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Background: Research on the relationship between dietary phytochemical intake and the anthropometric indices as well as the diabetic foot ulcers (DFUs) remains inconsistent. We aimed to investigate the associations of dietary phytochemical index (DPI) with the novel anthropometric indices and the severity of DFUs., Methods: This cross-sectional study was conducted on 339 adults with type 2 diabetes. Dietary intake was assessed using three 24-hour dietary recalls. To quantify the phytochemical content of the diet, the DPI estimation was done through an equation proposed by McCarty. The International Working Group on the Diabetic Foot (IWGDF) criteria and Wagner classification system were applied to assess DFUs. New anthropometric indices including a body shape index (ABSI), body roundness index (BRI) and abdominal volume index (AVI) were calculated based on formulas. We employed analysis of variance (ANOVA), analysis of covariance (ANCOVA) and logistic regression to explore associations between DPI and the anthropometric indices and DFU variables., Results: Our results revealed no significant association between DPI and the foot ulcer indices, following adjusting for the possible covariates. Furthermore, we also examined the relationship between diabetic neuropathy, as measured by monofilament score, and the DPI. Similarly, we did not find any substantial relationship between the DPI and monofilament score (OR: 1.18; 95% CI: 0.66-2.09; P trend = 0.56), as well as biochemical indices. Our analysis did not reveal any significant associations between the DPI and ABSI (OR: 0.70; 95% CI: 0.35-1.38; P trend = 0.30), BRI (OR: 0.80; 95% CI: 0.33-1.95; P trend = 0.59), and AVI (OR: 1.99; 95% CI: 0.92-4.33; P trend = 0.08)., Conclusions: Our study revealed no significant links between the DPI and foot ulcer indices, neuropathy measures, and anthropometric indices. These findings imply that factors beyond dietary phytochemical intake may exert greater influence on the development of foot ulcers in diabetes., (© 2024. The Author(s).)

BACKGROUND The relationship between different subgroups of type 2 diabetes (T2D) and the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) and liver fibrosis has not been thoroughly studied. This study aims to determine the association between T2D subgroups and the risk of developing advanced liver fibrosis using the Fibrosis-4 (FIB-4) index, a non-invasive marker for assessing liver fibrosis risk. MATERIAL AND METHODS A total of 1205 patients with T2D were categorized into 4 distinct subgroups: severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD). The FIB-4 index was calculated for each patient to estimate the degree of liver fibrosis, with the following cutoff points: <1.3 indicating no or mild fibrosis, 1.3-2.67 suggesting moderate fibrosis, and >2.67 indicating advanced fibrosis (F3-F4). Logistic regression was used to compare the odds of advanced fibrosis across these subgroups. RESULTS The SIRD subgroup exhibited significantly higher odds of advanced liver fibrosis (F3-F4), compared with the other subgroups, as indicated by elevated FIB-4 scores (P<0.05). In contrast, the SIDD and MOD subgroups had lower odds of advanced fibrosis, while the MARD subgroup showed an intermediate association. CONCLUSIONS The findings suggest that the FIB-4 index, as a noninvasive assessment tool, effectively stratifies liver fibrosis risk among different T2D subgroups. This stratification can inform more personalized management strategies for patients with MASLD, underscoring the importance of accounting for the heterogeneity within T2D in clinical assessments of liver fibrosis risk.

Background: Type 2 diabetes mellitus (T2DM) is a major 21st-century epidemic. T2DM elevates the risk of myocardial infarction and heart failure while also reducinges survival rates. Recently Ferroptosis has been found to be involved in the development of various cardiovascular diseases. TRPV1 is also a potential therapeutic target for cardioprotection. This study explores whether capsaicin, a transient receptor potential vanilloid receptor 1 (TRPV1) agonist, can prevent diabetic myocardial infarction-induced injury by inhibiting ferroptosis., Methods: T2DM model was induced by high-fat diet (HFD) feeding combined with streptozocin (STZ) injections, and the diabetic mice were treated with capsaicin(0.015 %) in their food. Myocardial infarction model was established as well. Mouse' general characteristics, cardiac function, and morphological histology were observed and analyzed. RNA-seq was used to investigate the possible mechanism of injury in AC16 cardiomyocytes cultured with high glucose and hypoxia. In addition, the potential mechanism of capsaicin against injury was further investigated in AC16 cardiomyocytes cultured with high glucose and hypoxia., Results: The RNA-seq analysis revealed that ferroptosis was associated with cell death induced by high-glucose in combination with hypoxia, and CAP treatment could effectively inhibit ferroptosis to enhance cell survival. In vivo studies demonstrated that CAP treatment significantly improved post-MI cardiac function, attenuated myocardial inflammation and fibrosis. Furthermore, it was observed that CAP reduced ferroptosis levels by activating TRPV1 in the heart, upregulating Nrf2 expression, promoting Nrf2 nuclear translocation and increasing the expression of the Nrf2 downstream molecule Heme oxygenase-1 (HMOX1)., Conclusions: Dietary capsaicin may inhibit cardiomyocyte ferroptosis through activation of myocardial TRPV1 and Nrf2/HMOX1 signaling pathway, which in turn exerts a protective effect on the myocardium after myocardial infarction in type 2 diabetic mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lactic acidosis is a rare metabolic complication that can occur in patients with diabetes mellitus type 2 who use metformin. We discuss a 79-year old woman with metformin-associated lactic acidosis (MALA) and acute kidney injury based on gastroenteritis. Patient reported acute blindness which in literature is described as a rare presentation of a metabolic acidosis (regardless of its underlying cause). Immediate treatment with hemodialysis led to improvement of the acidosis and complete recovery of the vision. It is important that patients who use metformin are instructed to consult their health care provider and/or discontinue metformin in case of intercurrent diseases.

Epidemiological surveys have shown that the incidence of type 2 diabetes mellitus (T2DM) and malignancies is rapidly increasing worldwide and has become a major disease that threatens human life. In this study, we quantitatively analyzed the proteome of tumor tissues and adjacent normal tissues from six patients withT2DM combined with colorectal cancer (CRC) and eight non-diabetic CRC, focusing on the effect of T2DM on tumor tissues. We analyzed the functional enrichment of differentially expressed proteins (DEPs) using clusterProfiler in R and the expression level of protein tyrosine phosphatase non-receptor type 11 (PTPN11) and other key proteins in the TIMER and GEPIA2 databases. The HPA database was used to validate PTPN11 protein expression. The correlation between PTPN11 expression and clinicopathological features was analyzed by UALCAN database. The impact of PTPN11 on clinical prognosis was evaluated utilizing Kaplan-Meier Plotter. The correlation between PTPN11 expression and tumor-infiltrated immune cells was investigated via TIMER and TISIDB databases. Gene set enrichment analysis (GSEA) was performed to examined the pathway of PTPN11 enrichment in CRC using data from The Cancer Genome Atlas (TCGA) database. Furthermore, small interfering (si) RNA was used to knock down PTPN11 in CRC cell line SW480. Western blot analysis was used to detect PTPN11 expression in tissue samples or cells and the effect of PTPN11 knockdown on key proteins related to PI3K/AKT and cell cycle pathway in SW480 cells. Cell proliferation and wound healing assays were used to detect the effects of cell proliferation and migration after knockdown of PTPN11 or treatment with high glucose. We found that metabolic pathways such as oxidative phosphorylation, glycolysis/gluconeogenesis, and insulin secretion were significantly enriched in tumor tissues from diabetic patients compared to non-diabetic patients. In addition, PTPN11, a marker gene associated with T2DM and CRC, were mined in diabetic tumor tissues. PTPN11 showed high expression in diabetic tumor tissues compared to normal tissues. High PTPN11 expression predicted poor prognosis in CRC. PTPN11 expression was strongly associated with immune infiltrating cells in CRC. GSEA analysis revealed that PTPN11 was enriched in cancer-related pathways. Western blotting analysis indicated that PTPN11 knockdown reduced the protein levels of p-PI3K, p-AKT, CDK1 and CYCLIN D, without altering PI3K and AKT protein levels. Cell proliferation and wound healing data showed that PTPN11 and high glucose could increase the proliferation and migration ability. These findings showed that PTPN11 may be a potential key biomarker for CRC in patients with diabetes, which will provide new potential targets for future intervention of T2DM complicated with CRC., (© 2024. The Author(s).)

Diabetes mellitus is a major worldwide health concern. Diabetes has been associated with a number of adverse mental health conditions including depression, anxiety, and loneliness that can negatively impact diabetes outcomes. This study aimed to investigate factors associated with depression, anxiety, and loneliness in people, in the community, suffering with diabetes in Bangladesh. A cross-sectional study was conducted with 600 people with type-2 diabetes (54.83% females; mean age: 52.70 ± 11.56 years) between July and September 2022. Purposive sampling method was used to recruit the participants. A validated semi-structured questionnaire was used to collect demographic and other data. Depression, anxiety, and loneliness were measured using the PHQ-9, GAD-7, and UCLA Loneliness scale, respectively. Bivariate and multivariable linear regression analyses were conducted to ascertain factors that were significantly associated with these mental health conditions. The prevalence of depression, anxiety, and loneliness was 31.17%, 21.83%, and 28.00%, respectively. A lack of formal education, and not taking part in physical activities were significantly associated with all three mental health states. Duration of diabetes and being on medication for high cholesterol were also associated with depression and anxiety. Older age and being widowed were significantly associated with loneliness. This study found that depression, anxiety, and loneliness are prevalent among Bangladeshi people with diabetes, with certain sociodemographic and diabetes-related factors associated with increased risk. The findings emphasize the need for targeted interventions to people within the communities, at grassroot levels in order to improve reduce health inequality, and improve the mental health of people living with diabetes., (© 2024. The Author(s).)

Silicon as a functional ingredient of restructured meat (RM) shows antidiabetic and hypocholesterolemic effects in a type 2 diabetes mellitus (T2DM) rat model. The present paper investigated the mechanisms involved in this cholesterol-lowering effect by studying the impact of silicon-RM consumption on bile acid (BA) and cholesterol metabolism. In addition, the main effects of cecal BA and short-chain fatty acids derived from the microbiota on intestinal barrier integrity were also tested. Rats were fed an RM high-saturated-fat, high-cholesterol diet (HSFHCD) combined with a low dose of streptozotocin plus nicotinamide injection (LD group) and for an 8 wk. period. Silicon-RM was included in the HSFHCD as a functional food (LD-Si group). An early-stage T2DM group fed a high-saturated-fat diet (ED group) was used as a reference. Silicon decreased the BA pool with a higher hydrophilic BA profile and a lower ability to digest fat and decreased the damaging effects, increasing the occludin levels and the integrity of the intestinal barrier. The ileal BA uptake and hepatic BA synthesis through CYP7A1 were reduced by FXR/FGF15 signaling activation. The silicon up-regulated the hepatic and ileal FXR and LXRα/β, improving transintestinal cholesterol (TICE), biliary BA and cholesterol effluxes. The inclusion of silicon in meat products could be used as a new therapeutic nutritional tool in the treatment of diabetic dyslipidemia.

Aims: According to the gut-kidney axis theory, gut microbiota (GM) has bidirectional crosstalk with the development of diabetic kidney disease (DKD). However, empirical results have been inconsistent, and the causal associations remain unclear. This study was aimed at exploring the causal relationship between GM and DKD as well as the glomerular filtration rate (GFR) and urinary albumin-to-creatinine ratio (UACR). Materials and Methods: Two-sample Mendelian randomisation (MR) analysis was performed with inverse-variance weighting as the primary method, together with four additional modes (MR-Egger regression, simple mode, weighted mode, and weighted median). We utilised summary-level genome-wide association study statistics from public databases for this MR analysis. Genetic associations with DKD were downloaded from the IEU Open GWAS project or CKDGen consortium, and associations with GM (196 taxa from five levels) were downloaded from the MiBioGen repository. Results: In forward MR analysis, we identified 13 taxa associated with DKD, most of which were duplicated in Type 2 diabetes with renal complications but not in Type 1 diabetes. We observed a causal association between genetic signature contributing to the relative abundance of Erysipelotrichaceae UCG003 and that for both DKD and GFR. Similarly, host genetic signature defining the abundance of Ruminococcaceae UCG014 was found to be simultaneously associated with DKD and UACR. In reverse MR analysis, the abundance of 14 other GM taxa was affected by DKD, including the phylum Proteobacteria, which remained significant after false discovery rate correction. Sensitivity analyses revealed no evidence of outliers, heterogeneity, or horizontal pleiotropy. Conclusion: Our findings provide compelling causal genetic evidence for the bidirectional crosstalk between specific GM taxa and DKD development, contributing valuable insights for a comprehensive understanding of the pathological mechanisms of DKD and highlighting the possibility of prevention and management of DKD by targeting GM., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Yun Zhang et al.)

Objective: To evaluate the prevalence and risk factors of painful diabetic peripheral neuropathy (PDPN) in patients with type 2 diabetic peripheral neuropathy (DPN) in Hunan Province, and establish and verify the prediction model., Methods: This was a retrospective study involving 4908 patients, all patients were randomly divided into the training dataset(3436 cases)and the validation dataset (1472 cases) in a ratio of 7:3. Electroneurogram, clinical signs,and symptoms were used to evaluate neuropathy. Least absolute shrinkage and selection operator (LASSO) regression was used to select the optimal factors, and multifactorial logistic regression analysis was used to build a clinical prediction model. Calibration plots, decision curve analysis (DCA), and subject work characteristic curves (ROC) were used to assess the predictive effects., Result: The prevalence of PDPN was 33.2%, and the multivariate logistic regression model showed that peripheral artery disease, duration of diabetes, smoking, and HBA1c were independent risk factors for PDPN in patients with type 2 diabetes. ROC analysis results showed that the AUC of the established prediction model was 0.872 in the training dataset and 0.843 in the validation dataset. The calibration curve and decision curve show that the model has good consistency and significant net benefit., Conclusion: 33.2% of DPN patients had PDPN in Hunan Province, China. Peripheral artery disease, duration of diabetes, smoking, and HBA1c are risk factors for PDPN in patients with type 2 diabetes. The prediction model is based on the above factors, which can well predict the probability of PDPN., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yu, Zhao, Cao and Xie.)

Background: Obesity is a predisposing risk factor for type 2 diabetes mellitus (T2DM). Actually, not only obese/overweight but also nonobese/lean individuals may be prone to T2DM. This study is aimed at identifying the contribution of adipose tissue to the development of nonobese diabetes (NOD) and obese diabetes (OD). Methods: Serum samples from the nonobese nondiabetes (NOND, n = 47, age = 46.8 ± 8.4, BMI ≤ 23.9 kg/m 2 ) controls, NOD ( n = 48, age = 50.7 ± 6.5, BMI ≤ 23.9 kg/m 2 ) and OD (n = 65, age = 49.8 ± 10.2, BMI ≥ 28 kg/m 2 ) patients were utilized to measure the expression of metabolic indicators, adipocytokines, inflammatory factors. Different adipose depots from offspring with corresponding blood glucose and obesity levels of a spontaneously diabetic gerbil line with various degrees of diabetic penetrance and body weights were examined for adipocytokines and inflammation factors detected by ELISA and western blot. Adipose tissue volume and fat cell size of the gerbils were evaluated by magnetic resonance imaging and immunohistochemistry, respectively. Results: The study yielded four key findings. Firstly, in comparison to the NOD group, the OD group exhibited more severe insulin resistance (IR) and metabolic dysfunction in both patients and gerbils, attributed to higher visceral adipose tissue mass and larger fat cell sizes. Secondly, in gerbils, gonadal fat deposition was linked to obesity development, whereas kidney fat deposition correlated with obesity and diabetes occurrence. Thirdly, in both patients and gerbils, the interplay between adiponectin and leptin levels in serum may significantly influence the development of obesity and diabetes. Lastly, heightened expression of MCP3 in gerbils' kidney adipose tissue may serve as a pivotal factor in initiating obesity-associated diabetes. Conclusions: Our study, which may be considered a pilot investigation, suggests that the interaction of adipocytokines and inflammation factors in different adipose depots could play diverse roles in the development of diabetes or obesity., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Hongjuan Fang et al.)

Background: Type 2 diabetes (T2D) is a chronic metabolic disorder that has a notable influence on mental well-being, contributing to elevated morbidity and mortality rates. Depression and anxiety disorders are the most common mental health concerns among patients with T2D worldwide. Therefore, the present study aimed to assess the impact of an online intensive lifestyle intervention (ILI) on mental health outcomes (depression and anxiety) in patients with T2D in India., Materials and Methods: This retrospective pre-post analysis included adult patients (aged > 18 years) diagnosed with T2D who were enrolled in a diabetes management program in India between June 2021 and June 2023. The intervention consisted of lifestyle modifications such as a customized plant-based diet, regular physical activity, psychological support through group and individual therapy, and medical management. Data were extracted from the electronic database of the clinic, including anthropometry, medical history, biochemical parameters, symptoms of depression, and anxiety (assessed using the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorders-7 (GAD-7) scale) at the start and end of the six-month intervention period., Results: Of the 1061 eligible patients (177 with prediabetes), 40.3% were female. The mean age, duration of diabetes, and HbA1c levels were 52 ± 10.4 years, 9.8 ± 7.8 years, and 8 ± 1.7%, respectively. The prevalence of symptoms of depression and anxiety (ranging from mild to severe) was 46% and 44.3%, respectively, which reduced to 28.7% and 29.2%, respectively, post-intervention., Conclusion: Integrated ILI successfully improved the symptoms of anxiety and depression, highlighting the importance of a multidisciplinary approach that includes diet, physical activity, psychological support, and medical management in enhancing mental health outcomes among patients with T2D. Future prospective studies are needed to explore the long-term effects of such interventions and develop effective strategies for promoting mental health in diverse populations., Trial Registration: The study was approved by the Freedom from Diabetes Research Foundation Institutional Ethics Committee (approval number FFDRF/IEC/2024/7) and registered in the Clinical Trials Registry of India (CTRI/2024/03/064596, registered on March 21, 2024)., (© 2024. The Author(s).)

Background: Diabetes mellitus is characterized by insulin resistance (IR) and dysfunctional insulin secretion from pancreatic β-cells. However, little research has been conducted on the relationship between IR and β-cell function in relation to diabetic complications among Korean diabetic patients. This study aimed to examine the differential associations between IR and β-cell function and various diabetic complications among Korean diabetic patients., Methods: The analysis employed a common data model (CDM). IR and β-cell function were quantified using the homeostasis model assessment for insulin resistance (HOMA-IR) and β-cell function (HOMA-β), respectively. Hazard ratios for diabetic nephropathy, diabetic retinopathy, and cardiovascular disease (CVD) events were calculated., Results: The study cohort consisted of 2,034 diabetic patients aged over 20 years who visited EUMC between January 2001 and December 2019. Among diabetic patients in the highest quartile of HOMA-IR, the adjusted hazard ratio for total CVD events was 1.76 (95% confidence interval [CI], 1.20-2.57) compared with those in the lowest quartile of HOMA-IR (P = 0.004). In contrast, diabetic patients in the lowest quartile of HOMA-β exhibited an adjusted hazard ratio of 3.91 (95% CI, 1.80-8.49) for diabetic retinopathy compared to those in the highest quartile of HOMA-β (P = 0.001)., Conclusion: Insulin resistance and β-cell function exhibited different associations with diabetic complications among Korean diabetic patients. Specifically, lower β-cell function was associated with an increased risk of diabetic retinopathy, whereas higher IR was associated with an increased risk of CVD events. Individuals with pronounced IR should prioritize CVD prevention measures, and those with significant β-cell dysfunction may benefit from early, intensive surveillance for diabetic retinopathy., Competing Interests: We declare that we have no conflict of interests., (Copyright: © 2024 Song et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Few studies have investigated the potential predictive value of glycosylated hemoglobin A (HbA1c) and clinical outcomes in diabetic patients after percutaneous coronary intervention (PCI), and the results of the reports have often been inconclusive and contradictory. We have organized a study to investigate the relationship between HbA1c and the occurrence of major adverse cardiovascular events (MACE) in diabetic patients after PCI., Methods: This case-cohort study was conducted on 563 diabetic patients who underwent PCI. All studied patients had an HbA1c level measured within 24 h before angioplasty. All patients were followed for six months regarding the occurrence of MACE, and the HbA1c level was measured again at the end of the sixth month of follow-up. In the case of MACE, the subjects were considered the case group, and other non-MACE patients were included in the control group., Results: 505 patients remained in the study at the end of follow-up. MACE occurred in 23 (4.6%) patients during the first month and in 57 (11.3%) patients by the end of the sixth month. Baseline HbA1c was an independent predictor of MACE and mortality at the end of month-6 (P = 0.008 and 0.001, respectively)., Conclusions: The level of HbA1c at the time of admission has a significant predictive value for the occurrence of MACE in diabetic patients who undergo PCI. However, post-PCI glycemic control may not effectively reduce the risk of MACE in this population., Clinical Trial Registration: Not applicable., (© 2024. The Author(s).)

Microvascular complications, affecting small blood vessels, can lead to serious conditions such as kidney failure, painful nerve damage, and vision loss. Early detection and effective treatment of these issues are vital for improving patient outcomes and reducing healthcare expenses. Thus, this study aimed to assess diabetic microvascular complications among adults with type 2 diabetes in Adama, central Ethiopia. An institutional-based cross-sectional study was conducted among 381 adult type 2 diabetes patients. A computer-generated simple random sampling method was used to select study participants. Data were collected using a structured data extraction checklist. The collected data were entered into Epi info version 7.2 and exported to SPSS version 27 for processing and analysis. Binary logistic regression was employed to model the association between diabetic microvascular complications and explanatory variables. An adjusted odds ratio (AOR) with a 95% confidence interval (CI) was used to estimate the strength of association, and statistical significance was proclaimed at a p-value < 0.05. The prevalence of diabetic microvascular complications was 21.8% (95% CI: 17.8-25.6) with diabetic neuropathy being the most common (16.8%), followed by diabetic retinopathy (4.2%), and diabetic nephropathy (2.9%). Poor glycemic control (AOR = 2.00, 95% CI: 1.01-3.98), and a history of hypertension (AOR = 2.36, 95% CI: 1.39-4.00) were positively associated with the development of diabetic microvascular complications. Conversely, being aged 41-60 years (AOR = 0.35, 95% CI: 0.18-0.68) was negatively associated with the development of these complications. About one in five patients developed at least one diabetic microvascular complication. Age, poor glycemic control, and a history of hypertension were associated with the development of these complications. Therefore, intervening to improve glycemic control and manage hypertension is crucial in preventing the onset of diabetic microvascular complications., (© 2024. The Author(s).)

Background: The therapeutic effects of ertugliflozin, a sodium-glucose cotransporter 2 inhibitor, on cardiovascular outcome are not fully understood. This study aimed to evaluate the efficacy and safety of ertugliflozin on cardiac function in people with type 2 diabetes and pre-heart failure., Methods: We conducted a 24-week randomized, double-blind, placebo-controlled trial involving individuals with type 2 diabetes inadequately controlled with antidiabetic medications. Participants with left ventricular hypertrophy, E/e' >15, or impaired left ventricular global longitudinal strain (LVGLS) were randomized 1:1 to receive either ertugliflozin (5 mg once daily) or a placebo. The primary outcome was the change in LVGLS. Secondary outcomes included changes in left ventricular mass index (LVMI) and left ventricular ejection fraction (LVEF). Prespecified exploratory outcomes, including angiotensin-converting enzyme 2 (ACE2) and angiotensin (1-7) levels, were also assessed., Results: A total of 102 individuals (mean age, 63.9 ± 9.2 years; 38% women) were included. The ertugliflozin group showed a significant improvement in LVGLS (- 15.5 ± 3.1% to - 16.6 ± 2.8%, P = 0.004) compared to the placebo group (- 16.7 ± 2.7% to - 16.4 ± 2.6%, P = 0.509), with a significant between-group difference (P = 0.013). Improvements in LVMI and LVEF were also observed. Additionally, significant reductions in HbA 1c , systolic blood pressure, whole-body and visceral fat, uric acid, proteinuria, N-terminal pro-B-type natriuretic peptide, and lipoprotein(a) were noted. ACE2 and angiotensin (1-7) levels significantly increased in the ertugliflozin group compared to the placebo group and correlated with changes in LVGLS [r = 0.456, P < 0.001 for ACE2; r = 0.541, P < 0.001 for angiotensin (1-7)]. Adverse events were similar between the two groups., Conclusions: This study demonstrated that ertugliflozin has beneficial effects on left ventricular function in individuals with type 2 diabetes and pre-heart failure, and it provided insights into potential underlying mechanisms., Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT03717194., (© 2024. The Author(s).)

Background and Objectives: Despite the mechanistic potential of sodium-glucose cotransporter 2 inhibitor (SGLT2i) to improve neurologic outcomes, the efficacy of SGLT2i in neurodegenerative disorders among patients with type 2 diabetes is not well established. This population-based cohort study aimed to investigate the association of SGLT2i use with risks of incident dementia and Parkinson disease (PD) in patients with type 2 diabetes., Methods: This was a retrospective examination of data from a cohort of 1,348,362 participants with type 2 diabetes (≥40 years), who started antidiabetic drugs from 2014 to 2019, evaluated using the Korean National Health Insurance Service Database. Propensity score matching (1:1; SGLT2i to other oral antidiabetic drugs [OADs]) produced a cohort of 358,862 participants. Primary outcomes were the individual incidence of Alzheimer disease (AD), vascular dementia (VaD), and PD. Secondary outcomes were all-cause dementia (AD, VaD, and other dementia) and a composite of all-cause dementia and PD. Cox proportional hazards models were used to investigate the association between SGLT2i use and the risks of dementia and PD., Results: From the 358,862 participants analyzed (mean [SD] age, 57.8 [9.6] years; 58.0% male), 6,837 incident dementia or PD events occurred. Regarding the individual endpoints, SGLT2i use was associated with reduced risks of AD (adjusted hazard ratio [aHR] 0.81, 95% CI 0.76-0.87), VaD (aHR 0.69, 95% CI 0.60-0.78), and PD (aHR 0.80, 95% CI 0.69-0.91) with a 6-month drug use lag period. In addition, use of SGLT2i was associated with a 21% lower risk of all-cause dementia (aHR 0.79, 95% CI 0.69-0.90) and a 22% lower risk of all-cause dementia and PD than use of other OADs (aHR 0.78, 95% CI 0.73-0.83). The association between the use of SGLT2i and the lowered risk of these neurodegenerative disorders was not affected by sex, Charlson Comorbidity Index, diabetic complications, comorbidities, and medications. Sensitivity analysis further adjusting for bioclinical variables from health screening tests, including blood pressure, glucose, lipid profiles, and kidney function, yielded generally consistent results., Discussion: In this nationwide population-based study, SGLT2i use significantly reduced the risks of neurodegenerative disorders in patients with type 2 diabetes independent of various factors including comorbidities and bioclinical parameters., Classification of Evidence: This study provides Class II evidence that SGLT2 antidiabetic drugs decrease the risk of dementia and PD in people with diabetes.

Background: People with type 2 diabetes (T2D) and chronic kidney disease (CKD) are at high risk for heart failure (HF) and premature death from cardiovascular (CV) causes. The FLOW (Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease), which enrolled participants with T2D and CKD, demonstrated that semaglutide, a glucagon-like peptide-1 receptor agonist, reduced the incidence of the primary composite outcome (persistent ≥50% decline in estimated glomerular filtration rate, persistent estimated glomerular filtration rate <15 mL/min/1.73 m 2 , kidney replacement therapy, and kidney or CV death) by 24%., Objectives: This prespecified analysis examined the effects of semaglutide on HF outcomes in this high-risk population., Methods: Participants were randomized (1:1) to once-weekly subcutaneous semaglutide 1 mg or placebo. The prespecified main outcome was a composite of HF events (new onset or worsening of HF leading to an unscheduled hospital admission or an urgent visit, with initiation of or intensified diuretic/vasoactive therapy) or CV death. HF data were collected by the investigator. CV death was adjudicated by an independent committee., Results: A total of 3,533 randomized participants were followed for a median of 3.4 years. HF was present at baseline in 342 participants (19.4%) in the semaglutide group and 336 (19.0%) in the placebo group. In the overall trial population, semaglutide increased time to first HF events or CV death (HR: 0.73; 95% CI: 0.62-0.87; P = 0.0005), HF events alone (HR: 0.73; 95% CI: 0.58-0.92; P = 0.0068), and CV death alone (HR: 0.71; 95% CI: 0.56-0.89; P = 0.0036). The risk reduction for the composite HF outcome was similar in those with (HR: 0.73; 95% CI: 0.54-0.98; P = 0.0338) and without (HR: 0.72; 95% CI: 0.58-0.89; P = 0.0028) HF at baseline. The risk of HF outcomes (HF events or CV death) was generally higher in participants categorized as NYHA functional class III and those with the HF reduced ejection fraction subtype, regardless of treatment., Conclusions: Semaglutide substantially reduced the risk of time to first composite outcome of HF events or CV death, as well as HF events and CV death alone, in a high-risk population with T2D and CKD. These effects were consistent regardless of history of HF. (A Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease [FLOW]; NCT03819153)., Competing Interests: Funding Support and Author Disclosures The FLOW trial was funded by Novo Nordisk A/S. Dr Pratley has received speaker fees paid to his employer, AdventHealth (through December 31, 2023) from Eli Lilly, Lilly USA LLC, and Novo Nordisk; has received consulting fees directed to his institution from AbbVie, AstraZeneca, Bayer AG, Bayer HealthCare Pharmaceuticals, Corcept Therapeutics, Dexcom, Endogenex, Gasherbrum Bio, Genprex, Getz Pharma, Hanmi Pharmaceutical, Hengrui (USA) Ltd, Intas Pharmaceuticals, Eli Lilly, Lilly USA LLC, Merck, Novo Nordisk, Pfizer, Rivus Pharmaceuticals, Scholar Rock, and Sun Pharmaceutical Industries; has received grants directed to his institution from Biomea Fusion, Carmot Therapeutics, Dompe, Endogenex, Fractyl, Eli Lilly, Novo Nordisk, and Sanofi; and has received personal fees (from January 1, 2024) from AdventHealth, a nonprofit entity. Dr Tuttle has received support from National Institutes of Health research grants R01MD014712, U2CDK114886, UL1TR002319, U54DK083912, U01DK100846, OT2HL161847, UM1AI109568, and OT2OD032581, and from Centers for Disease Control and Prevention project numbers 75D301-21-P-12254 and 75D301-23-C-18264; has received investigator-initiated grant support from Travere, Bayer, and the Doris Duke Foundation outside of the submitted work; has received consulting fees from Boehringer Ingelheim, Eli Lilly, and Novo Nordisk; and has received speaker fees from Novo Nordisk. Dr Rossing has received grants from Bayer, AstraZeneca, and Novo Nordisk; has received honoraria paid to the Steno Diabetes Centre Copenhagen from AstraZeneca, Astellas, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi, and Bayer; and has received consulting fees from AstraZeneca, Astellas, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi, and Bayer. Dr Perkovic has received honoraria for steering committee, data monitoring committee, or advisory board roles or for scientific presentations from AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, GSK, Janssen, Novo Nordisk, Novartis, Otsuka, Travere, Tricida, and UptoDate; and is Board Director for George Clinical, St Vincent’s Health Australia and several independent medical research institutes. Dr Mann has received grants from Novo Nordisk, the European Union, and McMaster University, Hamilton, Canada; has received consulting fees from Novo Nordisk, AstraZeneca, Bayer, and Boehringer Ingelheim; has received honoraria from Novo Nordisk, AstraZeneca, Bayer, and Novartis; and has participated on a data safety monitoring board or advisory board for AstraZeneca, Bayer, Sanofi, and Boehringer Ingelheim, as well as a leadership role in the Kidney Disease: Improving Global Outcomes group. Dr MacIsaac was a FLOW trial investigator and member of the FLOW global expert panel; has received research grants from Novo Nordisk, Servier, Medtronic, The Rebecca Cooper Medical Research Foundation, St Vincent’s Research Foundation, The Juvenile Diabetes Research Foundation, Grey Innovations, The Diabetes Australia Research Trust/Program, and The National Health and Medical Research Council of Australia; has received honoraria for lectures from Eli Lilly, Novo Nordisk, Sanofi, AstraZeneca, MSD, Novartis, and Boehringer Ingelheim; has been on the advisory boards for Novo Nordisk, Boehringer Ingelheim-Eli Lilly Diabetes Alliance, AstraZeneca, and MSD; has received travel support from Novo Nordisk, Sanofi, Boehringer Ingelheim, and AstraZeneca; and has been a principal investigator for industry-sponsored clinical trials run by Novo Nordisk, Sanofi, Bayer, Johnson-Cilag, and AbbVie. Dr Kosiborod has received research grant support from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on an advisory board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Kamenov has received speaker fees from Actavis, AstraZeneca, Bayer-Schering, Berlin Chemie, Boehringer Ingelheim, Eli Lilly, KRKA, Merck, MLD, MSD (Merck), Mundipharma, Mylan, Novartis, Novo Nordisk, Pfizer, Sandoz, Sanofi, Servier, TEVA Pharmaceuticals, Valentis, Vedra, and Viatris. Dr Hadjadj has received grants from Asdia, Asten, AstraZeneca, Homeperf, LVL, Nestle Home Care, Pierre Fabre, and VitalAire; has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi, Servier, and Valbiotis; has received speaker fees from Abbott, AstraZeneca, Boehringer Ingelheim, Bayer, Dino Santé, Eli Lilly, Novartis, Novo Nordisk, Pierre Fabre, Sanofi, Servier, and Valbiotis; and has received meeting invitations from AstraZeneca, Abbott, Dino Santé, Eli Lilly, and Novo Nordisk. Dr Bakris has received consulting fees from Bayer, KBP Biosciences, Ionis, Alnylam, AstraZeneca, Quantum Genomics, Novo Nordisk, and Dia Medica Therapeutics. Dr Mahaffey has received grants from the American Heart Association, Apple, Bayer, California Institute Regenerative Medicine, CSL Behring, Eidos, Ferring, Gilead, Google (Verify), Idorsia, Johnson and Johnson, Luitpold, Novartis, PAC-12, Precordior, and Sanifit; and has received consulting fees from Applied Therapeutics, Bayer, Bristol Myers Squibb, BridgeBio, CSL Behring, Elsevier, Fosun Pharma, Human, Johnson and Johnson, Moderna, Myokardia, Novartis, Novo Nordisk, Otsuka, PhaseBio, Portola, Quidel, and Theravance; and holds equity in Human, Medeloop, Precordior and Regencor. Drs Rasmussen, Nielsen, Idorn, Hansen, and Baeres are employees of and shareholders in Novo Nordisk., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Several reports, including our previous studies, indicate that hyperglycemia and diabetes mellitus exert differential effects on vascular function in males and females. This study examines sex differences in the vascular effects of type 2 diabetes (T2D) in an established monogenic model of obesity-induced T2D, Zucker Diabetic Fatty (ZDF) rats. Acetylcholine (ACh) responses were assessed in phenylephrine pre-contracted rings before and after apocynin, a NADPH oxidase (NOX) inhibitor. The mRNA expressions of aortic endothelial NOS (eNOS), and key NOX isoforms were also measured. We demonstrated the following: (1) diabetes had contrasting effects on aortic vasorelaxation in ZDF rats, impairing relaxation to ACh in females while enhancing it in male ZDF rats; (2) inhibition of NOX, a major source of superoxide in vasculature, restored aortic vasorelaxation in female ZDF rats; and (3) eNOS and NOX4 mRNA expressions were elevated in female (but not male) ZDF rat aortas compared to their respective leans. This study highlights sexual dimorphism in ACh-mediated vasorelaxation in the aorta of ZDF rats, suggesting that superoxide may play a role in the impaired vasorelaxation observed in female ZDF rats.

Cancer patients, especially long cancer survivors, are exposed to several cardio-metabolic diseases, including diabetes, heart failure, and atherosclerosis, which increase their risk of cardiovascular mortality. Therapy with glucagon-like peptide 1 (GLP1) receptor agonists demonstrated several beneficial cardiovascular effects, including atherosclerosis and heart failure prevention. Cardiovascular outcome trials (CVOTs) suggest that GLP-1 RA could exert cardiorenal benefits and systemic anti-inflammatory effects in patients with type-2 diabetes through the activation of cAMP and PI3K/AkT pathways and the inhibition of NLRP-3 and MyD88. In this narrative review, we highlight the biochemical properties of GLP-1 RA through a deep analysis of the clinical and preclinical evidence of the primary prevention of cardiomyopathies. The overall picture of this review encourages the study of GLP-1 RA in cancer patients with type-2 diabetes, as a potential primary prevention strategy against heart failure and atherosclerosis.

Diabetic nephropathy is one of the most frequent complications of diabetic patients and is the leading cause of end-stage renal disease worldwide. The complex physiopathology of this complication raises a challenge in the development of effective medical treatments. Therefore, a better understanding of this disease is necessary for producing more targeted therapies. In this work we propose human amylin as a possible mediator in the development of diabetic nephropathy. Islet amyloid polypeptide or amylin is a hormone co-secreted with insulin. The human isoform has the ability to fold and form amyloid aggregates in the pancreas of patients with type 2 diabetes mellitus, disrupting cellular homeostasis due to its ability to form pores in lipid bilayers. It has been described that hIAPP can be secreted and exported in extracellular vesicles outside the pancreas, being a plausible connecting mechanism between the β-cell and other peripheral tissues such as the kidney. Here, we demonstrate that tubular, podocytes and mesangial cells can incorporate hIAPP coming from β-cells. Then, this hIAPP can form aggregates inside these kidney cells, contributing to its failure. In order to study the consequences in vivo, we found amylin aggregates in the kidney of mice overexpressing hIAPP after feeding a high fat diet. In addition, we observed an increase in glomerulosclerosis index and inflammation. Specifically, there were significant changes in signalling pathways directly involved in the diabetic nephropathy such as an increased in mTORC1 signaling pathway, an alteration in mitochondrial dynamics and an increased in endoplasmic reticulum stress. All these results demonstrate the importance of hIAPP in the kidney and its possible contribution in the development of diabetic nephropathy., (© 2024. The Author(s).)

This study aimed to assess the impact of adding pancreatin (a pancreatic enzyme derivative) to standard treatment on patients diagnosed with Irritable Bowel Syndrome (IBS) and Type 2 Diabetes Mellitus (T2DM). IBS and T2DM frequently coexist, leading to significant gastrointestinal symptoms and a decrease in quality of life. Gastrointestinal symptoms arising in T2DM patients present challenges in management for both clinicians and patients. Standard treatments may not fully address these symptoms. Recent studies suggest that pancreatic enzyme replacement therapy may offer additional benefits. This study investigates whether adding pancreatin to standard treatment can improve gastrointestinal outcomes in this patient population. Conducted as a prospective observational study, the research involved patients diagnosed with IBS according to Rome IV criteria and having concomitant T2DM. The patients were divided into two groups: one receiving standard dual treatment (otilinium bromide + simethicone) and the other receiving a triple therapy including a pancreatin derivative in addition to the standard treatment. Various clinical scores and measurements, including Visual Analog Scale (VAS), Bristol Stool Chart (BSC), Irritable Bowel Syndrome-Severity Scoring System (IBS-SSS), and Irritable Bowel Syndrome Quality of Life Instrument (IBS-QOL), were assessed before and after treatment. The study comprised 121 patients, with a median age of 41 years (interquartile range [IQR] 38-48), of whom approximately 70.2% were female. Fifty-eight patients (47.9%) received dual therapy, while sixty-three patients (52.1%) received triple therapy. Before treatment, both groups exhibited similar pre-treatment Bristol stool scale results: normal (39.7% and 49.2%) and constipation (37.9% and 31.7%) in the dual and triple therapy subgroups, respectively (p > 0.05). Post-treatment, the triple therapy group showed a significantly higher proportion of normal cases on the Bristol stool scale (82.5%) compared to the dual therapy group (44.8%) (p < 0.001). After treatment, the triple therapy group demonstrated statistically significant improvements in VAS score (p < 0.001), IBS-SSS (p < 0.001), and IBS-QOL (p < 0.001) compared to the dual therapy group. There were no significant differences between groups in BMI, HbA1c levels, duration of diabetes, or diabetes treatment at baseline (p > 0.05 for all parameters). The findings suggest that adding pancreatin to standard therapies significantly enhanced the quality of life for patients with both IBS and T2DM, demonstrating improvements across various symptom measurements and indicating the potential benefits of this supplementary therapy in managing gastrointestinal symptoms in this population. Further studies are warranted to explore its broader clinical implications and mechanisms of action., (© 2024. The Author(s).)

Folates play a crucial role as cofactors in metabolic pathways, influencing biological methylation and nucleotide synthesis, which has a significant impact on overall health and disease susceptibility. Diabetic nephropathy (DN) is a prevalent and severe complication of diabetes mellitus (DM). The correlation between RBC folate and DN remains unclear currently. This study aims to assess whether RBC folate is associated with DN. Based on data from the NHANES (2011-2018), we conducted a cross-sectional study involving 3070 adults with type 2 DM (T2DM). Demographic factors, levels of folate and vitamin B12, dietary folate intakes, and relevant laboratory data were obtained from all participants. Logistic regression, fitting smooth curves, interaction effects were utilized to support the research objectives. Regression analyses demonstrated a positive relation between RBC folate and DN. (P < 0.001). A positive association between levels of RBC folate and the risk of DN was observed after full adjustment for all the confounding variables (odds ratio: 1.38, 95% confidence interval: 1.27-1.49, P < 0.001). Similar patterns of association were observed for subgroup analysis (all P values for interaction > 0.05). In addition, curve fitting after adjusting for all the confounding variables demonstrated that there was a linear relationship between RBC folate and DN (P for non-linearity = 0.147). Increased RBC folate levels were linked to a higher risk of DN in type 2 diabetes. RBC folate should be considered as a crucial indicator for folate status in DN., (© 2024. The Author(s).)

Background: Type 2 diabetes mellitus (T2DM) is a major risk factor for heart failure with preserved ejection fraction and cardiac arrhythmias. Precursors of these complications, such as diabetic cardiomyopathy, remain incompletely understood and underdiagnosed. Detection of early signs of cardiac deterioration in T2DM patients is critical for prevention. Our goal is to quantify T2DM-driven abnormalities in ECG and cardiac imaging biomarkers leading to cardiovascular disease., Methods: We quantified ECG and cardiac magnetic resonance imaging biomarkers in two matched cohorts of 1781 UK Biobank participants, with and without T2DM, and no diagnosed cardiovascular disease at the time of assessment. We performed a pair-matched cross-sectional study to compare cardiac biomarkers in both cohorts, and examined the association between T2DM and these biomarkers. We built multivariate multiple linear regression models sequentially adjusted for socio-demographic, lifestyle, and clinical covariates., Results: Participants with T2DM had a higher resting heart rate (66 vs. 61 beats per minute, p < 0.001), longer QTc interval (424 vs. 420ms, p < 0.001), reduced T wave amplitude (0.33 vs. 0.37mV, p < 0.001), lower stroke volume (72 vs. 78ml, p < 0.001) and thicker left ventricular wall (6.1 vs. 5.9mm, p < 0.001) despite a decreased Sokolow-Lyon index (19.1 vs. 20.2mm, p < 0.001). T2DM was independently associated with higher heart rate (beta = 3.11, 95% CI = [2.11,4.10], p < 0.001), lower stroke volume (beta = -4.11, 95% CI = [-6.03, -2.19], p < 0.001) and higher left ventricular wall thickness (beta = 0.133, 95% CI = [0.081,0.186], p < 0.001). Trends were consistent in subgroups of different sex, age and body mass index. Fewer significant differences were observed in participants of non-white ethnic background. QRS duration and Sokolow-Lyon index showed a positive association with the development of cardiovascular disease in cohorts with and without T2DM, respectively. A higher left ventricular mass and wall thickness were associated with cardiovascular outcomes in both groups., Conclusion: T2DM prior to cardiovascular disease was linked with a higher heart rate, QTc prolongation, T wave amplitude reduction, as well as lower stroke volume and increased left ventricular wall thickness. Increased QRS duration and left ventricular wall thickness and mass were most strongly associated with future cardiovascular disease. Although subclinical, these changes may indicate the presence of autonomic dysfunction and diabetic cardiomyopathy., (© 2024. Crown.)

Introduction: To explore the construction of a diagnostic prediction model of diabetic nephropathy (DN) in type 2 diabetic patients for prognostic risk prediction and observe the therapeutic effect of Epalrestat combined with Dapagliflozin on DN., Methods: The study consisted of two phases, phase I: A retrospective analysis was conducted on the case information and clinical treatment related data of a total of 460 patients who underwent kidney biopsy from June 2018 to June 2021. They were randomly divided into validation queue and training queue. The predictive factors of the diagnostic prediction model were obtained through multivariate logistic regression., Phase Ii: An interventional study of 94 patients with DN admitted between January 2022 and August 2023 was conducted, and they were randomized into a control group (n = 47) receiving Dapagliflozin and a research group (n = 47) receiving Epalrestat combined with Dapagliflozin. The glucose metabolism, renal function, and treatment safety of the two groups before and after treatment were compared. In addition, the adverse reactions during the treatment of the two groups were counted., Results: In the phase I of the study, the DN risk model established showed a good performance in the diagnosis and risk assessment of patients with DN and could provide certain reference opinions for future clinical practice. In the phase II of the study, the research group showed better glucose metabolism and renal function than the control group after treatment (P < .05), but no statistical difference was identified between groups in the incidence of adverse reactions (P > .05).  Conclusion. Epalrestat combined with Dapagliflozin is significantly effective in the treatment of DN, which can effectively improve glucose metabolism and renal function in DN patients.

Introduction: To explore PTEN-induced putative kinase 1 (PINK1) expression and its clinical value in diabetic nephropathy., Methods: Ninety patients with diabetic nephropathy were recruited and divided into metformin hydrochloride monotherapy group, telmisartan monotherapy group and combination therapy (metformin and telmisartan) group. Renal function indices and PINK1 expression, inflammatory factors, reactive oxygen species (ROS), mitochondrial membrane potential (MMP) levels were detected. The correlation between PINK1 and inflammatory factors, renal function indicators including estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR) and serum creatinine (SCr)] were analyzed by Pearson correlation., Results: Following treatments, the combination therapy group exhibited increased PINK1 expression levels and decreased ROS levels compared to the groups receiving metformin hydrochloride or telmisartan monotherapy. The combination therapy group showed significant improvements in renal function indices and inflammatory markers. Additionally, the MMP ratio in the combination therapy group was higher compared to the two monotherapy groups. Furthermore, PINK1 was negatively correlated with UACR, SCr, tumor necrosis factor (TNF-α) and interleukin-6 (IL-6), while positively correlated with eGFR and interleukin-2 (IL-2)., Conclusion: PINK1 exhibits low expression levels in patients with diabetic nephropathy and its expression is strongly associated with the inhibition of disease progression, thereby offering significant clinical diagnostic value. Additionally, it may serve as a potential biological marker for clinical diagnosis and treatment of diabetic nephropathy.

Purpose: To determine new-onset or worsening T2DM risk in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone acetate (AA) vs. enzalutamide (ENZA) in England., Methods: Records of patients on AA and/or ENZA (2015-2021) were analysed retrospectively from UK- or England-wide databases and data sets. The primary endpoint was new-onset or worsening T2DM, analysed using a Cox model., Results: Of 1382 patients, 84 (6.1%) met the primary endpoint; 42 of 826 patients (5.1%) received ENZA and 42 of 556 patients (7.6%) received AA. Among patients without baseline T2DM (n = 1049), 50 developed new-onset T2DM: 24 (3.9%) on ENZA and 26 (5.9%) on AA. Among patients with baseline T2DM (n = 333), 34 (10.2%) had worsening T2DM: 18 (8.3%) on ENZA and 16 (13.8%) on AA. Patients on ENZA had longer median follow-up (445 vs. 408 days) and treatment duration (164 vs. 139 days) than those on AA, who were also more likely to have new-onset or worsening T2DM than those on ENZA (HR: 1.8; 95% CI: 1.4-2.7; P = 0.0101). The number needed to harm for an additional patient to experience new-onset or worsening T2DM when receiving AA instead of ENZA was 40 overall, 50 in patients without baseline T2DM, and 18 in patients with baseline T2DM., Conclusion: Patients with mCRPC receiving AA were more likely to experience new-onset or worsening T2DM than those on ENZA, despite having a shorter treatment duration. Further research is required to substantiate these findings in earlier disease settings with longer treatment duration., (© 2024. The Author(s).)

Objective: The study aimed to assess whether thyroid hormone (TH) sensitivity is related to visceral fat area (VFA) and visceral obesity in euthyroid subjects with type 2 diabetes (T2D)., Methods: 750 euthyroid patients with T2D were enrolled. A VFA of 80 cm 2 or more was considered visceral obesity. Central TH sensitivity was conducted using thyrotrophic thyroxine resistance index (TT4RI), thyrotropin index (TSHI), and thyroid feedback quantile-based index (TFQI). Free triiodothyronine to free thyroxine (FT3/FT4) was utilized for assessing peripheral TH sensitivity., Results: The subjects had a mean age of 51.5 ± 11.1 years, and 540 (72.0%) of them were men. In multivariable regression analyses, there was a positive correlation of FT3/FT4 tertile with visceral obesity, after full adjustment for confounding variables (P < 0.05). The middle and highest FT3/FT4 tertiles were correlated with a 134% [95% CI (1.24, 4.44)] and 98% [95% CI (1.04, 3.78)] higher prevalence of visceral obesity than the lowest tertile, respectively. Conversely, elevated TFQI levels were linked to a decreased prevalence of visceral obesity. Stratified analysis revealed that these associations were particularly pronounced in participants who are neither overweight nor obese and those aged less than 60 years (all P < 0.05)., Conclusions: Higher TH sensitivity is correlated with visceral obesity and elevated VFA in euthyroid patients with T2D, particularly among those younger than 60 years and individuals who are neither overweight nor obese., (© 2024. The Author(s).)

Aim: To determine the treatment of hyperglycemia in the stroke unit, and to compare the morbidity and mortality of patients treated with an intravenous (iv) insulin therapy protocol compared to subcutaneous (sc) insulin when reaching glycemia levels of = 155 mg/dL., Patients and Methods: We performed a prospective observational study of patients admitted to our stroke unit between July and October 2022. Demographic, glycemic and prognostic variables were collected. Glycemic variability was defined as the standard deviation (SD) of the mean individual glycemia during the first 24-72 hours. Acute complications during admission and mortality at discharge and at 3 months were determined. The variables were analysed by subgroup according to the insulin regime in patients with type 2 diabetes mellitus (DM2) or stress hyperglycemia., Results: The sample consisted of 181 patients, of whom 63.5% were male, with a mean age of 74.2 (SD: 11.6) years. 25.4% required insulin due to glycemia = 155 mg/dL (18 patients iv and 28 sc). 31.5% had DM2 (82.6% of the group receiving insulin and 14% of group without insulin). The group receiving insulin presented higher levels of glycemic variability, at 33.3 (SD: 21.7) mg/dL vs. 11.7 (SD: 7) mg/dL (p < 0.01), more acute complications (43.5% vs. 19.2%; p < 0.01) and higher mortality at 3 months (19.5% vs. 6.6%; p = 0.04) than the group without insulin, and no differences were observed between the type of insulin regime in the subgroups with DM2 or stress hyperglycemia., Conclusions: The patients with glycemia = 155 mg/dL presented higher levels of glycemic variability, acute complications and mortality at 3 months, and no differences were observed in the type of insulin regime, regardless of whether they had DM2.

Background: Clinical studies have shown that glucagon-like peptide-1 receptor agonists (GLP-1 RA) can have beneficial effects on cardiopulmonary function. We conducted this longitudinal cohort study to compare the risk of cardiopulmonary outcomes and mortality between GLP-1 RA use and no use in patients with type 2 diabetes (T2D) and chronic obstructive pulmonary disease (COPD)., Methods: The study identified 8060 matched GLP-1 RA users and non-users from Taiwan's National Health Insurance Research Database from 1 January 2008 to 31 December 2019. Cox proportional hazards models were used to determine the risk of cardiopulmonary outcomes between GLP-1 RA users and non-users., Results: The mean follow-up time was 2.51 and 2.46 years for GLP-1 RA users and non-users, respectively. In the matched cohorts, GLP-1 RA users had a significantly lower risk of mortality (adjusted HR (aHR) 0.46, 95% CI 0.38 to 0.56), cardiovascular events (aHR 0.73, 95% CI 0.65 to 0.82), non-invasive positive pressure ventilation (aHR 0.66, 95% CI 0.47 to 0.93), invasive mechanical ventilation (aHR 0.64, 95% CI 0.51 to 0.8) and bacterial pneumonia (aHR 0.76, 95% CI 0.65 to 0.88) than GLP-1 RA non-users. The subsequent analyses for various subgroup and medication duration also showed that GLP-1 RA was associated with a significantly lower risk of mortality, cardiovascular events, ventilation support and bacterial pneumonia than non-GLP-1 RA., Conclusion: This nationwide cohort study showed that GLP-1 RA had a lower risk of cardiopulmonary outcomes and all-cause mortality than non-GLP-1 RA in patients with T2D and COPD. GLP-1 RA may help manage diabetes in people with COPD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To analyze the influencing factors of type 2 diabetes mellitus (T2DM) patients with mild cognitive impairment (MCI), and to explore the association between plasma osteopontin (OPN) levels and MCI. Methods: A retrospective analysis was conducted on the clinical data of 254 patients with T2DM admitted to Zhongda Hospital Affiliated to Southeast University from October 2021 to May 2023. The patients were divided into MCI group ( n =106) and normal cognitive function control group ( n =148) according to whether they had MCI. Clinical data were collected, cognitive function was assessed using neurological scales and plasma OPN levels were measured by enzyme linked immunosorbent assay. A multivariate logistic regression model was applied to analyze the influencing factors of MCI in T2DM patients. Interaction terms between gender, age, body mass index (BMI), and OPN were established to verify their significance levels. Receiver operating characteristic (ROC) curves were plotted to evaluate the predictive value of OPN for MCI in T2DM patients. The mediation model of OPN-FPG-montreal cognitive assessment(MoCA) was constructed with fasting plasma glucose (FPG) as the mediating variable to test the mediating effect, and the mediating effect percentage was calculated. Results: A total of 254 patients were included, including 162 males and 92 females, with an average age of (61.5±7.5) years old. Compared with the control group, the patients in MCI group were older[63.0(59.0, 69.0) years vs 60.0(54.2, 66.8) years], had a greater proportion of females [(43.4%(46/106) vs 31.1%(46/148)], shorter years of education[12(9, 12) years vs 12(9,15) years], longer duration of diabetes[15.0(8.0, 20.0) years vs 10.0(5.0, 15.0) years], and higher levels of FPG[7.78(6.07, 10.23) mmol/L vs 6.86(5.36, 8.59) mmol/L], insulin resistance index[2.93(2.47, 3.98) vs 2.79(2.27, 3.25)], glycated hemoglobin (HbA1c) [9.24%(7.89%, 10.96%) vs 7.97%(7.00%, 9.45%)], total cholesterol(TC)[(4.51±1.17) mmol/L vs (4.19±0.99) mmol/L], and OPN [11.30(8.68, 12.84) ng/ml vs 9.69(7.82, 11.74) ng/ml] (all P <0.05). The scores of various neuropsychological tests in MCI patients were lower than those in control group with normal cognitive function (all P <0.05). Spearman correlation analysis showed that age( r =-0.212), duration of diabetes mellitus( r =-0.156), duration of hypertension( r =-0.132), FPG( r= -0.207), insulin resistance index( r =-0.171), HbA1c( r =-0.271), OPN( r =-0.238), and total cholesterol ( r =-0.125) were negatively correlated with MoCA scores, whereas years of education( r =0.285) were positively correlated with MoCA scores(all P <0.05). Multifactorial logistic regression analysis showed that age, years of education, duration of diabetes mellitus, HbA1c, TC and OPN levels were the influencing factors of T2DM patients with MCI, and the risk of MCI increased by 15% for every 1 ng/ml increase in OPN ( OR =1.15, 95% CI : 1.021-1.295, P =0.021), and the relationship was not affected by age, gender and BMI(The interaction effects are all P >0.05). The area under the curve (AUC) of the working curve of subjects with OPN predicting combined MCI in patients with T2DM was 0.612 (95% CI : 0.541-0.682), and the AUC was 0.702 (95% CI : 0.638-0.767) after the combination of HbA1c and OPN. The results of the mediated effect model showed that FPG partially mediated the correlation between OPN and MoCA in T2DM patients, and the mediated effect accounted for 11.34% of the total effect. Conclusions: Plasma OPN level is associated with MCI in patients with T2DM,and the higher the OPN level, the higher the risk of T2DM patients developing MCI.

Objective: To evaluate whether the intense simplified strategy, which comprises short term intensive insulin therapy (SIIT) followed by subsequent oral antihyperglycaemic regimens, could improve long term glycaemic outcomes in patients with newly diagnosed type 2 diabetes mellitus and severe hyperglycaemia., Design: Multicentre, open label, randomised trial., Setting: 15 hospitals in China between December 2017 and December 2020., Participants: 412 patients with newly diagnosed type 2 diabetes and significant hyperglycaemia (HbA 1c ≥8.5%)., Interventions: All randomised participants initially received SIIT for 2-3 weeks, followed by linagliptin 5 mg/day, metformin 1000 mg/day, combination linagliptin plus metformin, or lifestyle modification alone (control) for 48 weeks., Main Outcome Measures: The primary outcome was the percentage of participants achieving HbA 1c <7.0% at week 48 after SIIT. Secondary outcomes included glycaemic control, β cell function, and variations in insulin sensitivity., Results: 412 participants were randomised. At baseline, the mean age was 46.8 (standard deviation 11.2) years, mean body mass index was 25.8 (2.9), and mean HbA 1c was 11.0% (1.9%). At week 48, 80% (78/97), 72% (63/88), and 73% (69/95) of patients in the linagliptin plus metformin, linagliptin, and metformin groups, respectively, achieved HbA 1c <7.0%, compared with 60% (56/93) in the control group (P=0.02 overall; P=0.003 for linagliptin plus metformin versus control; P=0.12 for linagliptin versus control; P=0.09 for metformin versus control). Additionally, 70% (68/97), 68% (60/88), and 68% (65/95) of patients in the linagliptin plus metformin, linagliptin, and metformin group, respectively, achieved HbA 1c <6.5% compared with 48% (45/93) in the control group (P=0.005 overall; P=0.005 for linagliptin plus metformin versus control; P=0.01 for linagliptin versus control; P=0.008 for metformin versus control; all were significant after adjustment for multiple comparisons). Thus, compared with the control group, participants in the linagliptin plus metformin group were more likely to achieve HbA 1c <7.0% at week 48 (odds ratio 2.78, 95% confidence interval 1.37 to 5.65; P=0.005). Moreover, the linagliptin plus metformin group showed the most significant improvement in fasting plasma glucose and β cell function indices. All treatments were well tolerated., Conclusions: The intense simplified strategy using subsequent oral therapies post-SIIT, especially the linagliptin plus metformin combination, sustainably improved glycaemic control and β cell function in patients with newly diagnosed type 2 diabetes mellitus and severe hyperglycaemia. This approach offers a promising direction for decision making in the clinical management of type 2 diabetes mellitus., Trial Registration: ClinicalTrials.gov NCT03194945., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Ministry of Science and Technology of China, Science and Technology Department of Guangdong Province, Guangzhou Science and Technology Bureau, and Boehringer-Ingelheim for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The presence of hypertension significantly increases the risk of diabetes, particularly type 2 diabetes. Recently, Visceral Adiposity Index (VAI) has been introduced as a straightforward and robust alternative indicator for early detection of metabolic syndrome, cardiovascular disease, and T2DM. Visceral adiposity, more dangerous than subcutaneous fat, is associated with metabolic syndrome and cardiovascular diseases. The VAI and Lipid Accumulation Product (LAP) are indices that quantify visceral fat and lipid overaccumulation, respectively. This study aims to explore the association between VAI, LAP, and type 2 diabetes mellitus (T2DM) in US adults with hypertension using NHANES data from 2005 to 2018., Methods: We analyzed data from 5,620 participants with hypertension in The National Health and Nutrition Examination Survey (NHANES). VAI and LAP were calculated using established formulas. The VAI is calculated based on a combination of waist circumference, body mass index (BMI), triglycerides, and high-density lipoprotein (HDL) cholesterol levels. Logistic regression models were applied to evaluate the association between these indices and T2DM, adjusting for potential confounders. Subgroup analyses by age and gender were also conducted to assess variations in risk., Results: In all, 5,620 participants were enrolled in our analysis, with 2,754 (49%) being female, and a mean (standard deviation, SD) age of 57 (15) years. The mean (SD) cumulative average VAI and LAP among all participants was 241 (2.71) and 75 (67), respectively. Totally, higher VAI and LAP indices were significantly associated with an increased risk of T2DM in individuals with hypertension. For VAI, the odds ratios (OR) for T2DM were higher in older adults (≥ 60 years) [95% confidence interval (CI): 1.37, 1.22-1.53, per 1 SD increase] and females [95% confidence interval (CI): 1.39, 1.27-1.52, per 1 SD increase], indicating age and gender differences in risk. Non-linear relationships were observed, suggesting thresholds beyond which the risk of T2DM escalates dramatically., Conclusions: Both VAI and LAP are reliable markers for assessing T2DM risk in individuals with hypertension. Incorporating these indices into clinical practice could enhance the identification of high-risk individuals and facilitate early intervention strategies. Future longitudinal studies are needed to confirm these associations and explore targeted interventions., (© 2024. The Author(s).)

Background: This study employed a bidirectional Mendelian Randomization (MR) approach to explore the causal relationships between Oral Lichen Planus (OLP), diabetes mellitus (DM), and glycemic control. It also aims to identify potential pharmacological and herbal treatments that effectively address both OLP and the metabolic dysfunctions associated with DM., Methods: This study employs a two-way MR approach to investigate the potential causal relationships between diabetes type and glycated hemoglobin (HbA1c) levels, and the risk of OLP. We analyzed differentially expressed genes from the OLP dataset in the Genomics Expression Omnibus (GEO) database, cross-referencing these with HbA1c-related genes for enrichment analysis. Additionally, the Drug-Gene Interaction Database (DGIdb) and Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) were utilized to assess the effectiveness of specific drugs, herbs, and ingredients in treating OLP while managing blood glucose levels., Results: The MR analysis revealed a significant association between Type 1 Diabetes mellitus (T1DM) and an increased risk of OLP, unlike Type 2 Diabetes mellitus (T2DM). This finding indicates a unique immunological interaction in T1DM that may predispose individuals to OLP. The drug prediction analysis focused on core targets linked to OLP and HbA1c, evaluating the therapeutic potential of retinoic acid, prednisone, and thalidomide for treating OLP and regulating blood glucose levels. Additionally, herbal medicines such as Ecliptae herbaand Amygdalus communis vas, along with herbal ingredients like quercetin, luteolin, and 17-beta-estradiol, were identified for their anti-inflammatory properties and potential to mitigate metabolic dysfunction in diabetes., Conclusion: The study highlighted a complex interplay between diabetes and OLP, underscoring the efficacy of integrated therapeutic strategies that target both conditions. The findings suggest that both pharmaceutical and herbal treatments can effectively manage the clinical manifestations of OLP and associated metabolic challenges. This holistic approach to treatment could significantly enhance patient outcomes by addressing the interconnected aspects of these chronic conditions., (© 2024. The Author(s).)

Background: The evidence regarding the relationship between different types of beverages and cardiovascular health in individuals with type 2 diabetes (T2D) is scarce., Aims: To prospectively examine the associations between individual beverage consumption, genetic predisposition, and risk of incident cardiovascular disease (CVD) among adults with T2D., Methods: We analyzed the associations of individual beverage intake with risks of CVD and ischemic heart disease (IHD) in 7315 participants with T2D, overall or stratified by genetic risk to CVD, using data from the UK Biobank study., Results: During a median follow-up of 6.1 years, 878 incident CVD cases were identified, including 517 IHD cases. Higher intakes of sugar-sweetened beverages (SSBs), artificially sweetened beverages (ASBs), and natural juices were each linearly associated with a higher CVD (Pnonlinearity > .05). Comparing the highest to lowest groups of beverage consumption, the multivariable-adjusted hazard ratios (95% confidence intervals) of CVD were 1.54 (1.14, 2.07) for SSBs, 1.34 (1.07, 1.69) for ASBs, and 1.33 (1.01, 1.76) for natural juices. Similar results were observed for incident IHD. Moreover, no significant interactions between these beverages and the CVD genetic risk score were observed. Replacing half-unit/day of SSBs or natural juices with coffee, tea, or yogurt, but not ASBs, was associated with a 20% to 46% lower risk of CVD and IHD., Interpretation: Higher intakes of SSBs, ASBs, and natural juices were each linearly associated with an increased risk of CVD among individuals with T2D, regardless of genetic predisposition. Our findings highlight the importance of selecting healthy beverage options to improve cardiovascular health in patients with T2D., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Due to the heterogenous clinical symptoms and deficits, the diagnosis of diabetic polyneuropathy (DPN) is still difficult in clinical routines, leading to increased morbidity and mortality., Objective: We studied the correlation of phase angle (PhA) of bioelectrical impedance analysis (BIA) with clinical, laboratory, and physical markers of DPN to evaluate PhA as a possible diagnostic method for DPN., Materials and Methods: In this cross-sectional observational study as part of the Heidelberg Study on Diabetes and Complications, we examined 104 healthy individuals and 205 patients with type 2 diabetes mellitus (T2D), among which 63 had DPN. The PhA was calculated from multifrequency BIA. Nerve conduction studies, quantitative sensory testing (QST) and diffusion-weighted magnetic resonance neurography to determine fractional anisotropy (FA) reflecting peripheral nerve integrity were performed., Results: T2D patients with DPN had lower PhA values (5.71 ± 0.10) compared to T2D patients without DPN (6.07 ± 0.08, P = .007, + 6.1%) and healthy controls (6.18 ± 0.08, P < .001, + 7.9%). Confounder-adjusted analyses showed correlations of the PhA with conduction velocities and amplitudes of the peroneal (β=.28; β=.31, P < .001) and tibial nerves (β=.28; β=.32, P < .001), Z-scores of QST (thermal detection β=.30, P < .05) and the FA (β=.60, P < .001). Receiver-operating characteristic analysis showed similar performance of PhA in comparison to the mentioned diagnostic methods., Conclusion: The study shows that PhA is, in comparison to other test systems used, at least an equally good and much easier to handle investigator-independent marker for detection of DPN., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

A 79-year-old male patient with type 2 diabetic nephropathy and hypertension was admitted to our hospital because of acute kidney injury with significantly elevated serum creatinine (8.12 mg/dL) and urinary β2-microglobulin (β2MG, 31,748 μg/L) levels. α-glucosidase inhibitor (α-GI) miglitol, started two weeks prior to presentation, was discontinued because drug-induced acute interstitial nephritis (AIN) was suspected. Renal biopsy revealed AIN and diabetic nephropathy. The drug-induced lymphocyte stimulation test for miglitol was also positive. After the discontinuation of miglitol, the urinary β2MG levels decreased to the normal range. This case raises the possibility that α-GI miglitol can worsen the renal function in patients with underlying renal dysfunction.

Glycemic variability (GV), independently of glycemic control, has emerged as a prognostic marker in patients with type 2 diabetes mellitus (DM). In this study, we assessed the prognostic value of long-term GV for predicting major adverse cardiovascular events (MACE) in our local population. We also assessed its prognostic value for diabetic microvascular complications (DMC) and its relationships with antidiabetic medications. This was a retrospective cohort study that recruited 680 patients with type 2 DM across 2015-2017. MACE were defined as: the composite of; total death, myocardial infarction (MI), stroke, hospitalization due to heart failure, and revascularization. GV was calculated for two glycemic control markers: glycated hemoglobin (G-Hb) and fasting blood sugar (FBS); via three metrics- standard deviation (SD), coefficient of variation (CV), and variability independent from the mean (VIM). Cox proportional hazard models and Kruskal-Wallis tests were used in the statistical analysis. 105 events classified as MACE were identified in 86 patients and 104 DMC in 98 patients in an average follow-up period of 78.43 months. Long-term GV was found to be an independent predictor of MACE, particularly for FBS-CV but not a predictor of DMC. FBS-CV ≥ 17.51% as compared with < 17.51% was a significant and independent predictor of MACE, with HR 1.589 (95% CI; 1.022, 2.472) (P = 0.040). DMC were predicted mainly by the duration of type 2 DM, and by the glycemic control; similarly represented by G-Hb and FBS. Patients on metformin, and dipeptidyl peptidase (DPP) 4 inhibitors, had the lowest GV, as compared with patients whose treatments included insulin/sulphonylureas (P < 0.001). In our population, long-term GV predicted MACE: with FBS-CV superior to the "gold standard" glycemic control marker G-Hb. Further, GV may be explained, partially at least, by the choice of antidiabetic medications: this finding might contribute to the cardiovascular protection attributed to one class rather than another., (© 2024. The Author(s).)

Cognitive impairment is frequently seen in patients with type 2 diabetes (T2DM), ranging from mild impairment to dementia. However, our knowledge of the specific profiles and risk factors for these different levels of impairment is limited. In this study involving 152 patients with T2DM, cognitive function was assessed using the Montreal Cognitive Assessment test. The Fuzzy C-means clustering algorithm was utilized to group individuals with similar cognitive characteristics. The study evaluated how well clinical parameters could classify characteristics of clusters using the Classification and Regression Trees algorithm. ROC analysis was then used to assess the classification success. Three distinct cognitive clusters were identified. Cluster 1 had the poorest cognitive performance and was characterized by more women, lower education levels, and lower levels of iron, hemoglobin, and creatine. Cluster 3, the amnestic cluster, was distinguished by low TSH levels. The decision tree model highlighted several parameters, including education level, hemoglobin, duration of diabetes mellitus (DM), iron, TSH, gender, family history of diabetes, and microalbumin/creatinine ratio, as significantly affecting the distinction of cognitive clusters. Diabetes-associated cognitive impairment stems from multifaceted pathophysiological mechanisms influenced by complex risk factors, resulting in diverse types of cognitive deficits., (© 2024. The Author(s).)

Background: Weight control has consistently been regarded as a significant preventive measure against diabetic nephropathy. however, the potential impact of substantial fluctuations in body fat during this process on the risk of diabetic nephropathy remains uncertain. This study aimed to investigate the association between body fat variation rate and diabetic nephropathy incident in American patients with type 2 diabetes., Methods: The study used data from the Action to Control Cardiovascular Risk in diabetes (ACCORD) trial to calculate body fat variation rates over two years and divided participants into Low and High groups. The hazard ratio and 95% confidence interval were estimated using a Cox proportional hazards model, and confounding variables were addressed using propensity score matching., Results: Four thousand six hundred nine participants with type 2 diabetes were studied, with 1,511 cases of diabetic nephropathy observed over 5 years. High body fat variation rate was linked to a higher risk of diabetic nephropathy compared to low body fat variation rate (HR 1.13, 95% CI 1.01-1.26). Statistically significant interaction was observed between body fat variation rate and BMI (P interaction = 0.008), and high level of body fat variation rate was only associated with increased risk of diabetic nephropathy in participants with BMI > 30 (HR 1.34 and 95% CI 1.08-1.66)., Conclusions: Among participants with Type 2 Diabetes Mellitus, body fat variation rate was associated with increased risk of diabetic nephropathy. Furthermore, the association was modified by BMI, and positive association was demonstrated in obese but not non-obese individuals. Consequently, for obese patients with diabetes, a more gradual weight loss strategy is recommended to prevent drastic fluctuations in body fat., Trial Registration: Clinical Trials. gov, no. NCT000000620 (Registration Date 199909)., (© 2024. The Author(s).)

Aims: The histone deacetylase 6 (HDAC6) inhibitor, tubastatin A (TubA), reduces myocardial ischaemia/reperfusion injury (MIRI) in type 1 diabetic rats. It remains unclear whether HDAC6 regulates MIRI in type 2 diabetic animals. Diabetes augments the activity of HDAC6 and the generation of tumour necrosis factor alpha (TNF-α) and impairs mitochondrial complex I (mCI). Here, we examined how HDAC6 regulates TNF-α production, mCI activity, mitochondria, and cardiac function in type 1 and type 2 diabetic mice undergoing MIRI., Methods and Results: HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent MIRI in vivo or ex vivo in a Langendorff-perfused system. We found that MIRI and diabetes additively augmented myocardial HDAC6 activity and generation of TNF-α, along with cardiac mitochondrial fission, low bioactivity of mCI, and low production of adenosine triphosphate. Importantly, genetic disruption of HDAC6 or TubA decreased TNF-α levels, mitochondrial fission, and myocardial mitochondrial nicotinamide adenine dinucleotide levels in ischaemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and improved cardiac function. Moreover, HDAC6 knockout or TubA treatment decreased left ventricular dilation and improved cardiac systolic function 28 days after MIRI. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. Hypoxia/reoxygenation augmented HDAC6 activity and TNF-α levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown., Conclusion: HDAC6 is an essential negative regulator of MIRI in diabetes. Genetic deletion or pharmacologic inhibition of HDAC6 protects the heart from MIRI by limiting TNF-α-induced mitochondrial injury in experimental diabetes., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective : To evaluate the effectiveness of empagliflozin in reducing all-cause mortality (ACM), hospitalization for heart failure (HHF), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), and end-stage renal disease (ESRD) in routine clinical practice in the Nordic countries of the Empagliflozin Comparative Effectiveness and Safety (EMPRISE) study. Methods : This noninterventional, multicountry cohort study used secondary data from four Nordic countries (Denmark, Sweden, Finland, and Norway). Propensity score (PS) matched (1:1) adults with type 2 diabetes (T2D) initiating empagliflozin (a sodium-glucose cotransporter-2 inhibitor) during 2014-2018 who were compared to those initiating a dipeptidyl peptidase-4 inhibitor (DPP-4i). Cox proportional hazards regression modelling was used to assess the risk for ACM, HHF, MI, stroke, CVM, and ESRD. Meta-analyses were conducted and hazard ratios (HRs) with 95% confidence intervals (CIs) from random-effects models were calculated. Results : A total of 43,695 pairs of PS-matched patients were identified. Patients initiating empagliflozin exhibited a 49% significantly lower risk of ACM (HR: 0.51, 95% CI 0.40-0.64) compared to DPP-4i. Additionally, empagliflozin was associated with a 36% significantly lower risk of HHF (HR: 0.64, 95% CI 0.46-0.89), a 52% significantly lower risk of CVM (HR: 0.48, 95% CI 0.37-0.63), and a 66% significantly lower risk of ESRD (HR: 0.34, 95% CI 0.15-0.77) compared to DPP-4i. No significant differences were observed in the risk of stroke and MI between patients initiating empagliflozin compared with those initiating a DPP-4i. Results were generally consistent for subgroups (with/without pre-existing CV disease or congestive heart failure) and in sensitivity analyses. Conclusion : Empagliflozin initiation was associated with a significantly reduced risk of ACM, HHF, CVM, and ESRD compared with initiation of DPP-4i in patients with T2D when examining routine clinical practice data from Nordic countries., Competing Interests: Dorte Vistisen has received research grants from Bayer A/S, Sanofi, Novo Nordisk A/S, and Boehringer Ingelheim. She holds shares in Novo Nordisk A/S. Bendix Carstensen declares no conflicts of interest. Sigrun Halvorsen has received speaker fees from Sanofi, Novartis, Boehringer Ingelheim, Bayer, Pfizer, and Bristol-Myers Squibb. Gisle Langslet has received consulting/lecture fees from Sanofi and Boehringer Ingelheim. Thomas Nyström has received unrestricted grants from AstraZeneca and Novo Nordisk and has been a national adviser of Abbot, Amgen, Novo Nordisk, Sanofi-Aventis, Eli Lilly, MSD, and Boehringer Ingelheim. Leo Niskanen has received speaker honoraria from Amgen, Boehringer Ingelheim, Novo Nordisk, Sanofi, MSD, and Astra Zeneca; research support from Novo Nordisk to the hospital; and has participated in the scientific advisory boards of Amgen, Boehringer Ingelheim, AstraZeneca, MSD, and Novo Nordisk. Paula Casajust is an employee of TFS Health Science. Giorgi Tskhvarashvili, Fabian Hoti, and Riho Klement are/were employees of IQVIA contracted by Boehringer Ingelheim to conduct the meta-analyses, interpret the results, review, and revise the manuscript. Christina Shay, Soulmaz Fazeli Farsani, Kristina Karlsdotter, Mikko Tuovinen, Anne Pernille Ofstad, and Maria Lajer were employees of Boehringer Ingelheim at the time of manuscript development. Lisette Koeneman is an employee of Eli Lilly and Company and owns stock in Eli Lilly and Company. Emilie Toresson Grip is an employee of Quantify Research that was contracted to conduct the country-specific studies in Finland, Norway, and Sweden., (Copyright © 2024 Gisle Langslet et al.)

Background: Type 2 diabetes mellitus (T2DM) is linked to a heightened likelihood of experiencing fractures. It is crucial to ascertain whether medications used to lower blood sugar levels can elevate the risk of fractures. We aimed to investigate and compare the effects of glucagon-like peptide 1 receptor agonists (GLP-1RA), Dipeptidyl Peptidase-4 Inhibitors (DPP-4i), and Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) on the fracture risk in patients with T2D in the real world., Methods: A network meta-analysis conducted an inclusive literature search in PubMed, Scopus, Web of Science, and Cochrane Library to select appropriate population-based cohort studies that investigated the risk of bone fractures of (GLP-1RA), (DPP-4i) or (SGLT-2i) in the real world. A network meta-analysis (NMA) was performed using R software to investigate the risk of total fractures as a primary outcome among patients who used (GLP-1RAs), (SGLT-2i) or (DPP-4i) versus each other or other glucose-lowering medications (GLMs). The odds ratio (OR) and 95% confidence interval (CI) were summarized overall network and for each pairwise direct and indirect comparison. The surface under the cumulative ranking curve (SUCRA) with the P-scores was calculated for each treatment in the network meta-analysis to detect their cumulative ranking probabilities in lowering the risk of total fractures., Results: In our NMA, we identified a set of 13 population-based cohort studies comprising a total of 1,064,952 patients. The risk of fracture was identified with the follow-up duration for each class. We found a significant decrease in the fracture risk by about 87% associated with patients who used SGLT2 inhibitors in combination with other glucose-lowering medications, followed by SGLT2 inhibitors alone by about 67%, then GLP-1 receptor agonists by about 60%, and at last DPP-4 inhibitors by about 55%., Conclusion: Our study's collective findings suggest a significant association of the low risk of fracture with the use of SGLT2i with other GLMs combination, SGLT2i alone, GLP-1RA, and DPP-4i, respectively. This population-based analysis offers the best available evidence and might be helpful for clinicians in the decision of the most suitable T2DM treatment strategies, especially for elderly type 2 diabetic patients, as they may be safe in terms of fracture., Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023448720., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mostafa and Alrasheed.)

Background: 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., Methods: 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., Results: 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., Conclusions: 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., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Diabetic kidney disease (DKD) is a serious microvascular complication of type 2 diabetes mellitus (T2DM). Despite the numerous genetic loci that have been associated with the disease in T2DM, the genetic architecture of DKD remains unclear until today. In contrast to SERPINE1 , the contribution of SERPINB2 has not been examined in DKD. Therefore, we conducted the first genetic association study of SERPINB2 to elucidate its role in DKD. In total, the study involved 197 patients with DKD, 155 patients with T2DM without microvascular complications (diabetic kidney disease, diabetic retinopathy, and diabetic neuropathy), and 246 healthy controls. The generalized odds ratio (OR G ) was calculated to estimate the risk on DKD development. The present association study regarding SERPINB2 SNPs (rs4941230, rs3819335, rs13381217, rs6140) did not reveal any significant association between SERPINB2 variants and DKD. Additional studies in other populations are necessary to further investigate the role of this gene in the progression of diabetes mellitus and development of DKD.

To investigate the associations of serum gamma-glutamyl transferase (GGT) levels with the risk of cardiovascular disease (CVD) and its subtypes in patients with type 2 diabetes mellitus (T2DM) in Jiangsu Province. Methods: The participants were enrolled in the Comprehensive Research project regarding 'Prevention and Control of Diabetes' in Jiangsu Province. The baseline survey was conducted from 2013 to 2014, and follow-up until December 31, 2021. After excluding the participants who self-reported with chronic liver disease/stroke/coronary heart disease at baseline survey and those with incomplete information on GGT, a total of 16 147 T2DM patients were included in the final analysis. Cox proportional hazard regression models were used to calculate the hazard ratio ( HR ) and their 95% CI of GGT for CVD, myocardial infarction, and stroke. Restricted cubic spline models were applied to analyze the dose-response relationship between GGT and the risk of CVD and its subtypes. Results: During the median follow-up time of 8.02 years, 2 860 CVD cases were registered, including 196 cases of myocardial infarction and 2 730 cases of stroke. Multivariate Cox proportional risk regression model indicated that compared to the lowest serum GGT level group, the highest GGT level group had a 24% increased risk of CVD ( HR =1.24, 95% CI : 1.09-1.41) and a 23% increased risk of stroke ( HR =1.23, 95% CI : 1.08-1.40). The restricted cubic spline model showed a nonlinear dose-response relationship between GGT and the risk of CVD, myocardial infarction, and stroke in T2DM patients. Conclusions: High levels of GGT may be associated with an increased risk of cardiovascular disease in T2DM patients, which needs further exploration and validation in future clinical practice.

Aims: Identifying patients with established cardiovascular disease (CVD) who are at high risk of type 2 diabetes (T2D) may allow for early interventions, reducing the development of T2D and associated morbidity. The aim of this study was to develop and externally validate the CVD2DM model to estimate the 10-year and lifetime risks of T2D in patients with established CVD., Methods and Results: Sex-specific, competing risk-adjusted Cox proportional hazard models were derived in 19 281 participants with established CVD and without diabetes at baseline from the UK Biobank. The core model's pre-specified predictors were age, current smoking, family history of diabetes mellitus, body mass index, systolic blood pressure, fasting plasma glucose, and HDL cholesterol. The extended model also included HbA1c. The model was externally validated in 3481 patients from the UCC-SMART study. During a median follow-up of 12.2 years (interquartile interval 11.3-13.1), 1628 participants with established CVD were diagnosed with T2D in the UK Biobank. External validation c-statistics were 0.79 [95% confidence interval (CI) 0.76-0.82] for the core model and 0.81 (95% CI 0.78-0.84) for the extended model. Calibration plots showed agreement between predicted and observed 10-year risk of T2D., Conclusion: The 10-year and lifetime risks of T2D can be estimated with the CVD2DM model in patients with established CVD, using readily available clinical predictors. The model would benefit from further validation across diverse ethnic groups to enhance its applicability. Informing patients about their T2D risk could motivate them further to adhere to a healthy lifestyle., Competing Interests: Conflict of interest: M.W. has received consultancy fees from Amgen and Freeline. The other authors have nothing to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The frequent concurrence of elevated blood pressure (BP) and type 2 diabetes markedly elevates the risk of cardiovascular disease and mortality. In this review, we discuss the evidence supporting the role of BP-lowering therapies in preventing cardiovascular events in people with type 2 diabetes and the most appropriate BP treatment target in these individuals. We outline possible reasons for the heterogeneous effect of BP lowering in patients with and without diabetes and consider several pathophysiological mechanisms that could potentially explain such differences. The review introduces a mediation model, delineating the intricate interplay between hypertension and diabetes and their joint contribution to cardiovascular and renal pathologies. Finally, we outline the role of lifestyle changes and other pharmacological options in attenuating cardiometabolic risks in patients with type 2 diabetes. We propose a comprehensive, patient-centred management strategy, integrating various antihypertensive therapeutic approaches and providing clinicians with a systematic framework for better decision-making., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Diabetes is a well-recognised risk factor for the development of heart failure, with a prevalence higher than 30% in patients with diabetes aged over 60 years. Heart failure often emerges as the primary cardiovascular manifestation in patients with type 2 diabetes and appears to be even more prevalent in type 1 diabetes. In Switzerland, there are approximately 500,000 individuals with diabetes, and the number of affected people has been steadily rising in recent years. Therefore, the consequences of heart failure will affect an increasing number of patients, further straining the Swiss healthcare system. Early lifestyle modification and initiation of appropriate treatment can prevent or at least significantly delay the onset of symptomatic heart failure by several years. These facts underscore the urgent need for early detection of individuals with subclinical heart failure, which often remains undiagnosed until the first episode of acute heart failure requiring hospital admission occurs. To address this issue, the European Society of Cardiology, the American Diabetes Association (ADA) and other international professional societies have published recommendations on heart failure screening, diagnosis and management. To address this issue in Switzerland, experts from the Swiss Society of Endocrinology and Diabetology, the Swiss Society of Cardiology and the General Internal Medicine specialty met and prepared a consensus report including a simple diagnostic algorithm for use in everyday practice.

Aims: To explore the predictive value of the IGF-1/IGFBP-3 ratio for the presence of thyroid nodules in patients with type 2 diabetes mellitus (T2DM)., Methods: This observational study prospectively enrolled patients with T2DM at the Second Hospital of Jilin University between May 2021 and January 2022. Thyroid nodule (TN) status was determined by ultrasonography. Receiver operating characteristic (ROC) curve analysis was performed to assess the predictive value of the serum IGF-1/IGFBP-3 molar ratio for TNs. Multivariable logistic regression analysis was conducted to identify risk factors for thyroid nodules in patients with T2DM., Results: A total of 122 patients (mean age ± standard deviation: 52.57 ± 11.71 years; 74 males) were enrolled. 37.7% (n=46) of patients did not have TNs, while 62.3% (n=76) had TNs. The duration of diabetes, age, and HDL-C level were significantly higher in the T2DM group with TNs compared to the group without TNs (all P < 0.05). The area under the ROC curve (AUC) for the combination of IGF-1, IGFBP-3, and the serum IGF-1/IGFBP-3 molar ratio in predicting TNs in T2DM patients was 0.619 (P < 0.001). Additionally, multivariable logistic regression analysis revealed that the duration of diabetes, age, fasting plasma glucose (FPG), fasting insulin (FINS), thyroid-stimulating hormone (TSH), IGF-1, and IGFBP-3 levels were independent risk factors for thyroid nodules, while the serum IGF-1/IGFBP-3 molar ratio level was an independent protective factor for thyroid nodules in patients with T2DM (all P < 0.05)., Conclusion: The combination of IGF-1, IGFBP-3, and the serum IGF-1/IGFBP-3 molar ratio may have a better predictive value for TNs in T2DM patients than using any single marker alone. The duration of diabetes, age, FPG, FINS, TSH, IGF-1, IGFBP-3, and the serum IGF-1/IGFBP-3 molar ratio levels were independently associated with thyroid nodules in patients with T2DM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu and Wang.)

Background: Higher prevalence rates of diabetes and its complications have been reported among individuals with poor physical activity and a sedentary lifestyle. This study explored the influence of six months of moderate-intensity supervised aerobic training on the serum lipid profile, hs-CRP level, and variable-related correlations in prediabetic and type 2 diabetes patients (T2DM)., Design: The study was based on a two-arm parallel group pretest‒posttest comparative design., Methods: A total of 50 subjects who were diagnosed with diabetes for more than five years and aged 30-70 years were included in this study. The subjects were classified into two groups on the basis of their glycated haemoglobin (HbA1c%) values: Group 1 (patients with the prediabetes; HbA1c % ≤ 6.5, n = 25) and Group 2 (patients with the T2DM; HbA1c % ≥ 6.5, n = 25). Blood sugar, HbA1c %, insulin, lipid profile, and highly sensitive CRP (hs-CRP) were measured via colorimetric and immunoassay techniques at baseline and six months postintervention with moderate aerobic exercise., Results: The results revealed that participation in moderate aerobic training interventions for six months resulted in a significant reduction in BMI, fasting blood sugar, glycosylated haemoglobin, hs-CRP, and lipid profile parameters such as T-Cholest, TG, and LDL-C as well as significant improvement in the level of insulin with a reduction in the values of HOMA-IR towards normal values in the patients with prediabetes (P < 0.01) in group 1 and patients with diabetes in group 2 (P < 0.001). The change in VO 2 max with good physical fitness significantly improved with the exercise program after six months. The reduced levels of hs-CRP, HOMA-IR, and lipid profile and improved levels of insulin were significantly positively correlated with the levels of glycated haemoglobin (HbA1c%) in the patients with prediabetes (P < 0.01) and those with diabetes (P < 0.001) following six months of moderate aerobic training interventions. Moreover, hs-CRP was positively correlated with T-Cholest, TG, and LDL-C (p = 0.01) and negatively correlated with HDL-C. The data revealed improved glycemic control factors, lipid profiles, and hs-CRP levels as cardio-predictive markers in patients with both prediabetes and diabetes as well. These findings suggest that the anti-inflammatory effect of physical activity gained from moderate exercise training for six months may counteract increased cardiovascular complications associated with increased CRP levels and lipid profiles in prediabetes and T2DM patients., Conclusions: Moderate aerobic training for six months favourably affects glycemic parameters, lipid profiles, and inflammatory hs-CRP indicators and improves VO 2 max, an indicator of physical fitness, in prediabetic and diabetic patients. The data obtained suggest the positive effect of moderate exercise training as a protective modulator of cardiovascular disorders, including the dyslipidaemic profile, glycaemic control, and hs-CRP inflammatory markers, in prediabetes and T2DM patients. Thus, regular exercise, owing to its anti-inflammatory effects and ability to improve cardiorespiratory fitness, lipid profiles, blood glucose levels, and insulin resistance, may help reduce the severity of cardiovascular diseases in prediabetes and T2DM patients and healthy controls., Trial Registration: Retrospectively registered with ClinicalTrials.gov PRS under trial identifier ID: NCT06246435 dated 30/01/2024., (© 2024. The Author(s).)