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Aims: Oral treatment extended-release naltrexone/bupropion (NB) leads to significant weight loss, but its effect on body composition remains unclear. We investigated changes in body composition with dual-energy x-ray absorptiometry after treatment with NB or placebo in a subgroup of participants from a randomized control phase 3 study (COR-I)., Materials and Methods: Observed changes from baseline to week 52 were estimated for total, lean, and fat mass. Changes in body composition were evaluated using linear regression and adjusted for baseline covariates., Results: The analysis included 82 participants (placebo, n = 26; NB, n = 56) with comparable baseline characteristics (age, BMI, sex). The NB group experienced a significant -7.8% change of total mass (-12.9% change in fat mass and -4.1% in lean mass), compared with a -2.8% change of total mass (-4.8% change in fat mass and -1.4% in lean mass) in the placebo group. The adjusted changes in lean-to-fat mass ratio of 0.069 in the NB group and -0.056 in the placebo group were significantly different (p < 0.05)., Conclusions: NB-induced weight loss is associated with significant reductions in total percent fat mass, increase in total percent lean mass, and change in lean-to-fat mass ratio, in comparison to placebo. Larger studies are needed to further elucidate the clinical significance of these changes and impact of a potentially healthier metabolism., (© 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Recent randomized controlled trials (RCTs) have investigated glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual or triple co-agonists for weight loss among adults with overweight or obesity and without diabetes., Purpose: To assess the efficacy and safety of GLP-1 RAs and co-agonists for the treatment of obesity among adults without diabetes., Data Sources: MEDLINE, Embase, and Cochrane CENTRAL from inception to 4 October 2024., Study Selection: Placebo-controlled RCTs in otherwise healthy participants with overweight or obesity., Data Extraction: The primary outcome was change in relative or absolute body weight from baseline to maximum on-treatment follow-up. Safety outcomes included death, serious adverse events (SAEs), any adverse events (AEs), and gastrointestinal AEs., Data Synthesis: A total of 26 RCTs comprising 15 491 participants (72% female; mean body mass index, 30 to 41 kg/m 2 ; mean age, 34 to 57 years) and 12 agents (3 commercially available agents [liraglutide, semaglutide, and tirzepatide] and 9 premarket agents for long-term weight management) were included. Treatment ranged from 16 to 104 weeks (median, 43 weeks). Compared with placebo, tirzepatide (15 mg once weekly) resulted in weight loss of up to 17.8% (95% CI, 16.3% to 19.3%) after 72 weeks of therapy; semaglutide (2.4 mg once weekly), up to 13.9% (CI, 11.0% to 16.7%) after 68 weeks; and liraglutide (3.0 mg once daily), up to 5.8% (CI, 3.6% to 8.0%) after 26 weeks. Retatrutide (12 mg once weekly) produced greater weight loss of up to 22.1% (CI, 19.3% to 24.9%) after 48 weeks; other novel single and combination GLP-1 agents were also efficacious to varying degrees. Although AEs were frequent (GLP-1 RA vs. placebo: 80% to 97% vs. 63% to 100%), the majority were gastrointestinal-related (47% to 84% vs. 13% to 63%, respectively), most commonly nausea, vomiting, diarrhea, and constipation. AEs requiring treatment discontinuation (0% to 26% vs. 0% to 9%, respectively) and SAEs (0% to 10% vs. 0% to 12%, respectively) were rare., Limitations: No head-to-head RCTs were available. Heterogeneity prevented meta-analysis., Conclusion: GLP-1 RAs and co-agonists are efficacious for weight loss, with reported safety concerns predominantly gastrointestinal in nature, when used among adults with overweight or obesity and without diabetes., Primary Funding Source: None. (PROSPERO: CRD42024505558)., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have become central in managing obesity and type 2 diabetes, primarily through appetite suppression and metabolic regulation. This review explores the mechanisms underlying GLP-1 RA-induced weight loss, focusing on central and peripheral pathways. Centrally, GLP-1 RAs modulate brain regions controlling appetite, influencing neurotransmitter and peptide release to regulate hunger and energy expenditure. Peripherally, GLP-1 RAs improve glycemic control by enhancing insulin secretion, reducing glucagon release, delaying gastric emptying, and regulating gut hormones. They also reduce triglycerides and low-density lipoprotein cholesterol, mitigate adipose tissue inflammation, and minimize ectopic fat deposition, promoting overall metabolic health. Emerging dual and triple co-agonists, targeting GLP-1 alongside glucose-dependent insulinotropic polypeptide, and glucagon pathways, may enhance weight loss and metabolic flexibility. Understanding these mechanisms is crucial as the therapeutic landscape evolves, offering clinicians and researchers insights to optimize the efficacy of current and future obesity treatments., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Efforts to improve glycemic control in type 1 diabetes are ongoing. We performed a randomized, double-blind, crossover trial to assess semaglutide as adjunct to automated insulin delivery therapy in adults with type 1 diabetes. At each intervention, participants were titrated up to 1 mg or the maximum tolerated dose of semaglutide or placebo over 11 weeks, followed by the use of an automated insulin delivery system for 4 weeks. The primary outcome was the percentage of time spent in the target glucose range of 3.9-10.0 mmol l -1 during the last 4 weeks of each intervention. Twenty-eight participants were randomized and 24 completed the trial. The primary endpoint was met. Compared to placebo, semaglutide increased time in the target range by a mean 4.8 (s.d. = 7.6) percentage points (P = 0.006), without increasing the time spent below 3.9 mmol l -1 (P = 0.19) or below 3.0 mmol l -1 (P = 0.65). While no diabetic ketoacidosis or severe hypoglycemia occurred during any of the interventions, there were two episodes of recurrent euglycemic ketosis without acidosis during semaglutide use. We conclude that semaglutide improves glycemic control with automated insulin delivery compared to placebo. ClinicalTrials.gov registration: NCT05205928., Competing Interests: Competing interests: M.-R.P. has received speaker honoraria from Medtronic Diabetes Canada and Abbott Diabetes Care. M.A.T. has received speaker honoraria from AstraZeneca, Bausch Health, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk and Sanofi. A.H. has acted as a consultant for Eli Lilly and has received drugs, supplies, equipment and other in-kind support from Tandem, Adocia, Dexcom, Eli Lilly and Ypsomed. A.K., W.A. and A.J. declare no competing interests., (© 2025. The Author(s).)

Aim: To identify unique clinical phenotypes in type 2 diabetes (T2D) and investigate their treatment response to canagliflozin using latent class analysis., Methods: This was a pooled latent class analysis of the individuals in the CANVAS Program and CREDENCE trial. The co-primary endpoints were hospitalization for heart failure (HHF) and the composite of cardiovascular death (CVD) or HHF. Secondary endpoints included three-point major adverse CV events, its individual components, and all-cause mortality. We completed Cox proportional hazards models to evaluate the effect of canagliflozin across phenotypes., Results: Four distinct phenotypes were identified: Phenotype 1 (n = 966, 6.6%), with the lowest prevalence of heart failure, kidney dysfunction and hypertension; Phenotype 2 (n = 4169, 28.7%), primarily comprising females with a high prevalence of atherosclerotic vascular disease (ASCVD); Phenotype 3 (n = 7108, 48.9%), predominately males with a high prevalence of ASCVD; and Phenotype 4 (n = 2300, 15.8%), possessing the highest prevalences of HF and renal dysfunction. A hierarchical increase in the risk of the primary endpoint was observed across the phenotypes, with the highest CV risk observed for Phenotype 4 (hazard ratio for HHF: 7.57 [95% CI: 4.19-13.69]). Canagliflozin significantly reduced HHF and the composite CVD or HHF across phenotypes (all P values for interaction > .05)., Conclusion: We identified four clinically distinct T2D phenotypes with differential CV risks. Canagliflozin reduced the risk of CV events, irrespective of the phenotype, emphasizing its broad therapeutic acceptability., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

In type 1 diabetes, high-fat meals require more insulin to prevent hyperglycemia while meals followed by aerobic exercises require less insulin to prevent hypoglycemia, but the adjustments needed vary between individuals. We propose a decision support system with reinforcement learning to personalize insulin doses for high-fat meals and postprandial aerobic exercises. We test this system in a single-arm 16-week study in 15 adults on multiple daily injections therapy (NCT05041621). The primary objective of this study is to assess the feasibility of the novel learning algorithm. This study looks at glucose outcomes and patient reported outcomes. The postprandial incremental area under the glucose curve is improved from the baseline to the evaluation period for high-fat meals (378 ± 222 vs 38 ± 223 mmol/L/min, p = 0.03) and meals followed by exercises (-395 ± 192 vs 132 ± 181 mmol/L/min, p = 0.007). The postprandial time spent below 3.9 mmol/L is reduced after high-fat meals (5.3 ± 1.6 vs 1.8 ± 1.5%, p = 0.003) and meals followed by exercises (5.3 ± 1.2 vs 1.4 ± 1.1%, p = 0.003). Our study shows the feasibility of automatically personalizing insulin doses for high-fat meals and postprandial exercises. Randomized controlled trials are warranted., (© 2024. The Author(s).)

Aim: The management of patients with type 2 diabetes is asynchronous, i.e. not coordinated in time, resulting in delayed access to care and low use of guideline-directed medical therapy (GDMT)., Methods: We retrospectively analysed consecutive patients assessed in the 'synchronized' DECIDE-CV clinic. In this outpatient clinic, patients with type 2 diabetes and cardiovascular or chronic kidney disease are simultaneously assessed by an endocrinologist, cardiologist and nephrologist in the same visit. The primary outcome was use of GDMT before and after the assessment in the clinic, including sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, renin-angiotensin system blockers and mineralocorticoid receptor antagonists. Secondary outcomes included the baseline-to-last-visit change in surrogate laboratory biomarkers., Results: The first 232 patients evaluated in the clinic were included. The mean age was 67 ± 12 years, 69% were men and 92% had diabetes. In total, 73% of patients had atherosclerotic cardiovascular disease, 65% heart failure, 56% chronic kidney disease and 59% had a urinary albumin-to-creatinine ratio ≥30 mg/g. There was a significant increase in the use of GDMT:sodium-glucose cotransporter 2 inhibitors (from 44% to 87% of patients), glucagon-like peptide 1 receptor agonists (from 8% to 45%), renin-angiotensin system blockers (from 77% to 91%) and mineralocorticoid receptor antagonists (from 25% to 45%) (p < .01 for all). Among patients with paired laboratory data, glycated haemoglobin, urinary albumin-to-creatinine ratio and N-terminal proB-type natriuretic peptide levels significantly dropped from baseline (p < .05 for all)., Conclusions: Joint assessment of patients with diabetes in a synchronized cardiometabolic clinic holds promise for enhancing GDMT use and has led to significant reductions in surrogate cardiovascular and renal laboratory biomarkers., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: We aimed to examine the effect of age of obesity onset, sex, and their interaction on abdominal and femoral subcutaneous adipose tissue (SAT) morphology (degree of adipocyte hyperplasia or hypertrophy)., Methods: In this cross-sectional study, we isolated adipocytes via collagenase digestion from abdominal and femoral SAT biopsies taken from male and female adults with childhood-onset obesity (CO; n = 8 males, n = 16 females) or adult-onset obesity (AO; n = 8 males, n = 13 females). Regional body composition was measured with dual-energy x-ray absorptiometry and a single-slice abdominal computed tomography scan. Mean adipocyte size was measured in abdominal and femoral SAT and was used to quantify morphology in android and gynoid subcutaneous fat, respectively., Results: Abdominal SAT morphology was more hyperplastic in females with CO than females with AO (p = 0.004) but did not differ between males with CO and males with AO (p = 0.996). Conversely, femoral SAT morphology was more hypertrophic in males and females with CO than those with AO., Conclusions: Age of obesity onset appears to affect SAT morphology differently in the abdominal and femoral regions of male and female adults. Our findings challenge the notion that SAT is uniformly hyperplastic in CO and hypertrophic in AO., (© 2024 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Background: In type 1 diabetes, carbohydrate counting is the standard of care to determine prandial insulin needs, but it can negatively affect quality of life. We developed a novel insulin-and-pramlintide closed-loop system that replaces carbohydrate counting with simple meal announcements., Methods: We performed a randomised crossover trial assessing 14 days of (1) insulin-and-pramlintide closed-loop system with simple meal announcements, (2) insulin-and-placebo closed-loop system with carbohydrate counting, and (3) insulin-and-placebo closed-loop system with simple meal announcements. Participants were recruited at McGill University Health Centre (Montreal, QC, Canada). Eligible participants were adults (aged ≥18 years) and adolescents (aged 12-17 years) with type 1 diabetes for at least 1 year. Participants were randomly assigned in a 1:1:1:1:1:1 ratio to a sequence of the three interventions, with faster insulin aspart used in all interventions. Each intervention was separated by a 14-45-day wash-out period, during which participants reverted to their usual insulin. During simple meal announcement interventions, participants triggered a prandial bolus at mealtimes based on a programmed fixed meal size, whereas during carbohydrate counting interventions, participants manually entered the carbohydrate content of the meal and an algorithm calculated the prandial bolus based on insulin-to-carbohydrate ratio. Two primary comparisons were predefined: the percentage of time in range (glucose 3·9-10·0 mmol/L) with a non-inferiority margin of 6·25% (non-inferiority comparison); and the mean Emotional Burden subscale score of the Diabetes Distress Scale (superiority comparison), comparing the insulin-and-placebo system with carbohydrate counting minus the insulin-and-pramlintide system with simple meal announcements. Analyses were performed on a modified intention-to-treat basis, excluding participants who did not complete all interventions. Serious adverse events were assessed in all participants. This trial is registered on ClinicalTrials.gov, NCT04163874., Findings: 32 participants were enrolled between Feb 14, 2020, and Oct 5, 2021; two participants withdrew before study completion. 30 participants were analysed, including 15 adults (nine female, mean age 39·4 years [SD 13·8]) and 15 adolescents (eight female, mean age 15·7 years [1·3]). Non-inferiority of the insulin-and-pramlintide system with simple meal announcements relative to the insulin-and-placebo system with carbohydrate counting was reached (difference -5% [95% CI -9·0 to -0·7], non-inferiority p<0·0001). No statistically significant difference was found in the mean Emotional Burden score between the insulin-and-pramlintide system with simple meal announcements and the insulin-and-placebo system with carbohydrate counting (difference 0·01 [SD 0·82], p=0·93). With the insulin-and-pramlintide system with simple meal announcements, 14 (47%) participants reported mild gastrointestinal symptoms and two (7%) reported moderate symptoms, compared with two (7%) participants reporting mild gastrointestinal symptoms on the insulin-and-placebo system with carbohydrate counting. No serious adverse events occurred., Interpretation: The insulin-and-pramlintide system with simple meal announcements alleviated carbohydrate counting without degrading glucose control, although quality of life as measured by the Emotional Burden score was not improved. Longer and larger studies with this novel approach are warranted., Funding: Juvenile Diabetes Research Foundation., Competing Interests: Declaration of interests MAT received speaker honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi. LL received research support from AstraZeneca and Merck; consultant fees from Abbott, Dexcom, Insulet, and Novo Nordisk; payment or honoraria and support for attending meetings or travel from Novo Nordisk; and participated on a data safety monitoring board and advisory board for the National Institutes of Health artificial pancreas programme. MV received research support from Abbott, Bausch Health, and Novo Nordisk; consultant fees from AbbVie, Abbott, Bausch Health, Boehringer Ingelheim, Lifescan, Lyceum, Novo Nordisk, Roche, and Sanofi; and speaker honoraria from Abbott, AbbVie, Bausch Health, Lifescan, Lilly, Merck, Novo Nordisk, Pfizer, Roche, and Sanofi. J-FY received research support from Bayer, Novo Nordisk, Novartis, and Sanofi; consultant fees from Abbott, Bayer, Boehringer Ingelheim, Dexcom, Eli Lilly, Janssen, Merck, Mylan, Novo Nordisk, and Sanofi; and speaker honoraria from Novo Nordisk and Eli Lilly. NG-P is employed by Tandem Diabetes Care. AH received research support from Adocia, Dexcom, Eli Lilly, and Tandem Diabetes Care; equipment, materials, drugs, medical writing, gifts, or other services from Dexcom, Ypsomed, and Tandem Diabetes Care; consulting fees from Eli Lilly; and intellectual property acquisition fees from Eli Lilly and Bigfoot. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Very few patient-reported outcomes have been published in regard to opinions of individuals with type 1 diabetes concerning adjunctive therapy. The aim of this subanalysis was to qualitatively and quantitatively assess the thoughts and experiences of participants with type 1 diabetes who have used low doses of empagliflozin as an adjunct to hybrid closed-loop therapy., Methods: Semi-structured interviews were performed with adult participants who completed a double-blinded, crossover, randomized controlled trial using low-dose empagliflozin as an adjunct to hybrid closed-loop therapy. Participant experiences were captured through qualitative and quantitative methods. A descriptive analysis was performed using a qualitative approach; attitudes toward relevant topics were extracted from interview transcripts., Results: Twenty-four participants were interviewed; 15 (63%) perceived differences between interventions despite blinding, due to glycemic control or side effects. Advantages that arose were better glycemic control, in particular postprandially, requiring less insulin, and ease of use. Disadvantages were thought to be adverse effects, increased incidence of hypoglycemia, and increased pill burden. Thirteen (54%) participants were interested in using low-dose empagliflozin beyond the study., Conclusions: Many participants had positive experiences with low-dose empagliflozin as an adjunct to the hybrid closed-loop therapy. A dedicated study with unblinding would be beneficial to better characterize patient-reported outcomes., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: A.H. received research support and material support from Eli Lilly, Dexcom, Tandem, Adocia, AgaMatrix, YpsoMed, and Medtronic; consulting fees from Eli Lilly; IP acquisition fees from Eli Lilly and YpsoMed; and has pending patents in the diabetes technology field. M.A.T. received research support from AgaMatrix and speaker honoraria from Eli Lilly, Novo Nordisk, Boehringher Ingelheim, Janssen, and AstraZeneca. No other authors have conflicts of interest.

The effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors on cardiovascular and renal outcomes has not been systematically reviewed across baseline kidney function groups. We conducted a systematic review and meta-analysis of randomized control trials (RCTs) with SGLT-2 inhibitors in patients with and without CKD. We performed a PubMed/Medline search of randomized, placebo-controlled, event-driven outcome trials of SGLT-2 inhibitors versus active or placebo control in patients with and without diabetes from inception to November 2022. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m 2 (PROSPERO registration CRD4202016054). The primary outcome was cardiovascular death. Secondary outcomes included hospitalization for heart failure, major adverse cardiovascular events, CKD progression, all-cause mortality, treatment discontinuation, and acute kidney injury (AKI). The relative risk (RR) was estimated using a random-effects model. Twelve RCTs were included in this meta-analysis (89,191 patients, including 38,949 with eGFR < 60 ml/min/1.73m 2 ). Use of an SGLT-2 inhibitor in patients with CKD was associated with a lower incidence of cardiovascular death (RR 0.87; 95% CI 0.79-0.95) and of heart failure (RR 0.67; 95% CI 0.61-0.75), compared with placebo. Heart failure risk reduction with SGLT-2 inhibitors was larger among patients with CKD compared with patients without CKD (RR for the interaction 0.87, 95% CI 0.75-1.02, and p-value for interaction 0.08). SGLT-2 inhibitors were associated with a lower incidence of CKD progression among patients with pre-existing CKD: RR 0.77 (95% CI 0.68-0.88), compared with placebo. Among patients with CKD, a lower risk of AKI (RR 0.82; 95% CI 0.72-0.93) and treatment discontinuation was seen with SGLT-2 inhibitors compared with placebo. SGLT-2 inhibitors offer substantial protection against cardiovascular and renal outcomes in patients with CKD. These results strongly advocate in favor of using them in patients with CKD and keeping them as kidney function declines., (© 2023. Springer Nature Limited.)

Objective: The aim of this study was to determine the effect of age of obesity onset on senescence-related markers in abdominal (AB) and femoral (FEM) subcutaneous adipose tissue (SAT) before and after moderate (~10%) weight loss., Methods: AB and FEM SAT were collected from human females with childhood-onset obesity (CO) or adult-onset obesity (AO) before and after diet- and exercise-induced weight loss. Immunofluorescence analysis of γH2AX/RAD51 (DNA damage/repair markers) and p53/p21 (senescence markers) was conducted in cultured preadipocytes, and senescence-associated β-galactosidase (SA-β-gal) activity was measured in SAT., Results: CO had proportionately more AB and FEM preadipocytes with DNA damage (γH2AX + ) and senescence markers (p53 + and/or p21 + ) than AO at baseline. The proportion of γH2AX + FEM preadipocytes declined with weight loss in CO and was similar between groups after weight loss. The number of γH2AX foci in γH2AX + preadipocytes decreased similarly between groups and regions with weight loss in parallel with an increase in RAD51. The proportion of p53 + and p21 + preadipocytes and SA-β-gal + cells in SAT did not change with weight loss, but the total p21 intensity in p53 + /p21 + FEM preadipocytes declined in AO., Conclusions: These results provide preliminary evidence that females with CO have an accelerated preadipocyte aging state that improves with weight loss in terms of DNA damage but not senescence., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Objectives: Although national diabetes guidelines recommend targets for various health parameters, studies have demonstrated a gap between recommendations and real-life practice. The objectives of the present study were to 1) assess measurements in type 2 diabetes (T2DM) care performed by diabetologists in tertiary care, 2) determine whether these measurements were within recommended targets by Canadian guidelines, and 3) identify how these measurements compare with previously published Canadian studies., Methods: A retrospective chart review analyzed electronic medical records of patients seen by diabetes specialists at the McGill University Health Centre (MUHC). Patients 18 to 75 years of age and diagnosed with T2DM were assessed for blood pressure <130/80 mmHg, low-density lipoprotein cholesterol (LDL-C) ≤2 mmol/L and glycated hemoglobin (A1C) ≤7%. Urinary albumin:creatinine ratio (uACR) was also assessed. Comparisons were made with existing literature data., Results: The percentages of patients with recent screening of A1C, LDL-C, blood pressure and uACR were higher compared with the earlier studies. The calculated means for A1C, LDL-C and blood pressure were comparable with those studies. The percentage of measurements achieving target was comparable with subspecialty care data but differed from primary care data., Conclusions: Patients with T2DM at the MUHC receive guideline-based measurements of health parameters more frequently than at other institutions. Achievement of target values was closer to that seen by Canadian specialists than by primary care. Although further analyses are necessary to help implement effective strategies for improvement, quality assurance is nonetheless an essential part of ensuring the standards of tertiary care., (Copyright © 2022 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Objective: To assess whether low doses of empagliflozin as adjunct to hybrid closed-loop therapy improve glycemia compared with placebo in adults with type 1 diabetes (T1D) who are not able to achieve targets with the system alone., Research Design and Methods: A double-blind crossover randomized controlled trial was performed in adults with suboptimally controlled T1D (HbA1c 7.0-10.5%) who were not able to achieve a target time in range (3.9-10.0 mmol/L) ≥70% after 14 days of hybrid closed-loop therapy. Three 14-day interventions were performed with placebo, 2.5 mg empagliflozin, or 5 mg empagliflozin as adjunct to the McGill artificial pancreas. Participants were assigned at a 1:1:1:1:1:1 ratio with blocked randomization. The primary outcome was time in range (3.9-10.0 mmol/L). Analysis was by intention to treat, and a P value <0.05 was regarded as significant., Results: A total of 24 participants completed the study (50% male; age 33 ± 14 years; HbA1c 8.1 ± 0.5%). The time in range was 59.0 ± 9.0% for placebo, 71.6 ± 9.7% for 2.5 mg empagliflozin, and 70.2 ± 8.0% for 5 mg empagliflozin (P < 0.0001 between 2.5 mg empagliflozin and placebo and between 5 mg empagliflozin and placebo). Mean daily capillary ketone levels were not different between arms. There were no serious adverse events or cases of diabetic ketoacidosis or severe hypoglycemia in any intervention., Conclusions: Empagliflozin at 2.5 and 5 mg increased time in range during hybrid closed-loop therapy by 11-13 percentage points compared with placebo in those who otherwise were unable to attain glycemic targets. Future studies are required to assess long-term efficacy and safety., (© 2022 by the American Diabetes Association.)

There is a need to optimize closed-loop automated insulin delivery in type 1 diabetes. We assessed the glycemic efficacy and safety of empagliflozin 25 mg d -1 as add-on therapy to insulin delivery with a closed-loop system. We performed a 2 × 2 factorial randomized, placebo-controlled, crossover two-center trial in adults, assessing 4 weeks of closed-loop delivery versus sensor-augmented pump (SAP) therapy and empagliflozin versus placebo. The primary outcome was time spent in the glucose target range (3.9-10.0 mmol l -1 ). Primary comparisons were empagliflozin versus placebo in each of closed-loop or SAP therapy; the remaining comparisons were conditional on its significance. Twenty-four of 27 randomized participants were included in the final analysis. Compared to placebo, empagliflozin improved time in target range with closed-loop therapy by 7.2% and in SAP therapy by 11.4%. Closed-loop therapy plus empagliflozin improved time in target range compared to SAP therapy plus empagliflozin by 6.1% but by 17.5% for the combination of closed-loop therapy and empagliflozin compared to SAP therapy plus placebo. While no diabetic ketoacidosis or severe hypoglycemia occurred during any intervention, uncomplicated ketosis events were more common on empagliflozin. Empagliflozin 25 mg d -1 added to automated insulin delivery improves glycemic control but increases ketone concentration and ketosis compared to placebo., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Exogenous insulin has been the mainstay treatment for individuals living with type 1 diabetes (T1D). Although there has been tremendous growth in both pharmacological and technological advancements, insulin monotherapy has proven to be insufficient for maintaining optimal glycaemic targets for most adults with T1D. At present, there is still no breakthrough for the treatment of T1D. Adjunctive pharmacotherapies might therefore complement insulin management to achieve better glycaemic control, while possibly offering additional benefits. Recent interest in re-purposing glucagon-like peptide-1 receptor agonists (GLP-1RAs), a leading antihyperglycaemic medication class approved for type 2 diabetes, has prompted the field to seek extended potential for the T1D population. The adjunctive use of GLP-1RAs has been at the forefront of T1D research, albeit with some conflicting trial findings to date. However, the potential of GLP-1 agonism for T1D may have been underestimated, possibly from missed opportunities or categorized effects. Moreover, some GLP-1RAs have demonstrated extra-pancreatic potential with emerging multi-organ protection involving the heart, kidneys, liver and brain in varied cohorts, which may bode well for the growing T1D profile of comorbid complications. This narrative review aims to summarize and critically appraise the current evidence-based literature from large-scale randomized controlled trials and closed-loop system pilot studies that examined GLP-1RAs as adjunctive therapy for T1D. Furthermore, we outline uncharted opportunities with GLP-1 agonism using versatile approaches in selected T1D populations that may inspire and re-direct future research in this field., (© 2022 John Wiley & Sons Ltd.)

Fatty acid desaturase 1 ( FADS1 ) polymorphisms alter fatty acid content in subcutaneous adipose tissue (SAT); however, existing evidence is limited and conflicting regarding the association between FADS1 variants and SAT inflammatory status. To advance this area, we conducted an exploratory study to investigate whether the common rs174537 polymorphism in FADS1 was associated with immune cell profiles in abdominal and femoral SAT in individuals with obesity. FADS1 gene expression and immune cell profiles in SAT depots were assessed by qPCR and flow cytometry, respectively. Although FADS1 gene expression was associated with genotype, no associations were observed with immune cell profiles in either depot. Our study provides additional evidence that rs174537 in FADS1 has minimal impact on inflammatory status in obese SAT.

Objectives: A fully automated insulin-pramlintide-glucagon artificial pancreas that alleviates the burden of carbohydrate counting without degrading glycemic control was iteratively enhanced until convergence through pilot experiments on adults with type 1 diabetes., Methods: Nine participants (age, 37±13 years; glycated hemoglobin, 7.7±0.7%) completed two 27-hour interventions: a fully automated multihormone artificial pancreas and a comparator insulin-alone artificial pancreas with carbohydrate counting. The baseline algorithm was a model-predictive controller that administered insulin and pramlintide in a fixed ratio, with boluses triggered by a glucose threshold, and administered glucagon in response to low glucose levels., Results: The baseline multihormone dosing algorithm resulted in noninferior time in target range (3.9 to 10.0 mmol/L) (71%) compared with the insulin-alone arm (70%) in 2 participants, with minimal glucagon delivery. The algorithm was modified to deliver insulin and pramlintide more aggressively to increase time in range and maximize the benefits of glucagon. The modified algorithm displayed a similar time in range for the multihormone arm (79%) compared with the insulin-alone arm (83%) in 2 participants, but with undesired glycemic fluctuations. Subsequently, we reduced the glucose threshold that triggers glucagon boluses. This resulted in inferior glycemic control for the multihormone arm (81% vs 91%) in 2 participants. Thereafter, a model-based meal-detection algorithm to deliver insulin and pramlintide boluses closer to mealtimes was added and glucagon was removed. The final dual-hormone system had comparable time in range (81% vs 83%) in the last 3 participants., Conclusion: The final version of the fully automated system that delivered insulin and pramlintide warrants a randomized controlled trial., (Copyright © 2021 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Background: For people with type 1 diabetes, there is currently no automated insulin delivery system that does not require meal input. We aimed to assess the efficacy of a novel faster-acting insulin aspart (Fiasp) plus pramlintide fully closed-loop system that does not require meal input., Methods: In this open-label, randomised controlled, crossover, non-inferiority trial we compared the Fiasp (Novo Nordisk, Bagsværd, Denmark) plus pramlintide closed-loop system with no meal input (fully artificial pancreas) and the Fiasp-alone closed-loop system with precise carbohydrate counting (hybrid artificial pancreas). Adults (≥18 years) who had a clinical diagnosis of type 1 diabetes for at least 12 months, had glycated haemoglobin 12% or lower, and had been on insulin pump therapy for at least 6 months were enrolled at McGill University Health Centre, Montreal, QC, Canada. The Fiasp plus pramlintide fully closed-loop system delivered pramlintide in a basal-bolus manner with a fixed ratio of 10 μg:U relative to insulin. A research staff member counted the carbohydrate content of meals to input in the hybrid closed-loop system. Participants completed the two full-day crossover interventions in a random order allocated by a computer-generated code implementing a blocked randomisation (block size of four). The primary outcome was the percentage of time spent within the glucose target range (3·9-10·0 mmol/L), with a 6% non-inferiority margin, assessed in all participants who completed both interventions. This trial is registered with ClinicalTrials.gov, NCT03800875., Findings: Between Feb 8, 2019, and Sept 19, 2020, we enrolled 28 adults, of whom 24 completed both interventions and were included in analyses. The percentage of time spent in the target range was 74·3% (IQR 61·5-82·8) with the fully closed-loop system versus 78·1% (66·3-87·5) with the hybrid Fiasp-alone closed-loop system (paired difference 2·6%, 95% CI -2·4 to 12·2; non-inferiority p=0·28). Eight (33%) participants had at least one hypoglycaemia event (<3·3 mmol/L) with the fully closed-loop system compared with 14 (58%) participants with the hybrid closed-loop system (2200-2200 h). Non-mild nausea was reported by three (13%) participants and non-mild bloating by one (4%) participant with the fully closed-loop system compared with zero participants with the hybrid closed-loop system., Interpretation: The Fiasp plus pramlintide fully closed-loop system was not non-inferior to the Fiasp-alone hybrid closed-loop system for the overall percentage of time in the glucose target range. However, participants still spent a high percentage of time within the target range with the fully-closed loop system. Outpatient studies comparing the fully closed-loop hybrid systems with patient-estimated, rather than precise, carbohydrate counting are warranted., Funding: Diabetes Canada., Competing Interests: Declaration of interests AH received research support or grants from Eli Lilly, Adocia, AgaMatrix, and Diabetes Canada; consulting fees and speaker fees or honoraria from Eli Lilly; insulin pumps, glucose sensors, and monitors from Dexcom, Tandem, and Medtronic; and pending patents in the artificial pancreas area (US patent application 16/893,084; US patent application 16/955,191; US patent application 16/608,054). MAT received research support from AgaMatrix, and speaker honoraria from Eli Lilly, Novo Nordisk, Boeringher Ingelheim, Janssen, and AstraZeneca. J-FY received research support or grants from Bayer, Sanofi, and Novo Nordisk and honoraria from Merck, AstraZeneca, Janssen, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Medtronic, Abbott, Dexcom, and Sanofi; and participated in advisory boards for Merck, AstraZeneca, Janssen, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Medtronic, Abbott, Dexcom, and Sanofi. LL received consulting fees from Dexcom, Insulet, and Novo Nordisk, grants or contracts from Merck and AstraZeneca; participated in advisory boards for the US National Institutes of Health, Novo Nordisk, Insulet, and Dexcom; and participated in data safety monitoring boards for the US National Institutes of Health. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

As closed-loop insulin therapies emerge into clinical practice and evolve in medical research for type 1 diabetes (T1D) treatment, the limitations in these therapies become more evident. These gaps include unachieved target levels of glycated hemoglobin in some patients, postprandial hyperglycemia, the ongoing need for carbohydrate counting, and the lack of non-glycemic benefits (such as prevention of metabolic syndrome and complications). Multiple adjunct therapies have been examined to improve closed-loop systems, yet none have become a staple. Sodium-glucose-linked cotransporter inhibitors (SGLTi's) have been extensively researched in T1D, with average reductions in placebo-adjusted HbA1c by 0.39%, and total daily dose by approximately 10%. Unfortunately, many trials revealed an increased risk of diabetic ketoacidosis, as high as 5 times the relative risk compared to placebo. This narrative review discusses the proven benefits and risks of SGLTi in patients with T1D with routine therapy, what has been studied thus far in closed-loop therapy in combination with SGLTi, the potential benefits of SGLTi use to closed-loop systems, and what is required going forward to improve the benefit to risk ratio in these insulin systems.

Aim: To assess whether a FiASP-and-pramlintide closed-loop system has the potential to replace carbohydrate counting with a simple meal announcement (SMA) strategy (meal priming bolus without carbohydrate counting) without degrading glycaemic control compared with a FiASP closed-loop system., Materials and Methods: We conducted a 24-hour feasibility study comparing a FiASP system with full carbohydrate counting (FCC) with a FiASP-and-pramlintide system with SMA. We conducted a subsequent 12-day outpatient pilot study comparing a FiASP-and-placebo system with FCC, a FiASP-and-pramlintide system with SMA, and a FiASP-and-placebo system with SMA. Basal-bolus FiASP-and-pramlintide were delivered at a fixed ratio (1 U:10 μg). Glycaemic outcomes were measured, surveys evaluated gastrointestinal symptoms and diabetes distress, and participant interviews helped establish a preliminary coding framework to assess user experience., Results: Seven participants were included in the feasibility analysis. Time spent in 3.9-10 mmol/L was similar between both interventions (81%-84%). Four participants were included in the pilot analysis. Time spent in 3.9-10 mmol/L was similar between the FiASP-and-placebo with FCC and FiASP-and-pramlintide with SMA interventions (70%), but was lower in the FiASP-and-placebo with SMA intervention (60%). Time less than 3.9 mmol/L and gastrointestinal symptoms were similar across all interventions. Emotional distress was moderate at baseline, after the FiASP-and-placebo with FCC and SMA interventions, and fell after the FiASP-and-pramlintide with SMA intervention. SMA reportedly afforded participants flexibility and reduced mealtime concerns., Conclusions: The FiASP-and-pramlintide system has the potential to substitute carbohydrate counting with SMA without degrading glucose control., (© 2021 John Wiley & Sons Ltd.)

Background: The real-world effect of intermittently scanned continuous glucose monitoring on glucose control in type 2 diabetes treated with basal insulin is uncertain. This retrospective real-world study aimed to evaluate change in glycated hemoglobin (HbA1c) amongst adults with type 2 diabetes managed with basal insulin starting flash glucose monitoring., Methods: Medical records were reviewed for adults with type 2 diabetes treated with basal insulin for ⩾1 year and using FreeStyle Libre TM Flash Glucose Monitoring for ⩾3 months. Prior to device use an HbA1c 8.0%-12.0% was recorded and a further HbA1c result was recorded 3-6 months (90-194 days) after starting device use., Results: Medical records ( n  = 91) analyzed from six Canadian diabetes centers showed HbA1c significantly decreased by 0.8% ± 1.1 (mean ± SD, [ p  < 0.0001]) from mean baseline HbA1c 8.9% ± 0.9 to 8.1% ± 1.0 at 3-6 months after initiating flash glucose monitoring. HbA1c improvement was not independently associated with age, BMI, insulin use duration, or sex., Conclusion: This Canadian real-world retrospective study showed significantly reduced HbA1c following initiation of flash glucose monitoring technology to further support management of type 2 diabetes treated with basal insulin.

Aim: To assess whether adding empagliflozin to closed-loop automated insulin delivery could reduce the need for carbohydrate counting in type 1 diabetes (T1D) without worsening glucose control., Materials and Methods: In an open-label, crossover, non-inferiority trial, 30 adult participants with T1D underwent outpatient automated insulin delivery interventions with three random sequences of prandial insulin strategy days: carbohydrate counting, simple meal announcement (no carbohydrate counting) and no meal announcement. During each sequence of prandial insulin strategies, participants were randomly assigned empagliflozin (25 mg/day) or not, and crossed over to the comparator. Mean glucose for carbohydrate counting without empagliflozin (control) was compared with no meal announcement with empagliflozin (in the primary non-inferiority comparison) and simple meal announcement with empagliflozin (in the conditional primary non-inferiority comparison)., Results: Participants were aged 40 ± 15 years, had 27 ± 15 years diabetes duration and HbA1c of 7.6% ± 0.7% (59 ± 8 mmol/mol). The system with no meal announcement and empagliflozin was not non-inferior (and thus reasonably considered inferior) to the control arm (mean glucose 10.0 ± 1.6 vs. 8.5 ± 1.5 mmol/L; non-inferiority p = .94), while simple meal announcement and empagliflozin was non-inferior (8.5 ± 1.4 mmol/L; non-inferiority p = .003). Use of empagliflozin on the background of automated insulin delivery with carbohydrate counting was associated with lower mean glucose, corresponding to a 14% greater time in the target range. While no ketoacidosis was observed, mean fasting ketones levels were higher on empagliflozin (0.22 ± 0.18 vs. 0.13 ± 0.11 mmol/L; p < .001)., Conclusions: Empagliflozin added to automated insulin delivery has the potential to eliminate the need for carbohydrate counting and improves glycaemic control in conjunction with carbohydrate counting, but does not allow for the elimination of meal announcement., (© 2021 John Wiley & Sons Ltd.)

Objective: The inflammatory environment in lower-body subcutaneous adipose tissue (SAT) has been largely unexplored. This study aimed to examine the effects of region (upper body vs. lower body) and sex on SAT immune cell profiles in young adults with obesity., Methods: Abdominal (AB) and femoral (FEM) SAT was collected from 12 males (mean [SEM] age = 30.8 [1.4] years; mean [SEM] BMI = 34.1 [1.1] kg/m 2 ) and 22 females (mean [SEM] age = 30.6 [0.6] years; mean [SEM] BMI = 34.0 [0.7] kg/m 2 ) with obesity via needle aspiration. Flow cytometry was used to quantify macrophage (CD68+) and T-cell (CD3+) subpopulations in the stromovascular fraction of each SAT region., Results: Females had a greater proportion of most T-cell types (CD3+CD4+CD45RA+, CD3+CD4+CD45RA-, and CD3+CD8+CD45RA+) in FEM compared with AB SAT, while males had similar proportions in both regions. Regardless of sex, the M1-like macrophage population (CD68+CD206-) was proportionally higher in AB SAT than in FEM SAT., Conclusions: Results showed that T-cell populations vary by SAT region in females but not males. Both sexes, however, have proportionately more proinflammatory macrophages in upper-body than in lower-body SAT. It remains to be seen how these unique immune cell profiles in males and females with obesity contribute to adipose tissue inflammation and metabolic disease risk., (© 2020 The Obesity Society.)

Objective: The rapid insulin-alone artificial pancreas improves glycemia in type 1 diabetes but daytime control remains suboptimal. We propose two novel dual-hormone artificial pancreas systems., Research Design and Methods: We conducted a randomized crossover trial comparing a rapid insulin-alone artificial pancreas with rapid insulin-and-pramlintide and with regular insulin-and-pramlintide artificial pancreas systems in adults with type 1 diabetes. Participants were assigned to the interventions in random order during three 24-h inpatient visits. Each visit was preceded by an outpatient hormonal open-loop run-in period of 10-14 days. The dual-hormone artificial pancreas delivered pramlintide in a basal-bolus manner, using a novel dosing algorithm, with a fixed ratio relative to insulin. The primary outcome was time in the range 3.9-10.0 mmol/L., Results: Compared with the rapid insulin-alone artificial pancreas system, the rapid insulin-and-pramlintide system increased the time in range from 74% (SD 18%) to 84% (13%) ( P = 0.0014), whereas the regular insulin-and-pramlintide system did not change the time in range (69% [19%]; P = 0.22). The increased time in range with the rapid insulin-and-pramlintide system was due to improved daytime control (daytime time in range increased from 63% [23%] to 78% [16%], P = 0.0004). There were 11 (1 per 2.5 days) hypoglycemic events (<3.3 mmol/L with symptoms or <3.0 mmol/L irrespective of symptoms) with the rapid insulin-alone system, compared with 12 (1 per 2.3 days) and 18 (1 per 1.4 days) with the rapid and regular insulin-and-pramlintide systems, respectively. Gastrointestinal symptoms were reported after 0% (0 of 112) of meals with the rapid insulin-alone system, compared with 6% (6 of 108) and 11% (11 of 104) with the rapid and regular insulin-and-pramlintide systems, respectively; none of the symptoms were severe., Conclusions: A novel rapid insulin-and-pramlintide artificial pancreas improves glucose control compared with a rapid insulin-alone artificial pancreas (ClinicalTrials.gov number NCT02814123)., (© 2020 by the American Diabetes Association.)

Objectives: To describe patient-reported outcomes (PROs) after initiation of treatment with canagliflozin (CANA) for type 2 diabetes mellitus (T2DM) in a real-world Canadian setting., Methods: CANadian CAnagliflozin REgistry (CanCARE) is a prospective, observational, single-arm, real-world Canadian study of the effectiveness and safety of CANA for the treatment of T2DM in 527 subjects. PRO measures were collected in CanCARE using the Current Health Satisfaction Questionnaire (CHES-Q) at baseline and after 3, 6 and 12 months of CANA treatment to examine patient satisfaction regarding weight and overall health. Associations between changes in satisfaction with weight, systolic blood pressure (SBP) and glycated hemoglobin (A1C) levels were also investigated., Results: Proportion of patients satisfied with their body weight and overall health increased from 22.1% and 26.9% at baseline to 32.4% and 49.2% after 12 months of CANA treatment, respectively. Satisfaction rates also increased on CHES-Q domains representing physical and emotional health. Correlations were found between improvement in satisfaction with body weight and weight loss (r=-0.29; p<0.01) and between improvements in satisfaction with overall health and weight loss (r=-0.13; p=0.03) and SBP (r=-0.17; p<0.01), but not with changes in A1C level., Conclusions: Treatment with CANA is associated with improvements in satisfaction with body weight and overall health, which may be important drivers of patient self-management and hold the potential to positively influence long-term outcomes in T2DM., (Copyright © 2019 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Objective: This meta-analysis aimed to assess the agreement between intra-abdominal adipose tissue (IAAT) quantified by alternative methods and the reference standards, computed tomography (CT) and magnetic resonance imaging (MRI)., Methods: MEDLINE and EMBASE electronic databases were systematically searched to identify studies that quantified IAAT thickness, area, or volume by a comparator method and CT or MRI. Using an inverse variance weighted approach (random-effects model), the mean differences and 95% limits of agreement (LoA) were pooled between methods., Results: The meta-analysis included 24 studies using four comparator methods. The pooled mean differences were -0.3 cm (95% LoA: -3.4 to 3.2 cm; P = 0.400) for ultrasound and -11.6 cm 2 (95% LoA: -43.1 to 19.9 cm 2 ; P = 0.004) for bioelectrical impedance analysis. Dual-energy x-ray absorptiometry (DXA) quantified both IAAT area and volume with mean differences of 8.1 cm 2 (95% LoA: -98.9 to 115.1 cm 2 ; P = 0.061) and 10 cm 3 (95% LoA: -280 to 300 cm 3 ; P = 0.808), respectively., Conclusions: Ultrasound and DXA measure IAAT with minimal bias from CT or MRI, while bioelectrical impedance analysis systematically underestimates IAAT. However, with the exception of DXA for IAAT volume, the wide LoA caution against clinical or research use of the comparator methods and emphasize the need to optimize alternatives to the reference standards., (© 2019 The Obesity Society.)

Aim: There is limited information concerning the effects of canagliflozin (CANA), a sodium-glucose co-transporter 2 inhibitor (SGLT2i) in a real-world clinical setting in Canada. CanCARE is a 12-month, prospective, observational analysis to demonstrate the effectiveness and safety of CANA in usual clinical practice in Canada., Materials and Methods: SGLT2i-naïve adult patients with type 2 diabetes mellitus (T2DM) (n = 527) on a stable antihyperglycemic agent (AHA) regimen with glycated hemoglobin (A1C) ≥ 7%, an estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m 2 , were initiated on CANA as part of their usual treatment approach, and were followed for a period of 12 months. The primary effectiveness objective was the mean change in HbA1c from baseline to 6 and 12 months., Results: Significant improvement from baseline in mean HbA1c levels were observed at 6 months (-0.90%; 95% CI, -1.02, -0.78) and at 12 months (-1.04%; 95% CI, -1.15, -0.92), regardless of duration of diabetes or background AHA treatment regimen. Similarly, significant decreases in systolic blood pressure (-4.65 mm Hg); body weight (-3.24 kg), waist circumference (-2.91 cm) and body mass index (-1.15 kg/m 2 ) were observed at 12 months. Additionally, 40.5% of patients achieved the double endpoint (≥0.5% HbA1c reduction and ≥ 3% weight loss), while 24.3% of patients achieved the triple composite endpoint (≥0.5% HbA1c reduction, ≥3% weight loss and ≥ 4 mm Hg systolic blood pressure reduction). No unexpected adverse events were reported., Conclusion: CANA provided sustained clinically meaningful improvements in cardiometabolic parameters in this study in a real-world setting, confirming findings from randomized controlled trials., (© 2018 John Wiley & Sons Ltd.)

Objective: To test whether protein anabolic resistance is an early defect in type 2 diabetes (T2D)., Research Design and Methods: Seven lean, normoglycemic T2D offspring (T2D-O) and eight matched participants without family history (controls; C) underwent a 3-hour hyperinsulinemic (40 mU/m 2 /min), euglycemic (5.5 mmol/L) and isoaminoacidemic clamp. Whole-body glucose and protein kinetics were measured with d-[3- 3 H]glucose and l-[l- 13 C]leucine, respectively. Plasma amino acids were measured by liquid chromatography-tandem mass spectrometry., Results: Fasting glycemia and glucose kinetic variables did not differ between groups. Clamp decreases in glucose rate of appearance were not different, but rate of disappearance increased 29% less in T2D-O, to a significantly lower rate. Fasting leucine was higher in T2D-O, but kinetics did not differ. Clamp increases in leucine oxidation and decreases in endogenous rate of appearance (protein breakdown) were equal, but in T2D-O, non-oxidative rate of disappearance (protein synthesis) did not increase and net balance (synthesis-breakdown) did not become positive as in C., Conclusions: Resistance of whole-body protein anabolism (synthesis and net balance) accompanies resistance of glucose uptake in T2D-O. Mechanisms responsible, possible roles in the increased risk of developing diabetes, and its potential impact on long-term protein balance require definition., Competing Interests: Conflicts of Interest: None declared.

Background: GLP-1 agonists, including liraglutide, have emerged as effective therapies for type 2 diabetes (DM) and obesity. Here, we attempted to delineate how liraglutide, at doses approved for DM, may impact circulating hormones influencing energy homeostasis in diabetics., Basic Procedures: Using a randomized, placebo-controlled, double-blind, cross-over trial of 20 patients with type 2 diabetes, we examined the effects of liraglutide as compared to placebo on fasting levels of circulating hormones important to energy homeostasis, including leptin, ghrelin, PYY, and GIP. After 17days (0.6mg for 7days, 1.2mg for 7days and 1.8mg for 3days) of treatment, we also studied changes in fMRI responses to food cues., Main Findings: By design, to avoid any confounding by weight changes, subjects were studied for 17days, i.e. before body weight changed. Participants on liraglutide had significantly increased GLP-1 levels (p<0.001), decreased percent change in leptin levels (p<0.01) and increased GIP levels (p<0.03) in comparison to placebo treated subjects. Whole brain regressions of functional activity in response to food cues reveal that increased GIP levels were associated with deactivation of the attention- and reward-related insula. Decreases in leptin levels were associated with activations in the reward-related midbrain, precuneus, and dorsolateral prefrontal cortex (DLPFC), and sensorimotor-related motor cortex and with deactivations in the attention-related parietal cortex and the cognitive control-related thalamus and pre-SMA., Principal Conclusions: We demonstrate herein short-term changes to circulating levels of GIP and leptin in response to GLP-1 agonist liraglutide therapy. These findings suggest that liraglutide may alter the circulating levels of hormones important in energy homeostasis that, in turn, influence CNS perception of food cues. This could possibly lead to compensatory changes in energy homeostasis that could over time limit the efficacy of liraglutide to decrease body weight. These novel findings, which, pointing to the potential advantages of combination therapies, may have therapeutic implications, will need to be confirmed by larger and longer-term trials., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aims/hypothesis: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome)., Methods: In 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrolment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days, and 1.8 mg for 3 days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (functional MRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center., Results: Immunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide -0.47 ± 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation., Conclusions/interpretation: For the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3 mg) recently approved for obesity., Trial Registration: ClinicalTrials.gov NCT01562678 FUNDING : The study was funded by Novo Nordisk, NIH UL1 RR025758 and 5T32HD052961.

Colorectal cancer, unlike many other malignancies, may be preventable. Recent studies have demonstrated an inverse association between nut consumption and incidence of colon cancer; however, the underlying mechanisms are not fully understood. An emerging concept suggests that microribonucleic acids (miRNAs) may help explain the relationship between walnut consumption and decreased colorectal neoplasia risk. Seven days after HT-29 colon cancer cell injection, mice were randomized to either control or walnut diets for 25 days of diet treatment. Thirty samples of tumor and of omental adipose were analyzed to determine changes in lipid composition in each dietary group. In the tumors of the walnut-containing diet, we found significant increases in α-linolenic, eicosapentaenoic, docosahexaenoic and total omega-3 acids, and a decrease in arachidonic acid, as compared to the control diet. Final tumor size measured at sacrifice was negatively associated with percentage of total omega-3 fatty acid composition (r=-0.641, P=.001). MicroRNA expression analysis of colorectal tumor tissue revealed decreased expression of miRNAs 1903, 467c and 3068 (P<.05) and increased expression of miRNA 297a* (P=.0059) in the walnut-treated group as compared to control diet. Our results indicate that changes in the miRNA expression profiles likely affect target gene transcripts involved in pathways of anti-inflammation, antivascularization, antiproliferation and apoptosis. We also demonstrate the incorporation of protective fatty acids into colonic epithelium of walnut-fed mice, which may independently alter miRNA expression profiles itself. Future studies of the mechanism of widespread miRNA regulation by walnut consumption are needed to offer potential prognostic and therapeutic targets., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Leptin is a hormone secreted by adipocytes that regulates energy metabolism via peripheral action on glucose synthesis and utilization as well as through central regulation of food intake. Patients with decreased amounts of fat in their adipose tissue (lipoatrophy) will have low leptin levels, and hypoleptinemic states have been associated with a variety of metabolic dysfunctions. Pronounced complications of insulin resistance, dyslipidemia and fatty liver are observed in patients suffering from congenital or acquired generalized lipodystrophy while somewhat less pronounced abnormalities are associated with human immunodeficiency virus (HIV) and the use of highly active antiretroviral therapy, the so-called HIV-associated lipodystrophy. Previous uncontrolled open-label studies have demonstrated that physiological doses of leptin repletion have corrected many of the metabolic derangements observed in subjects with rare fat maldistribution syndromes such as generalized lipodystrophy. In the much more commonly encountered HIV-associated lipodystrophy, leptin replacement has been shown to decrease central fat mass and to improve insulin sensitivity, dyslipidemia, and glucose levels. The United States Food and Drug Administration has recently granted approval for recombinant leptin therapy for congenital and acquired generalized lipodystrophy, however large, well-designed, placebo-controlled studies are needed to assess long-term efficacy, safety and adverse effects of leptin replacement. In this review, we present the role of leptin in the metabolic complications of congenital and acquired lipodystrophy and discuss current and emerging clinical therapeutic uses of leptin in humans with lipodystrophy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Receptors of leptin, the prototypical adipokine, are expressed throughout the cortex and several other areas of the brain. Although typically studied for its role in energy intake and expenditure, leptin plays a critical role in many other neurocognitive processes and interacts with various other hormones and neurotransmitters to perform these functions. Here, we review the literature on how leptin influences brain development, neural degradation, Alzheimer's disease, psychiatric disorders, and more complicated cognitive functioning and feeding behaviors. We also discuss modulators of leptin and the leptin receptor as they relate to normal cognitive functioning and may mediate some of the actions of leptin in the brain. Although we are beginning to better understand the critical role leptin plays in normal cognitive functioning, there is much to be discovered., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Analytical and experimental studies confirm relationships between the consumption of certain foods and cardiovascular disease, diabetes, and cancer. Mediterranean diet patterns have long been associated with a reduced risk of major diseases and many favorable health outcomes. Data from observational, longitudinal, and randomized controlled trials have demonstrated that Mediterranean-style diets can improve body mass index and body weight, reduce the incidence of diabetes mellitus and metabolic syndrome risk factors, decrease cardiovascular morbidity and coronary heart disease mortality, as well as decrease all-cause mortality. Recently, efforts have attempted to improve dietary habits in the workplace, by modifying food selection, eating patterns, meal frequency, and the sourcing of meals taken during work. Evidence supporting the Mediterranean diet and the potential cardioprotective role of healthier diets in the workplace are reviewed here, and promising strategies to improve metabolic and cardiovascular health outcomes are also provided.

Context: Irisin, a recently identified hormone, has been proposed to regulate energy homeostasis and obesity in mice. Whether irisin levels are associated with risk of the metabolic syndrome (MetS), cardiometabolic variables, and cardiovascular disease (CVD) risk in humans remains unknown., Objective: Our objective was to assess the associations between baseline serum irisin levels and MetS, cardiometabolic variables, and CVD risk., Design, Setting, and Subjects: We conducted a comparative cross-sectional evaluation of baseline circulating levels of the novel hormone irisin and the established adipokine adiponectin with MetS, cardiometabolic variables, and CVD risk in a sample of 151 subjects., Results: Baseline irisin levels were significantly higher in subjects with MetS than in subjects without MetS. Irisin was associated negatively with adiponectin (r = -0.4, P < .001) and positively with body mass index (r = 0.22, P = .008), systolic (r = 0.17, P = .04) and diastolic (r = 0.27, P = .001) blood pressure, fasting glucose (r = 0.25, P = .002), triglycerides (r = 0.25, P = .003), and homeostasis model assessment for insulin resistance (r = 0.33, P < .001). After adjustment for potential confounders, including body mass index, subjects in the highest tertile of irisin levels were more likely to have MetS (odds ratio [OR] = 9.44, 95% confidence interval [CI] = 2.66-33.44), elevated fasting blood glucose (OR = 5.80, 95% CI = 1.72-19.60), high triglycerides (OR = 3.89, 95% CI = 1.16-13.03), and low high-density lipoprotein cholesterol (OR = 3.30, 95% CI = 1.18-9.20). Irisin was independently associated with homeostasis model assessment for insulin resistance and general Framingham risk profile in multiple linear regression analyses after adjustment for confounders. Adiponectin demonstrated the expected associations with outcomes., Conclusions: Irisin is associated with increased risk of MetS, cardiometabolic variables, and CVD in humans, indicating either increased secretion by adipose/muscle tissue and/or a compensatory increase of irisin to overcome an underlying irisin resistance in these subjects.