BMJ Open Diabetes Research & Care最新文献

Introduction: As type 2 diabetes (T2D) prevalence increases in the USA and Africa, factors from both regions affect African immigrants.

Objective: T2D in African immigrants was characterized by examining: (a) insulin deficiency and insulin resistance; (b) phenotypic presentation; (c) sociodemographic factors.

Methods: In 633 African immigrants (male: 62%, age 39±11, (mean±SD), range 20-70 years), body mass index (BMI): 27.8±4.6, range 18.8-46.2 kg/m²), weight gain information was collected, BMI and waist circumference (WC) measured and OGTT performed. Insulin resistance was defined by the lowest quartile of the Matsuda Index (≤2.80); insulin secretion by the Insulin Secretion Index (ISI). Insulin deficiency was defined as less than the maximum ISI in participants with T2D without IR (0.430). WC thresholds defined central obesity (men: WC ≥94 cm; women ≥80 cm).

Results: Normal glucose tolerance, pre-diabetes and T2D occurred in 61%, 32% and 7%, respectively. Three subtypes of T2D were identified: insulin-deficient-T2D (ID-T2D) in 45%, insulin-resistant-T2D (IR-T2D) in 30%, insulin-deficient+insulin-resistant (ID+IR-T2D) in 25%. ID+IR-T2D had the highest glucose concentrations (all p<0.05), whereas insulins were highest in IR-T2D (all p<0.01). Phenotypic differences by T2D subtype were identified. In the ID-T2D group, 20% of participants had a healthy weight and central obesity occurred in 55%. In the IR-T2D and ID+IR-T2D groups, 100% had central obesity and a BMI in either the overweight or obese categories. Sociodemographic factors specifically, weight gain, sedentary lifestyle and percent married, increased across glucose tolerance category (p values <0.01) but did not differ by T2D subtype (p≥0.3).

Conclusions: Spanning the BMI spectrum from normal to obese, African immigrants have three subtypes of T2D. Weight gain was greatest in immigrants who developed T2D but did not differ by subtype. As life in America promotes weight gain, sharing information about the consequences of weight gain with all Americans, both native and foreign-born, is key to T2D prevention and treatment.

Introduction: The U.S. Food and Drug Administration (FDA) investigated the potential risk of suicidal ideation and behaviors for glucagon-like peptide 1 receptor agonists (GLP-1 RAs) on learning of post-marketing reports of suicidal ideation and behaviors in patients taking GLP-1 RAs. This study assessed a potential association with intentional self-harm comparing GLP-1 RAs to other antidiabetic products.

Research design and methods: We conducted an active-comparator, new-user cohort study-using FDA's Sentinel System-with data from October 1, 2015, to September 30, 2023. The study included health plan members ≥18 years old diagnosed with type 2 diabetes, newly initiated GLP-1 RAs (n=1 161 983), sodium-glucose cotransporter-2 inhibitors (SGLT-2is, n=1 081 155), or dipeptidyl peptidase-4 inhibitors (DPP-4is, n=1 396 382), and continuously enrolled in a health plan with medical and drug coverage for ≥183 days. The main outcome was intentional self-harm. We estimated hazard ratios (HR) and 95% confidence intervals (CI) for intentional self-harm events and used inverse probability of treatment weighting of propensity scores to control for confounding.

Results: The comparator groups had a mean age that was slightly above 60 years and similar percentages of males and females. Adjusted incidence rates of intentional self-harm per 1000 person-years were 1.13 for GLP-1 RAs, 1.22 for SGLT-2is, and 1.37 for DPP-4is. Adjusted HRs indicated no increased risk of intentional self-harm comparing GLP-1 RAs to SGLT-2is (HR 0.93; 95% CI 0.81 to 1.08) or DPP-4is (HR 0.94; 95% CI 0.82 to 1.07). Subgroup analyses by comorbid obesity and diabetes, psychiatric history, prior intentional self-harm, age, and sex yielded similar results.

Conclusions: The use of GLP-1 RAs did not show increased risk of intentional self-harm compared with SGLT-2is or DPP-4is, which provides some reassurance regarding the safety of GLP-1 RA use in patients with type 2 diabetes.

Background: Type 1 diabetes is believed to be associated with early genetic and environmental stressors. Epigenetic age acceleration (EAA) is also associated with environmental stressors and the pathogenesis of many chronic diseases. This study explored longitudinal changes in EAA among individuals at high risk for type 1 diabetes.

Methods: DNA methylation was measured longitudinally in subjects from the Diabetes Autoimmunity Study in the Young cohort, 2547 children born 1993-2006 at high risk for type 1 diabetes. Data were collected before and after islet autoimmunity (IA) seroconversion, a preclinical type 1 diabetes stage. EAA was estimated from DNA methylation using an epigenetic clock appropriate for pediatric blood samples. A linear mixed model was used to test for differences in EAA between 85 type 1 diabetes cases and 85 controls, before and after IA seroconversion.

Results: Change in EAA significantly differed between cases and controls (p=0.02). EAA significantly decreased in cases, from pre-IA to post-IA seroconversion by 0.367 units (95% CI -0.64 to 0.09, p=0.01), but not in controls (0.045, 95% CI 0.23 to 0.32, p=0.75).

Conclusion: These results suggest that EAA occurs in children who develop type 1 diabetes prior to IA seroconversion, highlighting the potential role of early environmental stressors in disease pathogenesis.

Introduction: Diabetic ketoacidosis (DKA) occurs frequently in children with type 1 diabetes (T1D). The inflammatory response to DKA may play a role in complications, but the inflammatory pattern is not well characterized. We aimed to describe the inflammatory profile during and after DKA.

Research design and methods: We evaluated inflammatory mediators (cytokines, chemokines, growth factors, and matrix metalloproteinases) using multiplex immunoassays in children (1) hospitalized with acute DKA (6-8 hours after beginning treatment, (n=15), (2) seen in the outpatient diabetes clinic 2-5 days after DKA (n=14), (3) hospitalized with new-onset T1D without DKA <24 hours after beginning insulin (n=9), and (4) referred to the outpatient diabetes clinic for new-onset T1D without DKA 2-5 days after beginning insulin (n=14). Children with chronic T1D and glycated hemoglobin <8.0% (n=59) undergoing routine phlebotomy served as a reference group.

Results: Compared with the reference group, children with acute DKA had significant alterations in interleukin 1 (IL-1) receptor antagonist (IL-1RA), IL-6, IL-8, IL-10, IL-18, chemokine C-X-C motif ligand (CXCL) 5, CXCL10, chemokine C-C motif ligand (CCL) 27, tumor necrosis factor-related apoptosis-inducing ligand, granulocyte colony-stimulating factor, tissue inhibitor of metalloproteinase 2 (TIMP-2), TIMP-4, matrix metalloproteinase 2 (MMP-2), MMP-3, MMP-7, MMP-9, and MMP-10. MMP-3, MMP-10, TIMP-1, and IL-1RA were also elevated 2-5 days after DKA (false discovery rate-adjusted p<0.10 for all). MMP-2 and MMP-9 levels were altered in children with new-onset T1D without DKA <24 hours after starting insulin, but no significant inflammatory changes were found in new-onset T1D 2-5 days after starting insulin.

Conclusions: DKA causes a unique inflammatory pattern distinct from inflammatory changes in acute hyperglycemia or T1D-related autoimmunity. Alterations in MMPs and their tissue inhibitors play a dominant role in this inflammatory profile.

Objective: To ascertain the cross-sectional association between cardiovascular autonomic dysfunction and arterial stiffness across glucose metabolism status.

Research design and methods: We performed a cross-sectional analysis of participants of the Maastricht study. Cardiovascular autonomic function was based on heart rate variability (HRV) indices from 24-hour ECG recordings and summarized in z-scores for time and frequency domains. Aortic and carotid stiffness were assessed by carotid-femoral pulse wave velocity (PWV) and carotid artery distensibility (CD), respectively. We used multiple linear regression to study the associations and adjusted for demographic and lifestyle factors and a range of cardiovascular risk factors. We tested for effect modification of the associations by glucose metabolism status.

Results: PWV and CD measures were available in 3673 and 1802 participants, respectively (median (25th; 75th percentile) age: 60 years (53; 66), 51% women, 20% type 2 diabetes by design. Participants with lower HRV had higher aortic stiffness. Per SD lower time-domain and frequency-domain HRV z-scores were associated with 2.8% (95% CI 2.1% to 3.4%) and 2.8% (95% CI 2.1% to 3.5%) higher PWV, respectively. Similar trends were observed for carotid stiffness, with 3.2% (95% CI 1.4% to 5.0%) and 3.1% (95% CI 1.2% to 5.0%) lower CD per SD lower time-domain and frequency-domain HRV, respectively. The magnitude of these associations was higher in groups with prediabetes and type 2 diabetes compared with those with normal glucose metabolism, with evidence of effect modification by glucose metabolism status (p value for interaction: <0.01 for prediabetes and <0.05 to <0.10 for type 2 diabetes, both compared with normal glucose metabolism).

Conclusion: Cardiovascular autonomic dysfunction is associated with higher aortic and carotid stiffness, especially in people with dysglycemia.

Background: Existing studies have demonstrated a close association between sleep duration and insulin resistance (IR), diabetes, and related metabolic disorders. The estimated glucose disposal rate (eGDR) serves as a reliable marker of IR. This study examined the association between weekday sleep duration and eGDR, and the moderating role of weekend catch-up sleep (WCS).

Methods: We analyzed data from the National Health and Nutrition Examination Survey (2009-2023) using a cross-sectional study design to examine the association between weekday sleep duration and eGDR, while further investigating the moderating role of WCS on this relationship. Restricted cubic splines (RCS) were employed to assess potential nonlinear associations between sleep duration and eGDR, with piecewise regression analyses conducted based on identified inflection points to evaluate threshold effects. Generalized linear models and multivariable regression models were used to analyze the associations between different weekday sleep duration categories, WCS, and eGDR.

Results: This analysis included 23 475 participants. RCS modeling revealed an inverted U-shaped relationship between sleep duration and eGDR, with an inflection point at 7.32 hours. Below this threshold, increased sleep improved eGDR (β=0.273, 95% CI 0.224 to 0.322, p<0.001), while exceeding it was inversely associated (β=-0.222, 95% CI -0.272 to -0.171, p<0.001). Multivariable regression showed that, for those with <7.32 hours of weekday sleep, 1-2 hours of WCS was associated with increased eGDR (β=0.296, 95% CI 0.107 to 0.484, p=0.002) compared with no WCS. The >2 hours WCS group negatively moderated the relationship between weekday sleep and eGDR (β=-0.568, 95% CI -0.970 to -0.167, p=0.005).

Conclusion: This study revealed a significant inverted U-shaped relationship between weekday sleep duration and eGDR, identifying an optimal duration of approximately 7.32 hours, and that WCS is beneficial only in moderation and specifically for those with weekday sleep debt, whereas it may be detrimental for those who already sleep sufficiently. These findings underscore the importance of personalized sleep recommendations.

Introduction: Infections precede nearly all hospitalizations and amputations related to diabetes-related foot disease. Focusing on antibiotic management, we aimed to report the outcomes of people presenting with a new diabetes-related foot infection (DFI).

Research design and methods: In this prospective study conducted in Australian and New Zealand hospitals between 2018 and 2020, patients with diabetes, a foot ulcer and a newly diagnosed DFI were eligible for enrollment. DFI was categorized as mild or moderate/severe DFI, with the latter further categorized according to the presence of osteomyelitis. The primary outcome was healing of the index ulcer or amputation site at 6 months. Multivariable logistic regression analyses adjusted for potential confounders were undertaken to investigate the relationship between ulcer healing and infection severity, intravenous antibiotic duration and total antibiotic duration.

Results: Of 234 included patients presenting to 20 centers (mean age 61 years, 77% male), 15% had mild DFI, 31% moderate or severe DFI without osteomyelitis, and 54% moderate or severe DFI with osteomyelitis. Methicillin-resistant Staphylococcus aureus was identified in 7% (16/214) and Pseudomonas aeruginosa in 3% (7/214). Median (IQR) days of total antibiotic management were 18 (10, 22) for mild DFI, 20 (11, 40) for moderate or severe DFI without osteomyelitis and 34 (15, 51) for moderate or severe DFI with osteomyelitis. Healing at 6 months was 73% (22/30) in those with mild DFI, 68% (42/62) in moderate or severe infections without osteomyelitis and 62% (69/111) in moderate or severe DFI with osteomyelitis. After adjusting for confounders, none of infection severity, intravenous antibiotic duration or total antibiotic duration were associated with ulcer healing.

Conclusions: Healing at 6 months following DFI does not appear to be associated with infection severity or antibiotic management. To plan clinical trials of antibiotic therapy for DFI, further work is required to define target subgroups and meaningful trial endpoints.

Introduction: To examine within-class sulfonylurea safety, we compared risks of major adverse cardiovascular events (MACE) and severe hypoglycemia among adults with type 2 diabetes (T2D) and moderate cardiovascular risk following sulfonylurea initiation.

Research design and methods: We conducted a target trial emulation including adults ≥21 years old with T2D and moderate cardiovascular risk who initiated glimepiride, glipizide or glyburide between 2014 and 2021, using claims data from Optum Labs Data Warehouse and the Medicare fee-for-service 100% sample. Study outcomes were MACE (primary), expanded MACE and its components and emergency department or hospital encounters for hypoglycemia, ascertained during follow-up through 2022. Inverse probability of treatment weighting (IPTW) was applied using propensity scores estimated using the super learner ensemble, and outcomes were examined using IPTW Cox proportional hazards models.

Results: The weighted study cohort comprised 314 699 patients (mean age 66.9 years, 52.0% men, 76.6% non-Hispanic white). At 1 year, MACE was experienced by 2.5%, 2.7% and 2.8% of patients starting glimepiride, glipizide and glyburide, respectively. Compared with glimepiride, glyburide and glipizide were associated with higher risk of MACE (HR 1.10, 95% CI 1.05 to 1.16 for glyburide; HR 1.05, 95% CI 1.03 to 1.07 for glipizide). At 1 year, severe hypoglycemia was experienced by 0.3%, 0.3% and 0.4% of patients starting glimepiride, glipizide and glyburide, respectively. Glyburide was associated with a greater risk of severe hypoglycemia compared with glipizide (HR 1.43, 95% CI 1.23 to 1.65), while glipizide was associated with a lower risk compared with glimepiride (HR 0.82, 95% CI 0.77 to 0.87).

Conclusions: Among adults with T2D and moderate cardiovascular risk, glimepiride was associated with lowest risk of MACE and glipizide with lowest risk of severe hypoglycemia. These results can help inform treatment selection if sulfonylureas are used for glucose-lowering.

Background: Despite therapeutic advances, diabetic ketoacidosis (DKA) hospitalizations continue to increase. The role of demographic factors, including age and sex in the outcomes of DKA remains underexplored. We aimed to investigate the interaction between age and sex on clinical outcomes, resource utilization and mortality in patients with type 1 diabetes hospitalized for DKA.

Methods: We conducted a retrospective cohort study using the National Inpatient Sample from 2016 to 2021. We identified adult hospitalizations with DKA in patients with type 1 diabetes, stratified into three age groups: 18-44, 45-64 and ≥65 years. Multivariable logistic regression models were used to analyze the association between sex and the primary outcome of in-hospital mortality, and secondary outcomes including acute kidney injury (AKI) and sepsis, adjusting for patient and hospital characteristics.

Results: Across all age groups, female sex was independently associated with significantly lower odds of AKI (aOR 0.56 in ages 18-44; 0.71 in 45-64; 0.79 in ≥65) but higher odds of sepsis (aOR 1.66, 1.31 and 1.17, respectively; all p<0.05). In young adults (18-44), women had significantly lower adjusted odds of mortality (aOR 0.72, 95% CI 0.60 to 0.86). This mortality benefit was not observed in middle-aged or older adults. Prepandemic (2016-2019), mortality trends diverged by sex and age, with rates increasing for young men but decreasing for young women. The pandemic (2020-2021) precipitated a sharp mortality increase across all age-sex groups, most dramatically in young men (from 0.48% to 0.89%).

Conclusion: Our study showed that age and sex were closely linked to acute complications and in-hospital death. Women had lower odds of AKI but higher odds of sepsis than men, with a survival advantage limited to young adults, and mortality rose during the COVID-19 years for both sexes, especially in young men.

Introduction: Diabetic vascular complications are predominantly caused by high glucose (HG)-induced endothelial dysfunction. Exosomes derived from endothelial progenitor cells (EPCs-EXOs) have shown therapeutic potential by modulating cellular functions through the delivery of bioactive cargos, particularly microRNAs (miRNAs). This study examines the role of EPCs-EXOs and their miRNA cargo in mitigating HG-induced endothelial dysfunction by targeting the Orai1-insulin-like growth factor-binding protein 3 (IGFBP3) signaling axis, a critical mediator of store-operated calcium entry (SOCE) and vascular pathology in diabetes.

Research design and methods: Human coronary artery endothelial cells (HCAECs) were cultured under HG (25 mM) or normal glucose (5.6 mM) conditions to model endothelial dysfunction. Cellular proliferation, apoptosis, and migration were evaluated through functional assays. EPCs-EXOs were isolated from mouse bone marrow-derived EPCs and characterized via nanoparticle tracking analysis, transmission electron microscopy. A type 2 diabetic mouse model was established using streptozotocin, and atherosclerotic plaque formation was quantified by Oil Red O staining. miRNA profiling identified miR-7116-3p as a potential regulator. HCAECs and mice with diabetes were treated with EPCs-EXOs, and miR-7116-3p mimics or inhibitors were employed to evaluate the specific effects on Orai1 and IGFBP3 expression and endothelial function.

Results: EPCs-EXOs significantly attenuated HG-induced abnormalities in HCAECs proliferation, apoptosis, and migration, and reduced atherosclerotic plaque formation in mice with diabetes. HG conditions upregulated Orai1 and IGFBP3 expression and promoted SOCE activity, whereas EPCs-EXOs suppressed these responses. Overexpression of Orai1 or IGFBP3 abolished the protective effects of EPCs-EXOs, underscoring their essential role. miRNA profiling identified miR-7116-3p within EPCs-EXOs as a key regulator that directly targets Orai1 and IGFBP3 messenger RNAs.

Conclusion: EPCs-EXOs alleviate HG-induced endothelial dysfunction by suppressing the Orai1-IGFBP3 signaling axis, with miR-7116-3p acting as a pivotal regulator of these targets. These findings reveal a novel mechanism and support the therapeutic potential of miR-7116-3p-enriched EPCs-EXOs for the treatment of diabetic cardiovascular diseases.