BACKGROUND The classification of ketosis-onset diabetes is controversial, and the prevalence and clinical characteristics of diabetic retinopathy (DR) in ketosis-onset diabetes mellitus remain unclear. AIM To compare the prevalence and risk factors of DR among patients with type 1 diabetes mellitus (T1DM), ketosis-onset diabetes, and non-ketotic type 2 diabetes mellitus (T2DM). METHODS This real-world observational study enrolled 1777 patients with newly diagnosed diabetes between January 2003 and December 2012, including 211 with T1DM, 673 with ketosis-onset diabetes, and 893 with non-ketotic T2DM. DR was assessed using digital nonmydriatic fundus photography, and its severity was graded based on the ETDRS classification. Clinical characteristics and risk factors of DR were compared across the three groups. RESULTS After controlling for age and sex, DR prevalence was significantly higher in ketosis-onset diabetes (9.5%) than in T1DM (5.7%, P = 0.034), but not significantly different from non-ketotic T2DM (12.3%, P = 0.105). Risk factors for DR in ketosis-onset diabetes and non-ketotic T2DM included increased estimated glomerular filtration rate (eGFR) and urinary albumin excretion. In contrast, elevated eGFR and 2-hour postprandial C-peptide were independent risk factors for DR in T1DM. The prevalence and risk factors for DR in ketosis-onset diabetes were similar to those in non-ketotic T2DM, but differed from T1DM. CONCLUSION These findings further support classifying ketosis-onset diabetes as a subtype of T2DM rather than idiopathic T1DM. However, the distinctive clinical features of ketosis-onset diabetes should not be ignored.

BackgroundComposite cardiometabolic and inflammatory indices can be calculated from routine anthropometric and laboratory measures, but their value for cardiovascular disease (CVD) risk assessment in Chinese populations remain unclear.MethodsWe analyzed 7,170 participants free of CVD at baseline from the China Health and Retirement Longitudinal Study (CHARLS) and the Shanghai Diabetes Study (SHDS). Mean follow-up was approximately 41 months in both cohorts. The evaluated indices included body mass index (BMI), Chinese visceral adiposity index (CVAI), lipid accumulation product (LAP), triglyceride-glucose index (TyG), atherogenic index of plasma (AIP), high-sensitivity C-reactive protein (hs-CRP), hs-CRP to high-density lipoprotein cholesterol ratio (hs-CRP/HDL-C), and hs-CRP-glucose index (CTI). Cox proportional hazards models were used to examine associations with incident CVD, with cohort interactions tested to assess cross-cohort consistency. Dose-response and nonlinearity were evaluated using quartile-based analyses and restricted cubic splines. Predictive performance and the added value of each index beyond a common clinical base model were evaluated in terms of clinical utility.ResultsDuring follow-up, 343 CVD events occurred in CHARLS and 148 occurred in SHDS. CVAI was the only index consistently associated with incident CVD across both cohorts and adjustment models. In the fully adjusted model, the HR per SD increase in CVAI was 1.221 (95% CI: 1.070–1.392, P = 0.003) in CHARLS, and 1.330 (95% CI: 1.067–1.656, P = 0.011) in SHDS. Other indices showed cohort-specific patterns: CTI, hs-CRP, and hs-CRP/HDL-C remained associated with CVD in CHARLS, whereas LAP remained associated across models in SHDS. Quartile-based and spline analyses generally supported approximately linear dose-response patterns. When added to the clinical base model, individual indices produced only modest changes in discrimination, and decision curve net benefit.ConclusionsIn two Chinese cohorts, CVAI showed the most reproducible association with short- to mid-term CVD risk, whereas other indices provided more cohort-specific signals. These indices may help describe cardiometabolic risk burden, but their incremental predictive value beyond conventional clinical factors was limited. Further studies with longer follow-up, verified outcomes, and more diverse populations are needed.

Purpose:Although metabolic diseases (MDs) in type 2 diabetes mellitus (T2DM) have been discussed, few studies have comprehensively investigated the prevalence, clinical features, and impact of multiple MDs in T2DM. We aimed to analyze the prevalence and clinical characteristics of multiple MDs including hypertension (HTN), obesity (OB), hyperlipidaemia (HLP), hyperuricaemia (HUA), atherosclerosis (AS), and metabolic dysfunction-associated fatty liver disease (MAFLD) in T2DM patients, and to evaluate the impact of multiple MDs on cardiovascular and kidney complications. Patients and Methods:This large real-world study involving 9453 T2DM patients was conducted from 2003 to 2012. The clinical features were compared between those with and without MDs. The impact of MDs on cardio-cerebrovascular events (CCBVEs) and chronic kidney disease (CKD) was investigated. Results:The overall prevalence of MDs was 92.6% in T2DM patients, which remained consistently high from 2003 to 2012 and increased with age and diabetes duration (DD) except for MAFLD. HLP had the highest prevalence in both males and females, while HUA had the lowest. Among T2DM patients, the prevalences of CCBVEs and CKD were significantly higher in those with MDs than in those without (all P<0.001), and increased progressively with the number of MDs (all P<0.001). Conclusion:The prevalence of comorbid MDs in T2DM patients was consistently high from 2003 to 2012. The presence of MDs in T2DM patients significantly increased the risk and severity of cardiovascular and kidney complications. Therefore, early screening and intervention for MDs may help to reduce the risk of macrovascular and microvascular complications in T2DM.

Background: To investigate the association of serum bilirubin within normal range, especially unconjugated bilirubin (UCB), with diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). Methods: In this cross-sectional, real-world study, 7617 T2DM patients were stratified into quartiles based on serum UCB levels. DR was determined by digital fundus photography and further classified into non-proliferative diabetic retinopathy (NPDR) and PDR. The associations of serum bilirubin levels and UCB quartiles with DR were investigated by logistic regression analysis. Results: After controlling for age, sex, and diabetes duration, the DR prevalence was significantly decreased across the serum UCB quartiles (40.4 %, 33.4 %, 29.7 %, 26.6 % for each quartile, respectively, p < 0.001 for trend). The subjects with DR had lower serum total bilirubin (TB) and UCB, rather than conjugated bilirubin (CB), compared with those without DR (p = 0.003 for TB, p < 0.001 for UCB, and p = 0.528 for CB, respectively), while all three types of serum bilirubin in the subjects with PDR were obviously lower than those with NPDR (p = 0.006 for TB, and p < 0.001 for UCB and CB, respectively). After adjustment for confounding factors, logistic regression demonstrated negative associations of serum TB and UCB levels, rather than CB, with the presence of DR (OR: 0.844, 95%CI: 0.774-0.920, p <0.001 for TB; OR: 0.828, 95%CI: 0.763-0.899, p < 0.001 for UCB; and OR: 0.984, 95%CI: 0.900-1.074, p = 0.713 for CB, respectively). Additionally, a fully-adjusted analysis revealed a negative correlation between UCB quartiles and DR (p < 0.001). Conclusion: High-normal serum TB and UCB were closely associated with the decreased odds of DR, while all types of serum bilirubin were negatively correlated with the severity of DR in T2DM patients. Serum bilirubin may be used as a potential indicator to assess the risk and severity of DR in T2DM.

We investigated the potential role of hydrogen sulfide (H 2 S) as a novel therapy for diabetic peripheral neuropathy in diabetic rats. A single dose of streptozotocin (60 mg/kg) was applied to the rats for the diabetic rat models. Sodium bisulfide (50 μmol/kg/d) was injected intraperitoneally daily for 2 weeks as H 2 S treatment. Electromyogram, haematoxylin eosin staining, transmission electron microscopy, western blotting and enzyme-linked immunosorbent assay were then performed. H 2 S treatment did not affect body weights, blood glucose levels or liver function of diabetic rats, while the creatine levels of the H 2 S-treated diabetic rats decreased compared with the diabetic control rats. H 2 S treatment for 2 weeks did not affect the sciatic nerve conduction velocity of the diabetic rats. However, H 2 S treatment relieved neurons loss and cell atrophy of dorsal root ganglion, and axon degeneration of sciatic nerve in diabetic rats. Serum super oxide dismutase (SOD) levels and SOD2 levels in the sciatic nerve of diabetic rats were lower than the non-diabetic rats but were restored after H 2 S treatment. Serum and sciatic nerve homogenate malondialdehyde and aldose reductase expression were higher in diabetic rats but decreased significantly after H 2 S treatment. Our study revealed that H 2 S alleviates neural degeneration in diabetic rats probably by reducing oxidative stress and downregulating aldose reductase expression.

Abstract Background Diabetic peripheral neuropathy(DPN) is one of the most common complications of diabetes. In this study, we investigated the potential role of H2S as a novel therapy for DPN in diabetic rats. Method All the rats were divided into non-diabetic control group(n = 10), diabetic control group (n = 10) and H2S treated diabetic group (n = 10). A single dose of streptozotocin (60mg/kg) was applied to the rats for the diabetic models. Sodium bisulfide (50µmol/kg/d) was intraperitoneally injected daily for 2 weeks as H2S treatment. Biochemical assay, electromyogram, hematoxylin eosin (HE) staining, transmission electron microscopy, western blot and enzyme linked immunosorbent assay (ELISA) were then performed. Results H2S treatment did not affect the body weight, blood glucose levels or liver and kidney function in diabetic rats. Cell atrophy and axon degeneration of sciatic nerve and dorsal root ganglion (DRG) in diabetic rats were relieved after H2S treatment through observation of light microscopy and transmission electron microscopy. Furthermore, superoxide dismutase levels in serum and superoxide dismutase2 in sciatic nerve of diabetic rats were lower than non-diabetic rats, but restored obviously after H2S treatment. Serum and sciatic nerve homogenate malondialdehyde and aldose reductase expression were obviously higher in diabetic rats, but decreased significantly after H2S treatment. Finally, the sciatic nerve conduction velocity of diabetic rats improved after H2S treatment compared with diabetic control group, however without statistical significance. Conclusions Our study revealed that H2S alleviates neural degeneration in diabetic rats probably through reducing oxidative stress and downregulating aldose reductase expression.

BackgroundThere remains controversy over the relationship between serum magnesium levels and obesity in type 2 diabetes mellitus (T2DM). Therefore, the aim of this study was to assess whether there is any association of serum magnesium levels with obesity and abdominal obesity in T2DM. MethodsThis cross-sectional, real-world study was conducted in 8,010 patients with T2DM, which were stratified into quintiles according to serum magnesium levels. The clinical characteristics and the prevalence of obesity and abdominal obesity were compared across serum magnesium quintiles in T2DM. Regression analyses were used to evaluate the relationship of serum magnesium with obesity and abdominal obesity in T2DM (clinical trial registration number: ChiCTR1800015893). ResultsAfter adjustment for age, sex, and duration of diabetes, the prevalence of obesity and abdominal obesity was significantly declined across magnesium quintiles (obesity: 51.3%, 50.8%, 48.9%, 45.3%, and 43.8%, respectively, P<0.001 for trend; abdominal obesity: 71.5%, 70.5%, 68.2%, 66.4%, and 64.5%, respectively, P=0.001 for trend). After controlling for confounders, there were clearly negative associations of serum magnesium levels and quintiles with obesity and abdominal obesity in T2DM. Moreover, C-reactive protein partly mediates the effect of serum magnesium on obesity and abdominal obesity (P=0.016 and P=0.004, respectively). ConclusionThe significantly negative relationship between serum magnesium and the risk of obesity and abdominal obesity was observed in T2DM. Furthermore, the independently negative association of serum magnesium with obesity may be explained by its anti-inflammatory functions. Serum magnesium levels may be applied to assess the risk of obesity and abdominal obesity in T2DM.

OBJECTIVE:To investigate the association between serum unconjugated bilirubin (UCB) within normal limits and chronic kidney disease (CKD) in T2DM patients.METHOD:This cross-sectional, real-world study was performed in 8661 hospitalised T2DM patients. The subjects were stratified into quintiles based on serum UCB levels. The clinical characteristics and CKD prevalence were compared among the UCB quantile groups. The associations of serum UCB levels and quintiles with CKD were also analysed by binary logistic regression.RESULTS:After controlling for age, sex, and diabetes duration (DD), the CKD prevalence (20.4%, 12.2%, 10.6%, 8.3%, and 6.4% for the first, second, third, fourth, and fifth quintiles, respectively, p < 0.001 for trend) was significantly decreased across the serum UCB quintiles. The fully adjusted regression model showed negative associations of serum UCB levels (OR: 0.660, 95% CI: 0.585-0.744; p < 0.001 for trend) and quintiles (p < 0.001) with the presence of CKD. Compared with the subjects in the lowest UCB quintile, the risk of CKD decreased by 36.2%, 54.3%, 53.8%, and 62.1%, respectively, in those from the second to the highest UCB quintile. Additionally, C-reactive protein (CRP) levels were significantly higher in the subjects with CKD than in those without CKD (p < 0.001), and significantly decreased across the UCB quintiles (p < 0.001 for trend).CONCLUSIONS:Serum UCB levels within the normal range were significantly and negatively linked to CKD in T2DM patients. High-normal UCB may be an independent protective factor for CKD by its antioxidant and the following anti-inflammatory activities through its signalling activity, which was indicated by clearly decreased CRP levels across the UCB quintiles.

Aims: To compare the associations between four anthropometric indices including waistto-height ratio (WHtR), waist circumference (WC), waist-hip-ratio (WHR) and body mass index (BMI) and cardio-cerebrovascular events (CCBVEs) in Chinese T2DM patients. Methods: The associations of four anthropometric measures with CCBVEs and metabolic syndrome (MetS) were compared by multiple regression model in 3108 T2DM patients. CCBVEs was defined as a history of myocardial infarction, angina, angioplasty, coronary artery bypass surgery, transient ischemic attack, ischemic or hemorrhagic stroke. Results: After controlling for age, sex and diabetes duration, the prevalence of CCBVEs and MetS significantly increased across the WHtR, WC, WHR and BMI quartiles in T2DM patients, respectively. However, when controlling for these four anthropometric measurements together, although four anthropometric measures were closely associated with MetS prevalence, only WHtR quartile was significantly associated with CCBVEs prevalence (6.5%, 13.8%, 16.9% and 21.3%, p < 0.001 for trend). After adjusting for multiple confounders including four anthropometric parameters, a regression analysis revealed that only WHtR was independently and positively associated with the presence of CCBVEs (p = 0.029). Conclusions: Compared with WC, WHR and BMI, WHtR have a stronger association with CCBVEs in T2DM subjects. WHtR maybe a better indicator than other anthropometric measurements for evaluating cardiovascular risks in T2DM. (c) 2021 Elsevier B.V. All rights reserved.

BACKGROUND:The association of serum retinol-binding protein (RBP) levels with nonalcoholic fatty liver disease (NAFLD) remains controversial. Furthermore, few studies have investigated their relationship in type 2 diabetes mellitus (T2DM) patients. Therefore, the aim of the present study was to explore the association between serum RBP levels and NAFLD in Chinese inpatients with T2DM.METHODS:This cross-sectional, real-world study included 2,263 Chinese T2DM inpatients. NAFLD was diagnosed by abdominal ultrasonography. The subjects were divided into four groups based on RBP quartiles, and clinical characteristics were compared among the four groups. The associations of both RBP levels and quartiles with the presence of NAFLD were also analyzed.RESULTS:After adjustment for sex, age, and diabetes duration, there was a significant increase in the prevalence of NAFLD from the lowest to the highest RBP quartiles (30.4%, 40.0%, 42.4%, and 44.7% for the first, second, third, and fourth quartiles, respectively, P<0.001 for trend). Fully adjusted multiple logistic regression analysis revealed that both increased RBP levels (odds ratio, 1.155; 95% confidence interval, 1.012 to 1.318; P=0.033) and quartiles (P=0.014 for trend) were independently associated with the presence of NAFLD in T2DM patients.CONCLUSION:Increased serum RBP levels were independently associated with the presence of NAFLD in Chinese T2DM inpatients. Serum RBP levels may be used as one of the indicators to assess the risk of NAFLD in T2DM patients.

Vitamin D deficiency is considered a pandemic and has been postulated to increase the risk of type 2 diabetes mellitus (T2DM). Activation of nod-like receptor protein 3 (NLRP3) signaling induced by hyperglycemia stress has been recognized as a key priming stage for pancreatic 13-cell inflammation in T2DM pathogenesis. AMPactivated protein kinase (AMPK) activation attenuates NLRP3 inflammasome upregulation in diabetes. This study investigated whether vitamin D3 could protect cells against high glucose-induced inflammation by modulating this critical step. A human cross-sectional study of 78 healthy, glucose-tolerant volunteers and 399 patients with type 2 diabetes was undertaken. The relationship between serum 25(OH)D3 levels and 13-cell function was assessed using Pearson correlation analysis and multiple linear regression, and a high-glucose dietinduced rat model of impaired glucose tolerance was used to evaluate the effects of cholecalciferol. Intraperitoneal glucose tolerance tests and an ELISA were performed to detect the function of pancreatic islets. Glucosestimulated insulin secretion, pyroptosis, reactive oxygen species (ROS) production, and NLRP3 pathway were evaluated together to determine the role of vitamin D in high glucose-induced pancreatic 13-cell dysfunction in INS-1E cells. The clinical results showed a positive association between serum 25(OH)D3 levels and 13-cell function in male patients with type 2 diabetes. In vivo, cholecalciferol significantly reduced blood glucose levels and improved insulin secretion in response to glucose loading in the high glucose diet-induced rat model. In vitro studies have demonstrated that 1,25(OH)2D3 promotes insulin release in both islets and INS-1E cells. Mechanistically, our results demonstrated that vitamin D3 can activate AMPK, inhibiting the mTOR pathway, thus inhibiting NLRP3 inflammasome activation and alleviating pyroptosis in 13-cell dysfunction. This study showed that vitamin D protects against high-glucose-induced 13-cell dysfunction by enhancing the AMPK pathway, thereby suppressing NLRP3 inflammasome activation.

Purpose: The association between serum osteocalcin (OCN) levels and metabolic dysfunction-associated fatty liver disease (MAFLD) is still controversial. Moreover, few studies have explored their relationship in type 2 diabetes mellitus (T2DM) patients so far. The present study aimed to investigate the association of serum OCN levels with MAFLD in Chinese T2DM patients. Methods: This cross-sectional, real-world study included 1889 Chinese T2DM inpatients. MAFLD was diagnosed by abdominal ultrasonography. Participants were divided into four groups according to serum OCN quartiles, among which the clinical characteristics were compared. The association of serum OCN levels with the presence of MAFLD was also analyzed in subjects. Results: After controlling for sex, age, and diabetes duration, the prevalence of MAFLD significantly decreased across the serum OCN quartiles (55.3%, 52.0%, 48.6%, and 42.1% for the first, second, third, and fourth quartiles, respectively, P < 0.001 for trend). A fully adjusted multiple logistic regression analysis showed that serum OCN levels were independently and negatively associated with the presence of MAFLD in T2DM patients (odds ratio, 0.832; 95% confidence interval, 0.719-0.962; P = 0.013). Furthermore, there were significant decreases in HOMA-IR (P = 0.001 for trend) and C-reactive protein (P < 0.001 for trend) levels across the serum OCN quartiles after controlling for sex, age, and diabetes duration. Conclusion: Serum OCN levels were independently and negatively associated with the presence of MAFLD in Chinese T2DM patients, partially due to the improvement of insulin resistance and inflammation mediated by OCN. Serum OCN may be used as a biomarker to assess the risk of MAFLD in T2DM patients.

Abstract Background There is still controversy regarding the associations of urinary albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) with atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Therefore, it is necessary to explore the correlation between them in T2DM patients. Methods We conducted a survey involving 2565 T2DM patients from a single center. The study cohort was classified into three groups based on the levels of albuminuria: normal UAE (UAE < 30 mg/24 h), moderate UAE (UAE between 30 and 299 mg/24 h) and high UAE (UAE ≥ 300 mg/24 h). Additionally, the patients were divided into three separate groups according to eGFR levels, including low eGFR (eGFR < 60 ml/min/1.73 m2), intermediate eGFR (eGFR 60–89 ml/min/1.73 m2) and normal eGFR (eGFR ≥ 90 ml/min/1.73 m2) groups. Atherosclerotic lesions were compared among the three UAE and eGFR groups. Regression analyses were used to assess the associations of atherosclerotic lesions with UAE and eGFR in T2DM. Results After controlling for age, sex and diabetes duration, the prevalence of atherosclerotic plaque and stenosis were significantly increased from the normal to high UAE groups (plaque: 72.2%, 78.6% and 87.3%, respectively, p = 0.016 for trend; stenosis: 14.0%, 25.5% and 37.3%, respectively, p < 0.001 for trend). Likewise, the values of carotid intima-media thickness (CIMT) and femoral intima-media thickness (FIMT) were also obviously increased from the normal to high UAE groups (CIMT: p < 0.001 for trend; FIMT: p = 0.001 for trend). Conversely, only the FIMT value was clearly increased from the low to normal eGFR groups (p = 0.001 for trend). Fully adjusted regression analyses revealed that UAE was closely associated with the presence of atherosclerotic plaque (OR 1.20, 95% CI 1.03–1.40, p = 0.020) and stenosis (OR 1.17, 95% CI 1.01–1.35, p = 0.036), and with the values of CIMT (β 0.05, 95% CI 0.01–0.10, p = 0.029) and FIMT (β 0.07, 95% CI 0.03–0.11, p = 0.001) in T2DM patients. However, there was no significant association between eGFR levels and atherosclerotic lesions in T2DM after adjustment for multiple confounding factors. Conclusions Overall, albuminuria rather than low eGFR is closely associated with atherosclerotic lesions in T2DM patients. Albuminuria is an independent risk factor for carotid and femoral atherosclerotic lesions in T2DM. Therefore, albuminuria may be a potential early marker to predict the development of atherosclerosis in patients with T2DM.

Background As an indicator of abdominal obesity, waist circumference (WC) varied with race and gender in diagnosing metabolic syndrome (MetS). Therefore, it is clinically important to find an alternative indicator of abdominal obesity independent of these factors to diagnose MetS. Our aims were to evaluate the association between waist-to-height ratio (WHtR) and MetS and further determine whether WHtR could be used as a simple and practical alternative to WC to diagnose MetS in patients with type 2 diabetes mellitus (T2DM). Methods This cross-sectional, real-world study recruited 8488 hospitalized T2DM patients including 3719 women (43.8%) aged from 18 to 94 years and 4769 men (56.2%) aged from 18 to 91 years. A WHtR cut-off of 0.52 was used to diagnose MetS in both men and women T2DM patients based on our previous study. The association of WHtR with MetS in T2DM patients was analyzed by binary logistic regression. The consistency of two diagnostic criteria for MetS according to WC and WHtR was determined by Kappa test. Results The prevalence of MetS according to WHtR was 79.4% in women and 68.6% in men T2DM patients, which was very close to the prevalence of MetS according to WC in both women (82.6%) and men (68.3%). The prevalence of MetS diagnosed by WC in both men and women with WHtR ≥ 0.52 was significantly higher than in those with WHtR < 0.52 after adjustment for age and duration of diabetes (89.2 vs. 38.7% for men; 92.8 vs. 57.4% for women; respectively, all p < 0.001). Binary logistic regression analysis displayed that after adjusting for confounding factors, WHtR was significantly associated with the presence of MetS in both men and women (men: OR = 4.821, 95% CI: 3.949–5.885; women: OR = 3.096, 95% CI: 2.484–3.860; respectively, all p < 0.001). Kappa test revealed that there was an excellent consistency between the diagnosis of MetS based on WC and on WHtR in T2DM patients (men: kappa value = 0.929, 95% CI: 0.918–0.940; women: kappa value = 0.874, 95% CI: 0.854–0.894; total: kappa value = 0.911, 95% CI: 0.901–0.921; respectively, all p < 0.001). Conclusion WHtR is independently associated with the presence of MetS and can be used as a simple and practical alternative to WC to diagnose MetS regardless of gender in T2DM patients.

Aims There is still a debate about the relationship between serum iron and metabolic dysfunction-associated fatty liver disease (MAFLD). Furthermore, few relevant studies were conducted in type 2 diabetes mellitus (T2DM). Therefore, this study aimed to explore the association of serum iron levels with MAFLD in Chinese patients with T2DM. Methods This cross-sectional, real-world study consisted of 1,467 Chinese T2DM patients. MAFLD was diagnosed by abdominal ultrasonography. Based on serum iron quartiles, the patients were classified into four groups. Clinical characteristics were compared among the four groups, and binary logistic analyses were used to assess the associations of serum iron levels and quartiles with the presence of MAFLD in T2DM. Results After adjusting for gender, age, and diabetes duration, significantly higher prevalence of MAFLD was found in the second (45.7%), third (45.2%), and fourth (47.0%) serum iron quartiles than in the first quartiles (26.8%), with the highest MAFLD prevalence in the fourth quartile ( p < 0.001 for trend). Moreover, increased HOMA2-IR ( p = 0.003 for trend) and decreased HOMA2-S ( p = 0.003 for trend) were observed across the serum iron quartiles. Fully adjusted binary logistic regression analyses indicated that both increased serum iron levels (OR: 1.725, 95% CI: 1.427 to 2.085, p < 0.001) and quartiles ( p < 0.001 for trend) were still closely associated with the presence of MAFLD in T2DM patients even after controlling for multiple confounding factors. Conclusions There is a positive correlation between the presence of MAFLD and serum iron levels in T2DM patients, which may be attributed to the close association between serum iron and insulin resistance. Serum iron levels may act as one of the indicators for evaluating the risk of MAFLD in T2DM individuals.

Objective Receptor-interacting serine/threonine-protein kinase 1 (RIP1) is a well-documented key regulator of TNF alpha-mediated inflammation, apoptosis, and necroptosis, which contribute to the development of obesity-related metabolic diseases such as nonalcoholic steatohepatitis. However, the mechanism regarding how RIP1 influences obesity-related insulin resistance remains elusive. Methods Primary hepatocytes with necrostatin 1 treatment or RIP1 expression were exposed to palmitic acid (PA), prior to the examination of cellular insulin signaling. Phosphorylation sites of RIP1 were detected by liquid chromatography with tandem mass spectrometry, and RIP1 variants with mutated phosphorylation sites were overexpressed in hepatocytes to identify the specific residue that influenced the RIP1-mediated insulin resistance. Adenovirus expressing RIP1 (S415A) mutant were administered into diet-induced obese mice to assess the effects on insulin sensitivity. Results This study uncovered an aberrant increase in RIP1 activity during the development of obesity-induced insulin resistance. Inhibition of RIP1 activity with necrostatin 1 ameliorated PA- or high-fat diet-caused hepatic insulin resistance. With liquid chromatography with tandem mass spectrometry analysis and mutagenesis screening, S415, a novel phosphorylation site of RIP1, was identified to be responsible for RIP1-mediated insulin resistance. Loss-of-function mutation of S415 efficiently blunted RIP1-evoked insulin resistance in PA-treated hepatocytes or diet-induced obese mice. Conclusions These findings highlight the diabetogenic role of RIP1 S415 and propose RIP1 as a promising therapeutic target for type 2 diabetes.

Interleukin (IL)‐17 is associated with autoimmunity. This study aimed to affirm the role of IL‐17A, IL‐17F and single nucleotide polymorphisms (SNPs) in genes related to them and their receptors in autoimmune type 1 diabetes (T1D) for Chinese population.

Background It is still debatable whether glycated albumin/glycated hemoglobin A1C (GA/HbA1C) ratio is associated with metabolic dysfunction-associated fatty liver disease (MAFLD), and few studies have been conducted in type 2 diabetes mellitus (T2DM). Therefore, we aimed to investigate the association between GA/HbA1C ratio and MAFLD and to evaluate whether GA/HbA1C ratio can be used an indicator of MAFLD in Chinese patients with T2DM. Methods This cross-sectional study consisted of 7117 T2DM patients including 3296 men and 3821 women from real-world settings. Abdominal ultrasonography was performed to diagnose MAFLD. In addition to comparing the clinical characteristics among the GA/HbA1C ratio quartile groups, we also investigated the associations of GA/HbA1C ratio and quartiles with MAFLD in T2DM subjects. Results There was a significantly decreased trend in the MAFLD prevalence across the GA/HbA1C ratio quartiles (56.3%, 47.4%, 37.8%, and 35.6% for the first, second, third, and fourth quartile, respectively, P < 0.001 for trend) after adjusting for gender, age, and diabetes duration. Fully adjusted Binary logistic regression indicated that both GA/HbA1C ratio (OR: 0.575, 95% CI: 0.471 to 0.702, P < 0.001) and quartiles (P < 0.001 for trend) were inversely associated with the presence of MAFLD among T2DM patients. Additionally, HOMA2-IR values were clearly increased in the T2DM subjects with MAFLD compared with those without MAFLD (P < 0.001), and markedly increased from the highest to the lowest GA/HbA1C ratio quartile (P < 0.001 for trend). Conclusions GA/HbA1C ratio is closely and negatively associated with MAFLD in T2DM subjects, which may attribute to that GA/HbA1C ratio reflects the degree of insulin resistance. GA/HbA1C ratio may act as a simple and practical indicator to evaluate the risk of MAFLD in T2DM.

Vitamin D deficiency is considered a pandemic and has been postulated to increase the risk of type 2 diabetes mellitus (T2DM). Activation of nod-like receptor protein 3 (NLRP3) signaling induced by hyperglycemia stress has been recognized as a key priming stage for pancreatic β-cell inflammation in T2DM pathogenesis. AMP-activated protein kinase (AMPK) activation attenuates NLRP3 inflammasome upregulation in diabetes. This study investigated whether vitamin D3 could protect cells against high glucose-induced inflammation by modulating this critical step. A human cross-sectional study of 78 healthy, glucose-tolerant volunteers and 399 patients with type 2 diabetes was undertaken. The relationship between serum 25(OH)D3 levels and β-cell function was assessed using Pearson correlation analysis and multiple linear regression, and a high-glucose diet-induced rat model of impaired glucose tolerance was used to evaluate the effects of cholecalciferol. Intraperitoneal glucose tolerance tests and an ELISA were performed to detect the function of pancreatic islets. Glucose-stimulated insulin secretion, pyroptosis, reactive oxygen species (ROS) production, and NLRP3 pathway were evaluated together to determine the role of vitamin D in high glucose-induced pancreatic β-cell dysfunction in INS-1E cells. The clinical results showed a positive association between serum 25(OH)D3 levels and β-cell function in male patients with type 2 diabetes. In vivo, cholecalciferol significantly reduced blood glucose levels and improved insulin secretion in response to glucose loading in the high glucose diet-induced rat model. In vitro studies have demonstrated that 1,25(OH)2D3 promotes insulin release in both islets and INS-1E cells. Mechanistically, our results demonstrated that vitamin D3 can activate AMPK, inhibiting the mTOR pathway, thus inhibiting NLRP3 inflammasome activation and alleviating pyroptosis in β-cell dysfunction. This study showed that vitamin D protects against high-glucose-induced β-cell dysfunction by enhancing the AMPK pathway, thereby suppressing NLRP3 inflammasome activation.