Loss of islet beta cell function and mass are critical in the pathogenesis of type 2 diabetes, a disease in which ~90% of individuals exhibit islet amyloid deposition. Amyloid deposits comprise the normal beta cell secretory product, human islet amyloid polypeptide (hIAPP), the aggregation of which is toxic to beta cells. While the underlying mechanism(s) for toxicity remain unknown, it is likely to involve mitochondrial dysfunction. We have shown that the mitochondrial cholesterol transport protein, steroidogenic acute regulatory protein (StAR), is upregulated in beta cells following amyloid deposition. Here, we examined the role of StAR in the toxicity of islet amyloidosis. Human islets from non-diabetic donors were cultured under amyloidogenic conditions and StAR expression was examined. StAR expression was also determined in islets isolated from transgenic mice expressing amyloidogenic hIAPP or non-transgenic littermates expressing non-amyloidogenic islet amyloid polypeptide, cultured under amyloidogenic conditions with or without the addition of an amyloid inhibitor. Total islet cholesterol content, mitochondrial cholesterol content, mitochondrial function and cell viability/death were compared in transgenic hIAPP and non-transgenic islets cultured in amyloidogenic conditions. Additionally, StAR localisation to islet cells, as well as its intracellular localisation, was examined. StAR was present in human islets at the mRNA and protein level, and expression increased significantly with amyloid formation in vitro. Further, in hIAPP transgenic mouse islets, StAR expression was amyloid-dependent. StAR was predominantly expressed in beta cells, and the amyloid-induced increase in StAR protein was found specifically in the mitochondrial fraction. While total and mitochondrial cholesterol content was unchanged between non-transgenic and hIAPP transgenic mouse islets cultured under amyloidogenic conditions, increased StAR expression was associated with decreased mitochondrial glucose-stimulated respiration and increased cell death. These findings are consistent with StAR having a pathophysiological role in the beta cell in type 2 diabetes, where its upregulation under conditions of islet amyloid deposition could contribute to mitochondrial dysfunction.

Physical education (PE) in adolescents with type 1 diabetes remains underexplored despite its key role in shaping adolescents' engagement with physical activity. While the only available data about inclusion of individuals with type 1 diabetes in PE lessons are based on interviews with teachers, this study aimed to explore the first-person perspectives of adolescents. This was a child-centred qualitative study using grounded theory. We conducted semi-structured interviews with 25 adolescents (11-15 years) with type 1 diabetes recruited from diverse middle schools. Students' experiences in PE are shaped by the balance between equal participation, recognition of diabetes-related needs and discreet support for autonomous glucose management, which together foster a psychologically healthy environment prompting competence, connection and autonomy. Fear of hypoglycaemia was not identified as a barrier to PE participation. Adolescents instead called for greater teacher support and regretted that excessive caution sometimes undermined their engagement and sense of competence. They sought equal participation without discrimination, with minimal adjustments for hypoglycaemic episodes. The practical constraints of insulin pumps further highlight the need for more discreet technological designs. The study emphasises teachers' central role and the need for education on self-regulating physical effort according to glucose levels, which remains underdeveloped. Practical recommendations are identified to better meet the needs of young people with type 1 diabetes in middle school PE.

Using a randomised, crossover design, we investigated whether exercise snacks could improve indices of glucose regulation assessed by continuous glucose monitoring, compared with an equivalent no-exercise control period in people living with non-insulin-treated type 2 diabetes. Previously inactive participants with well-controlled type 2 diabetes (n=31; 21 female participants, ten male participants; approximately 58 years old, BMI approximately 31 kg/m2, HbA1c approximately 48 mmol/mol [6.6%]) completed two experimental conditions in a randomised, counterbalanced order in the real world under a standardised diet. During the exercise snacks condition (ES), participants completed four 1min bouts of vigorous bodyweight exercise on two consecutive days, guided by instructional videos sent via email. The control condition (CON) involved two consecutive days of no exercise. Participants wore a continuous glucose monitor and a Fitbit watch to record glycaemic responses and heart rate, respectively. The primary outcome was mean glucose during each 48h condition. Secondary outcomes included 2h postprandial glucose responses after standardised meals and markers of glycaemic variability. The difference in mean glucose between ES and CON did not reach statistical significance (between-condition difference -0.2 mmol/l; 95% CI -0.4, 0.0; p=0.07). However, small but statistically significant improvements in standard deviation (-0.1 mmol/l; 95% CI -0.2, -0.1; p<0.001), coefficient of variation (-1%; 95% CI -2, 0; p=0.007), mean amplitude of glycaemic excursions (-0.3 mmol/l; 95% CI -0.5, 0.0; p=0.04) and time in tight range (3%; 95% CI 0, 6; p=0.04) were seen under the ES condition compared with CON. The 2h postprandial glucose average, peak, area under the curve and incremental area under the curve were also significantly lower after breakfast and dinner during the ES condition compared with CON (all p<0.05). Bodyweight exercise snacks totalling 4 min of vigorous activity per day led to small, yet statistically significant improvements in indices of glycaemic variability and postprandial hyperglycaemia in insufficiently active individuals living with well-controlled type 2 diabetes. Trial registration ClinicalTrials.gov NCT06382246.

Reactive oxygen species modulator 1 (ROMO1) is a highly conserved inner mitochondrial membrane protein that senses reactive oxygen species and regulates mitochondrial dynamics. ROMO1 is required for mitochondrial fusion in vitro, and silencing ROMO1 increases sensitivity to cell death stimuli. The physiological role of ROMO1 remains unclear. To determine the role of Romo1 in vivo, we used gene targeting in mice to ablate Romo1 in the whole mouse and to conditionally knock out Romo1 in the pancreatic beta cell. Mitochondrial functional analyses were performed on isolated mouse and human islets lacking Romo1/ROMO1. We show that ROMO1 is essential for embryonic development, as Romo1 null mice die before embryonic day 8.5, earlier than GTPases OPA1 or MFN1/2 which catalyse mitochondrial inner and outer membrane fusion. Knockout of Romo1 in adult pancreatic beta cells results in impaired glucose homeostasis in young male mice (4 months) due to an insulin secretion defect. Isolated islets from male, but not female, mice showed impaired glucose-stimulated insulin secretion. While mitochondria from female mice were morphologically normal, mitochondria in Romo1 adult beta cell knockout (RABKO) cells from male mice were swollen and fragmented, with a reduction in mtDNA content. Knockout of Romo1 did not affect basal respiration in males or females, but deletion of Romo1 in both sexes in mice and of ROMO1 in isolated human islets reduced spare respiratory capacity, which involved the specific loss of respiratory activity at complex II/succinate dehydrogenase. Ageing of female RABKO mice resulted in loss of spare respiratory capacity and glucose intolerance. Our data demonstrate that ROMO1 is a key regulator of mitochondrial bioenergetics and spare respiratory capacity and is required for effective nutrient coupling to insulin secretion in the beta cell. These observations point to a critical role for spare respiratory capacity in the maintenance of euglycaemia and to the potential for targeting ROMO1/complex II to promote glucose coupling in settings of insulin insufficiency.

Data-driven subtyping of type 2 diabetes has not been translated into clinical practice due to the lack of routine fasting glucose and insulin measurements. We aimed to identify type 2 diabetes subtypes in clinical settings using electronic health records and study their epidemiology. We identified 727,076 adults (≥18 years) with newly diagnosed type 2 diabetes from Epic Cosmos research platform data across all 50 states and the District of Columbia between 2012 and 2023. Classification models developed in cohort studies were applied to study the sociodemographic distribution of subtypes. Cox proportional hazards regression models, adjusted for age and sex, were used to assess the rates of microvascular complications (retinopathy, neuropathy and nephropathy) and macrovascular complications (severe atherosclerotic cardiovascular disease [ASCVD], other ASCVD and heart failure). Among newly diagnosed individuals (mean age 64.4 years [SD 13.3], 52% female), 21.6% were classified as having severe insulin-deficient diabetes (SIDD), 23.8% were classified as having mild obesity-related diabetes (MOD), 40.9% were classified as having mild age-related diabetes and 13.7% were classified as having the mixed subtype. Compared with those classified as having MOD, individuals classified as having SIDD had higher HRs for retinopathy (HR 2.83; 95% CI 2.73, 2.93), neuropathy (HR 1.57; 95% CI 1.54, 1.60), nephropathy (HR 1.34; 95% CI 1.32, 1.37), severe ASCVD (HR 1.49; 95% CI 1.46, 1.53), other ASCVD (HR 1.23; 95% CI 1.21, 1.25) and heart failure (HR 1.17; 95% CI 1.15, 1.20). SIDD and MOD were more prevalent among Hispanics (28.4% and 30.1%, respectively) and non-Hispanic Black people (25.5% and 30.0%, respectively) compared with non-Hispanic White people (20.1% and 21.6%, respectively), and were also more prevalent in the District of Columbia and Utah, respectively, compared with the rest of the country. Individuals with different type 2 diabetes subtypes, identified through electronic health records, differ in terms of their risk of vascular complications. These findings support leveraging routine electronic health record data to improve the characterisation of patient heterogeneity at the time of diabetes diagnosis.

Diabetic kidney disease (DKD), a prevalent complication of diabetes, is the leading cause of chronic kidney disease globally. The current standard of care cannot halt disease progression and thus new therapeutic targets are needed. We previously showed that the metalloprotease ADAM17 mediates the profibrotic response to high glucose in kidney mesangial cells. Its upregulation in high glucose conditions augments its profibrotic effects. Here we investigate regulation of the Adam17 promoter region -2304/-1567, previously shown to be glucose responsive, for which regulatory factors have not yet been identified. Adam17 promoter regulation, cell surface translocation and activation were assessed in primary rat mesangial cells using standard molecular biology techniques. Type 1 diabetes was induced in mice using streptozocin and kidney function and development of fibrosis were assessed after 24 weeks. Human and mouse kidneys were immunostained for LASP1. In rat mesangial cells, the LIM and SH3 protein 1 (LASP1) was identified as a regulator of the Adam17 promoter in response to high glucose by mass spectrometry of nuclear lysate proteins binding to the -2304/-1567 promoter region. Knockdown of LASP1 prevented glucose-induced Adam17 promoter activation and transcript and protein upregulation. LASP1 nuclear localisation and regulation of Adam17 promoter activity in high glucose required phosphorylation of LASP1 on S146 by protein kinase A, but not protein kinase G, and Y171 phosphorylation by Src kinase. LASP1 also regulated glucose-induced ADAM17 cell surface localisation and activation, dependent on its phosphorylation by Src and interaction with focal adhesion kinase. Profibrotic responses to glucose were inhibited by LASP1 downregulation. In vivo, LASP1 expression was increased in the kidneys of type 1 diabetic mice and in kidneys of patients with DKD. Mice with Lasp1 knockout showed attenuated development of DKD. LASP1 regulates the synthesis and activation of ADAM17 in mesangial cells and is required for the profibrotic response to high glucose. Its deletion protects against DKD in mice. Targeting LASP1 may have therapeutic value as an indirect method of ADAM17 inhibition to inhibit fibrosis in DKD.

We aimed to investigate whether maternal and fetal genetic predispositions to insulin deficiency and resistance affect offspring fetal growth through distinct pathways in multi-ethnic populations. In 5065 multi-ethnic mother-infant pairs, we examined the conditional associations of maternal and fetal partitioned polygenic risk scores (pPRSs) for type 2 diabetes-related pathways with fetal growth outcomes, including birthweight, sum of skinfold thicknesses (SSF), large-for-gestational-age (LGA) births and small-for-gestational-age (SGA) births. Two-sample Mendelian randomisation (2SMR) in Europeans was performed for triangulation. Exposures were eight type 2 diabetes-related pathways (n=1,812,017), eight beta cell function indices (n=26,356) and two insulin sensitivity indices (n=53,657). Outcomes were maternal and fetal genetically determined birthweight (n=406,063). Mediation analysis was used to assess the mediation effects of maternal glucose levels and BMI on maternal genetic effects and of cord blood C-peptide on fetal genetic effects. Co-localisation analyses were performed to test for shared causal variants. Fetal type 2 diabetes polygenic risk score (PRS) and pPRSs for lipodystrophy-related insulin resistance and impaired fasting glucose (IFG)-related insulin deficiency were associated with lower birthweight and SSF, while maternal type 2 diabetes PRS and pPRSs for IFG-related insulin deficiency and obesity-related insulin resistance were associated with higher offspring birthweight, SSF and LGA. These associations were consistent across five ethnic groups. Maternal post-load hyperglycaemia mediated 44.2% and 34.2% of the effects of type 2 diabetes PRS and IFG pPRS, respectively, while maternal BMI mediated 43.4% of the effect of Obesity pPRS. 2SMR found consistent results in Europeans and further revealed that fetal insulin sensitivity index and corrected insulin response were associated with higher birthweight. Some loci with shared causal variants acted through multiple pathways, including CDKAL1, TCF7L2, ADCY5 and MACF1. Reduced fetal growth may be driven by lipodystrophy-related insulin resistance and IFG-related insulin deficiency pathways. Targeting pregnant women with high type 2 diabetes PRS/pPRS and prescribing interventions to reduce their post-load hyperglycaemia and BMI may help reduce offspring risk of LGA.

The chemokine receptor C-X-C chemokine receptor type3 (CXCR3) is a key chemoattractant molecule that facilitates the migration of activated Tcells to the pancreas, leading to beta cell death. In this study, we investigated CXCR3 responses in Bcells during type 1 diabetes progression. Peripheral blood samples were obtained from individuals with recent-onset and long-duration type 1 diabetes, who were age- and sex-matched to non-diabetic donors. We isolated peripheral blood mononuclear cells (PBMCs) and examined changes in CXCR3 expression on lymphocytes from donors, performing multiparameter flow cytometry and functional cell culture assays. Human post-mortem pancreatic tissue was obtained from the Exeter Archival Diabetes Biobank. Immunofluorescence staining was used to assess CXCR3 expression in pancreatic tissues. We observed reduced CXCR3 expression on antigen-experienced Bcells in individuals with a long duration of type 1 diabetes, although Bcells remained responsive to IFNγ. In individuals who were recently diagnosed, IFNγ treatment resulted in increased CXCR3 expression compared with Bcells from non-diabetic donors. Bcells in pancreases that were recovered post-mortem from young recent-onset donors lacked CXCR3 expression, but co-staining to detect CD8+ T cells revealed a CXCR3+CD20+CD8+ Tcell population, with their circulating counterpart showing increased CXCR3 expression. We conclude that the CXCR3 response in antigen-experienced Bcells is dysregulated during the progression of type 1 diabetes. CXCR3 expression is limited in CD20+ Bcells in pancreases from recent-onset individuals diagnosed with type 1 diabetes under 7 years of age, but evident on CD8+ T cells that express CD20.