Association of high vibration perception threshold with reduced renal function in patients with type 2 diabetes.

Objective: To investigate the correlation between vibration sensory threshold (VPT) and renal function, including glomerulus and renal tubule, in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 1274 patients with T2DM who were enrolled in the Department of Endocrinology of the First Affiliated Hospital of Fujian Medical University between January 2017 and June 2020 were included. Patients were grouped according to VPT levels and divided into three groups, including the normal VPT group (VPT<15V), the mild-moderate elevated VPT group (VPT15~25V), and the severely elevated VPT group (VPT≥25 V). Linear correlation analysis was used to analyze the correlation between VPT and renal functions, including glomerulus markers urine microalbumin (MA) and urinary immunoglobulin G (U-IgG), and renal tubule marker α1-microglobulin (α1-MG). Chronic kidney disease (CKD) was defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. The binary logistic regression of the relation between VPT and CKD, eGFR<60 ml/min, and UACR >30 mg/g were expressed. Results: In the mild-moderate and severely elevated VPT group, injury biomarkers of glomerulus (MA and U-IgG), renal tubule (α1-MG), and the incidence of CKD, eGFR<60 ml/min, and UACR > 30 mg/g were gradually increased compared with the normal VPT group. Furthermore, patients with diabetes and severely elevated VPT had significantly higher levels of MA (ß=197.54, p=0.042) and α1-MG (ß=11.69, p=0.023) compared to those with normal VPT. Also, patients with mild-moderate elevated VPT demonstrate significantly higher levels of MA (ß=229.02, p=0.005). Patients in mild-moderate elevated VPT group (OR=1.463, 95% CI 1.005-2.127; OR=1.816, 95% CI 1.212-2.721) and severely elevated VPT group (OR=1.704, 95% CI 1.113-2.611; OR=2.027, 95% CI 1.248-3.294) are at a higher incidence of CKD and elevated levels of UACR>30mg/g compared to those in the VPT normal group. Moreover, the incidence of positive Upro was notably higher in the severely elevated VPT group (OR=1.738, 95% CI 1.182-2.556). However, this phenomenon was not observed in the incidence of eGFR <60 ml/min. Conclusion: A higher VPT is positively associated with the incidence of CKD in patients with T2DM, particularly with elevated UACR. VPT may serve as a marker for glomerulus and renal tubule injury.

Related Factors Mining of Diabetes Complications Based on Manifold-Constrained Multi-Label Feature Selection.

The primary cause of mortality among individuals with diabetes stems from complications. Identifying related factors for these complications holds immense potential for early prevention. Previous research predominantly employed traditional machine-learning techniques to establish prediction models utilizing medical indicators for related factor selection. However, uncovering the intricate correlations among complication labels and identifying similar characteristics among medical indicators has been challenging. We propose a novel embedded multi-label feature selection approach called LCFSM(Label Cosine and Feature Similar Manifold) to address the issue. LCFSM introduces manifold constraints into the objective function to uncover risk factors associated with diabetes complications. Label cosine similarity is set to optimize feature weights, forming label manifold constraints. Similarly, feature manifold constraints are established to utilize feature kernel similarity in optimizing feature weights. LCFSM formulates an objective function based on the l2,1 regularized Least Squares and previous manifolds constraints, employing the Sylvester equation for convergence assurance. The experimental evaluation compares LCFSM against eight baselines, demonstrating superior performance in top-10 feature selection and feature stacking.LCFSM is applied to identify primary risk factors for diabetes complications. Related factors involve Electromyogram, Urine Routine Protein Positive, etc, offering valuable insights for early treatment.

Suppression of IRF9 Promotes Osteoclast Differentiation by Decreased Ferroptosis via STAT3 Activation.

Osteoporosis is a chronic disease that endangers the health of the elderly. Inhibiting osteoclast hyperactivity is a key aspect of osteoporosis prevention and treatment. Several studies have shown that interferon regulatory factor 9 (IRF9) not only regulates innate and adaptive immune responses but also plays an important role in inflammation, antiviral response, and cell development. However, the exact role of IRF9 in osteoclasts has not been reported. To elucidate the role of IRF9 in osteoclast differentiation, we established the ovariectomized mouse model of postmenopausal osteoporosis and found that IRF9 expression was reduced in ovariectomized mice with overactive osteoclasts. Furthermore, knockdown of IRF9 expression enhanced osteoclast differentiation in vitro. Using RNA sequencing, we identified that the differentially expressed genes enriched by IRF9 knockdown were related to ferroptosis. We observed that IRF9 knockdown promoted osteoclast differentiation via decreased ferroptosis in vitro and further verified that IRF9 knockdown reduced ferroptosis by activating signal transducer and activator of transcription 3 (STAT3) to promote osteoclastogenesis. In conclusion, we identified an essential role of IRF9 in the regulation of osteoclastogenesis in osteoporosis and its underlying mechanism.

Early onset age increases the risk of musculoskeletal damage in patients with type 2 diabetes.

Introduction: It's not clear whether there are differences in musculoskeletal damage and body composition among different age groups of type 2 diabetes. Therefore, the purpose of this study is to analyze the difference between early-onset type 2 diabetes (EOT2D) and non-early-onset type 2 diabetes (NOT2D) in musculoskeletal damage. Methods: A total of 964 patients with type 2 diabetes mellitus were selected by 1:1 propensity score matching, including 534 males and 430 females, with an average age of 52 ± 7 years and an average course of 10 ± 8.5 years. Bone mineral density and body composition were measured, and combined with biochemical tests, linear regression and binary logic regression were used to analyze the relationship between EOT2D, NOT2D and musculoskeletal damage. In addition, 414 patients with T2DM were selected according to whether they were hospitalized twice or not, and the median follow-up period was 44 months. COX survival analysis further elucidates the relationship between EOT2D, NOT2D and musculoskeletal damage. Results: Compared with patients with non-early-onset type 2 diabetes, A/G was negatively correlated with the age of onset, and had statistical significance. EOT2D has a higher risk of sarcopenia, osteoporosis and even musculoskeletal damage. With the prolongation of the course of the disease, the risk of muscle mass and/or bone mineral density decrease in EOT2D increases. Conclusion: EOT2D brings a greater risk of sarcopenia and/or osteoporosis, as well as a higher risk of reduced ASM and BMD. In addition, fat distribution may be more central.

Combined with dynamic serum proteomics and clinical follow-up to screen the serum proteins to promote the healing of diabetic foot ulcer.

OBJECTIVE: Non-healing diabetic foot ulcers are a leading cause of disability and death in diabetic patients, which often results in lower limb amputation. This study aimed to investigate the impact of biomarkers on the healing of diabetic foot ulcers by utilizing dynamic serum proteomics and skin proteomic analysis, combined with clinical case follow-up studies. METHODS: To analyze dynamic serum proteomic changes in four groups, age-matched normal subjects, diabetic patients, pretreatment diabetic foot ulcer patients, and healed diabetic foot ulcer patients were selected. The differential proteins were screened in conjunction with normal and diabetic foot ulcer skin proteomics. In this study, a total of 80 patients with diabetic foot ulcers were enrolled and monitored for 3-6 months during treatment. To verify the significance of the differential proteins, age-matched diabetic patients (240 patients) and healthy controls (160 patients) were included as controls. RESULTS: Dynamic serum proteomics trend showed that the level of negative regulatory proteins related to endothelial cell migration, angiogenesis, and vascular development was significantly decreased after treatment of diabetic foot ulcer. GO enrichment analysis suggested that differentially expressed proteins were mainly enriched in protein activation cascade, immunoglobulin production, and complement activation. The researchers identified the core proteins APOA1, LPA, and APOA2 through a convergence of serum and skin proteomics screening. Clinical cases further validated that APOA1 levels are decreased in diabetic foot ulcer patients and are correlated with disease severity. In addition, animal experiments showed that APOA1 could promote wound healing in diabetic mice. CONCLUSIONS: Based on our dynamic proteomics and clinical case studies, our bioinformatic analysis suggests that APOA1 plays a critical role in linking coagulation, inflammation, angiogenesis, and wound repair, making it a key protein that promotes the healing of diabetic foot ulcers.

Suppression of TLR4 prevents diabetic bone loss by regulating FTO-mediated m6A modification.

Toll-like receptor-4 (TLR4) has been implicated in the development and progression of diabetic osteoporosis. However, the mechanisms underlying TLR4-regulated bone metabolism in diabetes are yet to be fully understood. Epigenetic modifications have been indicated as a possible mechanism leading to increased risk of osteoporosis and bone fracture. As N6-methyladenosine (m6A) is the most common epigenetic modification in eukaryotic mRNAs, we hypothesized that TLR4 regulates m6A modification in bone tissues of diabetic rats, thereby potentially explaining the pathogenesis of diabetic bone loss. m6A sequencing (m6A-seq) was performed in samples of the femur of TLR4-wild type (TLR4WT) and TLR4-knockout (TLR4KO) diabetic rats to identify genes with differential m6A modifications that may be associated with the bone loss phenotype. We found that in TLR4KO rats, the rapid weight loss of diabetic rats was prevented, and bone mineral density (BMD) was significantly increased. m6A-seq and Gene Ontology enrichment analysis revealed that m6A-modified genes in the femur of TLR4KO diabetic rats were associated with regulation of biological processes such as osteoclast differentiation. qRT-PCR analysis on the expression levels of the m6A-modified methyltransferases and demethylases demonstrated that only the m6A demethylase fat mass and obesity-associated protein（FTO）was decreased. Using an osteoclast cell model, we confirmed that TLR4-mediated osteoclast differentiation was induced by glycolipid toxicity via inhibition of FTO expression. Taken together, these results suggest that inhibition of TLR4 may prevent diabetic bone loss via regulation of FTO-mediated m6A modification.

Precedence of Bone Loss Accompanied with Changes in Body Composition and Body Fat Distribution in Patients with Type 2 Diabetes Mellitus.

Methods: A total of 596 patients with T2DM, including 308 male and 288 female patients, were included in the follow-up study; the median follow-up time was 2.17 years. We calculated the difference between the endpoint and the baseline of each body composition index and the annual rate. The research participants were divided into the increased body mass index (BMI) group, stable BMI group, and decreased BMI group. Some confounding factors were adjusted, such as BMI, fat mass index (FMI), muscle mass index (MMI), muscle/fat mass ratio (M/F), trunk fat mass index (TFMI), appendicular skeletal muscle mass index (ASMI), and appendicular skeletal muscle mass/trunk fat mass ratio (A/T). Results: The linear analysis showed that ΔFMI and ΔTFMI were negatively correlated with the change in femoral neck BMD (ΔFNBMD) and ΔMMI, ΔASMI, ΔM/F, and ΔA/T were positively correlated with ΔFNBMD. The risk of FNBMD reduction in patients with increased BMI was 56.0% lower than that in patients with decreased BMI; also, the risk in patients with stable M/F was 57.7% lower than that in patients with decreased M/F. The risk in the A/T increase group was 62.9% lower than that in the A/T decrease group. Conclusions: A reasonable muscle/fat ratio is still beneficial to maintaining bone mass. Maintaining a certain BMI value is conducive to maintaining FNBMD. Simultaneously, increasing the proportion of muscle mass and reducing fat accumulation can also prevent FNBMD loss.

Metformin promotes osteogenic differentiation and prevents hyperglycaemia-induced osteoporosis by suppressing PPARγ expression.

Metformin can prevent hyperglycaemia-induced osteoporosis and decrease the bone fracture rate, but the mechanism has not been fully elucidated. To reveal the mechanism by which metformin affects hyperglycaemia-induced osteoporosis, we treat a mouse osteoporosis cell model with metformin and find that osteoblast mineralization increases and PPARγ expression decreases. Single-cell mRNA sequencing analysis show that PPARγ is highly expressed in the bone tissue of osteoporosis patients, which highlights the role of PPARγ in osteoporosis. Furthermore, we find that PPARγ is the effector through which metformin prevents osteoporosis. We further examine the mechanism of PPARγ regulation and reveal that metformin regulates PPARγ expression through the AMPK pathway and that PPARγ affects osteoblasts through the endoplasmic reticulum stress (ERS) pathway. Moreover, we verify the association between the effect of metformin on bone metabolism and the expression of PPARγ in high-fat diet-induced diabetic rats. Thus, we identify and functionally validate that metformin prevents hyperglycaemia-induced osteoporosis by regulating the AMPK-PPARγ-ERS axis.

Activation of osteoblast ferroptosis via the METTL3/ASK1-p38 signaling pathway in high glucose and high fat (HGHF)-induced diabetic bone loss.

Diabetes mellitus (DM) and osteoporosis are two common diseases that may develop as a cause-and-effect relationship since the incidence of osteoporotic fractures is significantly increased in DM patients. However, the pathophysiology of diabetic osteoporosis is yet to be clearly understood. Iron overload has been reported to lead to bone loss and closely related to osteoporosis. In this study, we hypothesized that high glucose and high fat (HGHF) may induce osteoblastic ferroptosis for the pathogenesis of diabetic osteoporosis and explored the possible molecular mechanisms behind. Using the diabetic rat model established by HGHF feeding with a subsequent intraperitoneal injection of a single low dose of streptozocin, we found that the serum ferritin level (a biomarker for body iron store) was significantly elevated in HGHF-fed rats and the expression of SLC7A11 and GPX4 (inhibitory marker proteins for ferroptosis) was markedly attenuated in the bone tissue of the rats with diabetic bone loss as compared to the normal rats. In an osteoblast cell model, treatment of pre-osteoblastic MC3T3-E1 cells with high glucose and palmitic acid (HGPA) not only suppressed osteoblast differentiation and mineralization but also triggered ferroptosis-related osteoblastic cell death. m6 A-seq revealed that m6 A methylation on ASK1 was 80.9-fold higher in HGPA-treated cells. The expression of p-ASK1 and p-p38 was also significantly elevated in the HGPA-treated cells. Knockout of METTL3 (methyltransferase-like 3), one of the major m6 A methyltransferases, in MC3T3-E1 cells not only abrogated HGPA-induced activation of ASK1-p38 signaling pathway but also attenuated the level of ferroptosis. Therefore, HGHF-induced ferroptosis in osteoblasts may be the main cause of osteoporosis in DM via activation of METTL3/ASK1-p38 signaling pathway, and inhibition of ferroptosis in osteoblasts may provide a potential therapeutic strategy for diabetic osteoporosis.

Relationship between onset age of type 2 diabetes mellitus and vascular complications based on propensity score matching analysis.

AIMS/INTRODUCTION: To assess the relationship between type 2 diabetes mellitus onset age and vascular complications in China. MATERIALS AND METHODS: A retrospective review of 3,568 patients with type 2 diabetes mellitus using a propensity score-matched (PSM) cohort analysis was carried out in two different age of onset groups (age 40 and 60 years). These groups were then subdivided into two groups, early-onset diabetes (EOD40 and EOD60; the onset age before 40 and 60 years, respectively) and late-onset diabetes (LOD40 and LOD60: the onset age after 40 and 60 years, respectively). Macrovascular and microvascular complications were analyzed before and after PSM. RESULTS: Patients categorized in both the early-onset disease (EOD) groups had a higher risk of developing macro- and microvascular complications before PSM. After PSM, no differences existed between the EOD and late-onset disease groups in the risk of macrovascular complications. Compared with the late-onset disease group, the odds ratio of having a microvascular complication of diabetic retinopathy, chronic kidney disease and diabetic peripheral neuropathy in the 40-year-old EOD group increased to 2.906, 1.967 and 1.672 (P < 0.05), respectively. The odds ratio of diabetic retinopathy and diabetic peripheral neuropathy in the 60-year-old EOD group was 1.763 and 1.675 (P < 0.05), respectively. CONCLUSIONS: The earlier the onset of type 2 diabetes mellitus, the higher risk of microvascular, but not necessarily macrovascular, complications. It is not too late to prevent diabetes at any age. Pre-emptive microvascular treatment or preventative measures in EOD patients who do not yet show symptoms, might be beneficial.

Additive Effect of Sarcopenia and Anemia on the 10-Year Risk of Cardiovascular Disease in Patients with Type 2 Diabetes.

OBJECTIVE: To investigate the association between sarcopenia and anemia and the 10-year cardiovascular disease risk in diabetic patients. METHODS: A cross-sectional study was conducted involving 4673 hospitalized patients (2271 men and 2402 women) with type 2 diabetes mellitus, with an average age of 60.66 ± 11.93 years, of whom 542 were followed up for a median follow-up period of 24 months. All participants underwent body composition measurements, and they were grouped by sex and presence of sarcopenia using the Framingham risk model to assess their 10-year cardiovascular risk. According to the changes in the cardiovascular risk during follow-up, the patients were divided into four groups: low-low, low-high, high-low, and high-high. RESULTS: The prevalence of anemia was higher in the sarcopenia group than in the nonsarcopenia group (11.5% vs. 24.1% for men, P < 0.001; 13.9% vs. 19.7% for women, P < 0.05), and the difference remained significant after adjusting for confounders. Patients with sarcopenia and without anemia had a 46.2% increased risk of high 10-year cardiovascular disease (CVD) (odds ratio (OR) = 1.462, 95% confidence interval (CI) 1.085-1.972, P = 0.013), and the risk was twofold higher in patients with sarcopenia and anemia than in those without (OR = 3.283, 95% CI 2.038-5.289, P < 0.001). In follow-up studies, sarcopenia was associated with an increased risk of CVD at 10 years, and a reduction in appendicular skeletal muscle mass index independently predicted the increased risk of CVD. CONCLUSION: Sarcopenia is associated with an increased risk of anemia, and the presence of both has an additive effect on the 10-year CVD risk in patients with type 2 diabetes. Loss of muscle mass can independently predict an increased CVD risk in diabetic patients.

Association of decreased muscle mass with reduced bone mineral density in patients with Graves' disease.

AIM: This study aimed to determine the association of decreased muscle mass with reduced bone mineral density in patients with Graves' disease. METHODS: A total of 758 patients with Graves' disease at diagnosis (mean age 41.2 years) were enrolled for a cross-sectional study; of these, 287 were enrolled for a cohort study with a median follow-up of 24 months. Meanwhile, 1164 age- and sex-matched healthy controls were recruited. All participants underwent dual-energy x-ray absorptiometry and muscle mass index (ASMI) measurements. The changes in ASMI and bone mineral density (BMD) were calculated from the measurements made at a gap of 2 years. RESULTS: The BMD of patients with Graves' disease was still significantly lower after normalizing serum thyroid hormone levels compared with that of healthy controls. ASMI positively correlated with BMD in patients with Graves' disease (lumbar BMD, r = 0.210; femoral neck BMD, r = 0.259; hip BMD, r = 0.235; P < 0.001), and this relationship persisted after successful anti-thyroid therapy (lumbar BMD, r = 0.169; femoral neck BMD, r = 0.281; hip BMD, r = 0.394; P < 0.001). Low muscle mass was associated with low BMD (OR, 1.436; 95% CI, 1.026-2.010). Improving the muscle mass led to changes in the bone mass of the femoral neck (OR, 0.420; 95% CI, 0.194-0.911) and hip (OR, 0.217; 95% CI, 0.092-0.511) during the follow-up. However, this phenomenon was not observed in lumbar and bone turnover markers. CONCLUSIONS: The recovery of bone mass might be related to the recovery of the muscle mass. Patients with Graves' disease should be helped to regain their muscle mass and thus accelerate the recovery of bone mass while administering anti-thyroid therapy.

Association of sarcopenia with a higher risk of infection in patients with type 2 diabetes.

AIMS: This study aimed to determine whether patients with type 2 diabetes and sarcopenia had a higher risk of infection. STUDY DESIGNS: A cross-sectional study and a follow-up study were performed. METHOD: A total of 2562 patients were enrolled and assessed for body composition and infection status. They were classified into four groups according to body fat (BF) and muscle mass index (ASMI): obese, sarcopenic, sarcopenic obese, and normal. Among these, 275 patients were followed for a median follow-up period of 1.84 years to evaluate the relationship of changes in skeletal muscle with infection status. RESULTS: The sarcopenic and sarcopenic obese groups showed a higher risk of infection, an increase by 49.6% (OR = 1.496, 95% CI 1.102-2.031) and 42.4% (OR = 1.424, 95% CI 1.031-1.967) compared with the normal group, and also had a higher risk of respiratory infection, an increase by 56.0% (OR = 1.560, 95% CI 1.084-2.246) and 57.4% (OR = 1.574, 95% CI 1.080-2.293), respectively. Patients with the increased ASMI (OR = 0.079, 95% CI 0.021-0.298) represented a lower risk of infection than those with the decreased ASMI. Even a minor change (OR = 0.125, 95% CI 0.041-0.378) against age was beneficial to lowering the risk of infection. However, no association was found in the changes of body mass index and BF with infection status. CONCLUSIONS: Sarcopenia, especially in patients with diabetes who are also obese, increases the risk of infection. Maintaining or improving muscle mass is expected to reduce infections.

Identification of independent risk factors for diabetic neuropathy progression in patients with type 2 diabetes mellitus.

OBJECTIVE: To identify independent risk factors for diabetic neuropathy (DN) in patients with type 2 diabetes mellitus (T2DM). METHODS: We retrospectively analyzed 376 patients with T2DM at the First Affiliated Hospital of Fujian Medical University, China between January 2013 and October 2016. Multivariate logistic regression was used to explore potential risk factors for progression of DN in patients with T2DM. Effect sizes were estimated using odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The prevalence of DN in patients with T2DM was 43.1%. Multivariate logistic regression indicated that retinopathy (OR: 2.755, 95% CI: 1.599-4.746); diabetic nephropathy (OR: 2.196, 95% CI: 1.279-3.772); longer duration of T2DM (OR: 1.081, 95% CI: 1.045-1.120); use of insulin (OR: 1.091, 95% CI: 1.018-1.170); longer history of alcohol consumption (OR: 1.034, 95% CI: 1.010-1.059); and higher blood urea nitrogen (OR: 1.081, 95% CI: 1.009-1.159) were associated with increased risk of DN in patients with T2DM. CONCLUSIONS: Retinopathy, diabetic nephropathy, longer duration of T2DM, use of insulin, longer history of alcohol consumption, and higher blood urea nitrogen were independent risk factors for DN. These findings should be verified in large-scale prospective studies.

Glucotoxicity Activation of IL6 and IL11 and Subsequent Induction of Fibrosis May Be Involved in the Pathogenesis of Islet Dysfunction.

Background: Islet dysfunction is the main pathological process of type 2 diabetes mellitus (T2DM). Fibrosis causes islet dysfunction, but the current mechanism is still unclear. Here, bioinformatics analysis identified gene clusters closely related to T2DM and differentially expressed genes related to fibrosis, and animal models verified the roles of these genes. Methods: Human islet transcriptomic datasets were obtained from the Gene Expression Omnibus (GEO), and weighted gene coexpression network analysis (WGCNA) was applied to screen the key gene modules related to T2DM and analyze the correlations between the modules and clinical characteristics. Enrichment analysis was performed to identify the functions and pathways of the key module genes. WGCNA, protein-protein interaction (PPI) analysis and receiver operating characteristic (ROC) curve analysis were used to screen the hub genes. The hub genes were verified in another GEO dataset, the islets of high-fat diet (HFD)-fed Sprague-Dawley rats were observed by H&E and Masson's trichrome staining, the fibrotic proteins were verified by immunofluorescence, and the hub genes were tested by immunohistochemistry. Results: The top 5,000 genes were selected according to the median absolute deviation, and 18 modules were analyzed. The yellow module was highly associated with T2DM, and its positive correlation with glycated hemoglobin (HbA1c) was significantly stronger than that with body mass index (BMI). Enrichment analysis revealed that extracellular matrix organization, the collagen-containing extracellular matrix and cytokine-cytokine receptor interaction might influence T2DM progression. The top three hub genes, interleukin 6 (IL6), IL11 and prostaglandin-endoperoxide synthase 2 (PTGS2), showed upregulated expression in T2DM. In the validation dataset, IL6, IL11, and PTGS2 levels were upregulated in T2DM, and IL6 and PTGS2 expression was positively correlated with HbA1c and BMI; however, IL11 was positively correlated only with HbA1c. In HFD-fed Sprague-Dawley rats, the positive of IL6 and IL11 in islets was stronger, but PTGS2 expression was not significantly altered. The extent of fibrosis, irregular cellular arrangement and positive actin alpha 2 (ACTA2) staining in islets was significantly greater in HFD-fed rats than in normal diet-fed rats. Conclusion: Glucotoxicity is a major factor leading to increased IL6 and IL11 expression, and IL6-and IL11-induced fibrosis might be involved in islet dysfunction.

Relationship between Hyponatremia and Peripheral Neuropathy in Patients with Diabetes.

OBJECTIVES: Hyponatremia is a common complication of diabetes. However, the relationship between serum sodium level and diabetic peripheral neuropathy (DPN) is unknown. This study was aimed at investigating the relationship between low serum sodium level and DPN in Chinese patients with type 2 diabetes mellitus. METHODS: A retrospective study was performed on 1928 patients with type 2 diabetes between 2010 and 2018. The multivariate test was used to analyze the relationship between the serum sodium level and the nerve conduction function. A restricted cubic spline was used to flexibly model and visualize the relationship between the serum sodium level and DPN, followed by logistic regression with adjustment. RESULTS: As the serum sodium level increased, the prevalence of DPN had a reverse J-curve distribution with the serum sodium levels (69.6%, 53.7%, 49.6%, 43.9%, and 49.7%; P = 0.001). Significant differences existed between the serum sodium level and the motor nerve conduction velocity, sensory nerve conduction velocity, part of compound muscle action potential, and sensory nerve action potential of the participants. Compared with hyponatremia, the higher serum sodium level was a relative lower risk factor for DPN after adjusting for several potential confounders (OR = 0.430, 95%CI = 0.220-0.841; OR = 0.386, 95%CI = 0.198-0.755; OR = 0.297, 95%CI = 0.152-0.580; OR = 0.376, 95%CI = 0.190-0.743; all P < 0.05). Compared with low-normal serum sodium groups, the high-normal serum sodium level was also a risk factor for DPN (OR = 0.690, 95%CI = 0.526-0.905, P = 0.007). This relationship was particularly apparent in male participants, those aged <65 years, those with a duration of diabetes of <10 years, and those with a urinary albumin - to - creatinine ratio (UACR) < 30 mg/g. CONCLUSIONS: Low serum sodium levels were independently associated with DPN, even within the normal range of the serum sodium. We should pay more attention to avoid the low serum sodium level in patients with type 2 diabetes mellitus.

Stronger Association of Albuminuria with the Risk of Vascular Complications than Estimated Glomerular Filtration Rate in Type 2 Diabetes.

INTRODUCTION: Albuminuria is a risk factor for macro- and microvascular complications of type 2 diabetes (T2D).With an increasing trend of normoalbuminuria, however, of the 2 predictors - estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) - which one is a better predictor of vascular complications of T2D is not clear. OBJECTIVE: This study aimed to compare the impacts of albuminuria and eGFR on patients with T2D associated with micro- and macrovascular complications. METHODS: This retrospective study recruited 4,715 patients with T2D and grouped them based on the values of UACR (high UACR: ≥30 mg/g, low UACR: <30 mg/g) and eGFR (mL/[min × 1.73 m2]) (G1: eGFR ≥ 90; G2: eGFR = 60-89; G3-5: eGFR < 60) from April 2008 to November 2018. Logistic regression analysis was carried out for risk factors in patients with diabetic retinopathy (DR), diabetic peripheral neuropathy (DPN), peripheral arterial disease (PAD), left ventricular remodeling, diastolic disorders, and carotid atherosclerotic plaque in 6 different groups: low UACR + G1 (control group), low UACR + G2, low UACR + G3-5, high UACR + G1, high UACR + G2, and high UACR + G3-5. Patients were grouped according to the change in the UACR value (UACR-decreased group: ≤-30%, UACR-stable group: -30 to 30%, and UACR-increased group ≥30%), eGFR value (eGFR-decreased group: >3%, and eGFR-stable group: ≤3%) and followed up. RESULTS: Compared with the control group, patients with higher albuminuria and lower eGFR had higher adjusted odds ratio (OR) trends of complications, especially in the high UACR + G3-5 group. The OR of 2.010, 3.444, 1.633, 2.742, and 3.014 were obtained for DR, DPN, PAD, left ventricular remodeling, and diastolic disorders, respectively. No statistically significant difference was found in the risk of complications within each one of 2 phenotypes, regardless of the change in the eGFR. After grouping by eGFR, the regression analysis of the urinary protein level in each stage revealed that a majority of complications had a statistically significant difference, except for DR and PAD in the high UACR + G3-5 group. DR in the follow-up study had a higher risk in the UACR-stable/increased group than the UACR-decreased group (UACR stable: OR = 2.568; 95% confidence interval (CI): 1.128-5.849; p = 0.025; UACR increased: OR = 2.489; 95% CI: 1.140-5.433; p = 0.022). CONCLUSION: UACR is a more predictive risk factor for diabetic complications compared with a reduced eGFR.

Glycolipid toxicity induces osteogenic dysfunction via the TLR4/S100B pathway.

Diabetes can cause bone metabolism disorders and osteoporosis. The occurrence of both diabetes mellitus and osteoporosis increases the disability and mortality of elderly individuals due to pathological fracture. Abnormal metabolism of nutrientsis considered to be one of the important mechanisms of diabetes mellitus-induced osteoporosis. This study preliminarily explored the roles of TLR4 (Toll-like receptor 4) and S100B in osteogenic dysfunction induced by glycolipid toxicity. In this study, a diabetic rat model and TLR4-knockdown diabetic rat model were used in vivo. MC3T3-E1 cells in a high glucose and palmitic acid environment were used as glycolipid toxicity cell models in vitro. We investigated the effects of TLR4 and S100B on osteogenesis by overexpression or inhibition of TLR4 and S100B in vitro. We found that when TLR4 or S100B was inhibited, ALP and OCN were significantly up-regulated and p-ERK was significantly down regulated in the glycolipid model. These results suggest that TLR4/S100B may play a role in reducing glycolipid toxicity by regulating ERK phosphorylation.