AIMS To critically evaluate how communication between the endocrine and exocrine pancreas contributes to diabetes and to distinguish whole-pancreas involvement from mechanistically demonstrated crosstalk. METHODS We conducted a narrative review of anatomical, imaging, histological, molecular and experimental evidence on endocrine-exocrine communication, prioritising recent primary human and mechanistic studies. RESULTS Islets and exocrine tissue communicate through local vascular, neural, stromal and extracellular matrix routes. Diabetes is associated with distinct whole-pancreas phenotypes: type 1 diabetes (T1D) shows reduced pancreatic volume, acinar loss, exocrine immune infiltration and periductal or perivascular fibrosis, whereas type 2 diabetes (T2D) more often shows acinar-to-ductal metaplasia, lobular or parenchymal fibrosis, angiopathy and increased pancreatic fat fraction on imaging, although histological adiposity is inconsistent. The strongest mechanistic evidence supports insulin-mediated acinar protection, acinar protease effects on β-cells and transfer of mutant carboxyl ester lipase in maturity-onset diabetes of the young type 8 (MODY8), while stromal, matrix and immune signals represent important but less fully validated amplifying pathways. In T1D and T2D, crosstalk most plausibly acts as a stage-dependent amplifier rather than a universal initiating event. CONCLUSIONS Diabetes should be studied as a multicellular pancreatic disorder without interpreting associated pathology as evidence of causation. Longitudinal human studies and multicellular models that allow selective perturbation are required to identify clinically actionable interactions.
AIMS To evaluate the prognostic performance of Saint Elian Wound Score System (SEWSS) adjusted for age in predicting major amputation (MA) in patients with diabetic foot (DF). METHODS A retrospective cohort study was conducted, including 406 patients with DF treated at a hospital in Argentina in 2025. The primary outcome was MA, with wound healing and death considered competing events. A Fine and Gray model was used to assess the association between SEWSS and MA, adjusted for age. Model performance was evaluated in terms of discrimination, calibration and global precision. Internal validation was performed using bootstrap resampling. Sensitivity analyses were conducted to assess the impact of early loss to follow-up. RESULTS During follow-up, 14.3% of patients underwent MA, 57.1% achieved wound healing and 3.5% died. In the competing risks model, each one-point increase in the SEWSS was associated with a 41% increase in the subdistribution hazard of MA (sHR 1.41; 95% CI 1.31-1.51; p < 0.001), adjusted for age. The model demonstrated a 180-day good discriminative ability, with a bootstrap-corrected AUC of 0.848 and a Brier score of 0.097. Calibration was adequate in low and intermediate-risk ranges. CONCLUSIONS The SEWSS, when adjusted for age and analysed using a competing risks framework, shows good prognostic performance for predicting MA in patients with DF. The model may support risk stratification and clinical decision-making, although external validation in independent populations is required.
Abstract Background Obesity and type 2 diabetes mellitus (T2DM) accelerate chronic kidney disease (CKD) progression. Tirzepatide, a dual glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) receptor agonist, has demonstrated metabolic and potential renoprotective benefits in clinical trials. There have been limited reports of the implications of prescribing tirzepatide in a real‐world cohort of patients with advanced CKD. Methods This observational study includes a multi‐ethnic cohort of 62 adults with CKD stages 1–5 who initiated tirzepatide indicated for T2DM with concurrent obesity in a general nephrology clinic between June 2024 and October 2025. Patients were followed for a median of 21.4 weeks. Clinical outcomes including weight, glycated haemoglobin (HbA1c), estimated glomerular filtration rate (eGFR), urinary albumin‐to‐creatinine ratio (uACR), blood pressure, lipid profile and insulin requirements were collected. Results Tirzepatide significantly reduced median weight (103–100 kg; p < 0.0001), HbA1c (63 [7.9%] to 54 [7.1%] mmol/mol; p = 0.002) and uACR (111–44 mg/mmol; p = 0.008), while eGFR remained stable. Significant improvements were also observed in triglycerides, total cholesterol, LDL cholesterol and total daily insulin dose. Gastrointestinal symptoms and decreased serum bicarbonate were the most common adverse events. Conclusions In this real‐world, multi‐ethnic cohort, including patients with advanced CKD, tirzepatide was associated with clinically meaningful improvements in weight, glycaemic control, albuminuria, lipid profile and insulin requirements without adversely affecting kidney function. The introduction of tirzepatide to patients with CKD should be guided by a multidisciplinary team.
Abstract Type 1 diabetes results from an autoimmune‐mediated destruction of pancreatic β‐cells, yet considerable heterogeneity exists regarding disease onset, progression and severity. Emerging evidence suggests that this variability reflects not only differences in immune responses, but also differences in the architecture and immune landscape of the endocrine pancreas. Our recent Steve Morgan Foundation Grand Challenge studies have provided important ‘lessons from nature’, revealing that the endocrine tissue in the human pancreas exists as a continuum of endocrine objects (EOs), ranging from isolated endocrine cells and small clusters to large islets. These structures differ in their cellular composition, vascularisation, innervation and maturity, creating distinct β‐cell microenvironments that evolve throughout life and may shape susceptibility to autoimmune attack. Strikingly, β‐cells in small EOs are preferentially lost in type 1 diabetes, suggesting EO size and organisation contribute to β‐cell vulnerability. In parallel, we are advancing our understanding of changes in classical and non‐classical human leukocyte antigen (HLA‐I) expression in type 1 diabetes which can impact β‐cell visibility to autoreactive T cells, and have demonstrated that soluble forms of HLA‐I can be released from β‐cells under inflammatory conditions associated with type 1 diabetes. Taken together, our findings support a model in which disease progression is shaped by interactions between a heterogeneous immune response and a heterogeneous endocrine landscape that can vary across the life course. Improving our understanding of how endocrine architecture, immune niches and HLA‐mediated antigen presentation interact could identify new opportunities to protect and expand β‐cell populations through targeted therapies in the future.
Abstract Aims Regional administrative diabetes indicators are increasingly used for population surveillance and planning, yet they are generated through the healthcare system rather than measuring disease directly. We examined what two complementary indicator families—treatment‐side prescription quantities and screening‐side HbA1c—measure across 47 Japanese prefectures. Methods Cross‐sectional ecological study using the 10th NDB Open Data release. Indicator A was oral antidiabetic agent dispensing volume per population (drug classification 396), related to ageing, income, education and population density by ordinary least squares with VIF assessment and AIC‐based comparison. Indicator B comprised the HbA1c high‐value rate, mean HbA1c and the D005 laboratory‐testing rate, related to three claim‐rate outcomes by ordinary least squares with HC3 errors (five sensitivity specifications). Results For Indicator A, ageing was the only significant univariable predictor ( β = 9961; R 2 = 0.324); the lowest‐AIC model retained ageing and income ( R 2 = 0.394; VIF = 2.18; income β = 56.6, p = 0.030). For Indicator B, the HbA1c high‐value rate was associated with chronic dialysis management ( β = 195.1/%pt., p = 0.006, R 2 = 0.271); mean HbA1c showed a comparable association; the primary association was stable across all five specifications. Conclusions Neither indicator family provided a direct estimate of disease burden. Prescription quantities reflected demographic and income structure, whereas HbA1c indicators showed a selective ecological association with downstream service use. Both are better interpreted as ecological surveillance indicators than direct measures of disease burden or prevalence.
