( PCP visits + specialist tele-visits) and (ii) PCP in-person clinic visits only ( PCP visits only), with ongoing tele-consultation between PCPs and obesity specialists for both arms. Patients (N = 40, 10-17 years, BMI ≥ 95th percentile) were randomized to Group 1 or 2. Both groups had PCP visits every 3 months for 12 months. Using a cross-over protocol, Group 1 had PCP visits + specialist tele-visits during the first 6 months and PCP visits only during the second 6 months, and Group 2 followed the opposite sequence. Each of 12 tele-visits was conducted by a dietitian or psychologist with a patient and parent. Retention rates were 90% at 6 months and 80% at 12 months. BMI (z-score) decreased more for Group 1 (started with PCP visits + specialist tele-visits) vs. Group 2 (started with PCP visits only) at 3 months (-0.11 vs. -0.05, P = 0.049) following frequent tele-visits. At 6 months (primary outcome), BMI was lower than baseline within Group 1 (-0.11, P = 0.0006) but not Group 2 (-0.06, P = 0.08); however, decrease in BMI at 6 months did not differ between groups. After crossover, BMI remained lower than baseline for Group 1 and dropped below baseline for Group 2. An integrated care model utilizing telehealth holds promise for treating children with obesity.

Functional interactions between melanin-concentrating hormone, neuropeptide Y, and anorectic neuropeptides in the rat hypothalamus.

A growing body of evidence indicates that a number of peptides expressed in the mammalian hypothalamus are involved in the regulation of food intake and energy balance. Among these, melanin-concentrating hormone (MCH) and neuropeptide Y (NPY) are potent appetite stimulants, whereas alpha-melanocyte-stimulating hormone (alpha-MSH), neurotensin, and glucagon-like peptide (GLP)-1(7-36) amide have appetite-suppressing properties. However, the functional interactions between pathways involving these neuropeptides remain incompletely understood. In the current study, we describe the functional interactions between orexigenic (appetite-stimulating: MCH and NPY) and anorectic (appetite-suppressing: alpha-MSH, neurotensin, and GLP-1) peptides after intracerebroventricular (i.c.v.) administration in the rat. The i.c.v. administration of GLP-1 completely prevents the orexigenic effects of both MCH and NPY. However, i.c.v. administration of alpha-MSH prevents only the orexigenic effect of MCH, as we have previously shown, but does not prevent the effect of NPY on food intake. Similarly, i.c.v. administration of neurotensin prevents only the orexigenic effect of MCH, but does not prevent the appetite-stimulating effect of NPY. Thus, our study suggests that the functional interactions between these neuropeptides are specific, although the underlying mechanisms are as yet unexplored.

Absence of mutations in the human OB gene in obese/diabetic subjects.

The product of the obese (ob) gene, leptin, is a secreted protein that is important in the regulation of body weight. Mice with mutations in the ob gene are obese and diabetic and manifest reduced physical as well as metabolic activity. In this study, we tested the possibility that mutations in the OB gene may contribute to human obesity. We report the isolation and partial sequence of the human OB gene and the screening of 105 obese patients for mutations in the protein coding sequence using the technique of single-strand conformational polymorphism. No coding sequence polymorphism was found, suggesting that mutations in the coding sequence of the OB gene do not constitute a common cause of increased body weight in humans. We also identified a highly polymorphic simple dinucleotide repeat DNA polymorphism in this gene that will be useful for genetic studies.

Multi-component molecular-level body composition reference methods: evolving concepts and future directions.

Excess adiposity is the main phenotypic feature that defines human obesity and that plays a pathophysiological role in most chronic diseases. Measuring the amount of fat mass present is thus a central aspect of studying obesity at the individual and population levels. Nevertheless, a consensus is lacking among investigators on a single accepted 'reference' approach for quantifying fat mass in vivo. While the research community generally relies on the multi-component body volume class of 'reference' models for quantifying fat mass, no definable guide discerns among different applied equations for partitioning the four (fat, water, protein and mineral mass) or more quantified components, standardizes 'adjustment' or measurement system approaches for model-required labelled water dilution volumes and bone mineral mass estimates, or firmly establishes the body temperature at which model physical properties are assumed. The resulting differing reference strategies for quantifying body composition in vivo leads to small, but under some circumstances, important differences in the amount of measured body fat. Recent technological advances highlight opportunities to expand model applications to new subject groups and measured components such as total body protein. The current report reviews the historical evolution of multi-component body volume-based methods in the context of prevailing uncertainties and future potential.

Examination of the phosphoenolpyruvate carboxykinase gene promoter in patients with noninsulin-dependent diabetes mellitus.

Expression of phosphoenolpyruvate carboxykinase (PEPCK), a rate-limiting enzyme in gluconeogenesis, is under dominant negative regulation by insulin. In this study, we sought to test the hypothesis that mutations in the PEPCK gene promoter may impair the ability of insulin to suppress hepatic glucose production, thereby contributing to both the insulin resistance and increased rate of gluconeogenesis characteristic of NIDDM. The proximal PEPCK promoter region in 117 patients with noninsulin-dependent diabetes mellitus and 20 obese Pima Indians was amplified by PCR and analyzed with single strand conformation polymorphism techniques. In addition, limited direct DNA sequencing was performed on the insulin response sequence and flanking regions. No DNA sequence polymorphisms were found in any patient. This result suggests that mutations in cis-acting PEPCK gene regulatory elements do not constitute a common cause of noninsulin-dependent diabetes mellitus. The significance of genetic variation in promoter regions to human disease is discussed.

Should obese patients be counselled to follow a low-glycaemic index diet? Yes.

A reduction in dietary fat has been widely advocated for the prevention and treatment of obesity and related complications. However, the efficacy of low-fat diets has been questioned in recent years. One potential adverse effect of reduced dietary fat is a compensatory increase in the consumption of high glycaemic index (GI) carbohydrate, principally refined starchy foods and concentrated sugar. Such foods can be rapidly digested or transformed into glucose, causing a large increase in post-prandial blood glucose and insulin. Short-term feeding studies have generally found an inverse association between GI and satiety. Medium-term clinical trials have found less weight loss on high GI or high glycaemic load diets compared to low GI or low glycaemic load diets. Epidemiological analyses link GI to multiple cardiovascular disease risk factors and to the development of cardiovascular disease and type 2 diabetes. Physiologically orientated studies in humans and animal models provide support for a role of GI in disease prevention and treatment. This review examines the mechanisms underlying the potential benefits of a low GI diet, and whether such diets should be recommended in the clinical setting.

Dietary composition and physiologic adaptations to energy restriction.

BACKGROUND: The concept of a body weight set point, determined predominantly by genetic mechanisms, has been proposed to explain the poor long-term results of conventional energy-restricted diets in the treatment of obesity. OBJECTIVE: The objective of this study was to examine whether dietary composition affects hormonal and metabolic adaptations to energy restriction. DESIGN: A randomized, crossover design was used to compare the effects of a high-glycemic-index (high-GI) and a low-glycemic-index (low-GI) energy-restricted diet. The macronutrient composition of the high-GI diet was (as percent of energy) 67% carbohydrate, 15% protein, and 18% fat and that of the low-GI diet was 43% carbohydrate, 27% protein, and 30% fat; the diets had similar total energy, energy density, and fiber contents. The subjects, 10 moderately overweight young men, were studied for 9 d on 2 separate occasions. On days -1 to 0, they consumed self-selected foods ad libitum. On days 1-6, they received an energy-restricted high- or low-GI diet. On days 7-8, the high- or low-GI diets were consumed ad libitum. RESULTS: Serum leptin decreased to a lesser extent from day 0 to day 6 with the high-GI diet than with the low-GI diet. Resting energy expenditure declined by 10.5% during the high-GI diet but by only 4.6% during the low-GI diet (7.38 +/- 0.39 and 7.78 +/- 0.36 MJ/d, respectively, on days 5-6; P = 0.04). Nitrogen balance tended to be more negative, and energy intake from snacks on days 7-8 was greater, with the high-GI than the low-GI diet. CONCLUSION: Diets with identical energy contents can have different effects on leptin concentrations, energy expenditure, voluntary food intake, and nitrogen balance, suggesting that the physiologic adaptations to energy restriction can be modified by dietary composition.

Structure-function analysis of protein active sites with anti-idiotypic antibody.

Antigen and internal image-bearing anti-idiotypic antibody, owing to potential differences in size and chemical nature, need not necessarily demonstrate identical binding specificities. Such differences, termed "dissociability," may be exploited in structure-function analysis of receptor-ligand interaction to identify functionally important amino acid residues, define receptor class, or distinguish receptor conformation. In this sense, ligand and the anti-idiotypes they elicit constitute alternative and complementary probes of protein active sites.

Blood glucose and hormonal responses to small and large meals in healthy young and older women.

Blood glucose regulation in the fasting and fed states has important implications for health. In addition, the ability to maintain normal blood glucose homeostasis may be an important determinant of an individual's capacity to regulate food intake. We tested the hypothesis that aging is associated with an impairment in the ability to maintain normal blood glucose homeostasis following the consumption of large meals but not small ones, a factor that could help to explain age-related impairments in the control of food intake and energy regulation. The subjects were eight healthy younger women (25 +/- 2 years, SD) and eight healthy older women (72 +/- 2 years) with normal body weight and glucose tolerance. Following a 36-h period when diet and physical activity were controlled, subjects consumed test meals containing 0, 1046, 2092, and 4184 kJ (simulating extended fasting, and consumption of a snack, a small meal, and a moderately large meal), with 35% of energy from fat, 48% from carbohydrate, and 17% from protein. Each subject consumed each of the test meals on a separate occasion. Serial blood samples were collected at baseline and during 5 h after consumption of the meals. Measurements were made of circulating glucose, insulin, glucagon, free fatty acids, and triglycerides. There was no significant difference between young and older women in their hormone and metabolite responses to fasting and consumption of the 1046-kJ meal. However, following consumption of 2092 and 4148 kJ, older individuals showed exaggerated responses and a delayed return to premeal values for glucose (p = .023), insulin (p = .010), triglycerides (p = .023), and the ratio of insulin to glucagon (p = .026). In conclusion, these results suggest an impairment in the hormonal and metabolite responses to large meals in older women.

A low-glycemic index diet in the treatment of pediatric obesity.

CONTEXT: Conventional dietary approaches for the treatment of obesity have generally yielded disappointing results. OBJECTIVE: To examine the effects of a low-glycemic index (GI) diet compared with a standard reduced-fat diet in the management of pediatric obesity. DESIGN: Retrospective cohort study of children attending an outpatient pediatric obesity program from September 1997 to December 1998. SETTING: Academic medical center. PARTICIPANTS: One hundred seven obese but otherwise healthy children. MAIN OUTCOME MEASURES: Changes in body mass index (BMI [calculated as weight in kilograms divided by the square of height in meters]) and body weight from first to last clinic visit. RESULTS: A total of 64 patients received the low glycemic index diet and 43 received the reduced-fat diet for 4.3 vs 4.2 months' mean duration of follow-up, with 3.3 vs 3.3 mean number of visits, respectively. Body mass index (-1.53 kg/m(2) [95% confidence interval, -1.94 to -1.12] vs -0.06 kg/m(2) [-0.56 to + 0. 44], P<.001) and body weight (-2.03 kg [95% confidence interval -3. 19 to -0.88] vs +1.31 kg [ -0.11 to + 2.72], P<.001) decreased more in the low-GI group compared with the reduced-fat group. In multivariate models, these differences remained significant (P<.01) after adjustment for age, sex, ethnicity, BMI or baseline weight, participation in behavioral modification sessions, and treatment duration. Significantly more patients in the low-GI group experienced a decrease in BMI of at least 3 kg/m(2) (11 kg/m(2) [17. 2%] vs. 1 kg/m(2) [2.3%], P =.03). CONCLUSIONS: A low-GI diet seems to be a promising alternative to standard dietary treatment for obesity in children. Long-term randomized controlled trials of a low-GI diet in the prevention and treatment of obesity are needed.

Dietary fiber and body-weight regulation. Observations and mechanisms.

Dietary fiber may be related to body-weight regulation through plausible physiologic mechanisms that have considerable support in the scientific literature. Many short-term studies suggest that high-fiber foods induce greater satiation and satiety. Epidemiologic studies generally [figure: see text] support a role for fiber in body-weight regulation among free-living individuals consuming self-selected diets, although conclusive intervention studies addressing this point are lacking. Thus, there is considerable reason to conclude that fiber-rich diets, containing non-starchy vegetables, fruits, whole grains, legumes, and nuts, may be effective in the prevention and treatment of obesity in children. Such diets may have additional benefits, independent of changes in adiposity, in the prevention of cardiovascular disease and type 2 diabetes.

Anti-receptor antibodies designed to elicit "internal image"-bearing anti-idiotypes: a possible AIDS vaccine.

Two obstacles hinder the development of an AIDS vaccine: (1) the AIDS virus exhibits extensive amino acid heterogeneity between isolates and (2) antibodies elicited by virus during the course of natural infection are often non-neutralizing. A vaccine designed to induce anti-idiotypic antibodies against the virus' receptor on T-cells, T4, should, in principle, overcome these obstacles. Such antibody could contain an "internal image" of T4 and bind the receptor binding domain of the virus. Since this domain is both critical to function and, therefore, poorly susceptible to antigenic variation, anti-receptor anti-idiotypic antibodies may demonstrate broad, strain-independent crossreactivity and block viral adherence.