Prevalence and risk factors of diabetic peripheral neuropathy: A population-based cross-sectional study in China.

AIMS: To assess the prevalence of diabetic peripheral neuropathy (DPN) and its risk factors in the type 2 diabetes mellitus (T2DM) population. METHODS: This cross-sectional study enroled patients with T2DM between July and December 2017 from 24 provinces in China. Diabetic peripheral neuropathy and its severity were assessed by the Toronto clinical scoring system, neuropathy symptoms score (NSS) and neuropathy disability score. The prevalence of DPN and its risk factors were analysed. RESULTS: A total of 14,908 patients with T2DM were enroled. The prevalence of DPN was 67.6%. Among 10,084 patients with DPN, 4808 (47.7%), 3325 (33.0%), and 1951 (19.3%) had mild, moderate, and severe DPN, respectively. The prevalence of DPN in females was higher than in males (69.0% vs. 66.6%, P = 0.002). The prevalence of DPN increased with age and course of diabetes and decreased with body mass index (BMI) and education level (all P for trend <0.05). The comorbidities and complications in patients with DPN were higher than in those without DPN, including hypertension, myocardial infarction, diabetic retinopathy, and diabetic nephropathy (all P < 0.001). Age, hypertension, duration of diabetes, diabetic retinopathy, diabetic nephropathy, glycated haemoglobin, high-density lipoprotein cholesterol, and lower estimated glomerular filtration rate were positively associated with DPN, while BMI, education level, fasting C-peptide, and uric acid were negatively associated with DPN. CONCLUSIONS: Among patients with T2DM in China, the prevalence of DPN is high, especially in the elderly, low-income, and undereducated patients.

Schistosoma japonicum infection associated with membranous nephropathy: a case report.

BACKGROUND: Schistosomiasis is one of the most contagious parasitic diseases affecting humans; however, glomerular injury is a rare complication mainly described with Schistosoma mansoni infection. We report a case of membranous nephropathy associated with Schistosoma japonicum infection in a Chinese man. CASE PRESENTATION: A 51-year-old Chinese male with a long history of S. japonicum infection presented to the hospital with a slowly progressing severe lower limb edema and foaming urine for over 5 months. Serum S. japonicumantigen test was positive and immunohistochemistry showed that the glomeruli were positive for the antigens. The renal pathologic diagnosis was stage III membranous nephropathy. The patient was treated with glucocorticoid, praziquantel, and an angiotensin-converting enzyme inhibitor. The edema in both lower limbs disappeared within 2 weeks, but his renal function declined progressively and proteinuria persisted after 5 months of therapy. CONCLUSIONS: Different classes of schistosomal glomerulopathy have completely different clinical manifestation and prognosis. Therefore, efforts should focus on alleviating symptoms, prevention, and early detection. S. japonicumassociated with membranous nephropathy may show a good curative effect and prognosis. However, it is necessary to monitor the renal function in such patients.

Efficacy and safety of PEGylated exenatide injection (PB-119) in treatment-naive type 2 diabetes mellitus patients: a Phase II randomised, double-blind, parallel, placebo-controlled study.

AIMS/HYPOTHESIS: Glucagon-like peptide 1 receptor agonists (GLP-1 RA) such as exenatide are used as monotherapy and add-on therapy for maintaining glycaemic control in patients with type 2 diabetes mellitus. The current study investigated the safety and efficacy of once-weekly PB-119, a PEGylated exenatide injection, in treatment-naive patients with type 2 diabetes. METHODS: In this Phase II, randomised, placebo-controlled, double-blind study, we randomly assigned treatment-naive Chinese patients with type 2 diabetes in a 1:1:1:1 ratio to receive subcutaneous placebo or one of three subcutaneous doses of PB-119 (75, 150, and 200 µg) for 12 weeks. The primary endpoint was the change in HbA1c from baseline to week 12, and other endpoints were fasting plasma glucose, 2 h postprandial glucose (PPG), and proportion of patients with HbA1c < 53 mmol/mol (<7.0%) and ≤48 mmol/mol (≤6.5%) at 2, 4, 8 and 12 weeks of treatment. Safety was assessed in all patients who received at least one dose of study drug. RESULTS: We randomly assigned 251 patients to one of the four treatment groups (n = 62 in placebo and 63 each in PB-119 75 µg, 150 µg and 200 µg groups). At the end of 12 weeks, mean differences in HbA1c in the treatment groups were -7.76 mmol/mol (95% CI -9.23, -4.63, p < 0.001) (-0.72%, 95% CI -1.01, -0.43), -12.89 mmol/mol (95% CI -16.05, -9.72, p < 0.001) (-1.18%, 95% CI -1.47, -0.89) and -11.14 mmol/mol (95% CI -14.19, -7.97, p <0 .001) (-1.02%, 95% CI -1.30, -0.73) in the 75 µg, 150 µg and 200 µg PB-119 groups, respectively, compared with that in the placebo group after adjusting for baseline HbA1c. Similar results were also observed for other efficacy endpoints across different time points. There was no incidence of treatment-emergent serious adverse event, severe hypoglycaemia or death. CONCLUSIONS/INTERPRETATION: All tested PB-119 doses had superior efficacy compared with placebo and were safe and well tolerated over 12 weeks in treatment-naive Chinese patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03520972 FUNDING: The study was funded by National Major Scientific and Technological Special Project for Significant New Drugs Development and PegBio.

Alpha-mangostin improves endothelial dysfunction in db/db mice through inhibition of aSMase/ceramide pathway.

Diabetic vascular complications are the leading causes of death and disability in patients with diabetes. Alpha-mangostin has been reported to have anti-diabetic capacity in recent years. Here, we investigated the protective function of alpha-mangostin on endothelium in vitro and in vivo experiments. We also observed that alpha-mangostin improved impaired endothelium-dependent vasodilation (EDV) of diabetic animals while it limited the aSMase/ceramide pathway and up-regulated eNOS/NO pathway in aortas from diabetic mice. Meanwhile, alpha-mangostin inhibited elevated aSMase/ceramide pathway and reversed impaired EDV induced by high glucose in isolated mouse aortas. In addition, alpha-mangostin increased phosphorylation of eNOS and NO production in high glucose-treated aortas. Alpha-mangostin normalized high glucose-induced activation of aSMase/ceramide pathway and improved eNOS/NO pathway in endothelial cells with high glucose. In conclusion, alpha-mangostin regulates eNOS/NO pathway and improves EDV in aortas of diabetic mice through inhibiting aSMase activity and endogenous ceramide accumulation.

Alpha-mangostin attenuates diabetic nephropathy in association with suppression of acid sphingomyelianse and endoplasmic reticulum stress.

AIMS: Diabetic nephropathy is a common complication of diabetes, but there are currently few treatment options. The aim of this study was to gain insight into the effect of alpha-mangostin on diabetic nephropathy and possible related mechanisms. METHODS: Goto-Kakizaki rats were used as a diabetic model and received alpha-mangostin or desipramine treatment with normal saline as a control. Ten age-matched Sprague Dawley rats were used as normal controls and treated with normal saline. At week 12, blood glucose, albuminuria, apoptosis and renal pathologic changes were assessed. Protein levels for acid sphingomyelinase, glucose-regulated protein 78, phosphorylated PKR-like ER-resident kinase, activated transcription factor 4, CCAAT/enhancer-binding protein, homologous protein), and cleaved-caspase12 were measured. RESULTS: The level of acid sphingomyelinase was significantly increased, and ER stress was activated in diabetic rat kidneys when compared to the control animals. When acid sphingomyelinase was inhibited by alpha-mangostin, the expression of ER stress-related proteins was down-regulated in association with decreased levels of diabetic kidney injury. CONCLUSIONS: Alpha-mangostin, an acid sphingomyelinase inhibitor plays a protective role in diabetic neuropathy by relieving ER stress induced-renal cell apoptosis.

[Subclinical hypothyroidism and endocrine metabolic characteristics in women with polycystic ovary syndrome].

OBJECTIVE: To explore associations of subclinical hypothyroidism (SCH) with endocrine metabolic characteristics in women with polycystic ovary syndrome (PCOS).
 Methods: A total of 321 women who were newly diagnosed as PCOS were recruited from two endocrine outpatient clinics. The diagnosis of PCOS was established according to the 2003 Rotterdam consensus criteria. Thyroid function was examined by chemiluminescent immunoassay. Patients who had normal free thyroxine (FT4) were divided into different SCH subgroups according to two thyroid stimulating hormone (TSH) cutoff points (4.2 and 2.5 mU/L). Endocrine metabolic characteristics in different subgroups were compared and analyzed.
 Results: In PCOS women with normal FT4, the patients with TSH≥4.2 mU/L had higher prolactin (PRL), luteinizing hormone-to-follicle stimulating hormone ratio, and visceral adipose index (all P<0.05). There were trends toward an increase in triglyceride (P=0.085) and a decrease in high-density lipoprotein cholesterol (HDL-C) (P=0.060) in the patients with TSH≥4.2 mU/L compared with that in the patients with TSH<4.2 mU/L. Also in PCOS women with normal FT4, the patients with TSH≥2.5 mU/L had higher body mass index, PRL, triglyceride, visceral adipose index and lower HDL-C in comparison of that in the patients with TSH<2.5 mU/L (all P<0.05).
 Conclusion: SCH is associated with more severe endocrine abnormality, dyslipidemia, and visceral obesity in PCOS women. PCOS women with normal FT4 and endocrine metabolic characteristics are more prone to be different between the SCH group and the euthyroid group when setting 2.5 mU/L as a TSH cutoff for SCH, indicating that 2.5 mU/L is a good TSH cutoff for SCH in PCOS women.

[The predictive factors of good glycaemic control in Chinese patients receiving biphasic insulin as part 30: a subgroup analyses from the A1 chieve study].

OBJECTIVE: To identify the baseline factors associated with achievement of glycosylated haemoglobin A1c (HbA1c) < 7.0% in Chinese patients receiving biphasic insulin as part 30 (BIAsp 30), who were previously inadequately controlled with oral anti-diabetic drugs (OADs). METHODS: A1 chieve was a multinational, prospective, open-label, 24-week non-interventional study in patients with type 2 diabetes initiating insulin analogues in 28 countries. The patients were enrolled to take BIAsp 30 according to physician's clinical judgments, who was also responsible for the treatment regimen and dosage adjustment. Primary safety endpoints were the incidence of serious drug adverse reactions (SADRs) including serious hypoglycaemia. Major efficacy endpoints were change in HbA1c, fasting plasma glucose (FPG), 2h post-prandial plasma glucose (2 hPG) from baseline. Relationships between baseline predictive baseline factors and achievement of HbA1c < 7.0% after treatment were examined using multivariate analysis. RESULTS: In China, 4 100 patients initiated BIAsp 30 [54.2% males, age (56.2 ± 13.6) years]. No SADRs were reported. Mean HbA1c was reduced from (9.3 ± 2.1)% to (7.0 ± 1.0)%; FPG was reduced from (10.2 ± 3.3) mmol/L to (6.8 ± 1.3) mmol/L. Changes in 2 hPG after breakfast, lunch and dinner were (-5.6 ± 4.7), (-4.9 ± 4.3) and (-4.2 ± 4.1) mmol/L, respectively (all P < 0.001). The proportion of patients achieving HbA1c < 7.0% increased from 9.7% at baseline to 54.2% at week 24. Multivariate analysis revealed a negative relationship between baseline HbA1c, FPG, 2 hPG and HbA1c < 7.0% after treatment. CONCLUSIONS: In the Chinese subgroup of the A1 chieve study, lower baseline HbA1c, FPG, 2 hPG were predictive factors for achieving HbA1c < 7.0% after 24-week treatment of BIAsp 30, indicating that the earlier initiation of BIAsp 30 in patients poorly controlled with OADs, the more helpful for them to achieve treatment target.

[Efficacy and safety of alogliptin in treatment of type 2 diabetes mellitus: a multicenter, randomized, double-blind, placebo-controlled phase III clinical trial in mainland China].

OBJECTIVE: To evaluate the efficacy and safety of alogliptin in Chinese patients with type 2 diabetes (T2DM). METHODS: This was a multicenter, randomized, double-blind, placebo-controlled phase III trial. A total of 491 subjects with T2DM were randomized in a 1:1 ratio to receive alogliptin (25 mg once daily) or placebo for 16 weeks. Among them, 181 were in the monotherapy group (group A), 186 were in the add-on to metformin group (group B), and 124 were in the add-on to pioglitazone group (group C). RESULTS: After 16 weeks of therapy, glycosylated hemoglobin A1c (HbA1c) levels decreased in both alogliptin and placebo groups. The mean changes in HbA1c for alogliptin and placebo were 1.00% and 0.43% (P<0.001), 0.91% and 0.23% (P<0.001), and 0.76% and 0.25% (P<0.001) in group A, B and C, respectively. Compared with placebo, alogliptin treatment led to a greater decrease in fasting plasma glucose (FPG) and a higher percentage of subjects who achieved HbA1c targets of ≤ 6.5% and ≤ 7.0%. The percentage of subjects who experienced all adverse events including hypoglycemia with alogliptin were comparable to those with placebo. CONCLUSIONS: Alogliptin 25 mg once daily reduced HbA1c and FPG, and increased a greater proportion of subjects achieving HbA1c goals of ≤6.5% and ≤7.0% compared with placebo when used as a monotherapy, add-on to metformin, or add-on to pioglitazone. The hypoglycemia rates and safety profiles with alogliptin were similar to those with placebo.

Cell membrane damage is involved in the impaired survival of bone marrow stem cells by oxidized low-density lipoprotein.

Cell therapy with bone marrow stem cells (BMSCs) remains a viable option for tissue repair and regeneration. A major challenge for cell therapy is the limited cell survival after implantation. This study was to investigate the effect of oxidized low-density lipoprotein (ox-LDL, naturally present in human blood) on BMSC injury and the effect of MG53, a tissue repair protein, for the improvement of stem cell survival. Rat bone marrow multipotent adult progenitor cells (MAPCs) were treated with ox-LDL, which caused significant cell death as reflected by the increased LDH release to the media. Exposure of MAPCs to ox-LDL led to entry of fluorescent dye FM1-43 measured under confocal microscope, suggesting damage to the plasma membrane. Ox-LDL also generated reactive oxygen species (ROS) as measured with electron paramagnetic resonance spectroscopy. While antioxidant N-acetylcysteine completely blocked ROS production from ox-LDL, it failed to prevent ox-LDL-induced cell death. When MAPCs were treated with the recombinant human MG53 protein (rhMG53) ox-LDL induced LDH release and FM1-43 dye entry were significantly reduced. In the presence of rhMG53, the MAPCs showed enhanced cell survival and proliferation. Our data suggest that membrane damage induced by ox-LDL contributed to the impaired survival of MAPCs. rhMG53 treatment protected MAPCs against membrane damage and enhanced their survival which might represent a novel means for improving efficacy for stem cell-based therapy for treatment of diseases, especially in setting of hyperlipidemia.

TCR-induced, PKC-θ-mediated NF-κB activation is regulated by a caspase-8-caspase-9-caspase-3 cascade.

It has been documented that caspase-8, a central player in apoptosis, is also crucial for TCR-mediated NF-κB activation. However, whether other caspases are also involved this process is unknown. In this report, we showed that in addition to caspase-8, caspase-9 is required for TCR-mediated NF-κB activation. Caspase-9 induces activation of PKC-θ, phosphorylation of Bcl10 and NF-κB activation in a caspase-3-dependent manner, but it appears that Bcl10 phosphorylation is uncoupled from NF-κB activation. Furthermore, caspase-8 lies upstream of caspase-9 during T cell activation. Therefore, TCR ligation elicits a caspase cascade involving caspase-8, caspase-9 and caspase-3 which initiates PKC-θ-dependent pathway leading to NF-κB activation and PKC-θ-independent Bcl10 phosphorylation which limits NF-kB activity.

Ceramide mediates inhibition of the Akt/eNOS pathway by high levels of glucose in human vascular endothelial cells.

OBJECTIVE: To investigate how ceramide mediates the effects of high-glucose-induced inhibition of the Akt/endothelial nitric oxide synthase (eNOS) signalling pathway in human vascular endothelial cells (HUVECs). MATERIALS AND METHODS: NO levels were determined by ELISA. Endogenous ceramide levels were determined using a liquid chromatography-mass spectrometry assay. Akt and eNOS protein expressions were determined by Western blotting. RESULTS: High-glucose levels induce ceramide accumulation in a dose- and time-dependent manner (p<0.05). We also show that exposure of HUVECs to high-glucose conditions inhibits the insulin-mediated activation of Akt/eNOS signalling and the subsequent NO generation in a dose-dependent manner (p<0.05). Preventing de novo ceramide synthesis attenuated the antagonistic effects of high-glucose levels on the Akt/eNOS signalling pathway (p<0.05); conversely, inducing ceramide build-up augmented the inhibitory effects of high-glucose levels on the Akt/eNOS signalling pathway (p<0.05). CONCLUSION: Ceramide is both necessary and sufficient for mediating the inhibition of the Akt/eNOS signalling pathway by high-glucose levels in endothelial cells.

[The design and baseline characteristics of a phase III study to evaluate the efficacy and safety of alogliptin versus placebo in type 2 diabetes mellitus in Mainland China].

OBJECTIVE: To assess the design and the Mainland China subgroup baseline characteristics of the study to evaluate the efficacy and safety of alogliptin versus placebo in subjects with type 2 diabetes (T2DM) as monotherapy, add-on to metformin or add-on to pioglitazone. METHODS: This was a multi-center, randomized, double-blind, placebo-controlled, 16-week study comparing alogliptin (ALO, 25 mg, 1/d) versus placebo (PLA) as monotherapy (A), add-on to metformin (B) or add-on to pioglitazone ± metformin (C). The T2DM subjects with glycosylated hemoglobin A1c(HbA1c) between 7% and 10% and aged between 18 years and 75 years were enrolled and randomized to the alogliptin group and the placebo group in 1: 1 ratio with 16 weeks treatment. All patients were followed up every 4 weeks. The safety endpoints consisted of the incidence of hypoglycemia and other adverse events. RESULTS: A total of 491 patients were enrolled in the Mainland China subgroup of the study (181 in group A, 186 in group B and 124 in group C). In each treatment group, the baseline characteristics including age, gender, body mass index, diabetes duration, HbA1c, fasting plasma glucose, body weight, daily dosage of metformin and daily dosage of pioglitazone were all well balanced. CONCLUSION: The demographic data, medical history, glycemic profile and treatment regimen at baseline in Mainland China subgroup are well balanced. The result of this study will provide the clinical evidence for the use of alogliptin in Chinese T2DM patients.

Knowledge of blood sugar control standard brings the higher attainment rate of HbA1c.

OBJECTIVE: To analyze the important controllable factors which affect the glycemic control of diabetes. METHODS: A cross-sectional study was carried out to examine the role of relevant characteristics in glycemic control by a sampling investigation of 430 diabetic patients in Hunan, China. A questionnaire was designed for personal interviews to collect data. Univariate regression analysis and multiple linear regression analysis were used to evaluate the effects of various factors on glycated hemoglobin A1c (HbA1c) control. RESULTS: The level of HbA1c in 430 patients was (8.7±2.6)%, and the value in 34% patients among them was ≤ 7.0%. Base on univariate regression analysis some factors were associated with good HbA1c control, including age, diabetic education, self monitoring of blood glucose, knowledge of blood sugar control standard, living environment, and self-owned glucometer. However, the upgraded treatment was associated with poor control. Based on multiple linear regression analysis, the first four factors mentioned above were protective factors for HbA1c while upgraded treatment was risk factor for HbA1c. CONCLUSION: Knowledge of blood sugar control standard, diabetic education and self monitoring of blood glucose are important controllable factors for better glycemic control of diabetes.

[Effect of blood glucose fluctuation and the sustained high blood glucose on renal pathological change and collagen IV expression in diabetic rats].

OBJECTIVE: To observe the effect of blood glucose fluctuation and the sustained high blood glucose on renal pathological change and collagen IV (Col IV) expression in diabetic rats. METHODS: The 60 male Sprague-Dawley (SD) rats were randomly assigned into a normal control group (NC) and a model group (DM). The rats in the normal control group were fed with normal diet, while the rats in the model group were fed with high-sucrose-high-fat diet for 6 weeks. After that,streptozocin (STZ, 30 mg/kg) was injected to induce diabetic model. The model group was then randomly divided into 2 subgroups: a sustained high blood glucose group and a fluctuation blood glucose group (animals in the latter group were subcutaneously injected with insulin twice daily). Rats were sacrificed after 3 months and kidney tissues were dissected for HE and PAS staining, Col IV immunohistochemistry and Western blot. RESULTS: Compared with the normal control group, the renal glomeruli and capillary basal membrane in the diabetic rats was getting larger and thicker, respectively; the capsular space and ground substance was extended and increased, respectively; the volume of renal tubule, kidney hypertrophy index, glomeruler sclerosis index and Col IV content were all increased in the diabetic rats (P<0.01). Compared with the sustained high blood glucose group, the above mentioned pathological changes were more serious in the blood glucose fluctuation group. CONCLUSION: The capillary basal membrane of kidney in diabetic rats is thicker and the ground substance is increased. The degree of glomeruler sclerosis is more serious in the blood glucose fluctuation group compared with the sustained high blood glucose group, which is confirmed by the increased level of Col IV.

The effects of daily dose and treatment duration of metformin on the prevalence of vitamin B12 deficiency and peripheral neuropathy in Chinese patients with type 2 diabetes mellitus: A multicenter cross-sectional study.

AIMS: To evaluate the prevalence of vitamin B12 deficiency in Chinese patients with type 2 diabetes mellitus receiving metformin treatment and to investigate the effects of metformin daily dose and treatment duration on the prevalence of vitamin B12 deficiency and peripheral neuropathy (PN). MATERIALS AND METHODS: In this multicenter cross-sectional study, 1027 Chinese patients who had been taking ≥1000 mg/day metformin for ≥1 year were enrolled using proportionate stratified random sampling based on daily dose and treatment duration. Primary measures included the prevalence of vitamin B12 deficiency (<148 pmol/L), borderline B12 deficiency (148 pmol/L-211 pmol/L), and PN. RESULTS: The prevalence of vitamin B12 deficiency, borderline deficiency, and PN were 2.15%, 13.66%, and 11.59%, respectively. Patients receiving ≥1500 mg/day metformin had significantly higher prevalence of borderline vitamin B12 deficiency (16.76% vs. 9.91%, p = .0015) and serum B12 ≤221 pmol/L (19.25% vs. 11.64%, p < .001) than patients receiving <1500 mg/day metformin. No difference was found in prevalence of borderline vitamin B12 deficiency (12.58% vs. 15.49%, p = .1902) and serum B12 ≤221 pmol/L (14.91% vs. 17.32%, p = .3055) between patients receiving metformin for ≥3 and <3 years. Patients with vitamin B12 deficiency had numerically higher PN prevalence (18.18% vs. 11.27%, p = .3192) than patients without it. Multiple logistic analyses revealed that HbA1c and metformin daily dose were associated with the prevalence of borderline B12 deficiency and B12 ≤221 pmol/L. CONCLUSIONS: High daily dosage (≥1500 mg/day) played an important role in metformin-associated vitamin B12 deficiency while not contributing to the risk of PN.

Prevalence of painful diabetic peripheral neuropathy in type 2 diabetes mellitus and diabetic peripheral neuropathy: A nationwide cross-sectional study in mainland China.

AIM: The study aimed to assess the prevalence and risk factors of painful diabetic peripheral neuropathy (PDPN) in patients with type 2 diabetes mellitus (T2DM) and diabetic peripheral neuropathy (DPN) in mainland China. METHODS: This nationwide cross-sectional study enrolled T2DM patients with DPN from 25 provinces in China between July 2017 and December 2017. The prevalence, characteristics, and risk factors of PDPN were analyzed. RESULTS: Among 25,710 patients with T2DM and DPN, 14,699 (57.2%) had PDPN. The median age was 63 years old. Age over 40 years old, education level, hypertension, myocardial infarction, duration of diabetes of over five years, diabetic retinopathy and nephropathy, moderate total cholesterol, moderate and higher low-density lipoprotein (LDL) increased uric acid (UA) and decreased estimated glomerular filtration rate (eGFR) were independently associated with PDPN (all P < 0.05). Compared with low levels of C-peptide, moderate levels were independently associated with a higher risk of PDPN, while high levels were associated with a lower risk (all P < 0.001). CONCLUSIONS: In mainland China, more than half of the patients with DPN have neuropathic pain. Patients with older age, lower education level, longer duration of diabetes, lower LDL, increased UA, decreased eGFR, and comorbidities had an increased risk of PDPN.

High glucose facilitates cell cycle arrest of rat bone marrow multipotent adult progenitor cells through transforming growth factor-ß1 and extracellular signal-regulated kinase 1/2 signalling without changing Oct4 expression.

1. The transcription factor Oct4 is critical to the pluripotency, self-renewal and differentiation of stem cells. The aim of the present study was to investigate the effects of high glucose (HG) on the cell cycle progression of bone marrow multipotent adult progenitor cells (MAPC) and Oct4 expression, as well as the underlying mechanisms. 2. Rat MAPC were cultured in normal (5.5 mmol/L D-glucose) and HG (25.5 mmol/L D-glucose) media for up to 14 days. L-Glucose served as a high osmolarity control. Culture in HG media substantially increased the number of cells in the G(0)/G(1) phase and decreased the number in the S phase without changing the cell population in the G(2) phase. Expression of the cell cycle regulatory protein p21CIP/WAF-1 (p21), but not that of p27KIP-1 (p27), was significantly upregulated in cells cultured in HG media. Significant increases were seen in transforming growth factor (TGF)-ß1 levels in cells and MAPC-conditioned medium in the presence of HG, and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation was enhanced in cells cultured in the presence of HG medium without any changes in Akt phosphorylation. 3. Neutralizing TGF-ß1 antibody effectively prevented HG-induced increases in ERK1/2 phosphorylation, p21 expression and suppression of cell cycle progression of MAPC. Inhibiting ERK1/2 phosphorylation with PD98059 completely blocked HG-induced p21 expression and markedly reversed HG-induced inhibition of cell cycle progression in MAPC. The HG-induced suppression of cell cycle progression was not accompanied by inhibition of cell proliferation or Oct4 expression in these cells. 4. The data indicate that HG facilitates cell cycle arrest of rat MAPC through TGF-ß1-induced activation of ERK1/2 signalling and p21 expression, and that Oct4 expression in MAPC is independent of the cell cycle and/or TGF-ß1 or ERK1/2 signalling in HG medium.

KCNQ1 gene polymorphisms are associated with the therapeutic efficacy of repaglinide in Chinese type 2 diabetic patients.

The present study evaluated the effects of KCNQ1 rs2237892 and rs2237895 polymorphisms on repaglinide efficacy in Chinese patients with type 2 diabetes mellitus (T2DM). In all, 367 T2DM patients and 214 controls were genotyped. Forty of the T2DM patients were randomly selected to undergo 8 weeks repaglinide treatment. The frequency of the rs2237892 allele was lower in the T2DM patients than in the control group (P < 0.05). The frequency of the rs2237895 C allele was higher in T2DM patients than in healthy control subjects (P < 0.05). Diabetic patients with the rs2237892 risk C allele had lower fasting insulin levels (P < 0.01) and homeostasis model assessment of insulin resistance (HOMA-IR; P < 0.01) values than carriers of the T allele. Diabetic patients with the rs2237895 risk C allele had higher fasting plasma glucose (P < 0.01), postprandial plasma glucose (PPG) levels (P < 0.01) and HOMA-IR values (P < 0.01) than those with the A allele. Following repaglinide treatment, those T2DM patients with the rs2237892 T allele and rs2237895 C allele were more likely to have a positive response to repaglinide in terms of PPG levels (P < 0.05) than T2DM patients with the rs2237892 CC and rs2237895 AA genotypes. In conclusion, KCNQ1 rs2237892 and rs2237895 polymorphisms were found to be associated with the therapeutic efficacy of repaglinide in Chinese T2DM patients.

Gut microbiota is associated with differential metabolic characteristics: A study on a defined cohort of Africans and Chinese.

Objective: This study intended to determine the associations between gut microbiota and glucose response in healthy individuals and analyze the connection between the gut microbiome and glucose-metabolism-related parameters. Methods: Fecal bacterial composition and anthropometric, body composition, body fat distribution, and biochemical measures were analyzed. A 75-g oral glucose tolerance test (OGTT) was given to each participant to investigate changes in glucagon-like peptide 1 (GLP-1), insulin, and glucose. The whole body fat and the regions of interest of local body composition were analyzed using dual-energy X-ray absorptiometry (DEXA), and gut microbiota composition was assessed through variable regions (V3-V4) of the bacterial 16s ribosomal RNA gene using high-throughput sequencing techniques. Spearman correlation analysis was used to evaluate the association between gut microbiota and clinical and metabolic changes. Results: The number of operational taxonomic units (OTUs) demonstrated a reduction in the diversity and composition of gut microbiota associated with enhanced adiposity, dyslipidemia, insulin resistance, and hyperglycemia. The alpha diversity revealed that microbiota diversity, richness, and composition were higher in the African group and lower in the Chinese group. Principal coordinates analysis (PCoA) plots of beta diversity showed significant variability in gut microbial community structure between the two groups (p = 0.0009). LEfSe analysis showed that phylum Bacteroidetes was significantly more abundant in the Chinese group, and this group also harbored members of the order Bacteroidales, family Bacteroidaceae, and genus Bacteroides. In contrast, the phylum Verrucomicrobia was significantly more prevalent in the African group (all p < 0.05). Concerning species, metastats analysis revealed 8 species in the Chinese group and 18 species in the African group that were significantly abundant. Spearman's correlation analysis demonstrated that gut microbiota correlated with the factors that related to glucose metabolism. Conclusion: Our data suggest that there is an interaction between gut microbiota, host physiology, and glucometabolic pathways, and this could contribute to adiposity and pathophysiology of hyperlipidemia, insulin resistance, and hyperglycemia. These findings provide an important basis for determining the relation between the gut microbiota and the pathogenesis of various metabolic disorders.