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Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation.
Lingvay, I, Sumithran, P, Cohen, RV, le Roux, CW
Lancet (London, England). 2022;(10322):394-405
Abstract
Obesity is now recognised as a disease that is associated with serious morbidity and increased mortality. One of its main metabolic complications is type 2 diabetes, as the two conditions share key pathophysiological mechanisms. Weight loss is known to reverse the underlying metabolic abnormalities of type 2 diabetes and, as such, improve glucose control; loss of 15% or more of bodyweight can have a disease-modifying effect in people with type 2 diabetes, an outcome that is not attainable by any other glucose-lowering intervention. Furthermore, weight loss in this population exerts benefits that extend beyond glycaemic control to improve risk factors for cardiometabolic disease and quality of life. We review the evidence supporting the role of weight loss in the management of type 2 diabetes and propose that many patients with type 2 diabetes would benefit from having a primary weight-centric approach to diabetes treatment. We discuss the logistical challenges to implementing a new weight-centric primary treatment goal in people with type 2 diabetes.
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Evaluation of novel nutraceuticals based on the combination of oat beta-glucans and a green coffee phenolic extract to combat obesity and its comorbidities. A randomized, dose-response, parallel trial.
Mateos, R, García-Cordero, J, Bravo-Clemente, L, Sarriá, B
Food & function. 2022;(2):574-586
Abstract
Obesity and its associated comorbidities are a major public health concern worldwide. Reduced energy intake and increased physical activity interventions have limited success in the long term. Nutraceuticals might be an alternative means to help lose weight and reduce obesity-associated cardiometabolic risk factors without changes in the habitual diet. The objective of the present study was to comparatively evaluate the efficiency of nutraceuticals based on the combination of a decaffeinated green coffee bean extract (GCBE) and two types of oat beta-glucans (BG) with different physiochemical properties on obesity related biomarkers in overweight/obese subjects. A randomized, dose-response, parallel, blind study was carried out in four groups of subjects (n = 15 each) who consumed for 6 weeks, twice a day, a nutraceutical containing 3 g d-1 or 5 g d-1 doses of 35% or 70% BG and a fixed amount of GCBE providing 600 mg d-1 of phenols. 35% BG showed a 10 and 100 times higher molecular weight and viscosity, respectively, compared to 70% BG. Food intake, anthropometry and different cardiometabolic markers were assessed at the beginning and end of the intervention. According to the general model of variance with repeated measure analysis, the intervention caused positive changes in the levels of total cholesterol, LDL cholesterol, VLDL cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, haemoglobin A1c, insulin, systolic blood pressure (SBP), total body fat percentage (TBF%), visceral fat percentage, and waist and hip circumferences without differences among the treatments, except for SBP and TBF%. Looking into the rates of change [(end value - beginning value)/beginning value] of these parameters, 5 g - 70% BG was the treatment that lowered TBF% the most. In conclusion, 5 g - 70% BG may be more effective in helping to lose weight and additionally, it produced the least bloating according to participants' subjective perception.
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Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations.
Zhu, H, Bi, D, Zhang, Y, Kong, C, Du, J, Wu, X, Wei, Q, Qin, H
Signal transduction and targeted therapy. 2022;(1):11
Abstract
The ketogenic diet (KD) is a high-fat, adequate-protein, and very-low-carbohydrate diet regimen that mimics the metabolism of the fasting state to induce the production of ketone bodies. The KD has long been established as a remarkably successful dietary approach for the treatment of intractable epilepsy and has increasingly garnered research attention rapidly in the past decade, subject to emerging evidence of the promising therapeutic potential of the KD for various diseases, besides epilepsy, from obesity to malignancies. In this review, we summarize the experimental and/or clinical evidence of the efficacy and safety of the KD in different diseases, and discuss the possible mechanisms of action based on recent advances in understanding the influence of the KD at the cellular and molecular levels. We emphasize that the KD may function through multiple mechanisms, which remain to be further elucidated. The challenges and future directions for the clinical implementation of the KD in the treatment of a spectrum of diseases have been discussed. We suggest that, with encouraging evidence of therapeutic effects and increasing insights into the mechanisms of action, randomized controlled trials should be conducted to elucidate a foundation for the clinical use of the KD.
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Duodenal-Jejunal Bypass Liner for the management of Type 2 Diabetes Mellitus and Obesity: A Multicenter Randomized Controlled Trial.
Ruban, A, Miras, AD, Glaysher, MA, Goldstone, AP, Prechtl, CG, Johnson, N, Chhina, N, Al-Najim, W, Aldhwayan, M, Klimowska-Nassar, N, et al
Annals of surgery. 2022;(3):440-447
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Abstract
OBJECTIVE The aim of this study was to examine the clinical efficacy and safety of the duodenal-jejunal bypass liner (DJBL) while in situ for 12 months and for 12 months after explantation. SUMMARY BACKGROUND DATA This is the largest randomized controlled trial (RCT) of the DJBL, a medical device used for the treatment of people with type 2 diabetes mellitus (T2DM) and obesity. Endoscopic interventions have been developed as potential alternatives to those not eligible or fearful of the risks of metabolic surgery. METHODS In this multicenter open-label RCT, 170 adults with inadequately controlled T2DM and obesity were randomized to intensive medical care with or without the DJBL. Primary outcome was the percentage of participants achieving a glycated hemoglobin reduction of ≥20% at 12 months. Secondary outcomes included weight loss and cardiometabolic risk factors at 12 and 24 months. RESULTS There were no significant differences in the percentage of patients achieving the primary outcome between both groups at 12 months [DJBL 54.6% (n = 30) vs control 55.2% (n = 32); odds ratio (OR) 0.93, 95% confidence interval (CI): 0.44-2.0; P = 0.85]. Twenty-four percent (n = 16) patients achieved ≥15% weight loss in the DJBL group compared to 4% (n = 2) in the controls at 12 months (OR 8.3, 95% CI: 1.8-39; P = .007). The DJBL group experienced superior reductions in systolic blood pressure, serum cholesterol, and alanine transaminase at 12 months. There were more adverse events in the DJBL group. CONCLUSIONS The addition of the DJBL to intensive medical care was associated with superior weight loss, improvements in cardiometabolic risk factors, and fatty liver disease markers, but not glycemia, only while the device was in situ. The benefits of the devices need to be balanced against the higher rate of adverse events when making clinical decisions. TRIAL REGISTRATION ISRCTN30845205. isrctn.org; Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership reference 12/10/04.
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Effect of a Multicomponent mHealth Intervention on the Composition of Diet in a Population with Overweight and Obesity-Randomized Clinical Trial EVIDENT 3.
Lugones-Sánchez, C, Recio-Rodríguez, JI, Menéndez-Suárez, M, Saz-Lara, A, Ramirez-Manent, JI, Sánchez-Calavera, MA, Gómez-Sánchez, L, Rodríguez-Sánchez, E, García-Ortiz, L, Evident Investigators Group,
Nutrients. 2022;(2)
Abstract
A balanced diet can help in the prevention of chronic diseases. The aim of this study was to evaluate the effect of an mHealth intervention on the distribution of macronutrients and the intake of food groups. A total of 650 participants were included in this multi-center, clinical, randomized, controlled trial (Evident 3 study). All participants were given brief advice about diet and exercise. The intervention group received, in addition, an app (Evident 3) for the self-recording of their diet and an activity tracker wristband for 3 months. Follow-up visits were performed at 3 and 12 months to collect the diet composition using the Food Frequency Questionnaire. There were decreases in the intake of total calories, fat, protein and carbohydrates in both groups throughout the study, without significant differences between them. The intervention group reduced the intake of cholesterol (-30.8; 95% CI -59.9, -1.7) and full-fat dairies (-23.3; 95% CI -42.8, -3.8) and increased the intake of wholemeal bread (3.3; 95% CI -6.7, 13.3) and whole-grain cereals (3.4; 95% CI -6.8, 13.7) with respect to the control group. No differences were found in the rest of the nutritional parameters. The brief advice is useful to promote a healthier diet, and the app can be a support tool to obtain changes in relevant foods, such as integral foods, and the intake of cholesterol. Trial registration: ClinicalTrials.gov with identifier NCT03175614.
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Cardiovascular risk reduction throughout GLP-1 receptor agonist and SGLT2 inhibitor modulation of epicardial fat.
Iacobellis, G, Baroni, MG
Journal of endocrinological investigation. 2022;(3):489-495
Abstract
Epicardial adipose tissue is a novel cardiovascular risk factor. It plays a role in the progression of coronary artery disease, heart failure and atrial fibrillation. Given its rapid metabolism, clinical measurability, and modifiability, epicardial fat works well as therapeutic target of drugs modulating the adipose tissue. Epicardial fat responds to glucagon-like peptide 1 receptor agonists (GLP1A) and sodium glucose co-transporter 2 inhibitors (SGLT2i). GLP-1A and SGLT2i provide weight loss and cardiovascular protective effects beyond diabetes control, as recently demonstrated. The potential of modulating the epicardial fat morphology and genetic profile with targeted pharmacological agents can open new avenues in the pharmacotherapy of diabetes and obesity, with particular focus on cardiovascular risk reduction.
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TRIB3 Is Highly Expressed in the Adipose Tissue of Obese Patients and Is Associated With Insulin Resistance.
Lee, SK, Park, CY, Kim, J, Kim, D, Choe, H, Kim, JH, Hong, JP, Lee, YJ, Heo, Y, Park, HS, et al
The Journal of clinical endocrinology and metabolism. 2022;(3):e1057-e1073
Abstract
CONTEXT The upregulation of TRIB3 (Tribbles homolog 3), a stress-inducible gene encoding a pseudokinase, has been implicated in the development of insulin resistance in the skeletal muscle and liver of patients with obesity and type 2 diabetes. However, there is little information regarding TRIB3 expression in human adipose tissue. OBJECTIVE To investigate whether TRIB3 expression is dysregulated in human adipose tissue in the context of obesity and type 2 diabetes and whether TRIB3 expression in adipose tissues is associated with insulin resistance. METHODS We measured metabolic parameters and TRIB3 expression in abdominal subcutaneous and visceral adipose tissue in obese (with or without type 2 diabetes) and normal-weight women. Regulation of TRIB3 expression was studied in human adipocytes. RESULTS TRIB3 expression in both fat depots was higher in patients with obesity and/or type 2 diabetes; in addition, the expression level was significantly associated with insulin resistance. Incubating adipocytes under conditions mimicking the microenvironment of obese adipose tissue, including increased endoplasmic reticulum (ER) stress, induced TRIB3 expression. In human adipocytes, the overexpression of TRIB3 impaired insulin-stimulated protein kinase B (AKT) phosphorylation and caused dysregulation of the transcription of genes encoding bioactive molecules released from adipocytes, such as proinflammatory cytokines, adiponectin, and leptin. Pioglitazone, an insulin-sensitizing agent, reduced both these effects of TRIB3 and the ER stressor-induced expression of TRB3. CONCLUSION Our data indicate that TRIB3 expression in adipose tissue is enhanced in patients with obesity and suggest that increased TRIB3 dysregulates adipocyte function, which may contribute to the development of insulin resistance.
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Whole Grain Consumption and Inflammatory Markers: A Systematic Literature Review of Randomized Control Trials.
Milesi, G, Rangan, A, Grafenauer, S
Nutrients. 2022;(2)
Abstract
Whole grain foods are rich in nutrients, dietary fibre, a range of antioxidants, and phytochemicals, and may have potential to act in an anti-inflammatory manner, which could help impact chronic disease risk. This systematic literature review aimed to examine the specific effects of whole grains on selected inflammatory markers from human clinical trials in adults. As per the Preferred Reporting Items for Systematic Reviews (PRISMA) protocol, the online databases MEDLINE, Embase, Cochrane, CINAHL, and Scopus were searched from inception through to 31 August 2021. Randomized control trials (RCTs) ≥ 4 weeks in duration, reporting ≥1 of the following: C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor (TNF), were included. A total of 31 RCTs were included, of which 16 studies recruited overweight/obese individuals, 12 had pre-existing conditions, two were in a healthy population, and one study included participants with prostate cancer. Of these 31 RCTs, three included studies with two intervention arms. A total of 32 individual studies measured CRP (10/32 were significant), 18 individual studies measured IL-6 (2/18 were significant), and 13 individual studies measured TNF (5/13 were significant). Most often, the overweight/obese population and those with pre-existing conditions showed significant reductions in inflammatory markers, mainly CRP (34% of studies). Overall, consumption of whole grain foods had a significant effect in reducing at least one inflammatory marker as demonstrated in 12/31 RCTs.
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Early-life body mass index and risks of breast, endometrial, and ovarian cancers: a dose-response meta-analysis of prospective studies.
Byun, D, Hong, S, Ryu, S, Nam, Y, Jang, H, Cho, Y, Keum, N, Oh, H
British journal of cancer. 2022;(4):664-672
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Abstract
BACKGROUND The evidence for the associations between early-life adiposity and female cancer risks is mixed. Little is known about the exact shape of the relationships and whether the associations are independent of adult adiposity. METHODS We conducted dose-response meta-analyses of prospective studies to summarise the relationships of early-life body mass index (BMI) with breast, endometrial, and ovarian cancer risks. Pubmed and Embase were searched through June 2020 to identify relevant studies. Using random-effects models, the summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated per 5-kg/m2 increase in BMI at ages ≤ 25 years. A nonlinear dose-response meta-analysis was conducted using restricted cubic spline analysis. RESULTS After screening 33,948 publications, 37 prospective studies were included in this analysis. The summary RRs associated with every 5-kg/m2 increase in early-life BMI were 0.84 (95% CI = 0.81-0.87) for breast, 1.40 (95% CI = 1.25-1.57) for endometrial, and 1.15 (95% CI = 1.07-1.23) for ovarian cancers. For breast cancer, the association remained statistically significant after adjustment for adult BMI (RR = 0.80, 95% CI = 0.73-0.87). For premenopausal breast, endometrial, and ovarian cancers, the dose-response curves suggested evidence of nonlinearity. CONCLUSIONS With early-life adiposity, our data support an inverse association with breast cancer and positive associations with ovarian and endometrial cancer risks.
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LLF580, an FGF21 Analog, Reduces Triglycerides and Hepatic Fat in Obese Adults With Modest Hypertriglyceridemia.
Rader, DJ, Maratos-Flier, E, Nguyen, A, Hom, D, Ferriere, M, Li, Y, Kompa, J, Martic, M, Hinder, M, Basson, CT, et al
The Journal of clinical endocrinology and metabolism. 2022;(1):e57-e70
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Abstract
PURPOSE To evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction. METHODS A multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every 4 weeks for 3 doses. RESULTS Of 64 randomized study participants, 61 (mean ± SD: age 45 ± 11 years, 49% male, 80/15/5% Caucasian/African American/other, body mass index 36.1 ± 3.8 kg/m2) received LLF580 (n = 30) or placebo (n = 31) at 7 research sites in the United States. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, low-density lipoprotein cholesterol 12%, and increased high-density lipoprotein cholesterol 36% compared with placebo (all P < 0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P < 0.001) was also demonstrated in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P < 0.05). Insulin and C-peptide levels and insulin resistance by homeostatic model assessment for insulin resistance were all lower, and adiponectin higher with LLF580 treatment compared with placebo, whereas fasting glucose and glycated hemoglobin were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects. CONCLUSIONS In obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat, and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and nonalcoholic fatty liver disease. Assessments of longer term safety and efficacy are warranted. CLINICALTRIALS.GOV IDENTIFIER NCT03466203.