Diabetic encephalopathy is a type of central diabetic neuropathy resulting from diabetes mainly manifested as cognitive impairments. However, its underlying pathogenesis and effective treatment strategies remain unclear. In the present study, we investigated the effect of Lipin1, a phosphatidic acid phosphatase enzyme, on the pathogenesis of diabetic encephalopathy. We found that in vitro, Lipin1 exerts protective effects on high glucose-induced reductions of PC12 cell viability, while in vivo, Lipin1 is downregulated within the CA1 hippocampal region in a type I diabetes rat model. Increased levels of Lipin1 within the CA1 region are accompanied with protective effects including amelioration of dendritic spine and synaptic deficiencies, phosphorylation of the synaptic plasticity-related proteins, LIM kinase 1 (p-limk1) and cofilin, as well as increases in the synthesis of diacylglycerol (DAG), and the expression of phosphorylated protein kinase D (p-PKD). These effects are associated with the rescue of cognitive disorders as shown in this rat model of diabetes. In contrast, knockdown of Lipin1 within the CA1 region enhanced neuronal abnormalities and the genesis of cognitive impairment in rats. These results suggest that Lipin1 may exert neuroprotective effects involving the PKD/Limk/Cofilin signaling pathway and may serve as a potential therapeutic target for diabetic encephalopathy.

目的 探讨2型糖尿病患者促甲状腺激素与下肢动脉粥样硬化症的关系.方法 根据患者下肢有无下肢动脉粥样硬化症,将410名2型糖尿病患者分为两组,比较两组患者促甲状腺激素、游离甲状腺激素、游离甲状腺三碘原氨酸等资料.结果 B组患者TSH水平明显高于A组,差异具有统计学意义(p<0.05),多因素Logistic回归分析发现促甲状腺激素是下肢动脉粥样硬化症的独立危险因素.结论 2型糖尿病患者随促甲状腺激素水平的增加,下肢动脉粥样硬化症的发生率明显增加,2型糖尿病患者促甲状腺激素升高是下肢动脉粥样硬化症发生的独立危险因素.

Depression is considered a widespread neuropsychiatric disease associated with neuronal injury within specific brain regions. Fluoxetine, a selective serotonin reuptake inhibitor, has been widely used in depressed patients. Recently, fluoxetine has demonstrated neuroprotective effects apart from the effect on serotonin. However, the underlying mechanism involved in this neuroprotection remains unclear, in particular, whether fluoxetine exerts antidepressant effects via protecting against neuronal injury. Here, we found that treatment with fluoxetine (10 mg/kg, i.p.) for 2 weeks ameliorated depression-like behaviors in a chronic unpredictable mild stress (CUMS)-induced rat model of depression and was accompanied with an alleviation of glia activation and inhibition of interleukin-1β (IL-1β), interferon gamma (IFN-γ), and tumor necrosis factor-α (TNF-α) expression in the hippocampal dentate gyrus (DG) region. Meanwhile, CUMS rats treated with fluoxetine showed reductions in neuronal apoptosis and a downregulation of the apoptotic protein Bax, cleaved caspase 3, and caspase 9 levels. These effects appear to involve a downregulation of p38 mitogen-activated protein kinase (MAPK) signaling within the DG hippocampus as the specific inhibitor of p38 MAPK, SB203580, significantly suppressed apoptosis, as well as ameliorated depressive behaviors resulting from CUMS exposure. Moreover, fluoxetine could rescue neuronal deterioration and depression-like phenotypes caused by overexpression of p38 in DG. This finding extends our knowledge on the antidepressant-like effects of fluoxetine, which appear to at least partially profit from neuroprotection against inflammation and neuronal apoptosis via downregulation of the p38 MAPK pathway. The neuroprotective mechanisms of fluoxetine may provide some novel therapeutic avenues for stress-related neurological diseases.

Abstract Aims/Introduction The early pathological changes of diabetic peripheral neuropathy (DPN) are mainly small nerve fiber injuries. Corneal confocal microscopy (CCM) is an easy, rapid, non‐invasive and repeatable technique to detect the damage of small nerve fibers. The purpose of this study was to explore the application of CCM in DPN and other chronic complications of type 2 diabetes mellitus. Materials and Methods A total of 220 individuals (48 normal healthy control participants and 172 patients with type 2 diabetes mellitus) were included in the study. All participants were assessed and scored for neurological symptoms and neurological deficits, quantitative sensory test, neuroelectrophysiological test, and CCM. Results Corneal nerve fiber density, corneal nerve fiber length and corneal nerve branch density were significantly reduced in patients with type 2 diabetes mellitus compared with normal healthy control subjects (P < 0.001, P < 0.001 and P < 0.001, respectively). In the DPN group, corneal nerve fiber density, corneal nerve branch density and corneal nerve fiber length were significantly lower than for patients without DPN (P < 0.001, P < 0.001 and P < 0.001, respectively). Receiver operating characteristic analysis showed that the optimal cut‐off values were 24.68, 39 and 15.315, respectively, in which corneal nerve fiber density and corneal nerve fiber length had moderate sensitivity and specificity. Conclusion This study provides more support for the clinical use of CCM to diagnose type 2 diabetes mellitus‐related complications, especially DPN.

Cardiovascular and cerebrovascular diseases have become leading causes of death in China as the economy develop and lifestyles change. This study aimed to estimate the relationship of the age, gender, and glucose metabolism with the serum lipid and lipoprotein levels of middle-aged and elderly Chinese men and women in Shandong Province.

Objective: To investigate the prevalence of diabetes mellitus in Qingdao, analyze the correlation between diabetes and smoking, and explore the advantages of application of fasting blood glucose (FPG) combined with glycosylated hemoglobin (HbA1c) in the detection of diabetes mellitus. Methods: 6011 citizens who were examined in Health management center of Qilu Hospital of Shandong University (Qingdao) in 2017 were selected as subjects for blood glucose examination. Results: The prevalence of diabetes in smokers was 13.3%, which was higher than non-smokers (8.8%). Screening of FPG combined with HbA1c increased the detection rate by 5.27% of diabetes compared with simple FPG screening. Conclusion: The incidence of diabetes is related to smoking. The screening of FPG combined with HbA1c prominently increased the detection rate compared with simply FPG for diabetes.

Objective To explore the relationship between age,gender,BMI,blood pressure,status of glucose metabolism and serum lipids and lipoproteins among the middle-aged and elderly Chinese men and women in Shandong Province.Methods A cross-sectional study was conducted in Shandong Province among 10,028 adults aged ≥40 years.Demographic data were collected and oral glucose tolerance test was performed.Fasting serum total (Cho),low-density lipoprotein cholesterol （ LDL-C),high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were measured by standard methods.Results The estimates of serum Cho,LDL-C,HDL-C and TG were (5.35 ± 1.05)mmol/L,(3.18 ±0.86) mmol/L,(1.51 ±0.38) mmol/L and 1.34 mmol/L,respectively.The estimates of serum Cho,LDL-C,HDL-C and TG in female were higher than those in male,and differences in Cho,LDL-C and HDL-C were statistically significant (P ＜ 0.001).The levels of serum Cho,LDL-C and TG increased (P =0.005,P =0.012,P =0.043),while the level of serum HDL-C decreased (P =0.002) with the elevation of blood pressure.The levels of serum Cho,LDL-C and TG increased (P =0.013,P =0.023,P =0.007),while the level of serum HDL-C decreased with the increase of BMI (P =0.010).The levels of serum Cho,LDL-C between normal glucose tolerance population,pre-diabetes [impaired fasting glucose (IFG),impaired glucose tolerance (IGT) and IFG accompany with IGT] population and diabetic population increased first and then decreased (P ＜ 0.001),the level of serum HDL-C decreased gradually (P =0.007),and the level of TG increased gradually (P ＜0.001).Up to 36.92％ and 19.10％ adults had borderline high total cho (5.18-6.21 mmol/L) and high total cho (≥6.22 mmol/L);25.24％ and 13.39％ population had borderline high (3.37-4.13 mmol/L) and high (≥4.14 mmol/L) HDL-C;16.70％ and 17.47％ of the population had borderline high (1.70-2.25 mmol/L) and high (≥2.26 mmol/L) TG;5.64％ had low HDL-C (≤1.04 mmol/L).Condusion Serum total and low-density lipoprotein cholesterol levels are high in the population aged ≥40 years in Shandong Province.Age,gender,BMI,blood pressure and status of glucose metabolism can affect serum lipids and lipoproteins.Without effective prevention and intervention,incidence of cardiovascular and cerebrovascular diseases will keep growing in the future.

Objective. To investigate changes in the glycated hemoglobin A1c (A1c) level and those in β cell function and insulin resistance in newly diagnosed and drug naive type 2 diabetes patients and to evaluate the relationship between them. Design and Methods. A total of 818 newly diagnosed diabetic individuals who were ≥40 years of age were recruited. The subjects were grouped by A1c values (<6.5%, 6.5–7%, 7-8%, 8-9%, and ≥9%). The homeostasis model assessment (HOMA) was used to evaluate pancreatic β cell function (HOMA-β) and insulin resistance (HOMA-IR). ANOVA, t-tests, and binary logistic regression analysis were used for data analysis. Results. Compared with subjects with A1c values <6.5%, individuals with an A1c of 6.5–7% exhibited an increased HOMA-β index. However, the HOMA-β index was significantly decreased at A1c values ≥7% and further decreased by 9.3% and by 23.7%, respectively, at A1c values of 7-8% and 8-9%. As A1c increased to ≥9%, a 62% reduction in β cell function was observed, independently of age, gender, body mass index (BMI), blood pressure (BP), blood lipids, and hepatic enzyme levels. Meanwhile, insulin resistance was significantly increased with an increase in A1c values. Conclusions. Elevated A1c values (≥7%) were associated with substantial reductions in β cell function.

BACKGROUND:Insulin resistance (IR) plays an important pathophysiological role in the development of diabetes, dyslipidemia, hypertension, and cardiovascular disease. Moreover, IR can occur even in non-obese people without diabetes. However, direct detection of IR is complicated. In order to find a simple surrogate marker of IR early in non-obese people, we investigate the association of commonly-used biochemical markers (liver enzymes and lipid profiles) with IR in urban middle-aged and older non-obese Chinese without diabetes. METHODS:This cross-sectional study included 1 987 subjects (1 473 women). Fasting blood samples were collected for measurement of glucose, insulin, liver enzymes, lipid profiles and creatinine. Subjects whose homeostasis model of assessment-IR (HOMA-IR) index values exceeded the 75th percentile (2.67 for women and 2.48 for men) of the population were considered to have IR. The area under the receiver operating characteristic curve (ROC) was used to compare the power of potential markers in identifying IR. RESULTS:Triglycerides (TG) and ratio of TG to high-density lipoprotein cholesterol (TG/HDL-C) discriminated IR better than other indexes for both sexes; areas under the receiver operating characteristic (ROC) curves (AUC) values were 0.770 (95% confidence interval 0.733-0.807) and 0.772 (0.736-0.809), respectively, for women and 0.754 (0.664-0.844) and 0.756 (0.672-0.840), respectively, for men. To identify IR, the optimal cut-offs for TG and TG/HDL-C ratio were 1.315 mmol/L (sensitivity 74.3%, specificity 71.0%) and 0.873 (sensitivity 70.1%, specificity 73.4%), respectively, for women, and 1.275 mmol/L (sensitivity 66.7%, specificity 74.4%) and 0.812 (sensitivity 75.8%, specificity 69.2%), respectively, for men. CONCLUSION:TG and TG/HDL-C ratio could be used to identify IR in urban middle-aged and older non-obese Chinese without diabetes.

Endogenously produced hydrogen sulfide (H2S) may have multiple functions in the brain including potent anti-inflammatory effects. Activated microglia can secrete various pro-inflammatory cytokines and neurotoxic mediators, which may contribute to hypoxic injuries in the developing brain. The aim of this study is to investigate the potential role of H2S in altering hypoxia-induced neurotoxicity via its anti-inflammatory actions as examined in vitro and in vivo models. Using the BV-2 microglial cell line, we found that sodium hydrosulfide (NaHS), a H2S donor, significantly inhibited hypoxia-induced microglial activation and suppressed subsequent pro-inflammatory factor release. In addition, treating murine primary cortical neurons with conditioned medium (CM) from hypoxia-stimulated microglia induced neuronal apoptosis, an effect that was reversed by CM treated with NaHS. Further, NaHS inhibited phosphorylation of the p65 subunit of NF-κB, phosphorylation of ERK and p38 but not JNK MAPK in these hypoxia-induced microglia. When administered in vivo to neonatal mice subjected to hypoxia, NaHS was found to attenuate neuron death, an effect that was associated with suppressed microglial activation, pro-inflammatory cytokines and NO levels. Taken together, H2S exerts neuroprotection against hypoxia-induced neurotoxicity through its anti-inflammatory effect in microglia. This effect appears to be attributable to inhibition of iNOS, NF-κB, ERK and p38 MAPK signaling pathways. Our results suggest a potential therapeutic application of H2S releasing drugs in hypoxic brain damage treatment.

OBJECTIVE:To investigate the relationship between lipid profiles [including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C)] and a mild decline in the estimated glomerular filtration rate (eGFR) in subjects with normal serum lipid levels.DESIGN AND METHODS:In this study, we included 2647 participants who were ≥ 40 years old and had normal serum lipid levels. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to estimate the GFR. A mildly reduced eGFR was defined as 60-90 mL/min/1.73 m(2). First, multiple linear regression analysis was used to estimate the association of lipid profiles with the eGFR. Then, the levels of each lipid component were divided into four groups, using the 25th, 50th and 75th percentiles as cut-off points. Finally, multiple logistic regression analysis was used to investigate the association of different lipid components with the risk of mildly reduced eGFR.RESULTS:In the group with a mildly reduced eGFR, TG and LDL-C levels were significantly increased, but HDL-C levels were significantly decreased. After adjusting for age, gender, body mass index (BMI), systolic blood pressure (SBP), glycated hemoglobin (HbA1c), smoking and drinking, only TC and TG were independently related to the eGFR. Additionally, only TG showed a linear relationship with an increased risk of a mildly reduced eGFR, with the highest quartile group (TG: 108-150 mg/dl [1.22-1.70 mmol/L]) having a significantly increased risk after adjusting for the above factors.CONCLUSIONS:Triglyceride levels are closely associated with a mildly reduced eGFR in subjects with normal serum lipid levels. Dyslipidemia with lower TG levels could be used as new diagnostic criteria for subjects with mildly reduced renal function.

The role of obesity as a determinant of kidney dysfunction has not reached an agreement and the underlying reason may be due to the heterogeneity of obese phenotypes. The aim of the study was to explore the associations of different obese phenotypes with the change of estimated glomerular filtration rate (eGFR) and the roles of obesity and metabolic abnormalities in this association.

High‐lipid diet composed of saturated fatty acids (SFAs) has significant detrimental effects on brain homeostasis, and deleterious effects of SFAs on various cells have been well documented. However, the effects of SFAs on neural stem Cells (NSCs) function have not been fully explored. The aim of this study was to determine whether palmitic acid (PA) affected the proliferation and differentiation of murine‐derived NSCs. The results showed that PA dose dependently suppressed viability of NSCs and was cytotoxic at high concentrations. The toxic levels of PA inhibited the proliferation of NSCs as shown by reduced bromodeoxyuridine labeling of NSCs, which is correlated with reactive oxygen species generation. Pretreatment of the cells with the antioxidant N‐acetyl‐L‐cysteine inhibitor significantly attenuated the effects of PA on the proliferation of NSCs. Furthermore, nontoxic levels of PA promoted astrocytogenesis in the differentiated NSCs, associated with Stat3 activation and altered expression of serial of basic helix–loop–helix transcription factor genes. Altogether, our data have demonstrated that PA has a significant impact on proliferation and differentiation of NSCs in vitro and may be useful for elucidating the role of SFAs in regulating NSCs fate in physiological and pathological settings. © 2014 Wiley Periodicals, Inc.

The association of blood glucose [including fasting blood glucose (FBG), 2-h postload blood glucose, and glycated hemoglobin (HbA1c)] with the risk of a mild decline in the estimated glomerular filtration rate (eGFR) in healthy subjects was unclear. The aim of the study was to investigate this association in middle-aged and elderly healthy Chinese.

Objective To investigate how the glucose variability between fasting and a 2-h postload glucose state (2-h postload plasma glucose [2hPG]-fasting plasma glucose [FPG]) is associated with chronic kidney disease (CKD) in middle-aged and elderly Chinese patients previously diagnosed with type 2 diabetes. Design and Methods This cross-sectional study included 1054 previously diagnosed type 2 diabetes patients who were 40 years of age and older. First, the subjects were divided into two groups based on a glycated hemoglobin (HbA1c) value of 7%. Each group was divided into two subgroups, with or without CKD. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to estimate the glomerular filtration rate (GFR). CKD was defined as eGFR<60 mL/min/1.73 m2. Multiple linear regression analysis was used to estimate the association between the 2hPG-FPG and eGFR. The 2hPG-FPG value was divided into four groups increasing in increments of 36 mg/dl (2.0 mmol/L): 0–72, 72–108, 108–144 and ≥144 mg/dl, based on the quartiles of patients with HbA1c levels ≥7%; then, binary logistic regression analysis was used to investigate the association between 2hPG-FPG and the risk of CKD. Results In the patients with HbA1c levels ≥7%, the 2hPG-FPG was significantly associated with decreased eGFR and an increased risk of CKD independent of age, gender, body mass index (BMI), systolic blood pressure (BP), diastolic BP, smoking, and drinking, as well as fasting insulin, cholesterol, triglyceride, and HbA1c levels. The patients with 2hPG-FPG values ≥144 mg/dl showed an increased odds ratio (OR) of 2.640 (P = 0.033). Additionally, HbA1c was associated with an increased risk of CKD in patients with HbA1c values ≥7%. Conclusions The short-term glucose variability expressed by 2hPG-FPG is closely associated with decreased eGFR and an increased risk of CKD in patients with poor glycemic control (HbA1c≥7%).

OBJECTIVE:To investigate whether fluctuations between the fasting and 2-h postload glucose ([2-hPBG]-fasting blood glucose [FBG]) states are associated with glomerular hyperfiltration (GHF) in middle-aged and elderly Chinese patients with newly diagnosed diabetes.DESIGN AND METHODS:In this study, we included 679 newly diagnosed diabetes patients who were ≥ 40 years old. All the subjects were divided into two groups; those with HbA1c<7% and ≥ 7%. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to estimate the glomerular filtration rate (GFR). GHF was defined as an eGFR ≥ the 90th percentile. First, a multiple linear regression analysis was used to estimate the association of 2-hPBG-FBG with eGFR. Then, a generalized additive model was used to explore the possible nonlinear relationship between 2-hPBG-FBG and eGFR. Next, the 2-hPBG-FBG values were divided into four groups as follows: 0-36, 36-72, 72-108 and ≥ 108 mg/dl. Finally, a multiple logistic regression analysis was used to investigate the association of 2-hPBG-FBG with the risk of GHF.RESULTS:For the group with HbA1c<7%, the eGFR and the percentage of GHF were significantly higher compared with the group with HbA1c ≥ 7%. After adjusting for age, gender, body mass index (BMI), systolic blood pressure (BP), diastolic BP, fasting insulin, cholesterol, triglycerides, smoking, drinking and glycated hemoglobin (HbA1c), 2-hPBG-FBG was significantly associated with increased eGFR and an increased risk of GHF (the GHF risk increased by 64.9% for every 36.0 mg/dl [2.0 mmol/L] 2-hPBG-FBG increase) only in those patients with HbA1c<7%. Additionally, 2-hPBG-FBG and eGFR showed a nonlinear association (P<0.001).CONCLUSIONS:Increased fluctuations between the fasting and 2-h postload glucose states are closely associated with increased eGFR and an increased risk of GHF in newly diagnosed diabetes patients with HbA1c<7%.

OBJECTIVE To study the optimal waist circumference (WC) cut-off values for identifying metabolic risk factors in middle-aged and elderly subjects in Shandong Province of China. METHODS A total of 2,873 men and 5,559 women were included in this cross-sectional study. Metabolic syndrome (MetS) was diagnosed according to the definition of Chinese Diabetes Society in 2004. The relation between WC and MetS was analyzed by multivariate logistic regression analysis. The optimal WC cut-off values were identified using the area under the ROC curve and the different diagnostic criteria for central obesity were compared. RESULTS The WC was the risk factor for MetS independent of BMI, blood glucose, blood lipid, and blood pressure. The optimal WC cut-off value was 83.8 cm and 91.1 cm for identifying MetS in women and men, respectively. Compared with 80 cm and 85 cm for women and men, 85 cm and 90 cm had a higher Youden index for identifying all metabolic risk factors and MetS in women and men. CONCLUSION The appropriate WC cut-off value is 85 cm and 90 cm for identifying central obesity and MetS in women and men in Shandong Province of China.

Objective To evaluate the efficacy and safety of Tianmaixiaoke tablet combined with metformin in the treatment of newly diagnosed type 2 diabetes mellitus.Methods A total of 150 newly diagnosed type 2 diabetics including 83 men and 67 women aged 33-71 years were randomly assigned to two groups.Patients in combination treatment group received Tianmaixiaoke (2 tablet,bid) combined with metformin(500 mg,tid),while patients in the control group received metformin(500 mg,tid) only,and then followed-up for 12 weeks.All patients were required to receive laboratory examination before and after treatment,including glycosyiated hemoglobin (HbA1c),fasting plasma glucose (FPG),2 h postprandial blood glucose (2 hPG),and other related indicators as efficacy endpoints.Safety endpoints included adverse events and hypoglycemia.The independent samples t-test was used to test differences between two groups.A paired t test was used to test differences before and after treatment in the same group.Differences in ratio variables were tested by the x2 test.Results A total of 134 patients were included in the final analysis,including 65 in combination therapy group and 69 in control group.(1)HbA1c:After 12-week treatment,the reduction of HbA1c from baseline in combination therapy group was far more than in control group ((1.0±0.8) ％ vs (0.7±0.6)％; t =-3.205,P＜0.05).The HbA 1 c compliance rate in combination therapy group was higher than control group(44.9％ (31/69),26.2％ (17/65),respectively,x2=5.131,P＜ 0.05).(2)Blood glucose:The level of FPG (2.7± 1.4) and 2 hPG (5.2±2.9) in the combination therapy group was significantly lower than those in the control group (2.0± 1.8,3.8±2.4,respectively,t=-2.675,-2.930,both P＜0.01).(3)HOMA-IR:Compared with the control group,the HOMA-IR in the combination therapy group reduced more significantly (2.7 ±0.8 vs 3.2± 0.8,respectively,t=4.62,P＜ 0.05).There was no statistically significant difference between the both groups in HOMA-β index (t=-2.337,P＞ 0.05).(4) Adverse reaction:There was not statistically significant difference between the two groups in the incidence of adverse reactions.Conclusion Tianmaixiaoke tablet combined with metformin may increase the HbA1c compliance rate,improve insulin resistance,and has a good safety in the treatment of newly diagnosed type 2 diabetic mellitus.