Onset Of Diabetes Research Articles

Substantial morbidity and mortality due to cardiovascular diseases in hospitalized vaccinated and un-vaccinated patients with COVID-19 from 16 countries: the WHF COVID-19 Long-term study

Abstract Background Long-term adverse consequences of the COVID-19 affect many organ systems, and this requires the identification and appropriate care of diverse symptoms. Purpose The World Heart Federation (WHF) international study describes the burden of clinical sequelae of COVID-19 up to 1 year after hospitalization, including patients from low- middle-and high-income countries. Methods We prospectively recruited patients hospitalized due to COVID-19 from 16 countries between January 2022 and June 2023. Patients were followed up at 1, 3, 6, and 9-12 months after hospital discharge. A standardized questionnaire administered by telephone collected data on long COVID symptoms, quality of life using the EuroQol 5 Dimension scale (EQ-5D), and disease outcomes including new onset diabetes and hypertension, major adverse cardiovascular events (MACE), and mortality. We report a descriptive analysis including demographic characteristics and outcomes up to one year after initial hospitalization. Results Of 2504 patients, the majority were Asian (78%), and male (56%). Mean age was 59.2 years (SD 19.9). Low- and lower-middle-income country participants constituted 65% of the cohort, with upper middle-income and high-income representing 20% and 15%, respectively. Follow-up rate was complete for 86%. 55% had received at least two doses of COVID-19 vaccination. At 1 month, 63% reported at least one persistent symptom, which decreased to 28% at 9-12 months. Fatigue was reported by 45% at 1-month and 17% at final follow-up. Anxiety occurred in 20% and 9% at these respective timepoints, and breathlessness in 12% and 6%. At 9-12 months, moderate to severe impairment of usual activities as measured by EQ-5D occurred in 19%, anxiety/depression in 10%, and mobility problems in 10%. The most frequent post-discharge new-onset illnesses were pulmonary embolism (7%), kidney problems (4%), and hypertension (3%). In-hospital mortality was 4% (n=102), and a further 12% (265 patients) died by one-year. The most common cause was sudden cardiac death (59%), respiratory disease including pulmonary embolism (13%), and stroke (6%). Conclusions We observed a significant burden of post-COVID-19 complications with one fifth of patients with persistent difficulties in usual activities at one year. This underscores the urgent need to understand the underlying mechanisms for organ damage and death, and for targeted preventive strategies and proactive management approaches to reduce them.

Vaccination status and long COVID symptoms among patients hospitalized with COVID-19: the WHF COVID-19 Long-term Study

Abstract Background COVID-19 vaccinations have been found to be effective in reducing the severity of COVID-19 infection and in-hospital deaths; however, insufficient evidence exists about the effect of vaccination on long term morbidity and mortality after hospitalization in patients from low- and middle-income countries. Methods The global WHF COVID-19 Long-Term Follow-up Study recruited 2,504 COVID-19 hospitalized patients from 26 collaborating sites in 16 countries between January 2022 - June 2023. Patients were followed up , at 1, 3, 6, and 9-12 months post-discharge to examine short- and long-term physical and psycho-social outcomes. A standardised questionnaire was used to collect data on demographics, pre-existing comorbidities, COVID-19 symptoms on admission, vaccination status, and outcomes at discharge, including persisting symptoms, new onset hypertension or diabetes, major adverse cardiovascular events (MACE), and mortality. We compared persistent long COVID symptoms, MACE, and mortality outcomes up to one year by COVID-19 vaccination status. Results The majority of study participants were Asians (78%), males (56%) with a mean (SD) age of 59.2 (19.9) years and from low- and middle-income (65%), upper middle-income (20%) and high-income (15%) countries. The most commonly reported comorbidities were hypertension: 54% and diabetes: 38%. Approximately two-thirds of the patients had received at least one dose of COVID-19 vaccination prior to hospitalization. Unvaccinated patients were more likely to present with dyspnea (60% vs 53%, p-value<0.001) and acute respiratory infection (15% vs 9%, p-value<0.001) during hospitalization. Unvaccinated patients also had twice the in-hospital mortality rate, compared with vaccinated patients (6% vs 3%, p-value<0.001). Unvaccinated patients had a greater incidence of MACE (23% vs 18%, p-value=0.016) during hospitalization and across all follow-up visits. Unvaccinated patients also had a higher mortality rate across all follow-up visits (mortality at one year post-discharge 14% vs 10%, p<0.001). At the 9-12 month follow-up, about a quarter of the patients had at least one long COVID symptom, but unvaccinated patients had a higher rate of long COVID symptoms, including fatigue (23% vs 14%, p<0.001), palpitations (17% to 7%, p-value<0.001), and anxiety (13% to 7%, p=0.002). Conclusions Our data highlight the long-term protective effect of COVID-19 vaccination on reducing morbidity and mortality among COVID-19 patients after hospital discharge. However, a substantial proportion of COVID-19 vaccinated patients still showed persistent long COVID symptoms (22%) and mortality (10%). Future research is needed to investigate individual- and health system-level factors contributing to poor health outcomes post-COVID-19 infection.

Current Status of Diabetes Prevention and Control in China and Early-Stage Intervention Strategies

In recent years, the prevalence of diabetes in China has continued to rise, with the adult prevalence expected to reach 12.8% by 2023. To control this trend, the government has introduced several policies and invested substantial funds in the prevention and treatment of diabetes, achieving certain results. Prediabetes is a stage where blood glucose metabolism can still be restored. For individuals in this stage, dietary and exercise intervention programs are recommended to prevent or delay the onset of diabetes, improve quality of life, and reduce the burden of disease on individuals, families, and society.

Essential role of interferon-regulatory factor 4 in regulating diabetogenic CD4+ T and innate immune cells in autoimmune diabetes in NOD mice.

Haploinsufficiency of the transcription factor interferon-regulatory factor 4 (IRF4) prevents the onset of spontaneous diabetes in NOD mice. However, the immunological mechanisms of the IRF4-mediated disease regulation remain unclear. This study aims to investigate the role of IRF4 in the pathogenesis of autoimmune diabetes by conducting adoptive transfer experiments using donor IRF4 gene-deficient CD4+ T cells from BDC2.5-transgenic (Tg) NOD mice and recipient Rag1-knockout NOD mice, respectively. Through this approach, we analyzed both clinical and immunological phenotypes of the recipient mice. Additionally, IRF4-deficient BDC2.5 CD4+ T cells were stimulated to assess their immunological and metabolic phenotypes in vitro. The findings revealed that diabetes was completely prevented in the recipients with Irf4-/- T cells and was approximately 50% lower in those with Irf4+/- T cells than in wild type (WT) controls, whereas Irf4-/- recipients with WT T cells only showed a delayed onset of diabetes. Islet-infiltrating T cells isolated from recipients with Irf4+/- T cells exhibited significantly lower proliferation and IFN-γ/IL-17 double-positive cell fraction rates compared with those in WT controls. Irf4-/- BDC2.5 CD4+ T cells stimulated in vitro showed a reduced number of cell divisions, decreased antigen-specific T-cell markers, and impairment of glycolytic capacity compared with those observed in WT controls. We concluded that IRF4 predominantly regulates the diabetogenic potential in a dose-dependent manner by mediating the proliferation and differentiation of islet-infiltrating T cells while playing an adjunctive role in the innate immune responses toward diabetes progression in NOD mice.

Prevalence, Characteristics and Risk Factors Analysis of Prediabetes: A Cross-Sectional Study

Background Prediabetes, a reversible condition before the onset of diabetes, is a significant concern in healthcare globally. The global prediabetes epidemic has emerged and has considerably impacted health expenditures. Various risk factors play important roles in the progression of prediabetes to diabetes. Intensive lifestyle and pharmacological interventions can significantly reduce the risk of diabetes progression. Objective This study aimed to determine the prevalence, characteristics, and risk factors of prediabetes state of Medan in August 2023. Methods The sample consisted of 89 participants. This was an analytical cross-sectional study in the community that met the inclusion and exclusion criteria. The determination of prediabetes is based on the results of blood tests, namely, the examination of fasting blood sugar levels (FBGL), 2-hour postprandial oral glucose tolerance test (OGTT), and hemoglobin A1c (HbA1C). Other examinations included lipid profiling (total cholesterol, HDL-C, LDL-C, and triglycerides). Data processing was performed using SPSS via univariate and bivariate analyses (chi-square test). Results Of the 89 participants, the prevalence of prediabetes based on HbA1c, FBGL and 2-hours OGTT levels was 28.1%, 50.6%, and 28.1%, respectively. 82% of the participants were female, and 53.9% were overweight or obese based on body mass index (BMI). The risk factors for prediabetes were age >64 years, female, physical inactivity, and diastolic blood pressure ≥90 mmHg (p<0.05). Other risk factors such age <45-64 years, consumption of vegetables/fruits, BMI, HDL, LDL, trygliceride, total cholesterol, systolic blood pressure, achantosis nigricans, and waist-hip circumference did not associate significantly (p>0.05). Conclusion This study found that the prevalence of prediabetes was 67.4% in Medan. Age >64 years, female, physical inactivity, and diastolic blood pressure ≥90 mmHg were the most important risk factors for prediabetes.

Exploring the 3,5-Dibromo-4,6-dimethoxychalcones and Their Flavone Derivatives as Dual α-Glucosidase and α-Amylase Inhibitors with Antioxidant and Anticancer Potential.

The rising levels of type 2 diabetes mellitus (T2DM) and the poor medical effects of the commercially available antidiabetic drugs necessitate the development of potent analogs to treat this multifactorial metabolic disorder. It has been demonstrated that targeting two or more biochemical targets associated with the onset and progression of diabetes along with oxidative stress and/or cancer could be a significant strategy for treating complications related to this metabolic disorder. The 3,5-dibromo-4,6-dimethoxychalcones (2a-f) and the corresponding flavone derivatives (3a-f) were synthesized and characterized using spectroscopic (NMR, HR-MS and FT-IR) techniques. The inhibitory effect of both series of compounds against α-glucosidase and α-amylase was evaluated in vitro through enzymatic assays. Selected compounds were also evaluated for potential to activate or inhibit superoxide dismutase. Compound 3c was selected as a representative model for the flavone series and evaluated spectrophotometrically for potential to coordinate Cu(II) and/or Zn(II) ions implicated in the metal-catalyzed free radical generation. A plausible mechanism for metal-chelation of the test compounds is presented. Furthermore, the most active compounds from each series against the test carbohydrate-hydrolyzing enzymes were selected and evaluated for their antigrowth effect on the human breast (MCF-7) and lung (A549) cancer cell lines and for cytotoxicity against the African Green Monkey kidney (Vero) cell line. The parent chalcone 2a and flavone derivatives 3a, 3c and 3e exhibited relatively high inhibitory activity against the MCF-7 cells with IC50 values of 4.12 ± 0.55, 8.50 ± 0.82, 5.10 ± 0.61 and 6.96 ± 0.66 μM, respectively. The chalcones 2a and 2c exhibited significant cytotoxicity against the A549 cells with IC50 values of 7.40 ± 0.67 and 9.68 ± 0.80 μM, respectively. Only flavone 3c exhibited relatively strong and comparable cytotoxicity against the MCF-7 and A549 cell lines with IC50 values of 6.96 ± 0.66 and 6.42 ± 0.79 μM, respectively. Both series of compounds exhibited strong activity against the MCF-7 and A549 cell lines compared to the analogous quercetin (IC50 = 35.40 ± 1.78 and 35.38 ± 1.78 μM, respectively) though moderate compared to nintedanib (IC50 = 0.53 ± 0.11 and 0.74 ± 0.15 μM, respectively). The test compounds generally exhibited reduced cytotoxicity against the Vero cells compared to this anticancer drug. Molecular docking revealed strong alignment of the test compounds with the enzyme backbone to engage in hydrogen bonding interaction/s and hydrophobic contacts with the residues in the active sites of α-glucosidase and α-amylase. The test compounds possess favorable drug-likeness properties, supporting their potential as therapeutic candidates against T2DM.

Treatment switch from multiple daily insulin injections to sulphonylureas in an African young adult diagnosed with HNF1A MODY: a case report

BackgroundMaturity onset diabetes of the young is one of the commonest causes of monogenic diabetes and can easily be mistaken for type 1 diabetes. A diagnosis of maturity onset diabetes of the young can have direct implications for genetic counseling, family screening, and precision diabetes treatment. However, the cost of genetic testing and identifying individuals to test are the main challenges for diagnosis and management in sub-Saharan Africa. We report the very first documented case of HNF1A maturity onset diabetes of the young in the sub-Saharan African region.Case presentationA 20-year-old female Black African young adult diagnosed with type 1 diabetes aged 14 presented for routine out-patient diabetes consultation. She was on multiple daily insulin injections; total combined dose 0.79 IU/kg/day with an HbA1c of 7.7%. The rest of her laboratory examinations were normal. On extended laboratory analysis, she had good residual insulin secretion with post-meal plasma C-peptide levels at 1150 pmol/L. She tested negative for glutamic acid decarboxylase (GAD65), islet antigen-2 (IA-2), and zinc transporter 8 (ZnT8) islet autoantibodies. Targeted next-generation sequencing (t-NGS) for monogenic diabetes was performed using DNA extracted from a buccal sample. She was diagnosed with HNF1A maturity onset diabetes of the young, with the c.607C > T; p.(Arg203Cys) pathogenic variant, which has never been reported in sub-Saharan Africa. Her clinical practitioners provided genetic and therapeutic counseling. Within 10 months following the diagnosis of maturity onset diabetes of the young, she was successfully switched from multiple daily insulin injections to oral antidiabetic tablets (sulphonylurea) while maintaining stable glycemic control (HBA1c of 7.0%) and reducing hypoglycemia. She expressed a huge relief from the daily finger pricks for blood glucose monitoring.ConclusionThis case reveals that HNF1A maturity onset diabetes of the young (and probably other causes of monogenic diabetes) can present in sub-Saharan Africa. A diagnosis of maturity onset diabetes of the young can have significant life-changing therapeutic implications.

Impact of Continuous Glucose Monitoring on Hemoglobin A1c and Height Trends in Latin American Children with Type 1 Diabetes Onset over 3 Years: A Multicenter Study

ObjectiveTo evaluate changes in HbA1c levels and z-height over three years based on Continuous glucose monitoring (CGM) usage among children with new-onset type 1 diabetes (T1DM) from various Latin American centers. MethodsData on z-height, CGM access, and HbA1c (%) were collected for Latin American children aged six months to 18 years with T1DM onset from 19 centers in a retrospective analysis of medical records, from 2020 to 2023. A two-way ANOVA method with repeated measures and multiple regression analyses were performed. Results433 children (46.0% F) aged 8.7 ± 3.7 years were included, and 199 (45.9%) used CGM. Mean HbA1c was significantly lower in years 1, 2, and 3 than in baseline in children with CGM but not those without CGM. The z-height decreased significantly with the years in both groups. However, the CGM users showed a significantly greater height in years 2 and 3 than the non-users. Multiple linear regression analysis showed that CGM users exhibited a significantly lower incremental area under the curve (AUC) for HbA1c during follow-up than non-users. Furthermore, a lower incremental AUC for HbA1c was associated with a smaller decremental AUC for z-height (R2 = 0.19). Multiple logistic regression analysis revealed that children with CGM were 80% more likely (OR=0.22; 95% CI 0.1-0.6) to achieve an HbA1c < 7% in the third year of follow-up. ConclusionsThis study reveals a significant association between CGM use and lower HbA1c from the onset of T1DM over a three-year follow-up in Latin American children. Further prospective studies should be performed to confirm this finding.

Quantitative analysis of islet prohormone convertase 1/3 expression in human pancreas donors with diabetes.

Islet prohormone-processing enzymes convert peptide hormone precursors to mature hormones. Defective beta cell prohormone processing and the release of incompletely processed peptide hormones are observed prior to the onset of diabetes, yet molecular mechanisms underlying impaired prohormone processing during the development of diabetes remains largely unknown. Previous studies have shown that prohormone convertase 1/3 (PC1/3) protein and mRNA expression levels are reduced in whole islets from donors with type 1 diabetes, although whether PC1/3-mediated prohormone processing in alpha and beta cells is disrupted in type 1 diabetes remained to be explored. Herein, we aimed to analyse the expression of PC1/3 in islets from non-diabetic donors, autoantibody-positive donors and donors diagnosed with type 1 diabetes or type 2 diabetes. Immunostaining and high-dimensional image analysis were performed on pancreatic sections from a cross-sectional cohort of 54 donors obtained from the Network for Pancreatic Organ Donors with Diabetes (nPOD) repository, to evaluate PC1/3 expression patterns in islet alpha, beta and delta cells at different stages of diabetes. Alpha and beta cell morphology were altered in donors with type 1 diabetes, including decreased alpha and beta cell size. As expected, the insulin-positive and PC1/3-positive areas in the islets were both reduced, and this was accompanied by a reduced percentage of PC1/3-positive and insulin-positive/PC1/3-positive cells in islets. PC1/3 and insulin co-localisation was also reduced. The glucagon-positive area, as well as the percentage of glucagon-positive and glucagon-positive/PC1/3-positive cells in islets, was increased. PC1/3 and glucagon co-localisation was also increased in donors with type 1 diabetes. The somatostatin-positive cell area and somatostatin staining intensity were elevated in islets from donors with recent-onset type 1 diabetes. Our high-resolution histomorphological analysis of human pancreatic islets from donors with and without diabetes has uncovered details of the cellular origin of islet prohormone peptide processing defects. Reduced beta cell PC1/3 and increased alpha cell PC1/3 in islets from donors with type 1 diabetes pinpointed the functional deterioration of beta cells and the concomitant potential increase in PC1/3 usage for prohormone processing in alpha cells during the pathogenesis of type 1 diabetes. Our finding of PC1/3 loss in beta cells may inform the discovery of new prohormone biomarkers as indicators of beta cell dysfunction, and the finding of elevated PC1/3 expression in alpha cells may encourage the design of therapeutic targets via leveraging alpha cell adaptation in diabetes.

Promising predictors of diabetic peripheral neuropathy in children and adolescents with type 1 diabetes mellitus

BackgroundDiabetic peripheral neuropathy (DPN) in children and adolescents with type 1 diabetes mellitus (T1DM) is a growing issue, with controversial data in the terms of prevalence and evaluation timelines. Currently, there are no clear standards for its early detection. Therefore, our aim was to assess the contribution of the Michigan neuropathy screening instrument (MNSI), lipid profile, serum neuron specific enolase (NSE), and serum heat shock protein 27 (HSP 27) to the prediction of DPN in children and adolescents with T1DM.MethodsIn this case-control study, fifty children diagnosed with T1DM for at least five years were enrolled and evaluated through complete neurological examination, MNSI, and nerve conduction study (NCS). Additionally, HbA1c, lipid profile, serum NSE, and serum HSP 27 levels were measured for patients and controls.ResultsThe prevalence of DPN in our study was 24% by NCS, and electrophysiological changes showed a statistically significant lower conduction velocity for the posterior tibial and sural nerves, as well as a prolonged latency period for the common peroneal and sural nerves in neuropathic patients. In these patients, older age, earlier age of diabetes onset, longer disease duration, higher total cholesterol, triglycerides, low density lipoprotein cholesterol, HbA1c, serum NSE, and HSP27 levels were observed. The MNSI examination score ≥ 1.5 cutoff point had an area under the curve (AUC) of 0.955, with 75% sensitivity and 94.74% specificity, according to receiver operating characteristic curve analysis. However, the questionnaire’s cutoff point of ≥ 5 had an AUC of 0.720, 75% sensitivity, and 63% specificity, with improved overall instrument performance when combining both scores. Regarding blood biomarkers, serum NSE had greater sensitivity and specificity in discriminating neuropathic patients than HSP27 (92% and 74% versus 75% and 71%, respectively). Regression analysis revealed a substantial dependency for MNSI and serum NSE in predicting DPN in patients.ConclusionsDespite limited research in pediatrics, MNSI and serum NSE are promising predictive tools for DPN in children and adolescents with T1DM, even when they are asymptomatic. Poor glycemic control and lipid profile changes may play a critical role in the development of DPN in these patients, despite conflicting results in various studies.

Predicting vision-threatening diabetic retinopathy in patients with type 2 diabetes mellitus: Systematic review, meta-analysis, and prospective validation study.

Delayed diagnosis and treatment of vision-threatening diabetic retinopathy (VTDR) is a common cause of visual impairment in individuals with type 2 diabetes mellitus (T2DM). Identification of VTDR predictors is the key to early prevention and intervention, but the predictors from previous studies are inconsistent. This study aims to conduct a systematic review and meta-analysis of the existing evidence for VTDR predictors, then to develop a risk prediction model after quantitatively summarising the predictors across studies, and finally to validate the model with two Chinese cohorts. We systematically retrieved cohort studies that reported predictors of VTDR in T2DM patients from PubMed, Ovid, Embase, Scopus, Cochrane Library, Web of Science, and ProQuest from their inception to December 2023. We extracted predictors reported in two or more studies and combined their corresponding relative risk (RRs) using meta-analysis to obtain pooled RRs. We only selected predictors with statistically significant pooled RRs to develop the prediction model. We also prospectively collected two Chinese cohorts of T2DM patients as the validation set and assessed the discrimination and calibration performance of the prediction model by the time-dependent ROC curve and calibration curve. Twenty-one cohort studies involving 622 490 patients with T2DM and 57 107 patients with VTDR were included in the meta-analysis. Age of diabetes onset, duration of diabetes, glycosylated haemoglobin (HbA1c), estimated glomerular filtration rate (eGFR), hypertension, high albuminuria and diabetic treatment were used to construct the prediction model. We validated the model externally in a prospective multicentre cohort of 555 patients with a median follow-up of 52 months (interquartile range = 39-77). The area under the curve (AUC) of the prediction model was all above 0.8 for 3- to 10-year follow-up periods and different cut-off value of each year provided the optimal balance between sensitivity and specificity. The data points of the calibration curves for each year closely surround the corresponding dashed line. The risk prediction model of VTDR has high discrimination and calibration performance based on validation cohorts. Given its demonstrated effectiveness, there is significant potential to expand the utilisation of this model within clinical settings to enhance the detection and management of individuals at high risk of VTDR.

Non-linear relationship between relative fat mass and diabetes risk in Japanese adults: a retrospective cohort study

Background: Relative fat mass (RFM) represents a newly developed sex-specific anthropometric formula to estimate total body fat percentage. Nonetheless, research examining the correlation between RFM and the risk of diabetes remains scarce. This research assessed the link between RFM and DM risk within the Japanese demographic. Methods: From 2004 to 2015, 15,462 Japanese individuals without diabetes underwent physical evaluations at Murakami Memorial Hospital. The relationship between RFM and the onset of diabetes was analyzed separately using Cox proportional-hazards regression models. This study employed Cox proportional hazards regression incorporating cubic spline functions and smooth curve fitting to detect non-linear associations between RFM and new cases of diabetes, categorized by sex. Sensitivity analyses were performed to confirm the robustness of the link between RFM and incident diabetes. Results: After controlling for confounding factors, a significant positive correlation between RFM and diabetes risk was found in women (HR: 1.13, 95%CI: 1.04–1.24, P = 0.0061), while the association in men was not statistically significant (HR: 1.05, 95%CI: 0.98–1.13, P = 0.1511). Additionally, a non-linear relationship between RFM and the incidence of diabetes was detected in both genders. The RFM threshold was identified at 39.23 for women and 23.08 for men. For women, HR was 1.11 (95%CI: 1.01–1.21) below the threshold and 1.39 (95%CI: 1.17–1.65) above it. In men, an RFM above 23.08 was positively related to diabetes risk (HR: 1.16, 95%CI: 1.06–1.28, P = 0.0012), whereas an RFM below this point did not show a significant association (HR: 0.98, 95%CI: 0.91–1.06, P = 0.5899). Conclusion: Our findings suggest a non-linear relationship and threshold effect between RFM and the risk of diabetes. These findings imply that maintaining RFM at lower levels may be beneficial in mitigating the onset of DM.

The Relationship between Vitamin D and TyG Index in Prediabetes and Type 2 Diabetes Mellitus among an Indian Tribal Community: A Cross-Sectional Study

Background: Vitamin D deficiency is thought to increase the likelihood of insulin resistance (IR) and diabetes onset. The objective of this study was to examine the association between the triglyceride glucose (TyG) index and vitamin D levels in individuals with prediabetes and type 2 diabetes mellitus (T2DM) in the tribal community of India. Methods: This study included 270 participants, consisting of 90 individuals with prediabetes, 90 individuals with T2DM, and 90 control patients. Anthropometric and biochemical characteristics were evaluated in all participants. 25-hydroxyvitamin D [25(OH)D] levels were measured using a chemiluminescent immunoassay. The TyG index was computed as Ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)]/2. Spearman correlation analysis and linear regression analysis were performed to assess the relationship between the TyG index and 25(OH)D levels in people diagnosed with prediabetes and T2DM. The optimum cut-off value of the TyG index for detecting vitamin D deficiency was determined by receiver operating characteristic (ROC) curve analysis. Results: We observed a significant reduction in vitamin D levels in individuals with prediabetes and T2DM compared to those in the control group. However, the TyG index was significantly greater in individuals with prediabetes and T2DM than in controls. Statistical analysis revealed a significant negative correlation between the TyG index and 25(OH)D in both prediabetes and T2DM. Conclusions: The TyG index demonstrated a negative association with vitamin D levels and was identified as an independent predictor of vitamin D deficiency in individuals with prediabetes and T2DM.

Novel treatment options in patients with maturity onset diabetes of the young.

Maturity onset diabetes of the young (MODY) is the most common monogenetic form of diabetes with an autosomal dominant inheritance pattern. MODY is caused by mutations in genes that are important for the development and function of pancreatic beta cells, resulting in impaired insulin secretion capacity. To date, 14 different types have been described. While GCK-MODY (formerly MODY-2) generally requires no drug therapy, other forms of MODY such as HNF1A-MODY (formerly MODY-3) and HNF4A (formerly MODY-1) usually respond very well to sulfonylurea therapy. However, these MODY forms are characterised by a progressive course, meaning that insulin therapy is often required as the disease progresses. Both sulfonylurea therapy and insulin therapy are associated with an increased risk of hypoglycaemia and frequent weight gain. Newer blood glucose-lowering therapies, such as SGLT2 inhibitors (SGLT2i), DPP-4 inhibitors (DPP4i) and GLP-1 receptor agonists (GLP-1RA), have a much lower risk of hypoglycaemia and usually have a favourable effect on body weight. This review aims to provide an overview of the treatment of MODY patients with SGLT2i, DPP4i and GLP-1RA on the basis of previously published clinical studies, case series and case reports.

New insights on genetic background of major diabetic vascular complications

BackgroundBy 2045, it is expected that 693 million individuals worldwide will have diabetes and with greater risk of morbidity, mortality, loss of vision, renal failure, and a decreased quality of life due to the devastating effects of macro- and microvascular complications. As such, clinical variables and glycemic control alone cannot predict the onset of vascular problems. An increasing body of research points to the importance of genetic predisposition in the onset of both diabetes and diabetic vascular complications.ObjectivesPurpose of this article is to review these approaches and narrow down genetic findings for Diabetic Mellitus and its consequences, highlighting the gaps in the literature necessary to further genomic discovery.Material and methodsIn the past, studies looking for genetic risk factors for diabetes complications relied on methods such as candidate gene studies, which were rife with false positives, and underpowered genome-wide association studies, which were constrained by small sample sizes.ResultsThe number of genetic findings for diabetes and diabetic complications has over doubled due to the discovery of novel genomics data, including bioinformatics and the aggregation of global cohort studies. Using genetic analysis to determine whether diabetes individuals are at the most risk for developing diabetic vascular complications (DVC) might lead to the development of more accurate early diagnostic biomarkers and the customization of care plans.ConclusionsA newer method that uses extensive evaluation of single nucleotide polymorphisms (SNP) in big datasets is Genome-Wide Association Studies (GWAS).

8488 Sex-Specific Differences in an Alstrom Syndrome Mouse Model

Abstract Disclosure: Y. Carcamo-Bahena: None. J. Youn: None. E. Lartigue: None. S. Sisley: None. Background: Alström syndrome is a monogenic autosomal recessive disorder caused by loss of the ALMS1 gene that affects 1 in 1 million. Loss of a functional ALMS1 protein leads to global disorganization of microtubules. Patients are affected by progressive vision and hearing loss and are at risk of developing obesity and type 2 diabetes. Aside from reproductive system anomalies, no clinical reports have identified sex-specific difference in patients with Alström syndrome. Methods: Male and female Alms1tvrm[1]02/tvrm[1]02 (null), Alms1tvrm[1]02/+ (heterozygous) and wildtype littermate mice were weaned onto standard chow diet. At 16 weeks of age, they were changed to a 45% high fat diet (HFD). Weekly body weights were collected and intraperitoneal glucose tolerance tests (GTTs, 1.5 g/kg D20W) were performed at three different time points (11, 16, 25 weeks of age). Results:Alms1 null mice were heavier than wildtype and heterozygous mice on standard chow diet. In males, significant changes in weight gain in null mice occurred by 10 weeks compared to wildtype and heterozygous mice (p&amp;lt;0.05). In females, compared to null, this change was observed by 13 weeks (p&amp;lt;0.05). Although female mice are typically protected from diet-induced obesity, the null females weighed the same as the null males (65.0 ± 2.0 vs 67.7 ± 2.8 g) after 9 weeks on HFD. We observed sex and diet specific differences in GTT outcomes. On chow diet, Alms1 deficiency did not affect glucose levels during a GTT in female mice. However, after 9 weeks of HFD (25 weeks of age), baseline fasting glucose levels were higher in the null females compared to wildtype (p&amp;lt;0.05) and heterozygotes (p&amp;lt;0.01). Additionally, the GTT curve was monophasic, indicating onset of diabetes whereas wildtype and heterozygotes (p&amp;lt;0.0001) had normal curves. Null male mice showed an impaired glucose response at 11 weeks of age on chow diet compared to wildtype and heterozygous males (p&amp;lt;0.001) and by 16 weeks, the GTT glucose curve for Alms1 null mice was monophasic. After 9 weeks of HFD, no differences were observed in glucose levels during a GTT. Conclusions: We observed sex-specific differences in this Alms1 null mouse model related to body weight and glucose tolerance with male null mice exhibiting earlier obesity and impaired glucose tolerance and female mice showing more pronounced effects on a HFD. Future research should investigate if these sex-specific effects alter responses to dietary or pharmaceutical interventions. Presentation: 6/1/2024

7971 The Role of PDX1 In Beta Cell Response To GLP1

Abstract Disclosure: C. Bheeman: None. K. Vann: None. O. Astapova: None. Mature Onset of Diabetes of the Young Type 4 is a rare form of diabetes mellitus caused by a defect in the Pancreatic and Duodenal homeobox 1 (PDX-1) gene, which is predominantly expressed in β-cells and is an important factor in insulin gene transcription. We aim to study the impact that a PDX1 mutation (modeled after a patient) has on the beta cell response to GLP1. This was a 33-year-old nonobese man who presented to the clinic with new onset diabetes without ketosis. He was treated with insulin and metformin and his hemoglobin A1c decreased from 16% to 6.1% in six months. Other labs showed c-peptide of 8.9 ng/mL in setting of a blood glucose of 231 mg/dL, negative islet cell antibodies and glutamic acid antibodies. Of note, patient also had significant family history of diabetes. Due to high probability of MODY, genetic testing was obtained. He was found to have a heterozygous frameshift mutation in codons 228 -233 leading to a 17 base pair deletion in the PDX1 gene causing replacement of the 56 C- terminal amino acids with a shorter, missense C-terminal tail. Patient was started on dulaglutide 0.75 mg weekly but was hypoglycemic on the smallest dose so he was then switched to Semaglutide and has been maintained on less than 0.25 mg weekly. The clinical question we aim to answer was why was this patient so sensitive to GLP1 agonist activity. To study how the mutation affects response to GLP1 we are using mouse beta-TC-6 cell as they are insulin secreting, and regulated by glucose. The PDX-1 gene is highly conserved among species and the mouse PDX gene is comparable to the human gene. We used CRISPR-Cas9 to introduce the same 17 base-pair deletion into the mouse PDX-1 gene in beta-TC-6 cells. We first measured the glucose stimulated insulin secretion in control cells to examine first and second phases of insulin secretion, determining that the first phase of insulin occurs in twenty minutes and the second phase starts at about two hours. We also evaluated if these cells responded GLP-1 by increasing insulin secretion. We found that these cells respond to glucose and GLP1 in an additive manner. Insulin was measured by enzyme-linked immunosorbent assay (ELIZA). In the next phase of the experiment we aim to determine the effect of the GLP-1 in cell lines with the PDX1 deletion mutation as compared to control cell line. We will measure insulin secretion by ELISA in both mutant and the control cells treated with and without glucose and GLP1. We will measure insulin at 0 minutes and 30 minutes and insulin mRNA at 0 minutes and 6 hours to determine the first and second phases of insulin production. Our results will help guide personalized treatment for patients with MODY type 4 and improve our understanding of beta cell response to GLP1. Presentation: 6/2/2024

9334 Pancreatic Adenocarcinoma Presenting As Diabetic Ketoacidosis

Abstract Disclosure: J. Alvarez: None. M.H. Horani: None. Background: Pancreatic adenocarcinoma is often diagnosed at an advanced stage due to late onset of clinical features including poor appetite, weight loss, weakness, epigastric pain, and rarely impaired glucose tolerance. In patients who present with impaired glucose tolerance or diabetic ketoacidosis without prior history of diabetes, pancreatic adenocarcinoma should be considered. Clinical Case: Patient is a 45-year woman with depression, HTN, irritable bowel syndrome who was found unresponsive by family and presented to the ED for acute encephalopathy. On exam, she was obtunded, tachypneic, with fruity-smelling breath and dry mucous membranes. Initial labs showed glucose of 950 mg/dL (70-99 mg/dL), lipase 539 U/L (8-78 U/L), lactic acid 4 mmol/L 0.5-2 mmol/L), ketone-BHB 170.75 mg/dL (0-2.81 mg/dL), A1c 16.5%. She had no prior history or family history of diabetes. She was admitted to hospital for DKA management.CXR to evaluate dyspnea showed bilateral opacities so CT chest/abdomen/pelvis without contrast was ordered. This showed bilateral multilobar pneumonia, trace pleural effusions, 6.7 x 3.8 cm lobulated fluid collection along pancreatic tail, 12.1 x 6.6 x 4.4 cm RLQ cystic lesion and 4.4 cm lesion vs loculation along the right pelvic sidewall.Initially, GI recommended repeat imaging of the pancreas in 4-6 weeks. OBGYN was consulted for pelvic masses and recommended IR-guided biopsy of right pelvic mass which showed rare mildly atypical mucinous epithelium present, cystic mucinous neoplasm cannot be excluded.CEA and CA125 tumor markers returned elevated. These biopsies showed adenocarcinoma (solid component) and rare atypical mucinous epithelium consistent with cystic mucinous neoplasm (cystic fluid). Patient was deemed medically stable for discharge with recommended follow-up to appropriate specialists. Following discharge, she was officially diagnosed with Stage III (cT4, cN0, cM0) pancreatic adenocarcinoma and started on appropriate chemotherapeutic regimen. Discussion: The current understanding is long-standing type 2 diabetes mellitus as a risk factor for pancreatic cancer based on previous studies.The inverse relationship of pancreatic cancer causing new onset diabetes is more rare, but if cancer is suspected in these patients it could potentially help in the diagnosis of early stage adenocarcinoma. Other case reports have suggested implementation of the enriching new-onset diabetes for pancreatic cancer (ENDPAC) score in addition to CT and EUS as screening for pancreatic cancer may help with earlier diagnosis.

6893 The Interaction Effect Between BMI, Diabetes, and Age at Diabetes Onset on the Risk of Thyroid Cancer: A Population-Based Cohort Study

Abstract Disclosure: T. Hou: None. Y. Li: None. J. Tian: None. Z. Bloomgarden: None. Y. Shi: None. ObjectiveThe relationship between type 2 diabetes mellitus (T2DM) and thyroid cancer was confounded by some characteristics of diabetes. We aimed to determine the association of the presence of diabetes and, among persons with diabetes, the age at T2DM onset, BMI, and the interactive effect with the subsequent thyroid cancer risk. MethodsWe conducted a population-based longitudinal cohort study including 428,568 persons with new-onset T2DM matched with the general population (100,649,346 person-years). Risk of thyroid cancer by subgroups were calculated based on standardized incidence ratio (SIR), hazard ratio (HR), and Cox proportional hazards models. ResultsIn T2DM patients, 1142 thyroid cancer cases were identified during eight years of follow-up, with an incidence rate of 59.01/100,000 person-years and a higher SIR: 1.21 (95% CI: 1.14-1.28) compared to the general population. New-onset T2DM had an overall 21% higher risk of thyroid cancer. Both the earlier age at T2DM onset and higher BMI were associated with a significant increasing risk of thyroid cancer independently (T2DM onset age &amp;lt;50: SIR 1.46 (1.27-1.69); BMI ≥30.0 Kg/m2 SIR: 1.93 (1.57-2.38)). The highest risk of cancer appeared in the patients with both BMI ≥30.0 Kg/m2 and T2DM onset age &amp;lt;50 years (SIR=3.91, HR=3.04). Among patients with T2DM onset age &amp;lt;60 years, SIR shows an increasing trend of cancer risk with higher BMI levels, while no significant increasing trends with higher BMI in T2DM onset age ≥60 years. For patients with BMI ≥25.0 Kg/m2, SIR of cancer risk decreases with an later T2DM onset age, whereas no significant decreasing trends of cancer risk in BMI &amp;lt;24.9 Kg/m2 group. Obese (BMI ≥30.0 Kg/m2) patients had a significant higher HR of thyroid cancer only when T2DM onset age &amp;lt;60 years. ConclusionsBoth earlier age of T2DM onset (&amp;lt;50 years) and higher BMI (≥30 Kg/m2) contributed to higher risk of thyroid cancer. These results suggest that earlier screening of thyroid cancer might be appropriate in patients diagnosed with T2DM, especially in individuals with young-onset T2DM and obesity. Presentation: 6/3/2024

6674 Non-Progressive Diabetes Leading to Neurologic Diagnosis

Abstract Disclosure: F.L. Thelmo: None. M. Murugesh: None. B. Simon: None. Introduction: The autoantibody GAD (anti-glutamic acid decarboxylase) is highly associated with Type 1 diabetes (T1DM) and Latent Autoimmune Diabetes in Adulthood (LADA). If GAD is detected before the onset of overt diabetes, typically 80% of patients with abnormal glucose tolerance progress to insulin deficiency and the need for insulin treatment after 5 years.[1] Stiff Person Syndrome (SPS) is also associated with GAD antibodies, but in SPS, the GAD antibodies are believed to be different epitopes that target GABA production in neuromuscular pathways. We present a case of presumed LADA that did not progress for 30 years, with progressive neurologic symptoms leading to a diagnosis of SPS in later adulthood.Case: A 52-year-old female presented for evaluation of T1DM and worsening neuropathies. She had a long history of prediabetes, with mildly elevated glucose values noted on labs since her early twenties. There was no family history of T1DM or autoimmune conditions. Six years ago, she sought endocrine evaluation. HgbA1c values were 6.1 to 6.6%. Intermittent use of continuous glucose monitoring (CGM) revealed post-prandial hyperglycemia up to 180mg/dL, occasionally (but rarely) exceeding 200mg/dL. She recalls being told that she had positive antibodies (unclear which ones tested) and given a diagnosis of T1DM. She declined insulin and maintained glycemic control with carbohydrate restriction and exercise; there were no episodes of diabetic ketoacidosis. She then developed neurologic symptoms: fullness, tightness and bloating in the abdomen (diagnosed with gastroparesis on scanning) and after a COVID 19 booster in 2021, muscle spasms in the legs and back with worsening abdominal tightness. At the time of her current presentation, A1C was 6.4%, glycated albumin was 14.4% (prediabetes range 13.6 - 15.5%) and CGM time in range was 99%. A non-fasting C-peptide was 3.6 ng/mL (1.1- 4.4ng/mL) with glucose of 119 mg/dL. Repeat antibody testing revealed undetectable IA-2 and ZnT8 antibodies, but GAD was grossly elevated at 1,015.3 U/mL. Given the unusually high GAD titer, SPS was suspected, and this diagnosis was confirmed on referral to neurology. The patient was advised to liberalize diet and will be monitored with HgbA1c and serial C-peptide levels to assess progression in the future. Discussion: While high GAD antibody levels are associated with progression to insulin dependence in adults with LADA, in SPS the GAD titers tend to be even higher2. The presence of only one auto-antibody for T1DM (and not multiple), long-standing non-progressive hyperglycemia, and normal C-peptide pointed away from autoimmune diabetes being the etiology for mild glucose intolerance in this patient. If neurologic symptoms are present, high GAD should prompt the evaluation for other syndromes associated with GAD antibody epitopes such as SPS. Presentation: 6/2/2024