Jerry Richard Greenfield

Objective: This study aimed to examine changes in dietary intake, physical activity, appetite, and weight following laparoscopic adjustable gastric banding (LAGB), sleeve gastrectomy (SG), Roux‐en‐Y gastric bypass (RYGB), and dietary intervention in adults with severe obesity. Methods: This prospective, nonrandomized cohort included 57 adults undergoing LAGB ( n = 11), SG ( n = 21), RYGB ( n = 7), or dietary intervention (Diet; n = 18). Seven assessments over 36 months were analyzed using mixed‐effects models. Results: During the first 12 months, energy intake declined across groups ( β = −1322 kJ/visit; 95% CI: −2045, −599; p < 0.001), without between‐group differences in energy or macronutrient trajectories. Vigorous activity increased following SG relative to Diet (interaction β = +10 min/day/visit; 95% CI: 0.1, 20). During 12–36 months, energy intake increased in Diet ( β = +3089 kJ/visit; p < 0.001), whereas surgical groups maintained energy restriction (all interactions p ≤ 0.006). Changes in macronutrients, calcium intake, and physical activity were modest or transient, although protein intake increased after LAGB relative to Diet (interaction β = +8.6 percentage points; p = 0.006). SG produced sustained appetite reduction ( p ≤ 0.013). At 36 months, weight remained 25.1%, 26.4%, and 16.9% below baseline following SG, RYGB, and LAGB, respectively. Conclusions: Interventions demonstrated biphasic dietary and behavioral adaptation. Surgical procedures produced durable energy restriction and weight loss despite modest long‐term changes in dietary composition and physical activity. Trial Registration: ANZCTR: 12613000188730

Exercise enhances skeletal muscle insulin sensitivity, but the signaling mechanisms responsible are poorly understood. Understanding them may open new therapeutic avenues for individuals with limited exercise capacity. Here, we used rapamycin to inhibit mTORC1 in combination with exercise and insulin stimulation in healthy men. A single dose of rapamycin enhanced the insulin-sensitizing effect of exercise by 53% on average compared to placebo. Responses varied widely across individuals (-40% to 218%), and we leveraged this variance through personalized phosphoproteomics to map the mTORC1-dependent signaling network in skeletal muscle. This identified the protein kinase MKNK2 as a candidate downstream effector, which we then targeted for functional validation. Pharmacological inhibition of MKNK2 with eFT508 in insulin-clamped mice reduced both whole-body and skeletal muscle insulin sensitivity, confirming a functional role for MKNK2 activity in muscle glucose uptake. We then used eFT508 in ex vivo incubated human skeletal muscle to map the signaling network downstream of MKNK2, identifying the translational initiator eIF4G1 as a further regulatory node. Together, these findings indicate that exercise-induced insulin sensitization is actively constrained by a negative feedback pathway running from mTORC1 through the translational regulators MKNK2 and eIF4G1, raising the possibility that rapid translation of unidentified target proteins contributes to fine-tuning glucose uptake.

Objective: Bariatric surgery effectively reduces obesity-related comorbidities, however fat mass loss is often accompanied by lean mass reduction. This 36-month prospective study (N=55) examined body composition changes following three bariatric procedures compared with a diet-controlled group (Diet). Methods: Random intercept mixed-effects models assessed 36-month trajectories of fat and lean mass, comparing surgical groups with Diet, adjusting for age and sex. Associations between body composition changes, measured by dual-energy X-ray absorptiometry and adiponectin (fat-derived) and undercarboxylated osteocalcin (ucOC; bone-derived) hormones were evaluated at 0, 1, 3, 6, 12, 24, and 36 months. Results: Roux-en-Y gastric bypass produced the greatest fat mass loss (46.6%), followed by sleeve gastrectomy (30.1%) and laparoscopic adjustable gastric banding (20.5%). Corresponding lean mass losses were 14.2%, 11.7%, and 5.2%. In Diet changes in fat mass (−2.1%) and lean mass (+3.6%) were non-significant. Over 36 months, all surgical groups lost significantly more lean mass than Diet, with the greatest losses after RYGB (15.1%) and LAGB (14.8%). Women experienced 30% greater lean mass loss than men (95% CI: -34%, -26%). Each additional year of age was associated with a 0.2% lean mass decline (95% CI: -0.5%, 0%). After controlling for treatment procedure, age and sex, each twofold increase in adiponectin and ucOC was associated with 5.0% (95% CI: -9.4%, -2.4%) and 3.7% (95% CI: -5.0%, -1.3%) reductions in lean mass, respectively. Conclusions: These findings underscore the lean mass loss risk after bariatric surgery, particularly in women and older adults, and highlight the importance of long-term monitoring of body composition, nutrition and bone health. Clinical trial registration: The study was registered as ANZCTR: 12613000188730.

Aims/hypothesis Autoantibody-negative type 1 diabetes is an idiopathic subtype with unclear aetiology. We aimed to characterise and compare the clinical, immune, genetic and metabolic characteristics of individuals with autoantibody-negative vs autoantibody-positive type 1 diabetes. Methods Clinical features and deep immune phenotyping of 26 individuals with autoantibody-negative type 1 diabetes were analysed and compared with 30 individuals with autoantibody-positive type 1 diabetes and 25 normoglycaemic control participants. Genetic risk was assessed using the type 1 diabetes genetic risk score 2 (GRS2) and compared with individuals with autoantibody-positive type 1 diabetes and latent autoimmune diabetes in adults. Beta cell function was longitudinally assessed in 29 participants with recent-onset type 1 diabetes using glucagon stimulation tests. Mixed meal tests were performed on a subset of participants. Results Participants with autoantibody-negative and autoantibody-positive type 1 diabetes had similar age at diagnosis (33.5 ± 11.6 vs 31.6 ± 9.3 years, p=0.78), disease duration (median 3 [IQR 1–6] years for both) and BMI (24.1 ± 3.4 vs 23.4 ± 2.9 kg/m², p=0.82). Immune phenotyping revealed no significant differences. Mean GRS2 scores were comparable (19.6 in autoantibody-negative type 1 diabetes vs 19.4 in autoantibody-positive type 1 diabetes). Beta cell function was also similar in response to glucagon (peak C-peptide 0.25 [0.13–0.38] vs 0.30 [0.20–0.55] nmol/l, respectively, p=0.27) and mixed meal stimuli (C-peptide AUC 1.46 ± 0.29 vs 1.45 ± 0.31 nmol/l × min, respectively, p>0.99). Conclusions/interpretation Adults with autoantibody-negative type 1 diabetes share similar clinical, immunologic, genetic and metabolic features with those who are autoantibody-positive. Graphical Abstract

Background: Diabetic ketoacidosis (DKA) is a hyperglycaemic emergency, and insulin administration is highly protocolised with either variable‐ or fixed‐rate intravenous infusions. There are limited data supporting superiority of one regimen over another; however, international guidelines recommend fixed‐rate infusions.Aim: To characterise DKA management protocols used in Australian hospitals.Methods: An online survey of Australian endocrinologists and intensive care physicians between May and July 2024. The main outcome measure was the proportion of respondents using a fixed or variable rate, or combination, for the management of DKA. Secondary outcomes were the location of management, definition of resolution and intravenous fluid specification.Results: There were 31 respondents from individual hospitals around Australia, with 84% of endocrinologists and 84% from metropolitan hospitals. There was wide variation in insulin regimens including fixed (n = 12), variable (n = 14) and combination (n = 5) infusion protocols. Most (23/30, 77%) respondents had worked at another hospital that had a different DKA management protocol. There was a 50% split (n = 14 each) in personal preference for fixed‐ or variable‐rate infusion, with three respondents having no preference. Most (21/31, 68%) protocols defined resolution of DKA. Blood pH (15/21, 71%) and/or ketone level (18/21, 86%) were the most frequently used end points to define resolution.Conclusions: There are substantial variations in insulin regimens and resolution criteria in DKA management protocols across Australian hospitals. Clinician preference was diverse. This likely reflects the lack of high‐quality evidence to guide practice.

Type 1 diabetes is associated with excess cardiovascular risk, even after accounting for traditional cardiovascular risk factors, including glycaemia. Hence, there is an urgent need to document the metabolic abnormalities that contribute to the cardiovascular mortality gap in type 1 diabetes, and to examine whether cardioprotective type 2 diabetes medications prevent premature morbidity and mortality in this population.

Aims: The aim of this study was to examine contemporary trends in the use of, time to, and type of first add‐on anti‐hyperglycaemic therapy to metformin in Australia.Methods: We used the dispensing records of a 10% random sample of Pharmaceutical Benefits Scheme (PBS) eligible people. We included people aged 40 years and older initiating metformin from 1 January 2018 to 31 December 2020. Our primary outcome was first add‐on anti‐hyperglycaemic medicine within 2 years of metformin initiation. We analysed time to dispensing of first add‐on therapy. All analyses were stratified by metformin initiation year.Results: Overall, 38 747 people aged 40 years and older initiated metformin between 2018 and 2020. Approximately one‐third (n = 12 946) of people received add‐on therapy with the proportion increasing slightly by year of metformin initiation (32.3% in 2018 to 34.8% in 2020). Amongst people with add‐on therapy following metformin initiation, sodium‐glucose cotransporter 2 inhibitor (SGLT2i) use increased from 28.8% (2018) to 35.0% (2020), and glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) increased from 3.0% to 9.6%, respectively. Dipeptidyl peptidase‐4 inhibitors and sulfonylureas as first add‐on therapy decreased and insulin remained stable. One‐third of people with add‐on therapy initiated the therapy on the same day metformin was initiated, i.e. initial combination therapy.Conclusions: Amongst people initiating metformin from 2018 to 2020, there was an increasing proportion of SGLT2i and GLP‐1 RA being used as first add‐on therapy. However, the overall prevalence of add‐on therapy was low. Advocacy to promote add‐on therapy with cardiorenal beneficial medicines is critical to reduce type 2 diabetes morbidity and mortality.