Islet-resident macrophages (IRMs) have emerged as important regulators of pancreatic islet biology, operating at the intersection of metabolism and immunity. Beyond their classical roles as immune sentinels, accumulating evidence indicates that IRMs dynamically integrate β-cell activity, environmental cues, and metabolic stress, thereby coordinating islet homeostasis, adaptive remodelling, and disease progression. However, their context-dependent functions and therapeutic potential remain incompletely understood.
This review summarizes current evidence regarding IRM origins, phenotype, metabolic plasticity, and bidirectional crosstalk with β cells in health, type 1 diabetes, and type 2 diabetes. We further review emerging therapeutic concepts targeting macrophage metabolism, intercellular communication, and organelle function, while discussing current challenges in translating findings from murine IRMs to human disease.
Under physiological conditions, IRMs maintain islet integrity through surveillance, efferocytosis, trophic signalling, redox control, and maintenance of intercellular communication within the islet niche. In diabetes, chronic glucolipotoxicity, autoimmunity, oxidative stress, and amyloid-associated injury can redirect these homeostatic programs toward maladaptive inflammatory states that impair insulin secretion and accelerate β-cell loss. Collectively, these findings support a unified framework in which IRMs act as immunometabolic hubs integrating local and systemic signals to determine β-cell fate.
IRMs represent central immunometabolic hubs that orchestrate β-cell fate during health and diabetes. Emerging therapeutic strategies targeting macrophage metabolism, intercellular communication, and organelle function may help prioritize future mechanistic studies and guide safer macrophage-centered interventions for diabetes.
]]>Treatment response in type 2 diabetes (T2D) varies widely among individuals. This study aimed to quantify the contributions of clinical characteristics and genetic predisposition as measured through partitioned polygenic risk scores (pPRS) to variation in glycemic response to glucose-lowering therapies.
We analysed data from two population-based cohorts: the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) and the UK Biobank (UKBB). GoDARTS included 41 802 patients who initiated one of six major drug classes, of whom 11 615 had available genotype data. UKBB contributed 9371 individuals, including 8293 with genetic data. The primary outcome was glycaemic response, defined as the change in HbA1c 12 months after treatment initiation. Variables included demographic and clinical factors (age, sex, BMI, baseline HbA1c, kidney and liver function markers) and 14 pPRS representing T2D-related biological pathways. Linear regression models were fitted within each cohort and drug class (metformin, sulfonylureas, TZDs, DPP4i, SGLT2i, GLP-1RA), and effect estimates were combined using fixed-effect meta-analysis.
Baseline HbA1c was most strongly associated with glycemic response (p < 0.001). Older age was consistently associated with greater HbA1c reduction, while BMI and total cholesterol demonstrated drug-class-specific associations, with higher BMI associated with improved response to TZDs and higher total cholesterol generally associated with poorer glycaemic outcomes. Meta-analysis across GoDARTS and UK Biobank showed that higher overall T2D genetic risk was associated with greater HbA1c reduction with sulfonylureas (β = −0.46 mmol/mol, p = 0.013). Specific genetic profiles were also associated with drug responses, including β-cell function clusters with sulfonylureas (β = −0.57, p = 0.002), obesity-related variants with GLP-1RA (β = −1.49, p = 0.04), liver-lipid variants with SGLT2 inhibitors (β = −0.84, p = 0.05), and bilirubin pPRS with DPP-4 inhibitors (β = −0.69, p = 0.006).
Both clinical and genetic factors significantly contribute to inter-individual variability in T2D drug response. Partitioned PRSs provide mechanistic insights into drug-specific pathways and have the potential to inform precision prescribing and optimise therapeutic outcomes in routine diabetes care.
]]>We aimed to examine whether offspring exposed to maternal gestational diabetes mellitus (GDM) had different fat–lean balance trajectories from unexposed offspring and whether the estimated associations were attenuated after adjustment for maternal pre-pregnancy adiposity.
Using UK Millennium Cohort Study data, we analysed body composition outcomes, including fat mass (FM), body fat percentage (BF%), fat mass index (FMI), fat-free mass index (FFMI), and the FMI/FFMI ratio. Linear mixed-effects models characterised body composition trajectories from ages 7–17 years, with additional adjustment to assess the attenuation of the estimates after accounting for maternal pre-pregnancy adiposity.
The analysis included 14 329 offspring, of whom 170 were exposed to maternal GDM. In the primary adjusted model, GDM-exposed offspring had higher model-predicted values for all body composition indices than unexposed offspring across the observed ages. GDM-by-age interaction terms indicated age-varying between-group differences for FM, FMI, and the FMI/FFMI ratio (all p < 0.05), with borderline evidence for BF% (p = 0.050) and no clear evidence for FFMI. After additional adjustment for maternal pre-pregnancy adiposity, the estimated between-group differences were attenuated, and some age-specific contrasts, particularly at age 7 years, were no longer statistically significant. Nevertheless, age-varying between-group patterns remained evident for several body composition indices.
Maternal GDM exposure was associated with age-varying differences in offspring fat mass and fat–lean balance during childhood and adolescence, and these associations were attenuated after adjustment for maternal pre-pregnancy adiposity.
]]>Low energy diets (LEDs) are effective for body weight (BW) loss and improvement of type 2 diabetes (T2D) risk biomarkers. Emerging evidence suggests that whole fruit feijoa powder, rich in polyphenols and abscisic acid, may further support T2D prevention. The FERDINAND study investigated whether daily consumption of a whole fruit feijoa powder enhanced LED-driven improvements in fasting plasma glucose (FPG), BW, and other metabolic markers.
At in-clinic screening, 97 participants were enrolled into the trial and randomised to receive 1150 mg/day of whole fruit feijoa powder (Fx, n = 48) or Placebo treatment (n = 49) for 6 months. All participants underwent 2 months of LED-induced weight loss, followed by 4 months of dietary advice for weight loss maintenance. BW, FPG, and secondary outcomes including blood pressure (BP) were assessed at baseline (M0) and the end of months 2 (M2), 4 (M4), and 6 (M6). Data were analysed using linear mixed-effects models as intention-to-treat (ITT) with imputation for missing not-at-random data points.
BW decreased in both treatment groups during the 2-month LED, with a gradual upward trajectory over the subsequent 4 months (time0-6m: p < 0.001). There was no difference in BW between Fx and Placebo over the 6-month intervention (treatment×time0-6m: p = 0.74). FPG followed the weight loss trajectory in both treatment groups (time0-6m: p < 0.001), but with no between-group interaction over 6 months (treatment×time0-6m: p = 0.09, n = 97). Systolic BP (SBP), but not diastolic BP, declined over the 6 months between treatments (treatment×time0-6m: p = 0.01) in all participants, with SBP in Fx lower than Placebo at M4 and M6 (p < 0.05, both).
In adults with overweight (predominantly obesity) and prediabetes, Fx supplementation may enhance blood pressure improvement achieved through BW loss. The polyphenolic matrix of whole fruit feijoa, which contains a high proportion of catechins, may have contributed to vascular benefits.
]]>To examine the association between initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors and risk of incident depression compared with dipeptidyl peptidase-4 (DPP-4) inhibitors among adults with newly diagnosed Type 2 diabetes receiving metformin.
We conducted a nationwide active-comparator new-user cohort study with a 90-day adherent-survivor landmark design, using the Korean National Health Insurance Service database linked with national health check-up and mortality data (2014–2022). Adults with newly diagnosed Type 2 diabetes receiving metformin who newly initiated SGLT2 inhibitors or DPP-4 inhibitors as add-on therapy were identified. This study was designed as a 90-day adherent-survivor landmark analysis. Propensity score matching was performed in a 1:1 ratio, yielding 10 013 matched pairs. The primary outcome was incident depression, defined as ≥ 2 outpatient or inpatient claims with ICD-10 codes F32–F33. The secondary outcome was suicide mortality. Cox proportional hazards models were used to estimate hazard ratios (HRs) under intention-to-treat and as-treated approaches.
Among 38 297 eligible participants, 300 depression events occurred among SGLT2 inhibitor users and 391 among DPP-4 inhibitor users in the matched cohort. Initiation of SGLT2 inhibitors was associated with a lower risk of depression compared with DPP-4 inhibitors (HR 0.85, 95% CI 0.73–0.99). Similar findings were observed in as-treated analyses (HR 0.80, 95% CI 0.65–0.98). Associations were generally consistent across clinically relevant subgroups and appeared more pronounced among older adults, females and individuals with greater comorbidity burden. Suicide mortality was infrequent in both groups.
Among 90-day adherent survivors with Type 2 diabetes receiving metformin, initiation of SGLT2 inhibitors as add-on therapy was associated with a lower risk of incident depression compared with DPP-4 inhibitors.
]]>Circadian-disruptive behaviours (CDBs) may impair glucose regulation via central and peripheral clocks. This study investigated the association between CDB burden and glycemic outcomes during pregnancy.
In this prospective cohort study, 246 pregnant women were recruited at 18–24 weeks’ gestation. Four CDBs were assessed using dietary records and questionnaires: eating jetlag, predominant night-eating, social jetlag, and electronic media use before bedtime. Outcomes included oral-glucose-tolerance-test (OGTT) and insulin parameters (24–28 weeks’ gestation) and continuous-glucose-monitoring (CGM) metrics (18–24 weeks’ gestation). Skewed outcomes were log-transformed, and associations with the number of CDBs were examined using multivariable regression.
Compared with women without CDBs, those with two CDBs had higher fasting insulin [geometric mean ratio 1.23 (95% CI 1.02, 1.48)] and updated-homeostasis-model-assessment-of-insulin-resistance (HOMA2-IR) [1.23 (1.02, 1.47)]. Women with three or four CDBs had significantly higher fasting glucose [1.09 (1.04, 1.15)], 1-h glucose [1.17 (1.03, 1.33)], glucose area-under-the-curve [1.14 (1.03, 1.26)], and lower updated-homeostasis-model-assessment-of-β-cell-function (HOMA2-%B) [0.76 (0.62, 0.93)]. Furthermore, fetal sex modified the associations between CDBs and CGM-derived glycemic control measures, including mean glucose, glucose management indicator (GMI), and J-index (all p
interaction < 0.1). In stratified analyses, a higher cumulative CDB measure was significantly associated with higher glycemic control measures among women carrying female foetuses.
Higher CDB burden was associated with less favourable glycemic profiles and lower HOMA2-%B during pregnancy. These findings support investigating circadian-aligned lifestyle strategies to improve maternal metabolic health.
Trial Registration: ClinicalTrials.gov identifier: NCT03803345.
]]>To assess factors influencing closed-loop system choice, perceptions of treatment satisfaction and glycaemic targets, perceived benefits and expectations of therapy, and support needs among adults with Type 1 diabetes (T1D) using, awaiting initiation of or considering closed-loop therapy.
SELECT HCL was a cross-sectional survey study conducted at a specialist secondary care diabetes service between September 2025 and February 2026. Adults with T1D completed an anonymous online questionnaire assessing experiences and perspectives relating to closed-loop therapy. Descriptive, subgroup, and multivariable logistic regression analyses were performed.
Overall, 166 participants were included (median age 47 years; HbA1c 52 mmol/mol [6.9%]). Sensor accuracy (39.3%), glycaemic performance (37.6%) and patch pump without tubing (27.5%) were the most commonly prioritised factors when selecting sensors, algorithms and insulin pumps, respectively. Treatment satisfaction priorities differed by age (p = 0.006), with younger participants more frequently prioritising reduction in burden and quality of life (QoL), whereas older participants prioritised hypoglycaemia-related outcomes. Although 63.8% perceived time in tight range (TITR, 3.9–7.8 mmol/L) ≥ 50% as beneficial for their health, only 36.1% considered it an achievable target. Most participants reported that closed-loop therapy improved QoL (78.6%), reduced hyperglycaemia (75.0%) and hypoglycaemia (72.3%), and met expectations (81.1%). Adequate support during closed-loop initiation was associated with therapy meeting participants’ expectations (OR 16.6, 95% CI 5.0–52.4, p < 0.001).
Adults with T1D reported diverse priorities and experiences relating to closed-loop therapy, extending beyond glycaemic outcomes alone. Adequate support during closed-loop initiation may represent an important component of successful implementation in routine clinical care.
]]>Prediabetes affects 35% of Chinese adults and is associated with increased risks of cardiovascular disease and mortality. However, findings are inconsistent on the effects of lifestyle and pharmacological interventions in the prediabetes population achieving remission. This analysis aimed to compare the effects of metformin plus lifestyle intervention versus lifestyle intervention alone for prediabetes remission.
This was a secondary analysis of the China Diabetes Prevention Program (CDPP), a multicentre unblinded randomised controlled trial of 1678 participants aged 18–70 years with impaired glucose regulation from 43 hospitals across China (NCT 03441750). Participants were randomly assigned (1:1) using block randomisation stratified by glucose status (impaired fasting glucose or impaired glucose tolerance), presence of hypertension and use of anti-hypertensive medication. They received either metformin plus lifestyle intervention or lifestyle intervention alone for 2 years. The primary outcome was prediabetes remission rate.
During a median follow-up of 2.03 years, remission was achieved in 262/831 (31.5%) (138/396 men; 124/435 women) participants in the metformin plus lifestyle group versus 213/847 (25.1%) (106/397 men; 107/450 women) in the lifestyle alone group, with similar effects across subgroups. After adjusting for baseline characteristics, addition of metformin increased the rate of remission (HR 1.39, 95% CI 1.16–1.67, p < 0.001). Higher baseline HbA1c was associated with lower remission rates (HR 0.23, 95% CI 0.18–0.29, p < 0.001).
Adding metformin to a lifestyle intervention significantly improved prediabetes remission rates over lifestyle intervention alone in Chinese adults with impaired glucose regulation. This may be an effective approach for prediabetes management.
]]>To conduct indirect treatment comparisons (ITCs) of insulin efsitora alfa (efsitora) versus insulin icodec (icodec) in insulin-experienced individuals with Type 2 Diabetes Mellitus.
Efficacy, safety and patient reported outcomes were compared via matching-adjusted ITCs using results from randomised controlled trials: QWINT-3 versus ONWARDS 2 (basal-insulin experienced individuals) and QWINT-4 versus ONWARDS 4 (basal-bolus insulin-experienced individuals).
In basal insulin-experienced participants, efsitora was comparable to icodec for change from baseline (CfB) in HbA1c (%) (efficacy estimand mean difference [MD] [95% CI]: 0.137 [−0.058, 0.333]), proportion of participants (PoP) discontinuing treatment due to adverse event (risk difference: −0.0002 [−0.0223, 0.0220]) and CfB in Diabetes Treatment Satisfaction Questionnaire-Change (DTSQc) (MD: 1.01 [−0.243, 2.27]). Efsitora exhibited significantly reduced weight gain (MD: −1.52 kg [−2.60, −0.447]) and had lower event rates of Level 2 or 3 hypoglycaemia (rate ratio: 0.436 [0.241, 0.786]) versus icodec, despite no significant difference in PoP with Level 2 or 3 hypoglycaemia (odds ratio [OR]: 0.581 [0.294, 1.14]). In basal-bolus insulin-experienced participants, efsitora was comparable to icodec: CfB in HbA1c (%) (MD: −0.0447 [−0.252, 0.163]); CfB in body weight (kg) (MD: −0.316 [−1.45, 0.817]); PoP with Level 2 or 3 hypoglycaemia (OR: 1.10 [0.698, 1.73]); event rate of Level 2 or 3 hypoglycaemia (rate ratio [95% CI]: 1.03 [0.759, 1.39]).
These indirect comparisons suggest that efsitora had lower event rates of hypoglycaemia and less weight gain compared to icodec in basal insulin-experienced participants. Efsitora was comparable to icodec for all other endpoints.
]]>Young-onset non-type 1 diabetes (YOD, age-at-diagnosis ≤ 40) is associated with poor physical and mental health, presenteeism and productivity loss. We examined patient-perceived barriers to work productivity and key enablers to reduce presenteeism.
In this mixed-methods study, we utilized validated questionnaires to measure presenteeism (World Health Organization Health and Performance Questionnaire); self-care activities (Summary of Diabetes Self-Care Activities; Compliance Questionnaire for Medication); health-related quality of life (HRQoL, EQ-5D-3L) and psychological distress (Depression Anxiety Stress Scale; Chinese Diabetes Distress Scale) among participants with YOD in the Precision Medicine to Redefine Insulin Secretion and Monogenic Diabetes-Randomised Controlled Trial (PRISM-RCT). We conducted four semi-structured focus group discussions (FGDs) for inductive thematic analysis.
Employees with YOD (n = 465, mean age: 43.4 ± 6.4 years, disease duration: 10.9 ± 6.0 years, 59.8% male) had better cardiometabolic, psychological and HRQoL profiles than non-employees (n = 103). Among the employees, 67.4% had at least one sickness presenteeism episode in the preceding year, with a mean presenteeism score of 7.1 ± 1.6 (out of 10). Increased presenteeism was independently associated with diabetes-related emotional burden (β = −0.08, p = 0.029) and suboptimal HRQoL (β = 3.30, p = 0.041). [Correction added on 11 September 2026, after first online publication: In the preceding sentence, the beta and p values have been corrected.] Participants of FGDs (n = 16) reported distress contributors related to inter-personal (psychological/physical status, family collectivism), work (schedules/types, absence justification, colleagues’ attitudes) and societal factors (relationships with providers, out-of-pocket payment, stigmatisation). Enablers included public awareness, early diagnosis (genetic testing for offspring, regular health-check), peer support, treatment choices autonomy and insurance coverage.
In YOD, presenteeism is associated with interpersonal, work and societal factors accompanied by psychological distress, suboptimal diabetes care, self-management challenges, calling for holistic assessment and person-centred management.
]]>Glucagon-like peptide-1 (GLP-1) receptor agonists can produce rapid weight loss, but this loss is frequently accompanied by disproportionate loss of lean mass, particularly during the early phase of GLP-1-treatment. Physical activity (PA), particularly resistance training, is the most effective behavioural strategy for enhancing fat reduction while preserving lean mass. Our primary aim was to evaluate whether a 12-week virtual GLP-1 lifestyle companion programme that includes PA coaching was associated with increased weight and fat loss coupled with preservation of muscle mass among adults with obesity who initiated GLP-1 therapy for weight loss ≤ 8 weeks prior to baseline.
In this quasi-experimental trial, 245 adults (151 intervention and 94 control) received either a virtual GLP-1 lifestyle companion programme with personalised, strength-focused PA coaching or usual care. Body composition was captured using home bioelectrical impedance analysis scales. Primary outcomes were 12-week between-group differences in change in weight, percent body fat and percent muscle mass.
Participants in the GLP-1 lifestyle companion programme lost an adjusted mean of 6.0% of their baseline body weight versus 3.3% in the control group (between-group difference 2.8%, p < 0.001). Compared with controls, they also experienced a larger decline in body fat percentage (−3.3% vs. −1.6%, p < 0.001), a greater increase in muscle mass percentage (+0.6% vs. +0.2%, p < 0.01) and greater improvements in psychosocial and behavioural outcomes.
Personalised, virtually delivered PA programming may meaningfully improve the quantity and quality of weight loss during GLP-1 therapy.
]]>Whole blood viscosity (WBV) is associated with impaired microvascular circulation and cardiovascular risk in patients with Type 2 diabetes mellitus (T2DM) and peripheral artery disease (PAD). This study investigated the efficacy and safety of sarpogrelate compared with aspirin on WBV in patients with T2DM and PAD.
This randomised, open-label clinical trial enrolled adults with T2DM and PAD. A total of 66 participants were randomised to aspirin (n = 33) or sarpogrelate (n = 33) for 24 weeks. The primary endpoint was change in diastolic WBV at a shear rate of 1 s−1 from baseline to week 24. Secondary endpoints included tissue oxygen delivery index, pain visual analogue scale (VAS) and cold sensation scores.
After 24 weeks, diastolic WBV did not decrease significantly in both groups (sarpogrelate group: 31.91 ± 7.83 to 30.76 ± 7.08, mean change, −1.15 ± 9.25; p = 0.509; aspirin group: 33.32 ± 8.86 to 32.12 ± 9.60, mean change, −1.20 ± 8.36; p = 0.432). VAS scores improved significantly in both groups (mean change, −9.09 ± 18.09; p = 0.007 for sarpogrelate; −6.13 ± 16.47; p = 0.047 for aspirin), with no between-group difference. Cold sensation scores improved only in the sarpogrelate group (mean change, −0.21 ± 0.55; p = 0.033 vs. −0.23 ± 0.85; p = 0.147 for aspirin group), with no between-group difference.
In patients with T2DM and PAD, sarpogrelate did not significantly improve WBV compared with aspirin. VAS scores and cold sensation improved significantly within the sarpogrelate group with no between-group difference.
]]>This study aimed to perform an exploratory characterisation of metabolic phenotypes in primary care patients with type 2 diabetes mellitus (T2DM), using a predefined approach and examine their association with vitamin D status.
This cross-sectional study included 178 participants randomly selected in Sergipe, Brazil. Phenotypic clusters were derived using body mass index (BMI), glycated haemoglobin levels, age at diagnosis, insulin resistance (homeostatic model assessment (HOMA) for insulin resistance) and β-cell function (HOMA-B). To explore differences across phenotypes, we evaluated high-sensitivity C-reactive protein [hs-CRP] and serum ferritin levels, waist circumference and BMI, serum concentrations of 25-hydroxyvitamin D [25(OH)D] and therapeutic profile. Clustering was performed using the K-medoids algorithm. Group comparisons were performed using the Kruskal–Wallis and Fisher’s exact tests and associations were assessed using multivariable logistic regression. A p-value of < 0.05 was considered significant.
Four metabolic phenotypes were identified: two more severe clusters (severe insulin-deficient diabetes (SIDD)-like and severe insulin-resistant diabetes-like) and two milder clusters (mild obesity-related diabetes (MOD)-like and mild age-related diabetes (MARD)-like). Significant differences were observed in age, insulin use, waist circumference and fasting glucose, triglycerides and hs-CRP levels. Median 25(OH)D levels were lower in severe phenotypes compared with milder phenotypes. The SIDD-like group, characterised by marked insulin deficiency, showed 3.68-fold higher odds of vitamin D insufficiency (< 30 ng/mL) compared with the MARD-like phenotype (p = 0.013).
The metabolic phenotypes were explored in a primary care T2DM cohort, supporting their reproducibility across clinical settings. Vitamin D status varied by phenotype severity, with more severe phenotypes more likely to exhibit insufficiency.
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