Daily Endocrinology Research Analysis

BACKGROUND: Human insulins including intermediate-acting human insulin (ie, isophane insulin) remain widely used for children and young people with type 1 diabetes, especially in low-resource settings. We aimed to assess whether insulin glargine reduces the risk of serious hypoglycaemia or improves time in range when compared against human isophane insulin among children and young people with type 1 diabetes in low-income and middle-income countries. METHODS: HumAn-1 was a randomised, open label, parallel-group trial conducted at one site in Bangladesh and two sites in Tanzania. Participants aged 7-25 years with a clinical diagnosis of type 1 diabetes were randomly assigned (1:1) to receive insulin glargine (Basaglar, Eli Lilly, Indianapolis, IN, USA) or to continue usual care (ie, isophane insulin or premixed 70/30) for basal insulin coverage. Insulin glargine was administered subcutaneously, usually before bedtime. Isophane insulin or premixed 70/30 was administered once or twice per day, at the discretion of the treating clinician. Doses varied by participant. Randomisation was performed centrally and stratified by site. The coprimary outcomes, measured using blinded continuous glucose monitors at 6 months, were time in very low range (<3 mmol/L or 54 mg/dL) and time in target range (3·9 mmol/L to 10·0 mmol/L or 70 mg/dL to 180 mg/dL). The primary analysis was done for the overall intention-to-treat (ITT) population. The safety population included all participants who received at least one dose of study treatment and was analysed according to the treatment actually received. In this study, all participants received at least one dose of their randomly assigned intervention (ie, the ITT population is the same as the safety population). This trial is registered with ClinicalTrials.gov (NCT05614089). FINDINGS: Between March 1 and Dec 19, 2023, we assessed 426 children and young people for eligibility. Of these, 400 (94%) were randomly assigned to receive either glargine (n=199) or usual care (n=201). At 6 months, the mean time in very low range was 3·6% (SD 5·6) in the glargine group and 3·4% (4·3) in the usual care group. After adjustment for prespecified baseline covariates, the adjusted mean difference was 0·22% (97·5% CI -0·83 to 1·27, p=0·63). The mean time in target range was 40·5% (SD 18·4) for glargine and 38·1% (18·1) for usual care. The adjusted mean difference was 0·55% (97·5% CI -2·78 to 3·89, p=0·71). Serious adverse events (SAEs) were uncommon, with a total of six SAEs among five (3%) of 199 participants in the glargine group and 14 SAEs among 13 (6%) of 201 participants in the usual care group. INTERPRETATION: At 6 months, children and young people with type 1 diabetes living in low-resource settings randomly assigned to glargine had no evidence of effects on time in very low range and time in target range compared with those assigned to usual care. FUNDING: The Leona M. and Harry B. Helmsley Charitable Trust.

T cells contribute critically to obesity-induced adipose inflammation and insulin resistance, yet the co-stimulatory signals that govern their activation in adipose tissue remain unclear. Here, we systematically profile co-stimulatory molecules in adipocytes and adipose tissue macrophages and identify OX40 ligand (OX40L) as the most robustly upregulated in obesity. OX40L is also elevated in adipocytes from obese humans. Although macrophage-specific OX40L deletion has no metabolic impact, global OX40 deficiency or adipocyte-specific OX40L deletion reduces Th1 cell accumulation in visceral adipose tissue, attenuates inflammation and improves insulin sensitivity without affecting adiposity. These benefits are reversed by Th1 cell transfer. Therapeutic blockade of OX40L with a neutralizing antibody mimics the protective effects of genetic deletion. Our findings identify adipocyte-derived OX40L as a critical mediator of obesity-associated immune dysfunction and establish it as a targetable checkpoint for tissue-specific immunotherapy in metabolic disease.

BACKGROUND: The impact of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on peripheral artery disease (PAD) remains uncertain. We assessed the association between GLP-1RA use and major limb events in individuals with type 2 diabetes (T2D) and PAD. METHODS: We performed a literature search from inception to 31 March 2026 for randomized controlled trials and cohort studies comparing GLP-1RA use versus placebo, active comparators or non-use on lower limb outcomes in individuals with T2D and PAD. The primary outcome was a composite of major limb events, as defined by the investigators of the original studies included in the meta-analysis. Secondary outcomes included lower extremity amputation (LEA), revascularization, gangrene, major adverse cardiovascular events (MACE) and all-cause mortality. Subgroup analyses, leave-one-out sensitivity analyses, and meta-regression analysis were also performed. RESULTS: Twelve studies (2 RCTs and 10 matched cohort studies) with thirteen arms involving 418,282 participants were included. Treatment with GLP-1RAs was associated with a significantly lower risk of major limb events by 27% (thirteen arms, RR 0.73, 95% CI 0.65-0.82). Reduced risks were also observed for LEA (RR 0.76, 95% CI 0.66-0.87), revascularization (RR 0.81, 95% CI 0.77-0.86), gangrene (RR 0.80, 95% CI 0.77-0.85), MACE (RR 0.76, 95% CI 0.63-0.90) and all-cause mortality (RR 0.67, 95% CI 0.61-0.73). Subgroup and sensitivity analyses did not substantially change point estimates. CONCLUSION: Among adults with T2D and PAD, treatment with GLP-1RAs was associated with a lower risk of major limb events. There is a need of dedicated studies with standardized limb-specific endpoints to confirm the protective role of GLP-1RAs on limb events in people with T2D and PAD.