BMJ Open Diabetes Research & Care最新文献

Introduction: Current studies have shown that the asialoglycoprotein receptor 1 (ASGR1) is involved in glycolipid metabolism and is associated with systemic insulin resistance. This study aims to explore the correlation between serum soluble ASGR1 (sASGR1) levels and metabolic dysfunction-associated steatotic liver disease (MASLD) by assessing the relationship between sASGR1 concentrations and various biomarker levels.

Methods: The study included 148 patients diagnosed with MASLD from December 2021 to July 2024, and 98 control participants from the general population without MASLD. After collecting baseline clinical characteristics, ELISA kits were used to measure serum levels of sASGR1, fibroblast growth factor 21, and adiponectin.

Results: Compared with the control group, patients with MASLD had higher serum sASGR1 levels (p<0.05). Spearman correlation analysis showed that serum sASGR1 levels were significantly positively correlated with lipid metabolism indicators (triglycerides, total cholesterol, low-density lipoprotein cholesterol), glucose metabolism indicators (fasting plasma glucose, fasting insulin, glycosylated hemoglobin, homeostasis model assessment for insulin resistance), inflammatory markers (tumor necrosis factor α), liver function, and liver fibrosis. indicators (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase, procollagen type III, hyaluronic acid), and body mass index (p<0.05), and were significantly negatively correlated with high-density lipoprotein cholesterol (p<0.05). Further multiple linear regression analysis showed sASGR1 may be an independent risk factor for the occurrence of MASLD after adjusting for potential confounding factors (OR 2.644, 95% CI 1.138 to 6.143; p<0.05). The receiver operating characteristic curve revealed that the area under the curve for serum sASGR1 in predicting MASLD occurrence was 0.761 (95% CI 0.698 to 0.824), and its predictive performance increased to 0.863 (95% CI 0.813 to 0.913) when combined with AST and ALT.

Conclusions: In this group of patients with MASLD, sASGR1 levels are higher and are associated with the occurrence of MASLD, suggesting that sASGR1 may be an independent risk factor for MASLD.

Trial registration number: The expression of organokines in serum and its relationship with inflammation, insulin resistance in obese patients, ChiCTR2200059056.

Introduction: Shunting of glycolytic intermediates into the pentose phosphate pathway via transketolase activation by benfotiamine has been suggested to protect from hyperglycemia-induced microvascular damage, but the long-term effects of benfotiamine on diabetic sensorimotor polyneuropathy (DSPN) remain unclear.

Research design and methods: This 1:1 randomized double-blind, placebo-controlled parallel group monocentric phase II trial compared the efficacy and safety of 1-year treatment with benfotiamine 300 mg two times per day versus placebo over 12 months in participants with type 2 diabetes and mild-to-moderate symptomatic DSPN. The primary endpoint was the change in corneal nerve fiber length (CNFL) assessed by corneal confocal microscopy (CCM) from baseline to 12 months. Secondary endpoints included three other CCM parameters, skin biopsy (four parameters), nerve conduction studies (13 measures), quantitative sensory testing (six parameters), cardiovascular autonomic function tests (17 indices), sudomotor function tests (five parameters), 15 clinical scores and scales for neuropathic symptoms and signs and 13 health-related quality of life and depression instruments. Pharmacokinetics included measurement of six thiamine analytes in blood.

Results: A total of 57 participants underwent randomization. The changes from baseline to 12 months in CNFL did not differ between the two groups. The corresponding changes in the secondary morphometric, functional and clinical neuropathic outcomes as well as quality of life were also similar in the two groups. Only the Neuropathy Symptom Score tended to improve after benfotiamine treatment (p=0.098 vs placebo). Benfotiamine treatment increased the concentrations of all six thiamine analytes studied (p≤0.003 vs placebo). Safety analysis showed no relevant differences between the groups in the rates of adverse events.

Conclusions: In type 2 diabetes individuals with mild-to-moderate symptomatic DSPN, treatment with benfotiamine for 12 months was well tolerated, but had no significant effects on multiple morphometric, neurophysiological and clinical measures of neuropathy.

Trial registration number: European Clinical Trials Database (EudraCT) 2017-003054-16 registered on April 10 (https://eudract.ema.europa.eu/), 2018 and German Register for Clinical Trials DRKS00014832 registered on August 3, 2018 (https://drks.de/search/de).

Objective: Blue Cross and Blue Shield of Louisiana (BCBSLA) launched a zero-dollar co-pay (ZDC) pharmacy benefit on July 1, 2020, to reduce cost-related barriers to diabetes medications. This study evaluated the program's effect on antidiabetic medication adherence and use patterns.

Research design and methods: We conducted a retrospective cohort study using BCBSLA medical and pharmacy claims from 2019-2021. The study included 7,603 continuously enrolled members with diabetes: 3,045 fully insured members with ZDC coverage (ZDC group) and 4,558 administrative-services-only members without ZDC coverage (control group). Follow-up was July 1, 2020, to December 31, 2021. Outcomes included monthly proportion of days covered (PDC), drug counts, and monthly medication use. We applied propensity score odds weights and estimated weighted difference-in-differences models with individual and time fixed effects, adjusting for demographics, comorbidities, healthcare utilization, and spending. Subgroup analyses examined pre-ZDC users, pre-ZDC non-users, and complex users.

Results: Mean age was 48.8 (SD 12.5) years in the ZDC group and 52.9 (SD 11.3) years in controls; 57.4% and 55.6% were female, respectively. The ZDC program increased PDC by 4.4 percentage points (p<0.001), monthly medication use by 6.2 percentage points (p<0.001), and drug counts by 0.090 (p<0.001). For ZDC-eligible medications, increases were 5.4 percentage points for PDC, 7.6 percentage points for monthly use, and 0.074 for drug counts (all p<0.001). Improvements were observed among pre-ZDC users and complex users, but not among pre-ZDC non-users.

Conclusion: A zero-dollar co-pay pharmacy benefit improved antidiabetic medication adherence and increased medication use among BCBSLA members with diabetes.

Introduction: In the USA, patients with diabetes and end-stage renal disease are less likely to undergo deceased donor kidney transplantation (DDKT) or living donor kidney transplantation (LDKT). We explored the survival benefit of DDKT and LDKT among patients with diabetes.

Research design and methods: We used the United Network for Organ Sharing Standard Transplant Analysis and Research file to identify adults placed on the kidney waiting list between January 2014 and January 2024. Waitlist failure was evaluated with Fine and Gray analysis; life-years from transplant, equal survival (ES), and equal risk (ER) were extrapolated using lognormal survival regression; and life-years gained was quantified via restricted mean survival over 10 years.

Results: Patients with diabetes were more likely to experience 10-year waitlist failure (subdistribution HR 2.27, 95% CI 2.23 to 2.32) and receive inferior DDKT grafts (Kidney Donor Profile Index 49% vs 35%, p<0.001) compared with patients without diabetes. For patients with diabetes, LDKT, compared with DDKT, offered more life-years from transplant (18.2 years vs 14.1 years), resulted in more life-years gained (29% vs 24% relative increase over 10 years, p<0.001) and decreased ES by 19 months and ER by 30 months.

Conclusions: Proceeding to transplantation offers significant survival benefit for end-stage renal disease patients with diabetes, with LDKT offering superior survival compared with DDKT. By reducing time on the waiting list and providing superior grafts, the benefit of LDKT is particularly enhanced among patients with diabetes, and targeted efforts should be made to expand living donor access for this population.

Introduction: Type 1 diabetes is an autoimmune disease with a strong genetic basis. The aim of this study was to identify additional single-nucleotide polymorphisms (SNPs) for type 1 diabetes age at diagnosis and to replicate previously identified loci.

Research design and methods: Meta genome-wide association studies of age at diagnosis from eight cohorts (n=5910 in total) were performed in three models. Model 1 was age at diagnosis with no covariates. Model 2 was age at diagnosis adjusted for DR3/DR4 genotype categories. Model 3 was similar to model 2, including the most significant SNP from model 2 (coded additively). Models 1 and 2 were also performed for major histocompatibility complex (MHC) imputed data. In addition, we tested previously identified loci for age at diagnosis and type 1 diabetes risk for association with age at diagnosis in model 1.

Results: In model 1, we identified a genome-wide significant locus (rs2856721, p=3.3×10^-11) in the MHC region whose effect was attenuated in model 2 (p=0.03). In model 2, we identified another locus in the MHC region, rs76730244, p=4.9×10^-9, which was associated with age at diagnosis adjusted for DR3/DR4 genotypes. Model 3 and analysis of the MHC region did not reveal novel loci. Among 14 previously identified SNPs for age at diagnosis, 6 were confirmed; in addition, 11 out of 78 non-HLA loci for type 1 diabetes risk were associated with age at diagnosis.

Conclusions: We identified rs76730244 in the MHC region for age at diagnosis of type 1 diabetes, which was independent of the HLA-DR3/DR4 genotype categories. We also confirmed 6 previously identified SNPs and showed that 11 non-HLA loci for type 1 diabetes risk are associated with age at diagnosis.

Introduction: This study analyzed the effects of the COVID-19 pandemic and body weight on islet and endocrine autoimmunity in children with type 1 diabetes (T1D).

Research design and methods: Data from 11 973 children and adolescents aged 0.5 to <18 years with new-onset T1D (2015-2023) from the Diabetes Prospective Follow-up Registry were evaluated. Rates of autoantibodies against beta cells (islet antigen 2 (IA2), zinc transporter 8 (ZnT8), glutamic acid decarboxylase (GAD), insulin), thyroid, transglutaminase (TGA), and adrenals were assessed. Logistic regression models adjusted for age and sex examined associations with COVID-19 and body mass index (BMI).

Results: 6136 (51%) children were diagnosed with T1D before, and 5837 (49%) after the beginning of the COVID-19 pandemic. Beta-cell autoantibodies were present in 94.3%, thyroid autoantibodies in 7.7%, TGA autoantibodies in 8.3%, and adrenal autoantibodies in 5.6%. During versus before COVID-19, IA2 and GAD autoantibody positivity significantly increased (63.3% vs 60.5%, p=0.002, and 65.9% vs 64.0%, p=0.04, respectively), ZnT8 autoantibodies declined (68.0% vs 71.9%, p=0.002), while insulin autoantibodies remained unchanged (p=0.06). Prevalence of IA2, ZnT8, and insulin, but not GAD autoantibodies, showed positive associations with BMI. Thyroid and TGA autoantibodies were not related, while adrenal autoantibodies were negatively related to the pandemic.

Conclusions: The COVID-19 pandemic and body weight influenced autoimmunity in children with T1D. The rise in IA2 autoantibody positivity may suggest a faster progression from pre-existing autoimmunity to clinical disease. The pandemic did not appear to trigger associated endocrine autoimmunity.

Obesity medications may be part of a comprehensive care plan for adults with obesity. The Obesity Association, a division of the American Diabetes Association (ADA), developed comprehensive, evidence-based guidelines on the pharmacologic treatment of obesity in adults. When used in conjunction with lifestyle modifications, obesity medications have demonstrated efficacy in inducing and sustaining weight reduction while concurrently improving clinical outcomes of obesity and obesity-related diseases and complications. Healthcare professionals should engage people with obesity in a person-centered, shared decision-making approach when selecting an obesity medication to optimize health outcomes while emphasizing individual needs and preferences. The ADA's Obesity Association encourages healthcare professionals to adopt these guidelines for treatment of obesity in adults.

Introduction: Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes. MODY type 9 (MODY9) is a rare subtype caused by variants in the PAX4 gene. However, the pathogenicity and mechanisms of many PAX4 variants remain unclear. This study aimed to evaluate the clinical relevance and pathogenic mechanisms of three novel PAX4 variants identified in patients with suspected MODY.

Research design and methods: Three unrelated patients with early-onset diabetes and a family history of the disease were screened for PAX4 variants using whole-exome and Sanger sequencing. In silico predictions, evolutionary conservation analysis, and structural modeling were performed. Functional studies were conducted in MIN6 cells to assess protein expression, subcellular localization, and degradation pathways.

Results: Three novel PAX4 variants (c.83delA; p.Gln28ArgfsTer6, c.35T>C; p.Leu12Pro, and c.488G>C; p.Arg163Pro) were identified. Expression of p.Gln28ArgfsTer6 was undetectable, likely due to nonsense-mediated decay. In contrast, p.Leu12Pro and p.Arg163Pro retained nuclear localization but resulted in markedly reduced protein levels. Treatment with the proteasome inhibitor MG132 restored protein levels of the missense mutants, indicating enhanced proteasomal degradation as the likely mechanism. These findings suggest that certain PAX4 variants impair β-cell function by destabilizing the protein post-translationally.

Conclusions: This study expands the spectrum of PAX4 variants and provides novel mechanistic insights into the pathogenesis of MODY9. Our results highlight the importance of assessing protein-level consequences for variant interpretation and support the integration of functional assays into MODY genetic diagnostic workflows.

Background: Food insecurity (FI) is linked to mental health outcomes cross-sectionally, but little is known about temporal patterns of FI and changes in mental health. FI can exacerbate the mental health challenges of managing diabetes, creating a vicious cycle that worsens youth and young adults' (YYAs) mental well-being.

Purpose: We investigated the association of temporal patterns of FI with symptoms of depression, anxiety, and stress, and changes therein in YYAs with youth-onset type 1 (T1D) and type 2 diabetes (T2D).

Methods: Longitudinal data (2016-2022) including three time points (t₁, t₂, and t₃) from 747 YYAs with T1D and 97 YYAs with T2D were analyzed using multivariable linear regression. Ascertained with the Household Food Security Survey Module, food security was classified as persistently food secure, persistently food insecure (PFI), and intermittently food insecure (IFI). Mental health at t₃ and changes from t₂ to t₃ were characterized with the Center for Epidemiologic Studies Depression Scale, the Generalized Anxiety Disorder Scale, and Cohen's Perceived Stress Scale.

Findings: Among YYAs with T1D and T2D, 6.6% and 16.5% were PFI, 20.3% and 42.3% were IFI, respectively. In YYA with T1D, PFI and IFI were associated with greater depressive, anxiety, and stress symptoms at t₃, and with increased symptoms over time. In YYA with T2D, PFI was associated with greater depressive symptoms at t₃ but not with changes over time.

Interpretation: The study identified a previously unrecognized link between prolonged exposure to FI and increased incidence of mental health issues. Both persistent and intermittent FI were associated with adverse mental health symptoms in YYA with diabetes, more so for those with PFI. Subsequent research should prioritize interventions that address FI in this population to evaluate their effectiveness in enhancing both physical and psychological well-being. It should be designed to not only address FI, but also comprehensive support, including mental health services and education.

Introduction: Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease targeting insulin-producing cells in the pancreas. The rising global incidence, particularly in early childhood, suggests environmental triggers, such as infections, may contribute to its pathogenesis. Prior studies have reported spatiotemporal clustering of T1DM, and we aimed to further investigate spatial and spatiotemporal clustering in Finnish children using high-quality data with complete residential histories.

Research design and methods: We included patients under 18 diagnosed with T1DM between 1990 and 2019, identified from the Finnish Social Insurance Institution, based on insulin reimbursement. Each case was assigned three age-matched and sex-matched controls. Clustering was analyzed using the Cuzick-Edwards test, Knox test, and Jacquez's Q statistic. Multiple testing adjustments were applied using the Benjamini-Hochberg correction.

Results: The study included 16 307 cases and 48 914 controls (median age at diagnosis: 8.9 years; 56% male). The Cuzick-Edwards test identified modest spatial clustering among males 1 year prior to diagnosis, while the Knox test revealed significant spatiotemporal clustering across all cases. Analyses incorporating full residential histories confirmed these findings, with more pronounced spatiotemporal clustering in children over 6 years old.

Conclusions: These results demonstrate evidence of spatiotemporal clustering of T1DM in Finnish children, supporting the hypothesis of environmental triggers in T1DM etiology. These findings highlight the need for further research to identify the specific environmental factors and mechanisms behind the clustering.