In vitro and in vivo pharmacology of CP-945,598, a potent and selective cannabinoid CB1 receptor antagonist for the management of obesity

Cannabinoid CB₁ receptor antagonists exhibit pharmacologic properties favorable for the treatment of metabolic disease. CP-945,598 (1-[9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purin-6-yl]-4-ethylamino piperidine-4-carboxylic acid amide hydrochloride) is a recently discovered selective, high affinity, competitive CB₁ receptor antagonist that inhibits both basal and cannabinoid agonist-mediated CB₁ receptor signaling in vitro and in vivo. CP-945,598 exhibits sub-nanomolar potency at human CB₁ receptors in both binding (K_i = 0.7 nM) and functional assays (K_i = 0.2 nM). The compound has low affinity (K_i = 7600 nM) for human CB₂ receptors. In vivo, CP-945,598 reverses four cannabinoid agonist-mediated CNS-driven responses (hypo-locomotion, hypothermia, analgesia, and catalepsy) to a synthetic cannabinoid receptor agonist. CP-945,598 exhibits dose and concentration-dependent anorectic activity in two models of acute food intake in rodents, fast-induced re-feeding and spontaneous, nocturnal feeding. CP-945,598 also acutely stimulates energy expenditure in rats and decreases the respiratory quotient indicating a metabolic switch to increased fat oxidation. CP-945,598 at 10 mg/kg promoted a 9%, vehicle adjusted weight loss in a 10 day weight loss study in diet-induced obese mice. Concentration/effect relationships combined with ex vivo brain CB₁ receptor occupancy data were used to evaluate efficacy in behavioral, food intake, and energy expenditure studies. Together, these in vitro, ex vivo, and in vivo data indicate that CP-945,598 is a novel CB₁ receptor competitive antagonist that may further our understanding of the endocannabinoid system.     

The effects of zinc supplementation on metabolic profile and oxidative stress in overweight/obese patients with non-alcoholic fatty liver disease: A randomized,double-blind,placebo-controlled trial

BackgroundEvidence indicates the positive effects of zinc on insulin resistance and oxidative stress in metabolic syndrome or diabetes. Non-alcoholic fatty liver disease (NAFLD) is the main hepatic manifestation of insulin resistance and metabolic syndrome. The present study is the first clinical trial that evaluated the effects of zinc supplementation on metabolic and oxidative stress status in overweight/obese patients with NAFLD undergoing calorie- restriction diet. Methods: Fifty six overweight/obese patients with confirmed mild to moderate NAFLD using ultrasonography were randomly allocated to receive 30 mg elemental zinc supplement (n = 29) or placebo (n = 27) along with weight loss diet for 12 weeks. Serum levels of zinc, homeostasis model of assessment-estimated insulin resistance (HOMA-IR), lipid profile, serum superoxide dismutas1 (SOD1) and malondialdhyde (MDA) levels were assessed.ResultsSerum levels of insulin, SOD1, MDA and HOMA-IR were improved in the treatment group (p < 0.05). Within group comparison showed significant reduction in serum FBS, HbA_1C, TC, LDL-c and TG in the treatment group. Conclusion: Zinc supplementation for three months improved insulin resistance and oxidative stress status in overweight/obese NAFLD patients with no beneficial effects on lipid profiles over weight loss diet. Registration ID in IRCT (IRCT NO: 20181005041238N1).     

A Randomized,Double-Blind,Placebo-Controlled Trial of Adjunctive Metformin Therapy in Overweight/Obese Youth with Type 1 Diabetes

Context

Insulin resistance has been proposed as one of the causes of poor glycemic control in overweight/obese youth with type 1 diabetes (T1D). However, the role of adjunctive metformin, an insulin sensitizer, on glycemic control in these patients is unclear.

Objective

To compare the effect of metformin vs. placebo on hemoglobin A1c (HbA1c), total daily dose (TDD) of insulin, and other parameters in overweight/obese youth with T1D.

Hypothesis

Adjunctive metformin therapy will improve glycemic control in overweight/obese youth with T1D.

Design, Setting, and Participants

A 9-mo randomized, double-blind, placebo controlled trial of metformin and placebo in 28 subjects (13m/15f) of ages 10-20years (y), with HbA1c >8% (64 mmol/mol), BMI >85%, and T1D > 12 months was conducted at a university outpatient facility. The metformin group consisted of 15 subjects (8 m/ 7f), of age 15.0 ± 2.5 y; while the control group was made up of 13 subjects (5m/ 8f), of age 14.5 ± 3.1y. All participants employed a self-directed treat-to-target insulin regimen based on a titration algorithm of (-2)-0-(+2) units to adjust their long-acting insulin dose every 3rd day from -3 mo through +9 mo to maintain fasting plasma glucose (FPG) between 90–120 mg/dL (5.0–6.7 mmol/L). Pubertal maturation was determined by Tanner stage.

Results

Over the course of the 9 months of observation, the between-treatment differences in HbA1c of 0.4% (9.85% [8.82 to 10.88] for placebo versus 9.46% [8.47 to 10.46] for metformin) was not significant (p = 0.903). There were non-significant reduction in fasting plasma glucose (189.4 mg/dL [133.2 to 245.6] for placebo versus 170.5 mg/dL [114.3 to 226.7] for metformin), (p = 0.927); total daily dose (TDD) of short-acting insulin per kg body weight/day(p = 0.936); and the TDD of long-acting insulin per kg body weight per day (1.15 units/kg/day [0.89 to 1.41] for placebo versus 0.90 units/kg/day [0.64 to 1.16] for metformin) (p = 0.221). There was no difference in the occurrence of hypoglycemia between the groups.

Conclusions

This 9-month RCT of adjunctive metformin therapy in overweight and obese youth with T1D resulted in a 0.4% lower HbA1c value in the metformin group compared to the placebo group.

Trial Registration

ClinicalTrial.gov NCT01334125     

Effect of Vitamin D3 Supplementation on Inflammatory Markers and Glycemic Measures among Overweight or Obese Adults: A Systematic Review of Randomized Controlled Trials

BackgroundObesity induced low-grade chronic inflammation disrupts proper immune and metabolic function. Vitamin D deficiency increases inflammation, which is associated with cardiometabolic risk. This systematic review examines the association between oral vitamin D (VD) supplementation and circulating inflammatory biomarkers and glycemic outcomes from randomized controlled trials (RCTs) of overweight and/or obese adults.MethodsMEDLINE OVID, EMBASE and the Cochrane Central Register of Controlled Trials were searched according to a predefined protocol. Eligible RCTs included adults randomized to receive either oral VD or placebo. Two reviewers independently assessed RCTs for inclusion. Bias was assessed using the Cochrane Collaboration risk of bias tool. Mean differences were calculated comparing end-of-study sample means between the independent VD and placebo groups.ResultsEleven unique RCTs met inclusion criteria from a total of 3,383 identified citations, including 79 screened articles and 14 full text data extractions. Inflammatory and glycemic measures were reported in 7 and 10 RCTs, respectively. Most trial findings were non-significant with considerable heterogeneity in design, participants and outcomes. All but one trial was rated as either high or unclear risk of bias. Two RCTs reported significant changes in inflammatory biomarkers; however, the mean difference between groups was not statistically significant: C-reactive protein 0.19 mg/L (p = 0.88); Tumor Necrosis Factor -0.54 pg/ml (p = 0.20). Two other trials found significant mean differences in fasting plasma glucose -0.32 mmol/L (p = 0.03), Hemoglobin A1c -0.13% (p = 0.04), and Homeostatic Model Assessment -0.86 (p = 0.02) following VD supplementation.ConclusionsOverall, there is no clear established benefit of VD supplementation on inflammatory biomarkers among overweight/obese adults. Baseline serum VD possibly influences the effect of VD repletion on inflammatory markers. Risk of bias was present in most studies, thus supporting the need for higher quality studies in this area to more conclusively understand the role VD supplementation has on inflammatory pathways.     

Effect of Alginate on Satiation,Appetite, Gastric Function,and Selected Gut Satiety Hormones in Overweight and Obesity

Lack of control of food intake, excess size, and frequency of meals are critical to the development of obesity. The stomach signals satiation postprandially and may play an important role in control of calorie intake. Sodium alginate (based on brown seaweed Laminaria digitata) is currently marketed as a weight loss supplement, but its effects on gastric motor functions and satiation are unknown. We evaluated effects of 10 days treatment with alginate or placebo on gastric functions, satiation, appetite, and gut hormones associated with satiety in overweight or obese adults. We conducted a randomized, 1:1, placebo‐controlled, allocation‐concealed study in 48 overweight or obese participants with excluded psychiatric comorbidity and binge eating disorder. All underwent measurements of gastric emptying (GE), fasting, and postprandial gastric volumes (GVs), postprandial satiation, calorie intake at a free choice meal and selected gut hormones after 1 week of alginate (three capsules vs. matching placebo per day, ingested 30 min before the main meal). Six capsules were ingested with water 30 min before the GE, GV, and satiation tests on days 8–10. There were no treatment group effects on GE or volumes, gut hormones (ghrelin, cholecystokinin (CCK), glucagon‐like peptide‐1 (GLP‐1), peptide YY (PYY)), satiation, total and macronutrient calorie intake at a free choice meal. There was no difference detected in results between obese and overweight patients. Alginate treatment for a period of 10 days showed no effect on gastric motor functions, satiation, appetite, or gut hormones. These results question the use of short‐term alginate treatment for weight loss.     

The Effect of Glucagon-Like Peptide 1 Receptor Agonists on Weight Loss in Type 2 Diabetes: A Systematic Review and Mixed Treatment Comparison Meta-Analysis

Aims

To determine the effects of glucagon-like peptide-1 receptor agonists compared with placebo and other anti-diabetic agents on weight loss in overweight or obese patients with type 2 diabetes mellitus.

Methods

Electronic searches were conducted for randomised controlled trials that compared a glucagon-like peptide-1 receptor agonist therapy at a clinically relevant dose with a comparator treatment (other type 2 diabetes treatment or placebo) in adults with type 2 diabetes and a mean body mass index ≥ 25kg/m². Pair-wise meta-analyses and mixed treatment comparisons were conducted to examine the difference in weight change at six months between the glucagon-like peptide-1 receptor agonists and each comparator.

Results

In the mixed treatment comparison (27 trials), the glucagon-like peptide-1 receptor agonists were the most successful in terms of weight loss; exenatide 2mg/week: -1.62kg (95% CrI: -2.95kg, -0.30kg), exenatide 20μg: -1.37kg (95% CI: -222kg, -0.52kg), liraglutide 1.2mg: -1.01kg (95%CrI: -2.41kg, 0.38kg) and liraglutide 1.8mg: -1.51 kg (95% CI: -2.67kg, -0.37kg) compared with placebo. There were no differences between the GLP-1 receptor agonists in terms of weight loss.

Conclusions

This review provides evidence that glucagon-like peptide-1 receptor agonist therapies are associated with weight loss in overweight or obese patients with type 2 diabetes with no difference in weight loss seen between the different types of GLP-1 receptor agonists assessed.     

Effect of Pramlintide on Weight in Overweight and Obese Insulin‐Treated Type 2 Diabetes Patients

Objective: Several randomized, placebo‐controlled, double‐blind trials in insulin‐treated patients with type 2 diabetes have shown that adjunctive therapy with pramlintide reduces hemoglobin (Hb)A_1c with concomitant weight loss. This analysis further characterizes the weight‐lowering effect of pramlintide in this patient population. Research Methods and Procedures: This pooled post hoc analysis of two long‐term trials included all patients who were overweight/obese at baseline (BMI > 25 kg/m²), and who were treated with either 120 μg pramlintide BID (n = 254; HbA_1c 9.2%; weight, 96.1 kg) or placebo (n = 244; HbA_1c 9.4%; weight, 95.0 kg). Statistical endpoints included changes from baseline to week 26 in HbA_1c, body weight, and insulin use. Results: Pramlintide treatment resulted in significant reductions from baseline to week 26, compared with placebo, in HbA_1c and body weight (both, p < 0.0001), for placebo‐corrected reductions of ?0.41% and ?1.8 kg, respectively. Approximately three times the number of patients using pramlintide experienced a ≥5% reduction of body weight than with placebo (9% vs. 3%, p = 0.0005). Patients using pramlintide also experienced a proportionate decrease in total daily insulin use (r = 0.39, p < 0.0001). The greatest placebo‐corrected reductions in weight at week 26 were observed in pramlintide‐treated patients with a BMI >40 kg/m² and in those concomitantly treated with metformin (both, p < 0.001), for placebo‐corrected reductions of ?3.2 kg and ?2.5 kg, respectively. Discussion: These findings support further evaluation of the weight‐lowering potential of pramlintide in obese patients with type 2 diabetes.     

Body size phenotypes and inflammation in the Women's Health Initiative Observational Study

Individuals with "metabolically benign" obesity (obesity unaccompanied by hypertension, dyslipidemia, and diabetes) are not at elevated 10-year risk of cardiovascular disease (CVD) compared to normal weight individuals. It remains unclear whether these obese individuals or normal weight individuals with clustering of cardiometabolic factors display heightened immune activity. Therefore, we characterized levels of acute-phase reactants (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), white blood cell (WBC) count), adhesion molecules (E-selectin, vascular cell adhesion molecule-1), and coagulation products (fibrinogen, plasminogen activator inhibitor-1 (PAI-1)) among four body size phenotypes (normal weight with 0/1 vs. ≥2 metabolic syndrome components/diabetes and overweight/obesity with 0/1 vs. ≥2 metabolic syndrome components/diabetes) in cross-sectional analyses of 1,889 postmenopausal women from the Women's Health Initiative Observational Study (WHI-OS) nested case-control stroke study. Higher levels of all three inflammatory marker categories were found among women with overweight/obesity or ≥2 metabolic syndrome components or diabetes. Compared to normal weight women with 0 or 1 metabolic syndrome components, normal weight women with ≥2 metabolic syndrome components or diabetes were more likely to have ≥3 inflammatory markers in the top quartile (multivariate odds ratio (OR) 2.0, 95% confidence interval (CI): 1.3-3.0), as were overweight/obese women with 0 or 1 metabolic syndrome components (OR 2.3; 95% CI: 1.5-3.5). Overweight/obese women with ≥2 metabolic syndrome components or diabetes had the highest OR (OR 4.2; 95% CI: 2.9-5.9). Despite findings that metabolically benign obese individuals are not at increased 10-year risk of CVD compared to normal weight individuals, the current results suggest that overweight/obese women without clustering of cardiometabolic risk factors still possess abnormal levels of inflammatory markers.     

One-year changes in symptoms of depression and weight in overweight/obese individuals with type 2 diabetes in the Look AHEAD study

Depressed individuals are frequently excluded from weight loss trials because of fears that weight reduction may precipitate mood disorders, as well as concerns that depressed participants will not lose weight satisfactorily. The present study examined participants in the Look AHEAD study to determine whether moderate weight loss would be associated with incident symptoms of depression and suicidal ideation, and whether symptoms of depression at baseline would limit weight loss at 1 year. Overweight/obese adults with type 2 diabetes (n = 5,145) were randomly assigned to an Intensive Lifestyle Intervention (ILI) or a usual care group, Diabetes Support and Education (DSE). Of these, 5,129 participants completed the Beck Depression Inventory (BDI) and had their weight measured at baseline and 1 year. Potentially significant symptoms of depression were defined by a BDI score ≥10. Participants in ILI lost 8.6 ± 6.9% of initial weight at 1 year, compared to 0.7 ± 4.8% for DSE (P < 0.001, effect size = 1.33), and had a reduction of 1.4 ± 4.7 points on the BDI, compared to 0.4 ± 4.5 for DSE (P < 0.001, effect size = 0.23). At 1 year, the incidence of potentially significant symptoms of depression was significantly lower in the ILI than DSE group (6.3% vs. 9.6%) (relative risk (RR) = 0.66, 95% confidence interval (CI) = 0.5, 0.8; P < 0.001). In the ILI group, participants with and without symptoms of depression lost 7.8 ± 6.7% and 8.7 ± 6.9%, respectively, a difference not considered clinically meaningful. Intentional weight loss was not associated with the precipitation of symptoms of depression, but instead appeared to protect against this occurrence. Mild (or greater) symptoms of depression at baseline did not prevent overweight/obese individuals with type 2 diabetes from achieving significant weight loss.     

Acute effects of valsartan on insulin sensitivity in obese, non-hypertensive subjects with and without type 2 diabetes.

BACKGROUND: Two studies were designed to determine whether a single dose (80 mg) of the angiotensin II receptor blocker (ARB), valsartan, alters insulin sensitivity in obese, non-hypertensive subjects with and without Type 2 diabetes. METHODS: Insulin sensitivity (S(I)), glucose effectiveness (S(G)), and acute insulin response (AIR(0-10 min)) were measured by means of a 3-hour insulin-modified frequently sampled intravenous glucose tolerance test (FSIVGTT) before and after a single dose of valsartan. Study 1: obese, normotensive non-diabetic male subjects (n = 12), mean (SD) age 37.2 +/- 11.2 years, BMI 32.8 +/- 6.8 kg/m (2); Study 2: obese, normotensive Type 2 diabetic patients (n = 12), mean age 55.7 +/- 6.9 years, BMI 35.0 +/- 6.8 kg/m (2)/l. Both studies were randomised, double-blind, placebo-controlled, single-dose crossover group studies involving subjects in two study days, two weeks apart. After fasting samples were taken, a 300 mg/kg iv glucose bolus was injected at 0 min, and 0.05 U/kg iv insulin was given 20 min later. Blood samples for analysis of glucose and insulin were taken throughout the 3-hour study period. RESULTS: Study 1 (non-diabetic subjects) S(I) 2.81 vs. 2.63 x 10 (-4) min (-1) per microU/ml (p = 0.54), S(G) 0.020 vs. 0.020 min (-1) (p = 0.90), AIR(0-10) min 3305 vs. 3450 microU/min/ml (p = 0.71); Study 2 (patients with type 2 diabetes) S(I) 0.59 vs. 0.85 x 10 (-4) min (-1) per microU/ml (p = 0.15), S(G) 0.013 vs. 0.014 min (-1) (p = 0.71), AIR(0-10) min 65 vs. 119 microU/min/ml (p = 0.14), placebo vs. valsartan, respectively. CONCLUSION: In obese, non-hypertensive non-diabetic and Type 2 diabetic subjects a single dose of valsartan does not alter insulin sensitivity.     

Low Carbohydrate versus Isoenergetic Balanced Diets for Reducing Weight and Cardiovascular Risk: A Systematic Review and Meta-Analysis

Background

Some popular weight loss diets restricting carbohydrates (CHO) claim to be more effective, and have additional health benefits in preventing cardiovascular disease compared to balanced weight loss diets.

Methods and Findings

We compared the effects of low CHO and isoenergetic balanced weight loss diets in overweight and obese adults assessed in randomised controlled trials (minimum follow-up of 12 weeks), and summarised the effects on weight, as well as cardiovascular and diabetes risk. Dietary criteria were derived from existing macronutrient recommendations. We searched Medline, EMBASE and CENTRAL (19 March 2014). Analysis was stratified by outcomes at 3–6 months and 1–2 years, and participants with diabetes were analysed separately. We evaluated dietary adherence and used GRADE to assess the quality of evidence. We calculated mean differences (MD) and performed random-effects meta-analysis. Nineteen trials were included (n = 3209); 3 had adequate allocation concealment. In non-diabetic participants, our analysis showed little or no difference in mean weight loss in the two groups at 3–6 months (MD 0.74 kg, 95%CI −1.49 to 0.01 kg; I² = 53%; n = 1745, 14 trials; moderate quality evidence) and 1–2 years (MD 0.48 kg, 95%CI −1.44 kg to 0.49 kg; I² = 12%; n = 1025; 7 trials, moderate quality evidence). Furthermore, little or no difference was detected at 3–6 months and 1–2 years for blood pressure, LDL, HDL and total cholesterol, triglycerides and fasting blood glucose (>914 participants). In diabetic participants, findings showed a similar pattern.

Conclusions

Trials show weight loss in the short-term irrespective of whether the diet is low CHO or balanced. There is probably little or no difference in weight loss and changes in cardiovascular risk factors up to two years of follow-up when overweight and obese adults, with or without type 2 diabetes, are randomised to low CHO diets and isoenergetic balanced weight loss diets.     

Weight loss maintenance in a population-based sample of German adults

The objective of this study was to investigate the prevalence of weight loss maintenance in a population-based sample of the German adult population. German adults were recruited based on the random digital-dialing methodology. Using computer-assisted telephone interviewing, weight loss maintenance was assessed, defined as having intentionally lost at least 10% from maximum weight and having maintained it for at least 1 year at the time of the survey. A total of 2,095 noninstitutionalized adults were randomly selected from all parts of Germany and the data of 957 respondents were included into the analysis. Of those who were at least overweight (BMI >or= 25 kg/m(2)) at their maximum weight, 17.7% reported having maintained a current weight loss of >or=10% of their maximum weight for at least 1 year. Among participants who reported a maximum weight in the obese range (BMI >or= 30 kg/m(2)), 29.7% reported successful 1-year weight loss maintenance. Among at least overweight participants, being younger and female, and having a higher maximum BMI were significant predictors of successful 1-year weight loss maintenance. The results suggest that successful weight loss maintenance is not uncommon in the general population, particularly in formerly obese participants. More should be learned about the strategies that successful weight maintainers use to avoid regaining weight.     

Association of Obesity,but not Diabetes or Hypertension,with Glucocorticoid Receptor N363S Variant

Objective: To determine whether the N363S variant in the glucocorticoid receptor (encoded by nuclear receptor subfamily 3, group C, member 1: NR3C1) is associated with obesity, type 2 diabetes, or hypertension. Research Methods and Procedures: This was a cross‐sectional case‐control study involving 951 Anglo‐Celtic/Northern European subjects from Sydney. This study consisted of the following: 1) an obesity clinic group, most of whom had “morbid obesity” (mean BMI for group = 43 ± 8 kg/m²; n = 152); 2) a type 2 diabetes clinic group (n = 356); 3) patients with essential hypertension who had a strong family history (n = 141); and 4) normal healthy controls (n = 302). N363S genotype, BMI, and a range of other parameters relevant to each group were measured. Results: Compared with the frequency of 0.04 in nonobese healthy subjects, the S363 allele was significantly higher in obesity clinic patients (0.17; p = 5.6 × 10^?8), subjects with diabetes who were also obese (0.09; p = 0.0045), subjects with hypertension who were also overweight (0.08; p = 0.0016), and overweight healthy subjects (0.12; p = 0.0004). Discussion: The NR3C1 N363S variant is associated with obesity and overweight in a range of patient settings but is not associated with hypertension or type 2 diabetes.     

A metabolically healthy obese phenotype in hispanic participants in the IRAS family study

Objective: Some obese individuals appear to be protected from developing type 2 diabetes mellitus and cardiovascular disease (CVD). This has led to characterizing body size phenotypes based on cardiometabolic risk factors specifically as obese or overweight, and as metabolically healthy (MH) or metabolically abnormal (MA) based upon blood pressure, lipids, glucose homeostasis, and inflammatory parameters. The aim of this study was to measure the prevalence of and describe fat distribution across these phenotypes in a minority population. Design and Methods: Hispanic participants (N = 1054) in the IRAS Family Study were categorized into different body size phenotypes. Computed tomography (CT) abdominal scans were evaluated for measures of nonalcoholic fatty liver disease (NAFLD) and abdominal fat distribution. Statistical models adjusting for familial relationships were estimated. Results: Seventy percent (70%) of the Hispanic cohort was overweight (32%) or obese (38%). Forty‐one percent (n = 138) of overweight participants and 19% (n = 74) of obese participants met criteria for MH. Adjusted analyses showed the MH phenotype was associated with lower visceral adipose tissue (VAT) and higher liver density (indicating lower fat content) in obese participants (p = 0.0005 and p = 0.0002, respectively), and lower VAT but not liver density in overweight participants (p = 0.008 and p = 0.162, respectively) compared to their MA counterparts. Odds of NAFLD were reduced in MH obese (OR = 0.34, p = 0.0007) compared to MA obese. VAT did not differ between MH obese or overweight and normal weight groups. Conclusions: These findings suggest that lower levels of visceral and liver fat, despite overall increased total body fat, may be a defining feature of MH obesity in Hispanic Americans.     

Acute changes in dietary omega-3 fatty acid intake lowers soluble interleukin-6 receptor in healthy adult normal weight and overweight males

OBJECTIVE: To determine the effect of a short-term isocaloric exchange of alpha-linolenic acid (ALA, 18:3n3) for linoleic acid (LA, 18:2n6) on fasting levels of soluble interleukin-6 receptor (sIL6R), and soluble tumor necrosis factor-alpha receptors 1 and 2 (sTNFR1 and sTNFR2) in healthy normal weight and overweight/obese adult males. DESIGN: Four-day clinical intervention study with 0.5% or 5% of total energy from ALA. Fasting (10 h) blood samples were obtained on the morning of day 5 in both diet treatments to measure sTNFR1, sTNFR2, and sIL6R. SUBJECTS: Nine normal weight (BMI < 25 kg/m2) and seven overweight (BMI > or = 25 kg/m2) healthy males. RESULTS: Fasting sIL6R decreased significantly from the control (C) diet following four days on the high ALA isocaloric (ISO) diet in normal weight and overweight/obese subjects (normal weight: C = 34.89 +/- 3.17 ng/ml, ISO = 30.91 +/- 2.24 ng/ml, p < 0.05; overweight/obese: C = 38.19 +/- 3.92 ng/ml, ISO = 33.57 +/- 2.47 ng/ml, p , 0.05). The dietary intervention did not have a significant effect on fasting sTNFR1 or sTNFR2. CONCLUSIONS: The results suggest that an isocaloric exchange of ALA for LA can reduce fasting sIL6R concentration by approximately 11% after a four-day dietary intervention in both overweight/obese and normal weight subjects. The data also suggest that longer exposure to a similar diet may have the potential to reduce inflammatory burden and thus lower the risk of both cardiovascular disease as well as diabetes.     

Effect of oral CCK-1 agonist GI181771X on fasting and postprandial gastric functions in healthy volunteers

CCK influences satiation and gastric and gallbladder emptying. GI181771X is a novel oral CCK-1 agonist; its effects on gastric emptying of solids, accommodation, and postprandial symptoms are unclear. Effects of four dose levels of the oral CCK-1 agonist GI181771X and placebo on gastric functions and postprandial symptoms were compared in 61 healthy men and women in a randomized, gender-stratified, double-blind, double-dummy placebo-controlled, parallel group study. Effects of 0.1, 0.5, and 1.5 mg of oral solution and a 5.0-mg tablet of GI181771X on gastric emptying of solids by scintigraphy, gastric volume by (99m)Tc-single photon emission computed tomographic imaging, maximum tolerated volume of Ensure, and postprandial nausea, bloating, fullness, and pain were studied. On each of 3 study days, participants received their randomly assigned treatment. Adverse effects and safety were monitored. There were overall group effects of GI181771X on gastric emptying (P < 0.01) and fasting and postprandial volumes (P = 0.036 and 0.015, respectively). The 1.5-mg oral solution of GI181771X significantly delayed gastric emptying of solids (P < 0.01) and increased fasting (P = 0.035) gastric volumes without altering postprandial (P = 0.056) gastric volumes or postprandial symptoms relative to placebo. The effect of the 5.0-mg tablet on gastric emptying of solids did not reach significance (P = 0.052). Pharmacokinetic profiles showed the highest area under the curve over 4 h for the 1.5-mg solution and a similar area under the curve for the 0.5-mg solution and 5-mg tablet. Adverse effects were predominantly gastrointestinal and occurred in a minority of participants. GI181771X delays gastric emptying of solids and exhibits an acceptable safety profile in healthy participants. CCK-1 receptors can be modulated to increase fasting gastric volume.     

Obesity and Receipt of Clinical Preventive Services in Veterans

Although obese individuals utilize health care at higher rates than their normal weight counterparts, they may be less likely to receive certain preventive services. We conducted a retrospective cohort study of veterans with visits to 136 national Veterans Affairs (VA) outpatient clinics in the United States in the year 2000. The cohort included 1,699,219 patients: 94% men, 48% white, and 76% overweight or obese. Overweight and obese patients had higher adjusted odds of receiving each of the targeted clinical preventive services as recommended over 5 years compared with normal weight patients. The odds for receiving vaccinations increased linearly with BMI category: influenza (men: odds ratio (OR) = 1.13 for overweight to OR = 1.42 for obese class 3; women: OR = 1.15 for overweight to OR = 1.61 for obese class 3) and pneumococcus (men: OR = 1.02 for overweight to OR = 1.15 for obese class 3; women: OR = 1.08 for overweight to OR = 1.28 for obese class 3). The odds for receiving the cancer screening services typically peaked in the mild‐moderately obese categories. The highest OR for prostate cancer screening was in obese class 2 (OR = 1.29); for colorectal cancer, obese class 1 (men: OR = 1.15; women OR = 1.10); for breast cancer screening, obese class 2 (OR = 1.19); and for cervical cancer screening, obese class 2 (OR = 1.06). In a large national sample, obese patients received preventive services at higher, not lower, rates than their normal weight peers. This may be due to the VA health service coverage and performance directives, a more homogeneous patient demographic profile, and/or unmeasured factors related to service receipt.     

Is Obesity Associated With Anemia of Chronic Disease? A Population‐based Study

Obesity is characterized by chronic, low-grade, systemic inflammation, which, in turn, has been associated with anemia of chronic disease. We hypothesized that obesity may be associated with the features of anemia of chronic disease, including low hemoglobin concentration, low serum iron and transferrin saturation (TS), and elevated serum ferritin. We compared normal-weight to overweight and obese adult participants of the third National Health and Nutrition Examination Survey with respect to hemoglobin concentration and levels of serum iron, TS, and ferritin. Measured BMI was used to categorize participants into normal weight (BMI < 25 kg/m(2), n = 6,059), overweight (BMI 25 to <30 kg/m(2), n = 5,108), mildly obese (BMI 30 to <35 kg/m(2), n = 2,366), moderately obese (BMI 35 to <40 kg/m(2), n = 850), and severely obese (BMI > or = 40 kg/m(2), n = 465). After adjustment for age, gender, menstruation, race/ethnicity, education, alcohol consumption, smoking, blood donation, and dietary iron intake, serum ferritin was progressively higher with increasing BMI category, whereas serum iron and TS were progressively lower. However, compared to normal-weight persons, those in all other higher BMI categories did not have a significant change in hemoglobin concentration after adjustment for the above-mentioned confounders. Overweight and obesity were associated with changes in serum iron, TS, and ferritin that would be expected to occur in the setting of chronic, systemic inflammation. However, overweight and obese persons were not more likely to be anemic compared with normal-weight persons.     

A Dietary Supplement Containing Cinnamon,Chromium and Carnosine Decreases Fasting Plasma Glucose and Increases Lean Mass in Overweight or Obese Pre-Diabetic Subjects: A Randomized,Placebo-Controlled Trial

Background

Preventing or slowing the progression of prediabetes to diabetes is a major therapeutic issue.

Objectives

Our aim was to evaluate the effects of 4-month treatment with a dietary supplement containing cinnamon, chromium and carnosine in moderately obese or overweight pre-diabetic subjects, the primary outcome being change in fasting plasma glucose (FPG) level. Other parameters of plasma glucose homeostasis, lipid profile, adiposity and inflammatory markers were also assessed.

Methods

In a randomized, double-blind, placebo-controlled study, 62 subjects with a FPG level ranging from 5.55 to 7 mmol/L and a body mass index ≥25 kg/m², unwilling to change their dietary and physical activity habits, were allocated to receive a 4-month treatment with either 1.2 g/day of the dietary supplement or placebo. Patients were followed up until 6 months post-randomization.

Results

Four-month treatment with the dietary supplement decreased FPG compared to placebo (-0.24±0.50 vs +0.12±0.59 mmol/L, respectively, p = 0.02), without detectable significant changes in HbA1c. Insulin sensitivity markers, plasma insulin, plasma lipids and inflammatory markers did not differ between the treatment groups. Although there were no significant differences in changes in body weight and energy or macronutrient intakes between the two groups, fat-free mass (%) increased with the dietary supplement compared to placebo (p = 0.02). Subjects with a higher FPG level and a milder inflammatory state at baseline benefited most from the dietary supplement.

Conclusions

Four-month treatment with a dietary supplement containing cinnamon, chromium and carnosine decreased FPG and increased fat-free mass in overweight or obese pre-diabetic subjects. These beneficial effects might open up new avenues in the prevention of diabetes.

Trial Registration

ClinicalTrials.gov NCT01530685     

A randomized,phase 3 trial of naltrexone SR/bupropion SR on weight and obesity‐related risk factors (COR‐II)

Objective:

To examine the effects of naltrexone/bupropion (NB) combination therapy on weight and weight‐related risk factors in overweight and obese participants.

Design and Methods:

CONTRAVE Obesity Research‐II (COR‐II) was a double‐blind, placebo‐controlled study of 1,496 obese (BMI 30‐45 kg/m²) or overweight (27‐45 kg/m² with dyslipidemia and/or hypertension) participants randomized 2:1 to combined naltrexone sustained‐release (SR) (32 mg/day) plus bupropion SR (360 mg/day) (NB32) or placebo for up to 56 weeks. The co‐primary endpoints were percent weight change and proportion achieving ≥5% weight loss at week 28.

Results:

Significantly (P < 0.001) greater weight loss was observed with NB32 versus placebo at week 28 (?6.5% vs. ?1.9%) and week 56 (?6.4% vs. ?1.2%). More NB32‐treated participants (P < 0.001) experienced ≥5% weight loss versus placebo at week 28 (55.6% vs. 17.5%) and week 56 (50.5% vs. 17.1%). NB32 produced greater improvements in various cardiometabolic risk markers, participant‐reported weight‐related quality of life, and control of eating. The most common adverse event with NB was nausea, which was generally mild to moderate and transient. NB was not associated with increased events of depression or suicidality versus placebo.

Conclusion:

NB represents a novel pharmacological approach to the treatment of obesity, and may become a valuable new therapeutic option.