Phosphatidate phosphatase Lipin1 involves in diabetic encephalopathy pathogenesis via regulating synaptic mitochondrial dynamics.

Diabetic encephalopathy (DE) is a common central nervous system complication of diabetes mellitus without effective therapy currently. Recent studies have highlighted synaptic mitochondrial damages as a possible pathological basis for DE, but the underlying mechanisms remain unclear. Our previous work has revealed that phosphatidate phosphatase Lipin1, a critical enzyme involved with phospholipid synthesis, is closely related to the pathogenesis of DE. Here, we demonstrate that Lipin1 is significantly down-regulated in rat hippocampus of DE. Knock-down of Lipin1 within hippocampus of normal rats induces dysregulation of homeostasis in synaptic mitochondrial dynamics with an increase of mitochondrial fission and a decrease of fusion, then causes synaptic mitochondrial dysfunction, synaptic plasticity deficits as well as cognitive impairments, similar to that observed in response to chronic hyperglycemia exposure. In contrast, an up-regulation of Lipin1 within hippocampus in the DE model ameliorates this cascade of dysfunction. We also find that the effect of Lipin1 that regulating mitochondrial dynamics results from maintaining appropriate phospholipid components in the mitochondrial membrane. In conclusion, alterations in hippocampal Lipin1 contribute to hippocampal synaptic mitochondrial dysfunction and cognitive deficits observed in DE. Targeting Lipin1 might be a potential therapeutic strategy for the clinical treatment of DE.

Hydrogen sulfide protects against high glucose­induced lipid metabolic disturbances in 3T3­L1 adipocytes via the AMPK signaling pathway.

Aberrant lipid metabolism contributes to the development of type 2 diabetes mellitus. The mechanisms by which hydrogen sulfide (H2S), an endogenous gasotransmitter, regulates lipid metabolism remain unclear. The aim of the present study was to investigate if the protective effects of H2S during high glucose (HG)­induced lipid accumulation in 3T3­L1 adipocytes may be mediated by AMP­activated protein kinase (AMPK). Triglyceride (TG) content and the production of H2S were determined using adipogenesis colorimetric assay kits and H2S synthesis methods. The levels of monocyte chemoattractant protein­1 and adiponectin were evaluated by ELISA. Total AMPK and phosphorylated AMPK levels were assessed by western blot analysis. HG increased the cellular level of TG and decreased H2S production in 3T3­L1 adipocytes. The H2S donor, sodium hydrosulfide (NaHS) protected against the HG­induced accumulation of TG in 3T3­L1 adipocytes. Furthermore, NaHS suppressed HG­induced TG accumulation by activating AMPK. Collectively, the findings of the present study suggested that HG induced lipid accumulation in 3T3­L1 adipocytes, and AMPK activation may underlie the lipid­lowering effects of H2S.

Urinary Microvesicle-Bound Uromodulin: A Potential Molecular Biomarker in Diabetic Kidney Disease.

This study was designed to investigate the changes of urinary microvesicle-bound uromodulin and total urinary uromodulin levels in human urine and the correlations with the severity of diabetic kidney disease (DKD). 31 healthy subjects without diabetes and 100 patients with type 2 diabetes mellitus (T2DM) were included in this study. The patients with T2DM were divided into three groups based on the urinary albumin/creatinine ratio (UACR): normoalbuminuria group (DM, n = 46); microalbuminuria group (DN1, n = 32); and macroalbuminuria group (DN2, n = 22). We use a specific monoclonal antibody AD-1 to capture the urinary microvesicles. Urinary microvesicle-bound uromodulin and total urinary uromodulin levels were determined by enzyme-linked immunosorbent assay (ELISA). Our results showed that the levels of urinary microvesicle-bound uromodulin in DN1 and DN2 groups were significantly higher than those in control group and DM group (P < 0.01). Multiple stepwise linear regression analysis showed that UACR was independent determinant for urinary microvesicle-bound uromodulin (P < 0.05) but not for total urinary uromodulin. These findings suggest that the levels of urinary microvesicle-bound uromodulin are associated with the severity of DKD. The uromodulin in urinary microvesicles may be a specific marker of DKD and potentially may be used to predict the onset and/or monitor the progression of DKD.

Therapeutic Effect of Metformin on Chemerin in Non-Obese Patients with Non-Alcoholic Fatty Liver Disease (NAFLD).

BACKGROUND: Chemerin is an important risk factor of insulin resistance. Non-alcoholic fatty liver has typical characteristics of insulin resistance. The aim of this study was to explore the potential role of chemerin in NAFLD. METHODS: 45 subjects included 22 control subjects (A group) and 23 subjects diagnosed with non-alcoholic fatty liver disease (B group) participated in the study. 23 patients in the NAFLD group received oral daily metformin at a dose of 20 mg/kg/day for 24 weeks follow-up. Chemerin and insulin resistance markers were determined at baseline and 24 weeks. RESULTS: The levels of WHR, BMI, FINS, HOMA-IR, TG, ALT, AST, and Chemerin in B group were significantly higher than A group. After 24 weeks of metformin treatment, the levels of WHR, AST, ALT, TG, chemerin and HOMA-IR were significantly reduced (p < 0.05) and other indexes were not changed significantly. Correlation analysis indicated that serum chemerin concentrations were positively correlated with BMI, WHR, HOMA-IR, FINS, TG, ALT, and AST levels. Logistic regression analysis showed chemerin, TG, and ALT were independent variables associated with NAFLD. CONCLUSIONS: These findings showed a significant increase of chemerin level in NAFLD patients. Metformin treatment can improve NAFLD and decrease the level of chemerin. Chemerin, TG, and ALT were independent variables associated with NAFLD.

Evaluation of a risk factor scoring model in screening for undiagnosed diabetes in China population.

OBJECTIVE: To develop a risk scoring model for screening for undiagnosed type 2 diabetes in Chinese population. METHODS: A total of 5348 subjects from two districts of Jinan City, Shandong Province, China were enrolled. Group A (2985) included individuals from east of the city and Group B (2363) from west of the city. Screening questionnaires and a standard oral glucose tolerance test (OGTT) were completed by all subjects. Based on the stepwise logistic regression analysis of Group A, variables were selected to establish the risk scoring model. The validity and effectiveness of this model were evaluated in Group B. RESULTS: Based on stepwise logistic regression analysis performed with data of Group A, variables including age, body mass index (BMI), waist-to-hip ratio (WHR), systolic pressure, diastolic pressure, heart rate, family history of diabetes, and history of high glucose were accepted into the risk scoring model. The risk for having diabetes increased along with aggregate scores. When Youden index was closest to 1, the optimal cutoff value was set up at 51. At this point, the diabetes risk scoring model could identify diabetes patients with a sensitivity of 83.3% and a specificity of 66.5%, making the positive predictive value 12.83% and negative predictive value 98.53%. We compared our model with the Finnish and Danish model and concluded that our model has superior validity in Chinese population. CONCLUSIONS: Our diabetes risk scoring model has satisfactory sensitivity and specificity for identifying undiagnosed diabetes in our population, which might be a simple and practical tool suitable for massive diabetes screening.