The dawn phenomenon in type 2 diabetes: its association with glucose excursions and changes after oral glucose-lowering drugs.

BACKGROUND: We investigated the association between glucose excursions and the dawn phenomenon, and the effects of oral-glucose lowering drugs on the dawn phenomenon in patients with type 2 diabetes (T2D). METHODS: We conducted a post hoc analysis using data from a previous randomized trial. Patients with T2D on metformin monotherapy were randomized to receive add-on acarbose or glibenclamide for 16 weeks. Ambulatory continuous glucose monitoring (CGM) was conducted before randomization and at the end of the study. Using the CGM data, we assessed glucose excursions as indicated by mean amplitude of glycemic excursions (MAGE). The magnitude of the dawn phenomenon was calculated as the difference between the nocturnal nadir (0:00 to 6:00 a.m.) and prebreakfast glucose level. RESULTS: A total of 50 patients with T2D [mean age 53.5 ± 8.2 years, mean glycated hemoglobin (HbA1c) 8.4 ± 1.2%] were analyzed. There was an independent association between MAGE and the dawn phenomenon [ß coefficient 0.199, 95% confidence interval (CI) 0.074-0.325, p = 0.003]. HbA1c improved significantly after treatment with acarbose or glibenclamide. However, only treatment with acarbose significantly improved glucose excursions. The dawn phenomenon decreased significantly only in patients treated with acarbose (from 35.9 ± 15.7-28.3 ± 16.5 mg/dl, p = 0.037), but not in those treated with glibenclamide (from 35.9 ± 20.6-34.6 ± 17.0 mg/dl, p = 0.776). CONCLUSION: Glucose excursions were independently associated with the dawn phenomenon in patients with T2D on metformin monotherapy. Both glucose excursions and the dawn phenomenon improved after treatment with acarbose, but not after treatment with glibenclamide.

A novel chorismate mutase from Erysiphe quercicola performs dual functions of synthesizing amino acids and inhibiting plant salicylic acid synthesis.

Pathogens secrete effectors to establish a successful interaction with their host. It is well understood that plant pathogens recruit classically secreted chorismate mutase (Cmu) as an effector to disrupt plant salicylic acid (SA) synthesis. However, the identity and function of the Cmu effector from powdery mildew fungi remain unknown. Here, we identified a novel secreted Cmu effector, EqCmu, from rubber (Hevea brasiliensis Muell) powdery mildew fungus (Erysiphe quercicola). Unlike the classically secreted Cmu, EqCmu lack signal peptide, and exhibited characteristics of non-classically secreted proteins. EqCmu could fully complement a Saccharomyces cerevisiae ScAro7 mutant that was deficient in the synthesis of phenylalanine and tyrosine. In addition, transient expression of EqCmu could promote infection by Phytophthora capsici and reduce the levels of SA and the mRNA of PR1 gene in Nicotiana benthamiana in response to P. capsici infection, while confocal observations showed that EqCmu was localized within the cytoplasm and nucleus of transfected N. benthamiana leaf cells. These non-homologous systems assays provide evidences that EqCmu may serve as a "moonlighting" protein, which is not only a key enzyme in the synthesis of phenylalanine and tyrosine within fungal cells, but also has the function of regulating plant SA synthesis within plant cells. This is the first study to identify and functionally validate a candidate effector from E. quercicola. Overall, the non-classical secretion pathway is a novel mechanism for powdery mildew fungal effectors secretion and might play an important role in host-pathogen interactions.

[Effects of Cotton Stalk Biochar on the Structure and Function of Fungi Community in Alkaline Rhizosphere Soil of Rice Under Cadmium Pollution].

To study the effects of cotton stalk biochar on the regulation of fungal diversity, the structure and function of alkaline rice rhizosphere soil under cadmium pollution was investigated. An outdoor pot experiment was conducted by adding cotton stalk biochar (0%, 1%, and 5%) to an alkaline paddy soil with a cadmium concentration of 0.1 and 8 mg·kg-1. Taking rice rhizosphere soil as the research object, Illumina HiSeq sequencing was used to analyze the effects of cotton stalk biochar and cadmium pollution on the diversity, structure, abundance, and function of fungi in an alkaline rhizosphere soil, and to explore the correlation between soil environmental factors and the fungal community under the control of cotton stalk biochar. The results showed that:① the application of cotton stalk biochar significantly increased the soil pH, available nutrients, and organic matter, and reduced the content of reducible cadmium in the soil (P<0.05). ② The distribution of rice rhizosphere soil fungi was mainly Ascomycota, Aphelidiomycota, and Chytridiomycota, which accounted for 57% of all mycophytes. The genus was mainly Mortierella, Alternaria, and Fusarium. There was a significant difference in the α-diversity of the fungal community among the treatments (P<0.05). In the absence of cotton stalk biochar (C0), the increase in the cadmium concentration reduced the relative abundance and fungal diversity index (Shannon index) of Chytridiomycota, Mortierella, and Alternaria in the soil. Under different concentrations of cadmium (Cd0, Cd1, and Cd8), increasing cotton stalk biochar reduced the fungal community richness index (Chao1 index) and Shannon index. Cadmium pollution resulted in an increase in the relative abundance of Chytridiomycota in the soil, but decreased the abundance of Alternaria. The application of cotton stalk biochar could significantly increase the relative abundance of Chytridiomycota (P<0.05). Cadmium pollution reduced the abundance of Mortierella and Alternaria, but the application of cotton stalk biochar could increase the relative abundance of Alternaria. Increasing cotton stalk biochar means that soil will have more endophytes, plant pathogens, and saprophytes; while increasing cadmium pollution will reduce endophytes, plant pathogens, and saprophytes in the soil. ③ The main environmental factors affecting the diversity and structure of fungal communities are the available potassium, organic matter, and pH of the soil. The reducible cadmium content, which comprises the largest proportion of cadmium in rice soil, was significantly positively correlated to Rotifera, Aphelidiomycota, and Ascomycota (P<0.05), but negatively correlated to other mycophytes (P<0.05). The results indicate that cotton stalk biochar plays a certain role in the microecological regulation of alkaline cadmium-contaminated soil.

[Control of Cadmium Migration and Transformation in Alkaline Paddy Soil-Rice Using Cotton Stalk Biochar].

We investigated the effects of cotton stalk biochar addition on the soil nutrient characteristics of alkaline paddy soil and the migration and transformation of cadmium in a soil-rice system. An outdoor pot experiment was conducted with Tefengyou 2 rice as the testing material. We added cotton stalk biochar (0%, 1%, 2.5%, and 5%) in the alkaline paddy soil with cadmium content of 0, 1, 4, and 8 mg·kg-1. After rice harvesting, the effects of different concentrations of cotton stalk biochar on alkaline soil physical and chemical properties, cadmium enrichment and transfer in rice, and the occurrence of cadmium in soil were analyzed under different concentrations of cadmium stress. The results showed that ① adding cotton stalk biochar can effectively increase soil nutrient (P<0.05). After the addition of cotton stalk biochar, the organic matter increased by 25.74%-47.53%, and the available potassium content increased by 3.16-4.25 times. ② Cotton stalk carbon can reduce the cadmium content in soil and rice, especially after the application of 5% cotton stalk carbon, The cadmium content of brown rice at Cd4 and Cd8 concentrations decreased from 0.31 mg·kg-1 and 0.43 mg·kg-1 to 0.15 mg·kg-1 and 0.10 mg·kg-1, respectively, reaching the national standard. Cotton stalk biochar can significantly reduce the enrichment and transfer coefficient of cadmium in soil-rice systems and can increase the cadmium content in the residual cadmium but decrease the acid extractable cadmium, reducible cadmium, and oxidizable cadmium content (P<0.05). ③ Soil pH, conductivity, and nutrient indicators were significantly negatively correlated with cadmium content in rice and acid extractable cadmium, reducible cadmium, and oxidizable cadmium content in soil and were positively correlated with cadmium content in residual cadmium. The above results indicate that the application of cotton stalk biochar can significantly improve the soil nutrient of alkaline cadmium-contaminated paddy soil, and the application of cotton stalk biochar has a significant control effect on the migration and transformation of cadmium in alkaline soil and rice.

Effect of diabetes mellitus on risk of latent TB infection in a high TB incidence area: a community-based study in Taiwan.

OBJECTIVE: To investigate the association between diabetes and latent tuberculosis infections (LTBI) in high TB incidence areas. DESIGN: Community-based comparison study. SETTING: Outpatient diabetes clinics at 4 hospitals and 13 health centres in urban and rural townships. A community-based screening programme was used to recruit non-diabetic participants. PARTICIPANTS: A total of 2948 patients with diabetes aged older than 40 years were recruited, and 453 non-diabetic participants from the community were enrolled. PRIMARY AND SECONDARY OUTCOME MEASURES: The interferon-gamma release assay (IGRA) and the tuberculin skin test were used to detect LTBI. The IGRA result was used as a surrogate of LTBI in logistic regression analysis. RESULTS: Diabetes was significantly associated with LTBI (adjusted OR (aOR)=1.59; 95% CI 1.11 to 2.28) and age correlated positively with LTBI. Many subjects with diabetes also had additional risk factors (current smokers (aOR=1.28; 95% CI 0.95 to 1.71), comorbid chronic kidney disease (aOR=1.26; 95% CI 1.03 to 1.55) and history of TB (aOR=2.08; 95% CI 1.19 to 3.63)). The presence of BCG scar was protective (aOR=0.66; 95% CI 0.51 to 0.85). Duration of diabetes and poor glycaemic control were unrelated to the risk of LTBI. CONCLUSION: There was a moderately increased risk of LTBI in patients with diabetes from this high TB incidence area. This finding suggests LTBI screening for the diabetics be combined with other risk factors and comorbidities of TB to better identify high-risk groups and improve the efficacy of targeted screening for LTBI.

GLUCOSE CHANGES IN A PATIENT WITH INSULIN AUTOIMMUNE SYNDROME DEMONSTRATED BY CONTINUOUS GLUCOSE MONITORING.

OBJECTIVE: Insulin autoimmune syndrome (IAS) is an unusual cause of hypoglycemia in individuals without underlying diseases. Continuous glucose monitoring (CGM) has rarely been applied for IAS. We present a case of IAS with available 6-day CGM data. METHODS: A 61-year-old Taiwanese man was admitted because of impaired consciousness while driving, caused by a low blood glucose level of 30 mg/dL. He regained consciousness fully after parenteral glucose administration. RESULTS: During the prolonged fasting test, his C-peptide and insulin levels were respectively 11 ng/mL and 169.34 µIU/mL when plasma glucose was 41 mg/dL. Abdominal magnetic resonance imaging did not show any pancreatic abnormality. His 6-day CGM data revealed fasting hypoglycemia, several instances of postprandial hyperglycemia, and low blood glucose levels before lunch and dinner. Additional diagnostic findings included elevated anti-insulin antibody of 78.2%, thyrotoxicosis due to Graves disease, and gastric ulcer. He was discharged home on prednisolone at 5 mg daily, methimazole at 10 mg daily, and esomeprazole at 40 mg daily. Hypoglycemia and impairment of consciousness did not recur throughout the subsequent year-long follow up. CONCLUSION: We proposed a novel approach using CGM coupled with measurements of plasma insulin, C-peptide, and anti-insulin antibodies as the initial investigation for hypoglycemia in non-diabetic subjects. These relatively inexpensive tests may lead to earlier detection of IAS and thus render hospital admission and more costly explorations unnecessary.

Diabetes mellitus increased all-cause mortality rate among newly-diagnosed tuberculosis patients in an Asian population: A nationwide population-based study.

AIMS: To investigate the effect of diabetes mellitus (DM) on all-cause mortality among patients with newly-diagnosed tuberculosis (TB) in an Asian population. We also identified risk factors for mortality in these patients. METHODS: The data were obtained from the National Health Insurance Research Database and included 9831 newly-diagnosed TB individuals and 1627 TB mortality cases in the period of 2000-2010. The mortality data were divided into a DM group and a non-DM group. We measured the incidence density of mortality and identified the risk factors of mortality. RESULTS: The all-cause mortality of newly-diagnosed TB patients progressively increased with an average rate of 16.5% during 2000-2010. DM is an independent risk factor for all-cause mortality with HRs 1.17-1.27 by various models. TB patients with ages above 75years had the highest risk of mortality (HR=11.93) compared with those under 45 years. TB patients with heart failure, peripheral vascular disease, ischemic heart disease, cerebral vascular disease, hypertension, chronic kidney disease, pulmonary disease, liver disease, cancer, peptic ulcer disease, gout, and autoimmune disease had higher mortality compared to those without the aforementioned factors. CONCLUSIONS: The one-year all-cause mortality after TB diagnosis was high among TB patients in Taiwan and it tended to increase in the past decade. While treating these newly-diagnosed TB patients, it is crucial to detect the factors predisposing to death, such as old age, male gender, certain kinds of aforementioned factors and diabetes.

miR-181d regulates human dendritic cell maturation through NF-κB pathway.

OBJECTIVES: MicroRNAs (miRNAs) are considered as the cellular regulators which post-transcriptionally modulate gene expression in diverse biological processes including cell development and immunity. In this study, we investigated functions of miR-181d in dendritic cells (DCs) maturation, and the underlying mechanisms were also explored. MATERIALS AND METHODS: Here we did the miRNA screening in human DCs in response to lipopolysaccharides (LPS) by quantitative real-time PCR (qRT-PCR). The expressions of DCs maturation markers were measured after miRNA mimics transfections. The pharmacological inhibitors of signalling pathways were applied to examine miR-181d effect on DCs maturation by Western blot. Luciferase assay and mixed lymphocyte reaction (MLR) were also performed to reveal the target gene of miR-181d and test the viability of T cells treated with miR-181d transfected DCs. RESULTS: Overexpression of miR-181d per se is sufficient to promote DCs maturation, and up-regulate CD80 and CD83 expressions without LPS. Besides, we showed that miR-181d activated NF-κB pathway and also promoted the expression of pro-inflammatory cytokine IL12 and TNF-α. Inhibition of NF-κB pathway suppressed DCs maturation. Luciferase reporter assay and target gene knockdown assay indicated that miR-181d targets regulator cylindromatosis (CYLD), a primary negative regulator of NF-κB pathway. MLR assay showed that miR-181d-transfected DCs could promote T-cell proliferation than iDCs in vitro. CONCLUSION: Our study demonstrates that miR-181d is required for DCs maturation through the activation of NF-κB pathway by targeting CYLD.

Glycemic excursions are positively associated with HbA1c reduction from baseline after treatment with acarbose in patients with type 2 diabetes on metformin monotherapy.

BACKGROUND: The aim of the present study was to examine the association between glycemic excursions before treatment and HbA1c reduction after treatment intensification with acarbose or glibenclamide in patients with type 2 diabetes (T2D). METHODS: Patients receiving single or dual oral antidiabetic drug treatment with an HbA1c of 7.0-11.0 % (53-97 mmol/mol) were switched to metformin monotherapy (500 mg, t.i.d.) for 8 weeks, followed by randomization to either acarbose (100 mg, t.i.d.) or glibenclamide (5 mg, t.i.d.) as add-on treatment for 16 weeks. Glycemic excursions were assessed as mean amplitude of glycemic excursions (MAGE) with 72-h ambulatory continuous glucose monitoring. Treatment efficacy was evaluated as relative HbA1c reduction (%), calculated as (baseline HbA1c - post-treatment HbA1c)/baseline HbA1c × 100. RESULTS: Fifty patients (mean [±SD] age 53.5 ± 8.2 years, 48 % men, mean baseline HbA1c 8.4 ± 1.2 %) were analyzed. Baseline MAGE was positively correlated with relative HbA1c reduction from baseline in patients treated with acarbose (r = 0.421, P = 0.029) but not glibenclamide (r = 0.052, P = 0.813). Linear regression analysis revealed that the association between baseline MAGE and relative HbA1c reduction from baseline (ß = 0.125, P = 0.029) in patients treated with acarbose remained significant after adjustment for several confounders (P < 0.05 for all models). CONCLUSIONS: In patients with T2D on metformin monotherapy, baseline MAGE was positively correlated with relative HbA1c reduction from baseline after treatment with acarbose, but not glibenclamide. These findings highlight the importance of glycemic excursions in individualized treatment for patients with T2D.

Glycemic excursions are positively associated with changes in duration of asymptomatic hypoglycemia after treatment intensification in patients with type 2 diabetes.

AIM: The aim of this study was to examine the association between glycemic excursions and duration of hypoglycemia after treatment intensification in patients with type 2 diabetes (T2D). METHODS: Patients with T2D on oral anti-diabetes drug (OAD) with glycated hemoglobin (HbA1c) of 7.0-11.0% were switched to metformin monotherapy (500 mg thrice daily) for 8 weeks, followed by randomization to either glibenclamide or acarbose as add-on treatment for 16 weeks. Glycemic excursions were assessed as mean amplitude of glycemic excursions (MAGE) with 72-h ambulatory continuous glucose monitoring (CGM) before randomization and at the end of study. Hypoglycemia was defined as sensor glucose level of less than 60 mg/dl in two or more consecutive readings from CGM. RESULTS: A total of 50 patients (mean age 53.5 ± 8.2 years, male 48%, mean baseline HbA1c 8.4 ± 1.2%) were analyzed. Duration of hypoglycemia significantly increased after treatment with glibenclamide (from 5.5 ± 13.8 to 18.8 ± 35.8 min/day, p=0.041), but not with acarbose (from 2.9 ± 10.9 to 14.7 ± 41.9 min/day, p=0.114). Post treatment MAGE was positively associated with change from baseline in duration of hypoglycemia after treatment with either glibenclamide (ß coefficient 0.345, p=0.036) or acarbose (ß coefficient 0.674, p=0.046). The association remained significant after multivariate adjustment (p<0.05 for all models). CONCLUSIONS: Post treatment glycemic excursions are associated with changes in duration of hypoglycemia after treatment intensification with OAD in patients with T2D. Glycemic excursions should be an important treatment target for T2D to reduce the risk of hypoglycemia.

High diabetes mellitus prevalence with increasing trend among newly-diagnosed tuberculosis patients in an Asian population: A nationwide population-based study.

AIMS: Our aims were to investigate the prevalence of diabetes mellitus (DM) among patients with newly-diagnosed tuberculosis (TB) and to determine its associated factors in an Asian population. METHODS: The data were obtained from the National Health Insurance Research Database and included 9831 newly-diagnosed TB individuals in the period of 2000-2010. The data were divided into a DM group and a non-DM group. We measured the prevalence and the associated comorbidities of DM. RESULTS: During 2000-2010, the prevalence of DM progressively increased, with an average prevalence rate of 27.9%. The patients with ages of 55-64 years had the highest association of DM (OR=3.53) compared with those under 45 years. TB patients with heart failure, ischemic heart disease, cerebral vascular disease, hypertension, dyslipidemia, chronic kidney disease, and liver disease were more likely to associate with DM (ORs=1.27, 1.23, 1.30, 2.32, 3.26, 1.6, and 1.68, respectively) compared to those without the variables. CONCLUSIONS: The prevalence of DM among TB patients in Taiwan was high and tended to increase in the past decade. Clinically, inquiring about DM history and screening routinely for those without DM history among TB patients should be carried out in Taiwan.

High levels of testosterone inhibit ovarian follicle development by repressing the FSH signaling pathway.

The effect of high concentrations of testosterone on ovarian follicle development was investigated. Primary follicles and granulosa cells were cultured in vitro in media supplemented with a testosterone concentration gradient. The combined effects of testosterone and follicle-stimulating hormone (FSH) on follicular growth and granulosa cell gonadotropin receptor mRNA expression were also investigated. Follicle growth in the presence of high testosterone concentrations was promoted at early stages (days 1-7), but inhibited at later stage (days 7-14) of in vitro culture. Interestingly, testosterone-induced follicle development arrest was rescued by treatment with high concentrations of FSH (400 mIU/mL). In addition, in cultured granulosa cells, high testosterone concentrations induced cell proliferation, and increased the mRNA expression level of FSH receptor (FSHR), and luteinized hormone/choriogonadotropin receptor. It was concluded that high concentrations of testosterone inhibited follicle development, most likely through regulation of the FSH signaling pathway, although independently from FSHR downregulation. These findings are an important step in further understanding the pathogenesis of polycystic ovary syndrome.

The Association Between Body Mass Index and All-Cause Mortality in Patients With Type 2 Diabetes Mellitus: A 5.5-Year Prospective Analysis.

Abundances of study in different population have noted that obese cardiovascular disease (CVD) patients have a better prognosis than leaner patients, which refer to the phenomenon of obesity paradox. However, data on the association between body mass index (BMI) and mortality among Asian patients are limited, especially in patients with type 2 diabetes mellitus (T2DM). We investigate the association between BMI and all-cause mortality in Taiwanese patients with T2DM to define the optimal body weight for health.We conducted a longitudinal cohort study of 2161 T2DM patients with a mean follow-up period of 66.7 ±â€Š7.5 months. Using Cox regression models, BMI was related to the risk of all-cause mortality after adjusting all confounding factors.A U-shaped association between BMI and all-cause mortality was observed among all participants. Those with BMIs <22.5 kg/m had a significantly elevated all-cause mortality as compared with those with BMIs 22.5 to 25.0 kg/m, (BMIs 17.5-20.0 kg/m: hazard ratio 1.989, P < 0.001; BMIs 20.0-22.5 kg/m: hazard ratio 1.286, P = 0.02), as did those with BMIs >30.0 kg/m (BMIs 30.0-32.5 kg/m: hazard ratio 1.670, P < 0.001; BMIs 32.5-35.0 kg/m: hazard ratio, 2.632, P < 0.001). This U-shaped association remained when we examined the data by sex, age, smoking, and kidney function.Our study found a U-shaped relationship between all-cause mortality and BMI in Asian patients with T2DM, irrespective of age, sex, smoking, and kidney function. BMI <30 kg/m should be regarded as a potentially important target in the weight management of T2DM.

A workable model for the management of hyperglycemia in non-critically ill patients in an Asian population.

OBJECTIVE: The clinical efficacy of applying a western model for managing hyperglycemia in hospitalized patients in Asia has not been studied. METHODS: For this observational case-control study, we divided six medical wards into two groups, an intervention group and a control group. The intervention group, consisting three medical wards on the same floor, received care under a computer-assisted consulting model in which special care was automatically indicated for patients who had two successive high glucose measurements in 1 day. The control group, consisting of another three medical wards distributed on different floors, received regular care. Outcome measures were baseline and post-intervention patient-day weighted mean glucose, percentage of patient-day weighted glucose ≥180 mg/dL, proportion of glucose level 100-180 mg/dL, and prevalence of inpatient hyperglycemia (>180 mg/dL) and hypoglycemia (individual measurement <70 mg/dL and patient-day with any measurement <70 mg/dL). RESULTS: At baseline, the patient-day weighted mean glucose level was 181.6 mg/dL. All parameters were comparable between the intervention and control groups with the exception of prevalence of hypoglycemia, which was found to be higher in the intervention group. After intervention, patient-day weighted mean glucose levels for intervention and control groups were 169.9 mg/dL and 176.7 mg/dL, respectively (p < 0.001). The intervention group had a reduction in hypoglycemia and the control group an increase. CONCLUSION: This computer-assisted consulting model was found to be potentially very workable for the management of inpatient hyperglycemia in hospitals with high patient volumes in Asia.

Glycosylated hemoglobin level and number of oral antidiabetic drugs predict whether or not glycemic target is achieved in insulin-requiring type 2 diabetes.

AIMS: Factors predicting success (glycosylated hemoglobin (A1C)<7%) with insulin therapy in patients with insulin-requiring type 2 diabetes need to be identified. METHODS: A retrospective, multi-center, observational study was conducted for outpatients with oral antidiabetic drug (OAD)-treated type 2 diabetes whose A1C levels remained above 7%. Patients were begun on basal insulin between January 2005 and December 2006. Biochemical variables and demographic data were collected before and after 52 weeks of insulin therapy. RESULTS: A total of 565 patients (age, 60.4±11.9 years; A1C levels, 10.11 ±1.81%; duration of diabetes, 11.5±6.8 years) were studied. By study end, 63 patients (11.2%) had achieved the glycemic goal (A1C<7%). The glycemic goal attainment rate was only 9.1% in patients with A1C>8.8% and who were taking >2 OADs at baseline. The highest rate (32.7%) of successful glycemic control was observed in the group of patients with A1C ≤ 8.8% and who used ≤ 2 OADs at baseline. CONCLUSIONS: Insulin-naïve diabetic patients with A1C>8.8%, especially those who are taking >2 OADs, have small chance to achieve good glycemic control with adding only basal insulin therapy.

High levels of testosterone inhibit ovarian follicle development by repressing the FSH signaling pathway / 华中科技大学学报（医学）（英德文版）

The effect of high concentrations of testosterone on ovarian follicle development was investigated. Primary follicles and granulosa cells were cultured in vitro in media supplemented with a testosterone concentration gradient. The combined effects of testosterone and follicle-stimulating hormone (FSH) on follicular growth and granulosa cell gonadotropin receptor mRNA expression were also investigated. Follicle growth in the presence of high testosterone concentrations was promoted at early stages (days 1-7), but inhibited at later stage (days 7-14) of in vitro culture. Interestingly, testosterone-induced follicle development arrest was rescued by treatment with high concentrations of FSH (400 mIU/mL). In addition, in cultured granulosa cells, high testosterone concentrations induced cell proliferation, and increased the mRNA expression level of FSH receptor (FSHR), and luteinized hormone/choriogonadotropin receptor. It was concluded that high concentrations of testosterone inhibited follicle development, most likely through regulation of the FSH signaling pathway, although independently from FSHR downregulation. These findings are an important step in further understanding the pathogenesis of polycystic ovary syndrome.

Post-meal ß-cell function predicts the efficacy of glycemic control in patients with type 2 diabetes inadequately controlled by metformin monotherapy after addition of glibenclamide or acarbose.

BACKGROUND: This study aimed to explore parameters which will predict good control of HbA1c after adding a second anti-diabetic drug in patients with type 2 diabetes mellitus (T2DM) inadequately controlled with metformin monotherapy. METHODS: Fifty-one patients (M/F: 25/26, mean age: 53.7 ± 8.2 years, mean glycated hemoglobin [HbA1c] 8.4 ± 1.2%) with T2DM inadequately controlled with metformin were randomized to add-on glibenclamide or acarbose for 16 weeks. Before and after combination therapy, the subjects underwent a 2-hour liquid mixed meal tolerance test to determine insulin secretion (HOMA-ß, insulinogenic index, and disposition index [DI]) and insulin sensitivity (HOMA-IR and Matsuda insulin sensitivity index). RESULTS: At baseline, there was a significant inverse relationship between DI120 and HbA1c (p = 0.001) in all subjects. The addition of glibenclamide and acarbose improved HbA1c significantly from 8.6 ± 1.6% to 7.4 ± 1.2% (p < 0.001), and from 8.2 ± 0.8% to 7.5 ± 0.8% (p < 0.001), respectively. In the glibenclamide group, DI120 significantly increased from 51.2 ± 24.2 to 74.9 ± 41.9 (p < 0.05), and in the acarbose group, from 62.5 ± 31.4 to 91.7 ± 36.2 (p < 0.05), respectively. Multiple regression analyses showed that both baseline HbA1c and DI120 independently predicted reduction of HbA1c as well as final HbA1c after combination therapy. CONCLUSIONS: In patients with T2DM inadequately controlled with metformin, add-on oral anti-diabetic agent with glibenclamide or acarbose resulted in the significant HbA1c reduction and improvement of ß-cell function. Subjects with greater baseline ß-cell function reserve displayed better glycemic response in the combination therapy of metformin with glibenclamide or acarbose. TRIAL REGISTRATION: This study was registered in the ClinicalTrials.gov with registration number of NCT00417729.