BMJ Open Diabetes Research & Care

BackgroundSkeletal muscle insulin resistance in diabetes is characterized by impaired GLUT4 availability and dysregulated AMP-activated protein kinase (AMPK) signaling. We investigated whether 4-hexylresorcinol (4HR) modulates glucose metabolism and AMPK-acetyl-CoA carboxylase (ACC)-GLUT4 signaling in vitro and in streptozotocin (STZ)-induced diabetic rats. MethodsDifferentiated C2C12 myotubes were treated with 4HR (0.1-10 {micro}M) and assessed for glucose uptake, GLUT4 translocation, protein stability, proteasome involvement, and AMPK/ACC phosphorylation. In vivo, streptozotocin (STZ)-induced diabetic rats received subcutaneous 4HR (10 mg{middle dot}kgL{superscript 1}, 5 times/week for 7 weeks). Glycemic control, insulin secretion, muscle glycogen content, and serum protein profiles were evaluated. Results4HR markedly increased glucose uptake (>5-fold vs. control, p<0.05), accompanied by increased phosphorylation of AMPK (Thr172) and ACC (Ser79), and redistribution of GLUT4 toward the cell periphery. Cycloheximide chase and proteasome inhibition experiments indicated partial stabilization of GLUT4. In diabetic rats, 4HR reduced fasting glycemia, improved glucose tolerance, elevated circulating insulin, and restored glycogen-rich fibers in skeletal muscle. Serum profiling revealed a metabolic and anti-inflammatory shift, with increased AMPK, p-ACC, GLUT1, LGR4, LDHA, and PGC-1, alongside suppression of NF-{kappa}B and TNF-. Conclusion4HR improves skeletal muscle glucose metabolism in STZ-induced diabetes, associated with activation of AMPK-ACC signaling, preservation of GLUT4 expression, and restoration of glycogen content. These findings highlight 4HR as a promising candidate for further investigation in diabetic muscle dysfunction and metabolic disease.

This study investigates the challenges and enablers of self-management in type 2 diabetes, the role of primary care in diabetes management, and patients preferences for additional support services in Switzerland. Participants reported significant difficulties in sustaining behavioral changes and emphasized the need for more structured guidance to improve self-management. Many felt unsupported in primary care, stating that their general practitioners could have intervened earlier when they were at high risk but before an official diagnosis. Additionally, patients highlighted the lack of centralized, up-to-date diabetes resources in Switzerland, contrasting it with structured systems like the National Health Service in the United Kingdom. There was also a strong demand for a unified digital health platform to consolidate glucose readings, blood pressure data, and medication lists, ensuring seamless integration with healthcare providers. These findings underscore the need for patient-centered diabetes management strategies that integrate digital innovations, proactive primary care interventions, and accessible, evidence-based resources to enhance self-management.

Aims/hypothesisHuman islet amyloid polypeptide (hIAPP) deposition is a common feature of type-2 diabetes (T2D). Previous studies have demonstrated hIAPP-mediated endothelial cell (EC) dysfunction and inflammation, but little is known about islet microvascular stability or pericyte function in hIAPP-containing islets. This study investigates how islet endothelial cells and pericytes are influenced by hIAPP aggregation. MethodsBulk RNAseq and qPCR were conducted on hIAPP or vehicle treated MS-1 cells and bead-purified human islet CD31+ cells from donors with or without T2D to determine how islet ECs respond to hIAPP exposure. Confocal imaging of living pancreatic slices obtained from hIAPP transgenic mice was conducted to evaluate the effect of hIAPP deposition on islet pericyte function and vasomotor responses. ResultshIAPP-treated MS-1 cells and ECs purified from T2D islets demonstrate downregulation of leading-edge genes associated with extracellular matrix and cell adhesion pathways. Pericytes from hIAPP-expressing mouse islets appear detached from underlying endothelial cells, which was associated with impaired vasomotor responses to constrictive or dilatory stimuli. Conclusions/interpretationhIAPP induces vascular destabilization by downregulating mRNA of key extracellular matrix and cell adhesion molecules in ECs, likely promoting the breakdown of EC-EC and EC-pericyte coupling. hIAPP disrupts EC-pericyte connections, and pericyte detachment ultimately impairs pericytes ability to modulate capillary diameter without impairing intracellular Ca2+ dynamics. Our data suggest that amyloid deposition compromises EC health and survival by altering islet microvascular morphology, stability, and function. This, in turn, may disrupt islet microvascular stability and exacerbate endocrine cell dysfunction in T2D. Research in contextO_ST_ABSWhat is already known about this subject?C_ST_ABS- hIAPP is cytotoxic to islet endothelial cells and beta cells, and contributes to islet failure in type-2 diabetes (T2D) - hIAPP transgenic mice demonstrate islet capillary dilation, loss of vascular structures, and increased pericyte density - Impaired pericyte anchorage and vascular fragmentation drive diabetes-related vasculopathies in other tissues, like the retina, kidney, and brain What is the key question?- How does the surviving microvasculature in islets respond to hIAPP deposition? What are the new findings?- Endothelial cells demonstrate transcriptional downregulation of key genes involved in cytoskeleton, ECM, and cell-adhesion maintenance, including Thbs1, Tln1, and Plec. - Amyloid deposits disrupt homeostatic interactions between endothelial cells and pericytes. - Amyloid-adjacent islet pericytes are detached from endothelial cells and display impaired ability to modulate capillary diameter. How might this impact on clinical practice in the foreseeable future?- Therapies targeting endothelial cell-pericyte interactions may restore islet microvascular stability and improve islet function, especially in the context of early T2D.

ObjectiveCardiovascular autonomic neuropathy (CAN) in diabetes is associated with increased mortality and morbidity and is a non-treatable complication. We investigated associations between circulating metabolites and presence of CAN in persons with type 1 diabetes (T1D). MethodsCAN was assessed by cardiovascular reflex tests (CARTs) in 302 persons with T1D as heart rate response to: deep breathing; lying-to-standing test; and the Valsalva manoeuvre. More than 1 pathological CART defined the CAN diagnosis. Serum metabolomics and lipidomics profiles were analysed with two complementary non-targeted massspectrometry methods. Cross-sectional associations between single metabolites and CAN were assessed by linear regression. Models were fitted with and without adjustments for relevant confounders and multiple testing. ResultsParticipants were mean (IQR) aged 55(49, 63) years, 50% males, with diabetes duration 39(32, 47) years, HbA1c 63(55,69) mmol/mol and 34% had the CAN diagnosis. A total of 75 metabolites and 106 lipids were examined. In crude models, CAN diagnosis was associated with higher levels of hydroxy fatty acids (2,4- and 3,4-dihydroxybutanoic acids, 4-deoxytetronic acid), creatinine, sugar derivates (ribitol, ribonic acid, myo-inositol), citric acid, glycerol, phenols, phosphatidylcholines and lower levels of free fatty acids and amino acid methionine (p<0.05). Upon adjustment, positive associations with CAN were retained with hydroxy fatty acids, tricarboxylic acid (TCA) cycle-based sugar derivates, and citric acid and phenols (Padjusted<0.05). ConclusionsMetabolic pathways, including the TCA cycle, hydroxy fatty acids, phosphatidylcholines and sugar derivatives, were associated with CAN in T1D. These novel metabolic pathways associated with CAN could prove to be future modifiable risk factors.

BackgroundClinical guidelines for most adults with diabetes recommend maintaining hemoglobin A1c (HbA1c) [&le;]7.0% (<53 mmol/mol) to avoid microvascular and macrovascular complications. People with diabetes of different ages, sexes, and socioeconomic statuses may differ in their ease of attaining this goal. As a team of people with diabetes, researchers, and health professionals, we aimed to explore patterns in HbA1c results among people with type 1 or type 2 diabetes in Canada. Our research question was identified by people living with diabetes. MethodsWe used generalized estimating equations to analyze the effects of age, sex and socioeconomic status in 947,543 HbA1c results measured from 2010 to 2019 among 90,770 people living with type 1 or 2 diabetes in Canada. People living with diabetes reviewed and interpreted the results. ResultsHbA1c results at or below 7.0% represented 30.5% (male people living with type 1 diabetes), 21.0% (female people living with type 1 diabetes), 55.0% (male people living with type 2 diabetes) and 59.0% (female people living with type 2 diabetes) of results in each subcategory. We observed higher HbA1c values during adolescence and, for people living with type 2 diabetes, among people living in lower income areas. Among those with type 1 diabetes, female people tended to have lower HbA1c than male people during childbearing years but higher HbA1c than male people during menopausal years. Team members living with diabetes confirmed that the patterns we observed reflected their own life courses and suggested these results be communicated to health professionals and other stakeholders to improve treatment for people living with diabetes. InterpretationA substantial proportion of people with diabetes in Canada are insufficiently supported to maintain guideline-recommended glycemic control goals. Blood sugar management goals may be particularly challenging for people who are going through adolescence, menopause, or living with fewer financial resources. Health professionals should be aware of the challenging nature of glycemic management and policymakers in Canada should provide more support for people with diabetes to live healthy lives.

AimsTo identify barriers and facilitators to physical activity (PA) in adults with type 1 diabetes (T1D) living in the United States (U.S.) and identify sociodemographic factors related to meeting recommended PA. MethodsWe conducted a cross-sectional online survey study of adults with T1D aged [&ge;]18 years recruited through online-based platforms. Quantitative questions related to exercise quantity and intensity, demographic characteristics, and exercise barriers and facilitators. Wilcoxon rank sum tests or independent t-tests were used to compare quantitative responses in individuals meeting or below target PA. Barriers and facilitators were also assessed qualitatively with open-ended questions. Logistic regression was performed to determine if the following characteristics were independently associated with meeting PA recommendations: age, sex, income level, and automated insulin delivery system use. ResultsOf 281 respondents who completed questions about exercise quantity, 162 (57.7%) were women, mean age 52.6 {+/-} 16.6 years, and 151 (53.7%) met PA guideline recommendations. Common barrier themes related to T1D included hypoglycemia, time, lack of knowledge about glycemic management, cost, and failure of available treatments to accommodate exercise. Common facilitator themes were insurance reimbursement of exercise program/facility, peer exercise groups, health/fitness advising, and T1D tailored fitness. Middle (vs. upper) income level was independently associated with lower odds of meeting PA recommendations (adjusted odds ratio 0.46, 95% CI: 0.27, 0.78, p = 0.004). ConclusionsIn this predominately U.S. cohort with T1D, financial factors were common novel themes related to PA. Further validation in more socioeconomically diverse cohorts and research examining PA reimbursement cost-efficacy are needed. Novelty statementO_ST_ABSWhat is already known?C_ST_ABSO_LIIn prior qualitative studies in type 1 diabetes, hypoglycemia is a commonly reported barrier to physical activity (PA) engagement. Most studies were conducted outside the United States (U.S.). C_LI What this study foundO_LIIn a predominately U.S. cohort of adults with type 1 diabetes, cost is a newly identified barrier to PA. C_LIO_LIInsurance reimbursement of PA programs/facilities was a reported facilitator. C_LIO_LIIndividuals with highest income were 54% more likely to achieve recommended PA compared to other income categories. C_LI What are the implications of the study?O_LICost-efficacy research examining PA programs/facility reimbursement in type 1 diabetes is needed. C_LI

AimsTo investigate whether kidney injury, determined by albumin creatinine ratio, was associated with current non-healing foot wounds in type 2 diabetes. Materials and MethodsEighty-nine Barbadians with diabetes were recruited. Cases had a current foot wound and controls had no current foot wound and no history of a non-healing foot wound. Cases were matched to controls using sex, age and duration of diabetes. Participants were from wound dressing and diabetes clinics at the Queen Elizabeth Hospital and Polyclinics, and from private healthcare practitioners. The relationship between albumin creatinine ratio and foot ulceration, adjusting for selected potential risk factors, was analyzed using logistic regression and presented as odds ratios. ResultsForty-four cases and 45 controls were matched, with no statistically significant difference in matching criteria. There were statistically important differences in measures of neuropathy, blood glucose, HbA1c and Albumin:creatinine ratio between cases and controls. Cases were 3 times more likely than controls to have microalbuminuria (95% CI 0.9 - 10.2; p=0.08). Cases were 7.4 times more likely than controls to have macroalbuminuria (95% CI 1.2 - 47.5; p=0.04). ConclusionsThe possible association of albumin:creatinine ratio with diabetic foot wounds raises the possibility of its use in earlier identification of persons on the pathway to developing diabetic foot.

AimsPeople with diabetes experience a significantly higher prevalence of mental health issues, particularly depression. This adversely affects their diabetes management and overall health. This scoping review aims to develop a conceptual framework for understanding the connection between depression and diabetes outcomes globally, specifically focusing on intermediary factors that may influence this relationship. MethodsPubMed, EMBASE, PsycINFO, and Global Index Medicus were searched using relevant keywords on 17th May 2024. The inclusion criteria encompassed peer-reviewed studies involving adults diagnosed with Type 2 diabetes that assessed depression and analysed its impact on diabetes outcomes through various pathways ResultsThe review identified 30 studies examining the association between depression and diabetes outcomes. Results indicate that while depression is linked to poorer diabetes outcomes, the mechanisms are complex and often mediated by factors such as self-efficacy, social support, and diabetes-related distress. Notably, self-efficacy emerged as a critical mediator in the relationship between depression and self-management behaviours. Furthermore, social support was identified as a protective factor that can reduce the adverse effects of depression on glycaemic control. ConclusionsAddressing mental health concerns in diabetes care is essential for improving patient outcomes. This review underscores the need for integrated interventions that consider psychosocial factors to enhance self-management and glycaemic control among individuals with Type 2 diabetes. Future research should focus on exploring these relationships in diverse populations to inform tailored strategies for effective diabetes management. {blacksquare}Individuals with diabetes experience higher rates of mental health issues, particularly depression, which negatively impacts diabetes management and health outcomes. {blacksquare}This scoping review identified 30 studies linking depression to poorer diabetes outcomes and developed a conceptual framework that highlights the complex mechanisms involved, including factors such as self-efficacy, self-management, illness perception and social support. {blacksquare}The findings emphasize the importance of addressing mental health in diabetes care

Aims/hypothesisThis study aims to develop an accessible, machine learning-derived tool for people with type 1 diabetes that predicts hypoglycaemia risk at the start of exercise, facilitating quick, clear risk assessment that can directly support safer exercise habits. MethodsWe integrated data from four diverse studies encompassing 16,477 exercise sessions from 834 participants aged 12-80, using various insulin delivery methods. The XGBoost algorithm was used to develop a comprehensive and simplified model to predict hypoglycaemia during exercise, determined by continuous glucose monitor readings below 3.9 mmol/L (70 mg/dL). ResultsThe comprehensive model demonstrated a mean ROC AUC of 0.89, while the simplified model, relying solely on glucose levels at the start of exercise, duration of exercise and glucose rate of change arrows, achieved an ROC AUC of 0.87. This model was shown to be effective for any type of exercise and for people on a variety of insulin delivery devices. This simplified model was then translated, through collaborative efforts with type 1 diabetes participants, into "GlucoseGo," a user-friendly, traffic-light heatmap that visually demonstrates risk of hypoglycaemia during exercise based on these three variables. Conclusions/interpretation The GlucoseGo heatmap offers a simple, readily available tool for predicting hypoglycaemia risk at the onset of exercise. This advancement empowers users to manage their exercise routines more safely, with potential to reduce hypoglycaemia incidents and enhancing exercise engagement among the type 1 diabetes population. Research in contextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIExercise is crucial for managing type 1 diabetes, yet adherence to recommended guidelines is low. C_LIO_LIExercise-induced hypoglycaemia is a major barrier to exercise for those with type 1 diabetes. C_LIO_LIExisting machine learning models for predicting hypoglycaemia during exercise often require complex data inputs, limiting their practical use. C_LI What is the key question?O_LICan a machine learning model using minimal data effectively predict exercise-induced hypoglycaemia in type 1 diabetes? C_LI What are the new findings?O_LIWe developed a simplified machine learning model using only three variables; starting glucose levels, glucose rate of change arrows and exercise duration - that nearly matches the performance of more complex models, with an ROC AUC of 0.87 versus 0.89. C_LIO_LIThis model was transformed into "GlucoseGo," user-friendly heatmaps, designed collaboratively with individuals with type 1 diabetes, that visually indicate exercise-induced hypoglycaemia risk. C_LIO_LISubgroup analyses show consistently good performance in predicting hypoglycaemia risk across diverse patient profiles and exercise types, validating its broad applicability. C_LI How might this impact clinical practice in the foreseeable future?GlucoseGo offers a practical tool for safely managing exercise, potentially reducing hypoglycaemic incidents and increasing exercise participation among those with type 1 diabetes.

BackgroundCept1 is essential for de novo phopholipogenesis and is impacted by diabetes. We previously demonstrated that conditional knockdown of Cept1 in the endothelium leads to reduced hindlimb angiogenesis and tissue recovery. We hypothesized that Cept1 may also be sufficient in promoting post-ischemic angiogenesis and recovery in the setting of diabetes. MethodsCEPT1 content was evaluated in peripheral arteries of patients with peripheral arterial disease (PAD), and with or without diabetes. An endothelial cell (EC)-specific Cept1 overexpression mouse model was developed (Cept1fl/flCre+) in adult C57BL6 mice. Murine aortae were harvested, for single-cell RNA sequencing (scRNA-seq), and unilateral hindlimb ischemia was used to evaluate angiogenesis in Cept1fl/flCre+ mice. Primary ECs were isolated and HUVECs transduced with Cept1 cDNA were developed, and evaluated using molecular assays, in vitro functional assays, and mass spectrometry. ResultsIn humans, arterial intima CEPT1 was elevated in the setting of PAD and diabetes, along with ACOX1, VEGF2R, p-Akt, and p-eNOS. In mice, scRNA-seq demonstrated that ECs with Cept1 overexpression were enriched with wound healing, angiogenesis, sprouting, and cell migration pathways. Diabetic Cept1fl/flCre+ mice had improved hind-limb perfusion and angiogenesis, and their aortic rings had increased ex vivo capillary sprouting. Cept1 overexpression in ECs significantly increased migration, tubule formation, and proliferation as predicted by scRNA-seq. Cept1 overexpression in ECs led to increased Ppar, Acox1, Vegfa, and Vegf2r. Similarly, treatment with siPpar, and inhibitors for PPAR (GW6471), VEGFR2 (ZM323881), Akt (LY294002), and eNOS (L-NAME) abrogated CEPT1-induced EC migration. ConclusionsCept1 overexpression promotes EC function and post-ischemic recovery. The impact of CEPT1 on ECs is at least in part dependent on p-Akt/p-eNOS angiogenic signaling and PPAR. Since CEPT1 is elevated in diseased human peripheral arterial tissue, these findings suggest that CEPT1 may be playing an important compensatory role in vascular recovery and reperfusion following ischemic injury in the setting diabetes. HighlightsO_LICEPT1 content is higher in the peripheral arteries of individuals with peripheral arterial disease (PAD) and type 2 diabetes. C_LIO_LICept1 over expression induces endothelial cell activation and function and enhances post-ischemia angiogenesis in vivo. C_LIO_LICEPT1 induces endothelial pAkt/p-eNOS signaling and VEGF-A production in a PPAR dependent fashion. C_LIO_LICEPT1 may be an important regenerative signal that is increased in the peripheral arteries in the setting of PAD. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/642511v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@dde6ecorg.highwire.dtl.DTLVardef@63c6c4org.highwire.dtl.DTLVardef@8e753dorg.highwire.dtl.DTLVardef@b314cd_HPS_FORMAT_FIGEXP M_FIG C_FIG

Purpose: It has been known for some time that normal retinal signaling is disrupted early on in diabetes, before the onset of the vascular pathologies associated with diabetic retinopathy. There is growing evidence that levels of retinal dopamine, a neuromodulator that mediates light adaptation, may also be reduced in early diabetes. Previously, we have shown that after six weeks of diabetes in a mouse model, light adaptation is impaired at the level of ON-sustained (ON-s) ganglion cells. The purpose of this study was to determine whether changes in dopamine receptor sensitivity contribute to this dysfunction. Here we used single cell retinal patch-clamp recordings from the mouse retina to determine how activating dopamine type D4 receptors (D4Rs) changes the light-evoked and spontaneous excitatory inputs to ON-s ganglion cells, in both control and diabetic animals. We also used in-situ fluorescent hybridization to assess whether D4R expression was impacted by diabetes. We found that D4R activation had a smaller impact on light-evoked excitatory inputs to ON-s ganglion cells in diabetic retinas compared to controls. This impaired D4R signaling is not attributable to a decline in D4R expression, as we found increased D4R mRNA density in the outer plexiform layer in diabetic retinas. This suggests that the cellular machinery of dopaminergic signaling is itself disrupted in early diabetes and may be amenable to chronic dopamine supplementation therapy.

BackgroundDiabetic foot complications are a leading cause of morbidity, disability, and healthcare costs worldwide, yet they are largely preventable through proper self-care. In Palestine, evidence on patient adherence to recommended practices is scarce. This study aimed to assess the knowledge, attitudes, and practices of foot self-care among adults with diabetes in the West Bank and to identify factors associated with adherence. MethodsA cross-sectional study was conducted among 300 diabetic patients attending primary care clinics across the West Bank. Data were collected using a structured and validated questionnaire covering knowledge, attitudes, and practices. Statistical analyses included reliability testing, factor analysis, bivariate correlations, and multivariable regression models to identify independent predictors of adherence. ResultsAdherence to recommended foot care practices was generally low, with only 13% of participants reporting daily engagement in all recommended behaviors. While daily foot washing was widely practiced (80.9%), preventive measures were less consistent: 33.1% inspected their feet daily, 45.1% dried between toes, and 40.3% inspected shoes. Risky practices were also common, including foot soaking (28.6%), barefoot walking (20.2%), and wearing shoes without socks (15.9%). Reliability testing of the foot care scale revealed poor internal consistency (Cronbachs alpha = 0.39), suggesting a multidimensional structure. Multivariable regression showed that higher education (adjusted B = -4.05 for no schooling vs. undergraduate, p = 0.049), higher income (B = +3.91, p = 0.028), and longer diabetes duration (B = +1.02 per 5 years, p = 0.035) were associated with better adherence. Male sex was linked to lower adherence (OR 0.46, p = 0.017). Exposure to structured education and professional foot examinations also strongly predicted improved practices. ConclusionAdherence to preventive foot self-care among diabetic patients in the West Bank is suboptimal, particularly in practices directly related to ulcer prevention. Socioeconomic disparities, health literacy, and limited clinical reinforcement emerged as key barriers. Culturally tailored education, structured provider counseling, and policy-level interventions are urgently needed to reduce the burden of diabetic foot disease in Palestine.

BACKGROUNDEffective cardiovascular disease (CVD) risk management is a cornerstone of optimal diabetes care. Here, we estimated the prevalence and determinants of CVD risk factor control amongst individuals with diagnosed diabetes in Mexico. METHODSWe analyzed data from individuals with diagnosed diabetes [&ge;]20 years from the 2016-2023 Mexican National Health and Nutrition Surveys. We estimated the prevalence of glycemic, blood pressure (BP), non-current smoking, and combined CVD risk factor control. LDL-C control was assessed using SCORE2-Diabetes risk categories. We estimated the prevalence of BP-lowering, cholesterol-lowering, and glucose-lowering medication use, and explored determinants of control achievement using logistic regression. RESULTSWe analyzed data representing 43.2 million adults with diagnosed diabetes during 2016-2023. In 2023, glycemic control was 29% (95%CI 21%-38%), BP control 22.9% (95%CI 14%-31%), and non-current smoking 89% (95%CI 81%-96%). The proportion of people classified as high or very-high CVD risk increased from 59.8% (95%CI 52.1%-67.0%) in 2016 to 68.4% (95%CI 55.6%-78.9%) in 2023, representing [~]5.1 million adults. LDL-C control prevalence increased from 2.8% (95%CI 1.2%-4.4%) in 2016 to 6.6% (95%CI 1.9%-11.2%) in 2023. Combined risk factor control achievement was low primarily due to suboptimal LDL-C control, despite high medication use; this was more likely achieved in females, younger individuals, and those with college education or living in states with higher socioeconomic position. CONCLUSIONSDespite increasing CVD risk during this period, comprehensive glycemic and CVD risk factor management for adults with diabetes in Mexico remains suboptimal. Our findings highlight the need for strategies to address gaps in CVD risk management to reduce premature mortality in this population. Lay summaryThis study examined how well adults with diabetes in Mexico are controlling key risk factors for cardiovascular disease, such as blood glucose levels, blood pressure, smoking, and cholesterol levels. Authors used nationally representative surveys from 2016-2023 analyzing data which represents over 43.2 million adults living with diagnosed diabetes. O_LIIn 2023, fewer than one-third of individuals with diabetes had adequate blood glucose control, and fewer than one in ten met recommended cholesterol targets, despite high rates of medication use. Cardiovascular risk increased for those at the highest risk by nearly 9% between 2016 and 2023. C_LIO_LIBetter control of these risk factors was more common among women, younger individuals, those with higher education, and those living in more socioeconomically advantaged areas. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/24313926v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@66e47dorg.highwire.dtl.DTLVardef@122fd03org.highwire.dtl.DTLVardef@10f992org.highwire.dtl.DTLVardef@71094f_HPS_FORMAT_FIGEXP M_FIG C_FIG

In the context of type 2 diabetes mellitus (T2DM), the concept of organ-specific insulin resistance (IR) as a localized manifestation has garnered increasing attention. A scoping review was conducted to investigate the clinical relevance of IR confined to individual organs without systemic metabolic implications. Utilizing a methodological framework adapted from Arksey and OMalley, a comprehensive search of PubMed was performed, focusing on the period between January 1990 and October 2024. The search strategy combined Medical Subject Headings terms and keywords related to IR and specific organs. Notably, while "insulin resistance" yielded a substantial number of results, the subset of "organ-specific insulin resistance" returned a more limited dataset, highlighting a gap in current literature. The systematic selection process encompassed identification, screening, eligibility, and inclusion stages to ensure robust inclusion criteria. This scoping review underscores the importance of exploring organ-specific IR in the diabetic milieu and sets the stage for further research to elucidate its role in the pathogenesis of T2DM. Conclusion: The findings suggest that investigating organ-specific IR in the context of T2DM is a promising avenue for future research to deepen our understanding of disease pathophysiology. Thus, this scoping review answers the following question "In Situ Resistance Insulin - Localized Type 2 Diabetes Mellitus or Type 6 Diabetes Mellitus?", emphasizing the need for targeted investigations into localized manifestations of IR and their implications for DM management strategies.

BackgroundThe COVID-19 pandemic disrupted healthcare services, potentially affecting diabetes management and complications. ObjectiveTo investigate the impact of the pandemic on lower extremity amputation (LEA) rates among individuals with type 1 and type 2 diabetes mellitus, focusing on social determinants of health. MethodsA retrospective observational cohort study using de-identified claims data from a large U.S. health plan. LEA rates were compared before and after the onset of the COVID-19 pandemic using interrupted time series analysis. ResultsIndividuals with type 2 diabetes experienced an initial decline in LEA rates followed by a significant increase (p=0.022) as delayed care needs were addressed. Individuals with type 1 diabetes showed no significant fluctuations in amputation rates. Social determinants were significantly associated with changes in LEA rates among individuals with type 2 diabetes. Lower-income ([&le;]$40,000/year) and less educated individuals experienced significant increases in amputation rates (p=0.027 and p=0.043, respectively). Individuals aged 45-64 years showed a significant increase in LEA rates (p=0.013), while those aged 18-44 experienced a decrease (p=0.017). Metropolitan residents saw significant increases in LEA rates (p=0.021). ConclusionsThe COVID-19 pandemic significantly disrupted healthcare access for individuals with type 2 diabetes, leading to increased LEA rates. Social determinants of health exacerbated existing disparities in diabetes outcomes. These findings underscore the need for targeted interventions to address healthcare disparities, especially during public health crises.

Background: Prediabetes is a critical intermediate stage in the development of type 2 diabetes mellitus and is increasingly prevalent in the Eastern Mediterranean Region. In Qatar, high levels of metabolic and lifestyle-related risk factors underscore the need for scalable, non-invasive risk stratification tools within primary care. The Prediabetes Risk Score in Qatar (PRISQ) was developed as a population-specific screening tool; however, its distribution and associated risk patterns within national primary care settings remain insufficiently characterized. This study aimed to assess the population-level distribution of PRISQ scores among adults attending primary care in Qatar and to identify key sociodemographic and clinical correlates of elevated prediabetes risk. Methods: A cross-sectional analysis was conducted among adults ([&ge;]18 years) registered with the Primary Health Care Corporation (PHCC), using data derived from the HEALTHSIGHT study. PRISQ scores were calculated based on five non-invasive clinical parameters: age, sex, body mass index, waist circumference, and blood pressure. Participants were categorized into low, moderate, and high-risk groups using established PRISQ cut-offs. Descriptive analyses summarized risk distributions, and multivariable linear regression was used to identify independent predictors of PRISQ scores. Results: Among 1,116 participants included in the final analysis, the mean PRISQ score was 26.5 {+/-} 11.0. Nearly half of the study population (47.7%) was classified as high risk for prediabetes, while 34.4% and 17.9% were categorized as moderate and low risk, respectively. Increasing age was the strongest contributor to higher PRISQ scores, followed by body mass index, waist circumference, and blood pressure (all p < 0.001). High-risk individuals were more frequently male, older, overweight or obese, and long-term residents of Qatar, with variation across nationality groups. Conclusions: A substantial proportion of adults attending primary care in Qatar are at high predicted risk for prediabetes. These findings support the utility of PRISQ as a risk stratification and engagement tool in primary care to guide early lifestyle counselling and targeted preventive interventions. Longitudinal studies are needed to assess progression to dysglycemia and to further refine risk-based screening strategies.

IntroductionType 2 diabetes mellitus (T2DM) is a lifelong condition that has large societal, economic and clinical implications, and treatment should be supported by healthy lifestyle factors. Interventions for effective self-management are essential to the sustainability of treatment, however there is no standard approach. Research Design and MethodsSix hundred and five participants diagnosed with Type 2 Diabetes Mellitus were recruited from four countries (UK, France, Netherlands, Belgium) to complete the 12-week DWELL (Diabetes and WELLbeing) psychoeducational intervention. The programme was delivered at community and hospital-based settings and comprised of four key areas: education, nutrition, physical activity and wellbeing. Metabolic health (weight, waist size, BMI and HbA1c) and self-reported psychological measures were taken at four points: pre- and post-intervention, and two follow up points (at 6 and 12 months) to assess the impact of the programme. ResultsParticipants showed a significant reduction in all metabolic health measures, with improvements in both weight and BMI being maintained at 6-month follow-up. Participation in the programme also led to enhanced levels of participant empowerment, with significant improvements also seen in perceptions of diabetes, eating behaviours, mental and physical health, and self-care behaviours. ConclusionsThe study results demonstrated that an empowerment-based, holistic and flexible approach to diabetes self-management education programmes has a wider impact in improving longer term coping behaviours which help in achieving and sustaining positive metabolic and psychological changes. Key Messages What is already known on this topicDiabetes education has evolved from a compliance and knowledge-oriented approach to an empowerment and self-management-oriented approach. Yet, type 2 diabetes self-management education (DSME) programmes are mainly evaluated in relation to impact on metabolic (glycaemic) outcomes than on wider psychosocial outcomes. What this study addsParticipation in the DWELL programme led to significant improvements in metabolic health measures and produced significant positive changes across a range of psychological measures such as patient empowerment, illness perceptions, eating behaviours and self-care behaviours. How this study might affect research, practice or policyThe DWELL DSME programme which was co-designed with patients, healthcare professionals and family carers, focussed on patient empowerment and self-control, by offering flexibility and choice of options as well as peer support. Programme outcomes indicated that this approach led to positive changes in empowering and enabling health behaviour changes and improvements in metabolic health. The study adds to the body of knowledge of patient-led DSME practice with a holistic approach. Further research could shed light on the cultural and intersectional aspects of such approach that can inform more targeted programmes supporting T2DM patients with multiple co-morbidities such as serious mental health conditions.

BackgroundDigital delivery of lifestyle interventions offers a potentially effective, affordable, and convenient option for patients to prevent and monitor type 2 diabetes (T2D) (Khan et al., 2019). Hemoglobin A1c (A1c) is a measure used to monitor T2D progression. Standard of care- based approaches to encourage lifestyle modification have been shown to decrease A1c, yet high healthcare costs and travel-related barriers limit the accessibility of these strategies. Rising T2D rates globally underscore the immediate need to identify the most comparably effective options that decrease A1c and address disease prevention and management. ObjectivesThis systematic review examines the effectiveness of digital delivery of lifestyle interventions in decreasing A1c among adults globally both overall and compared to standard ofcare and monitoring only based approaches. MethodsBased on application of the Navigation Guide systematic review methodology, 10 studies conducted in eight countries met the inclusion criteria and were evaluated for bias, quality, and strength of evidence. Conclusions were drawn from evaluating quantitative results. ResultsA systematic review of the literature demonstrated sufficient evidence of an association between digital delivery of lifestyle interventions and decreased A1c trends. Research did not show significant differences in A1c changes among the intervention groups when compared to the standard of care and monitoring only based control groups. ConclusionsThese results indicate that while the digital delivery of lifestyle interventions is effective in lowering A1c levels in T2D patients, these interventions do not outperform standard of care and monitoring only based approaches to prevent and manage T2D.

ObjectiveSignaling through Prostaglandin E3 Receptor (EP3), a G protein-coupled receptor for E series prostaglandins such as prostaglandin E2 (PGE2), has been linked to the beta-cell dysfunction and loss of beta-cell mass in type 2 diabetes (T2D). In the beta-cell, EP3 is specifically coupled to the unique cAMP-inhibitory G protein, Gz. Divergent effects of EP3 agonists and antagonists or Gz loss on beta-cell function, replication, and survival depending on whether islets are isolated from mice or humans in the lean and healthy, type 1 diabetic, or T2D state suggest a divergence in biological effects downstream of EP3/Gz dependent on the physiological milieu in which the islets reside.\n\nMethodsWe determined the expression of a number of genes in the EP3/Gz signaling pathway; PGE2 production pathway; and the beta-cell metabolic, proliferative, and survival responses to insulin resistance and its corresponding metabolic and inflammatory derangements in a panel of 80 islet preparations from non-diabetic human organ donors spanning a BMI range of approximately 20-45. In a subset of islet preparations, we also performed glucose-stimulated insulin secretion assays with and without the addition of an EP3 agonist, L798,106, and a glucagon-like peptide 1 receptor agonist, exendin-4, allowing us to compare the gene expression profile of each islet preparation with its (1) total islet insulin content (2), functional responses to glucose and incretin hormones, and (3) intrinsic influence of endogenous EP3 signaling in regulating these functional responses. We also transduced two independent islet preparations from three human organ donors with adenoviruses encoding human Gz or a GFP control in order to determine the impact of Gz hyperactivity (a mimic of the T2D state) on human islet insulin content and functional response to glucose.\n\nResultsIn contrast to results from islets isolated from T2D mice and human organ donors, where PGE2-mediated EP3 signaling actively contributes to beta-cell dysfunction, PGE2 production and EP3 expression appeared positively associated with various measurements of functional beta-cell compensation. While Gz mRNA expression was negatively associated with islet insulin content, that of each of the Gz-sensitive adenylate cyclase (AC) isoforms were positively associated with BMI and cyclin A1 mRNA expression, suggesting increased expression of AC1, AC5, and AC6 is a compensatory mechanism to augment beta-cell mass. Human islets over-expressing Gz via adenoviral transduction had reduced islet insulin content and secretion of insulin in response to stimulatory glucose as a percent of content, consistent with the effects of hyperactivation of Gz by PGE2/EP3 signaling observed in islets exposed to the T2D physiological milieu.\n\nConclusionsOur work sheds light on critical mechanisms in the human beta-cell compensatory response, before the progression to frank T2D.

The integration of chrono-medicine into disease management has potential for cost-effective improvements, particularly in type 2 diabetes care. While both exercise and metformin are effective in lowering glycaemia, their combined effect is non-additive. Individual circadian rhythms suggest that personalised timing of interventions may optimise outcomes. This study aims to investigate the heterogeneity in response to the timing of exercise and metformin intake using an n-of-1 approach within a randomised crossover trial, thereby exploring the potential for individualised chrono-medicine strategies. A previously published 16-week randomised crossover study was conducted to explore the potential therapeutic effects of prescribed moderate exercise timings in participants undergoing metformin monotherapy. Physical activity, heart rate, sleep, and glucose levels were tracked using wearable technology and continuous glucose monitors. Data were collected during baseline, and throughout the intervention periods. Analysis focused on individual responses to the timing of exercise and metformin intake. Morning exercise significantly lowered 24-hour post-exercise blood glucose levels compare to evening exercise. Both exercise timings reduced mean blood glucose levels, but morning exercise had a greater effect (mean difference: -0.63 mmol/L, p<0.001) than evening exercise (mean difference: -0.34 mmol/L, p=0.016). Individual responses varied, with some participants displaying a substantial reduction in glucose levels in response to morning or evening exercise, while others did not benefit from either exercise intervention. Pre-breakfast metformin intake significantly lowered area under the curve (AUC) glucose values in response to morning exercise compared to post-breakfast, an effect not observed with evening exercise. Morning exercise combined with pre-breakfast metformin intake is the most effective strategy for lowering blood glucose levels in the greatest number of participants with type 2 diabetes. However, individual response heterogeneity suggests that chrono-medicine approaches must be personalised. Further research is needed to understand the underlying mechanisms of individual variability in response to exercise and medication timing. Research in ContextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIExercise prescription and metformin treatment are both effective in lowering glycaemia but their combined effect is non-additive. C_LIO_LIIt is unknown how individual circadian rhythmicity interacts with these diabetes treatment strategies. C_LI What is the key question?O_LIIs there potential for personalisation of a chrono-medicine approach to diabetes management? C_LI What are the new findings?O_LIMorning exercise combined with pre-breakfast metformin intake is the most effective strategy for lowering blood glucose levels in the greatest number of participants with type 2 diabetes. C_LIO_LIFurther research is needed to understand the underlying mechanisms of individual variability in response to exercise and medication timing. C_LI How might this impact on clinical practice in the foreseeable future?O_LIOur study shows that integrating chrono-medicine into disease management has potential for cost-effective improvements, particularly in type 2 diabetes care. C_LI