Caveolin-1 Is Essential for the Improvement of Insulin Sensitivity through AKT Activation during Glargine Treatment on Diabetic Mice.

Insulin treatment was confirmed to reduce insulin resistance, but the underlying mechanism remains unknown. Caveolin-1 (Cav-1) is a functional protein of the membrane lipid rafts, known as caveolae, and is widely expressed in mammalian adipose tissue. There is increasing evidence that show the involvement of Cav-1 in the AKT activation, which is responsible for insulin sensitivity. Our aim was to investigate the effect of Cav-1 depletion on insulin sensitivity and AKT activation in glargine-treated type 2 diabetic mice. Mice were exposed to a high-fat diet and subject to intraperitoneal injection of streptozotocin to induce diabetes. Next, glargine was administered to treat T2DM mice for 3 weeks (insulin group). The expression of Cav-1 was then silenced by injecting lentiviral-vectored short hairpin RNA (shRNA) through the tail vein of glargine-treated T2DM mice (CAV1-shRNA group), while scramble virus injection was used as a negative control (Ctrl-shRNA group). The results showed that glargine was able to upregulate the expression of PI3K and activate serine phosphorylation of AKT through the upregulation of Cav-1 expression in paraepididymal adipose tissue of the insulin group. However, glargine treatment could not activate AKT pathway in Cav-1 silenced diabetic mice. These results suggest that Cav-1 is essential for the activation of AKT and improving insulin sensitivity in type 2 diabetic mice during glargine treatment.

Association of the Monocyte-to-High-Density Lipoprotein Cholesterol Ratio With Diabetic Retinopathy.

Background: Chronic inflammation in type 2 diabetes mellitus (T2DM) is an essential contributor to the development of diabetic retinopathy (DR). The monocyte-to-high-density lipoprotein cholesterol (HDL-C) ratio (MHR) is a novel and simple measure related to inflammatory and oxidative stress status. However, little is known regarding the role of the MHR in evaluating the development of DR. Methods: A total of 771 patients with T2DM and 607 healthy controls were enrolled in this cross-sectional study. MHR determination and eye examination were performed. The association of MHR with the prevalence of DR in T2DM patients was analyzed. Results: The MHR in patients with DR was significantly higher than that in both non-DR diabetic patients (P < 0.05) and healthy controls (P < 0.01). No significance was observed in the MHR of different DR severity grades. Moreover, the MHR was similar between patients with non-macular oedema and those with macular oedema. Logistic regression analysis demonstrated that MHR was independently associated with the prevalence of DR in diabetic patients [odds ratio (OR) = 1.438, 95% confidence interval (CI): 1.249-1.655, P < 0.01]. After additional stratification by HbA1c level and diabetic duration, the MHR was still independently associated with the prevalence of DR. Conclusions: Our study suggests that the MHR can be used as a marker to indicate the prevalence of DR in patients with T2DM.

High-Normal Serum Thyrotropin Levels Increased the Risk of Non-Alcoholic Fatty Liver Disease in Euthyroid Subjects with Type 2 Diabetes.

PURPOSE: The aim of this study was to investigate the association between high-normal thyrotropin (TSH) levels and the prevalence of non-alcoholic fatty liver disease (NAFLD) in euthyroid patients with T2DM. METHODS: A total of 2289 euthyroid adults with T2DM were included in this cross-sectional study conducted at the Third Affiliated Hospital of Sun Yat-sen University from January 2016 to December 2018. NAFLD was diagnosed by abdominal ultrasound. Thyroid function parameters, including the levels of TSH, free triiodothyronine (FT3) and free thyroxine (FT4), were analyzed. The patients were stratified by quartiles (Q1-4) of TSH levels. Multivariate logistic regression models were used to evaluate the association between the quartiles of TSH levels and the risk of NAFLD in euthyroid adults with T2DM. RESULTS: There were 940 (41.1%) euthyroid adults with T2DM who were diagnosed with NAFLD. The subjects were divided according to the thyroid function parameter quartiles. The prevalence of NAFLD increased with increasing TSH level quartiles (Q1 to Q4: 34.8%, 37.5%, 44.9% and 47.0%, P<0.01) but not with increasing FT3 or FT4 level quartiles. In the multivariate logistic regression model, compared with the lowest TSH level quartile (Q1), the highest TSH level quartile (Q4) (OR=1.610, 95% CI=1.131-2.289, P=0.008) was independently associated with an increased risk of NAFLD in euthyroid adults with T2DM after adjusting for multiple confounders. After additional stratification by the level of glycosylated haemoglobin (HbA1c) and body mass index (BMI), the highest TSH level quartile was still independently associated with an increased risk of NAFLD in euthyroid patients with T2DM who had an HbA1c level≥7% or a BMI<28 kg/m2. CONCLUSION: High-normal serum TSH levels are significantly associated with the presence of NAFLD in T2DM patients with euthyroid function, which provide novel insight for treating NAFLD.

Comparison of two regimens for patients with thyroid-associated ophthalmopathy receiving intravenous methyl prednisolone: A single center prospective randomized trial.

Intravenous (i.v.) glucocorticoid is recommended for active moderate-to-severe thyroid-associated ophthalmopathy (TAO). However, the details of the treatment schedule are still debatable. The present prospective randomized trial was performed to compare clinical outcomes and serum cytokines between the two regimens. A cohort of 90 patients with active moderate-to-severe TAO was randomized to receive i.v. methyl prednisolone on a weekly protocol or daily scheme. The response rate was evaluated at the 12-week follow-up visit. Serum interleukin (IL)-2, IL-6 and IL-17 levels were measured in 160 patients with TAO, 60 patients with isolated Graves' disease (GD) and 60 normal control (NC) at baseline, as well as patients with active moderate-to-severe TAO at the 12th week after treatment. The daily scheme had a higher response rate than the weekly protocol without a significant difference (77.8 vs. 63.6%, P>0.05). No major adverse events were recorded under either regimen. Overall, minor events were more common on the daily scheme (11.36 vs. 4.35%, P<0.05)than on the weekly protocol, whereas the deterioration of eye symptoms (two patients) was only reported on the weekly protocol. At baseline, the IL-17 level in the TAO group was higher than that in the isolated GD and NC groups (P<0.05). In addition, the IL-17 level in the active TAO group was higher than that in the inactive TAO group (P<0.05). Furthermore, the IL-17 level had significantly decreased under the two regimens at the 12-week visit (P<0.05). In conclusion, for patients with active moderate-to-severe TAO, daily i.v. glucocorticoid therapy has a relative higher response rate than the weekly protocol with a few more minor adverse events. These two regimens have their own merits with regard to adverse effects. IL-17 has the potential to be a biomarker for evaluating TAO activity and treatment effects.

Females with Type 2 Diabetes Mellitus Are Prone to Diabetic Retinopathy: A Twelve-Province Cross-Sectional Study in China.

AIMS: To investigate the distribution of diabetic retinopathy (DR) by sex in patients with type 2 diabetes mellitus (T2DM) in a twelve-province cross-sectional study in China. METHODS: Patients with T2DM, whose ages were ≥18 years, were recruited from 76 cities/counties in 12 provinces in mainland China between January 2015 and December 2018. All participants received a standardized interview, eye examinations, and digital fundus photography. The presence and severity of DR were diagnosed and classified by retina specialists according to the DR domestic typing method. RESULTS: A total of 12,766 participants (5963 males and 6803 females) were eligible for this study. The total prevalence of DR was 30.1%. Females exhibited a significantly higher prevalence of DR than males (31.1% vs. 29.0%, P = 0.011). A multivariate logistic regression analysis confirmed that female sex was an independent predictor for a higher prevalence of DR after adjusting for age, the duration of diabetes, economic status, and the presence of hypertension (OR: 1.096, 95% CI: 1.013-1.186, P = 0.023). Even after stratification by the diabetic duration, age, and economic status, female sex was still independently associated with the presence of DR in patients whose T2DM history was more than 10 years, whose ages were over 60 years, or who were in a relatively intermediate economic area. CONCLUSION: Females had a higher prevalence of DR than males in T2DM patients with a diabetic history of more than 10 years, ages over 60 years, or a relatively intermediate economic status.

Effect of basal insulin supplement therapy on diabetic retinopathy in short-duration type 2 diabetes: A one-year randomized parallel-group trial.

BACKGROUND: In this study, we compared the effect on diabetic retinopathy (DR) between oral antidiabetic drugs (OADs) alone and in combination with basal insulin-supported OADs therapy (BOT). [Correction added on 11 November 2019, after first online publication: In Abstract under Background section, "DR" has been corrected into "diabetic retinopathy (DR)".] METHODS: Between January 2015 and January 2018, this study enrolled 290 patients (age 18-65 years) with diabetes duration between 0 and 5 years. Patients were randomly assigned to receive OADs or BOT after 14 days intensive insulin treatment. Examinations were performed at the beginning and end of the study. RESULTS: Fewer patients developed DR in the BOT than OADs group (8 [6.06%] vs 12 [8.3%], respectively), and all cases of DR were non-proliferative. Blood glucose concentrations were higher in the BOT than OADs group at the 3rd month, but lower in the former at the 6th and 12th month. The rate of reaching target HbA1c ≤7% was lower in the BOT than OADs group at the 3rd month (63.6% vs 72.2%, respectively), similar between the two groups at the 6th month (60.6% vs 66.6%, respectively) and higher in the BOT group at the 12th month (75.0% vs 61.1%, respectively). The SD of fasting blood glucose (FBG), coefficient of variation of FBG, SD of blood glucose (SDBG), and mean amplitude of glycemic excursions were lower in the BOT than OADs group. Changes in the levels of three cytokines (interleukin [IL]-1ß, IL-6, and IL-17α) were significantly less in the BOT than OADs group. CONCLUSIONS: Twelve months of BOT decreased the incidence of DR in short-duration type 2 diabetes by reducing glycemia more effectively, stably, and completely than OADs alone.

Ginsenoside Rb1 attenuates intestinal ischemia/reperfusion­induced inflammation and oxidative stress via activation of the PI3K/Akt/Nrf2 signaling pathway.

Ginsenoside Rb1 (GRb1), one of the major active saponins isolated from ginseng, has recently been reported to protect various organs against ischemia/reperfusion (IR) injury; however, the mechanisms underlying these protective effects following intestinal IR (IIR) remain unclear. The present study aimed to evaluate the effects of GRb1 on IIR injury and determine the mechanisms involved in these effects. Sprague Dawley rats were subjected to 75 min of superior mesenteric artery occlusion, followed by 3 h of reperfusion. GRb1 (15 mg/kg) was administered intraperitoneally 1 h prior to the induction of IIR, with or without intravenous administration of Wortmannin [WM; a phosphoinositide 3­kinase (PI3K) inhibitor, 0.6 mg/kg]. The degree of intestinal injury and oxidative stress­induced damage was determined by histopathologic evaluation and measurement of the serum activity levels of D­lactate, diamine oxidase and endotoxin, and the levels of malondialdehyde (MDA), superoxide dismutase (SOD) and 8­iso­prostaglandin F2α (8­iso­PGF2α). The protein expression levels of p85, phosphorylated (p)­p85, protein kinase B (Akt), p­Akt and nuclear factor erythroid 2­related factor 2 (Nrf2) were determined via western blotting, and the concentrations of tumor necrosis factor­α (TNF­α), interleukin (IL)­1ß and IL­6 were measured via ELISA. It was revealed that IIR led to severe intestinal injury (as determined by significant increases in intestinal Chiu scores), which was accompanied with disruptions in the integrity of the intestinal mucosal barrier. IIR also increased the expression levels of TNF­α, IL­1ß, IL­6, MDA and 8­iso­PGF2α in the intestine, and decreased those of SOD. GRb1 reduced intestinal histological injury, and suppressed inflammatory responses and oxidative stress. Additionally, the protective effects of GRb1 were eliminated by WM. These findings indicated that GRb1 may ameliorate IIR injury by activating the PI3K/protein kinase B/Nrf2 pathway.

A Randomized Trial of Insulin Glargine plus Oral Hypoglycemic Agents versus Continuous Subcutaneous Insulin Infusion to Treat Newly Diagnosed Type 2 Diabetes.

AIMS: Basal insulin plus oral hypoglycemic agents (OHAs) has not been investigated for early intensive antihyperglycemic treatment in people with newly diagnosed type 2 diabetes. This study is aimed at comparing the short-term (over a period of 12 days) effects of basal insulin glargine plus OHAs and continuous subcutaneous insulin infusion (CSII) on glycemic control and beta-cell function in this setting. METHODS: An open-label parallel-group study. Newly diagnosed hospitalized patients with type 2 diabetes and fasting plasma glucose (FPG) ≥11.1 mmol/L or glycated hemoglobin (HbA1c) ≥9% (75 mmol/mol) were randomized to CSII or insulin glargine in combination with metformin and gliclazide. The primary outcome measure was the mean amplitude of glycemic excursions (MAGE), and secondary endpoints included time to reach glycemic control target (FPG < 7 mmol/L and 2-hour postprandial plasma glucose < 10 mmol/L), markers of ß-cell function, and hypoglycemia. RESULTS: Subjects in the CSII (n = 35) and basal insulin plus OHA (n = 33) groups had a similar significant reduction from baseline to end of treatment in glycated albumin (-6.44 ± 3.23% and- 6.42 ± 3.56%, P = 0.970). Groups A and B have comparable time to glycemic control (3.6 ± 1.2 days and 4.0 ± 1.4 days), MAGE (3.40 ± 1.40 mmol/L vs. 3.16 ± 1.38 mmol/L; p = 0.484), and 24-hour mean blood glucose (7.49 ± 0.96 mmol/L vs. 7.02 ± 1.03 mmol/L). Changes in the C-peptide reactivity index, the secretory unit of islet in transplantation index, and insulin secretion-sensitivity index-2 indicated a greater ß-cell function improvement with basal insulin plus OHAs versus CSII. CONCLUSIONS: Short-term insulin glargine plus OHAs may be an alternative to CSII for initial intensive therapy in people with newly diagnosed type 2 diabetes.

Utility of Neck Circumference for Identifying Metabolic Syndrome by Different Definitions in Chinese Subjects over 50 Years Old: A Community-Based Study.

AIMS: Whether neck circumference (NC) could be used as a valuable tool for identifying metabolic syndrome (MS) by different criteria in Chinese is still unclear. METHODS: We conducted a cross-sectional survey from October 2010 to January 2011 in Shipai community, Guangzhou, Guangdong Province, China. A total of 1473 subjects aged over 50 years were investigated. We measured height, weight, NC, waist circumference, blood pressure, blood glucose, and lipids in all subjects. MS was identified by criteria of the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III), Chinese Diabetes Society (CDS), and International Diabetes Federation (IDF). RESULTS: Mean NC was 38.0 ± 2.7 cm in men and 34.2 ± 2.5 cm in women. By using receiver operating characteristic curves, the area under the curve (AUC) of NC for identifying MS (IDF) was 0.823 in men and 0.777 in women, while for identifying MS (CDS), it was 0.788 in men and 0.762 in women. The AUC of NC for diagnosing MS (ATP III) was 0.776 in men and 0.752 in women. The optimal cut points of NC for MS were 38.5 cm by three definitions in men, while those were 34.2 cm, 33.4 cm, and 34.0 cm in women by IDF, ATP III, and CDS definitions, respectively. No significant difference was observed between the AUC of NC and BMI for diagnosing MS by using different criteria (all p > 0.05). CONCLUSIONS: NC is associated with MS by different definitions in Chinese subjects over 50 years old. It may be a useful tool to identify MS in a community population.

The Postprandial-to-Fasting Serum C-Peptide Ratio is a Predictor of Response to Basal Insulin-Supported Oral Antidiabetic Drug(s) Therapy: A Retrospective Analysis.

INTRODUCTION: Basal insulin is widely recommended for the treatment of type 2 diabetes mellitus (T2DM) patients who are unable to achieve glycemic control with oral antidiabetic drug(s) (OADs). However, some patients are still unable to control their blood glucose levels even when on basal insulin-supported OAD(s) therapy (BOT). The aim of this study was to investigate the factor(s) predicting patient response to BOT. METHODS: A total of 212 patients with T2DM, ranging in age from 18 to 65 years, admitted to the university hospital of Sun Yat-sen University, Guangzhou, China, were enrolled in the study between January 2013 and July 2016. All patients had fasting blood glucose levels of ≥ 10.0 mmol/L despite receiving OAD(s) treatment. According to study design, these patients first received intensive insulin therapy for 2 weeks to attain and maintain their glycemic goals and then were switched to BOT. Responders were defined as subjects who maintained their glycemic targets with BOT for at least 3 months; all others were considered to be non-responders. The characteristics between responders and non-responders were compared. RESULTS: Compared with non-responders, responders had a shorter duration of diabetes (5.1 ± 5.0 vs. and 10.1 ± 3.2 years; P  < 0.001) and a higher 2-h postprandial C-peptide-to-fasting C-peptide ratio (2 h-PCP/FCP: 1.95 ± 0.51 vs. 1.67 ± 0.32; P  < 0.01). Responders showed a lower proportion of previous treatment with insulin (69/100 vs 40/3; P  < 0.001) and sulfonlureas or glinides (116/50 vs 40/0; P <0.001) than non-responders. Multivariate logistic regression analysis showed that previous insulin treatment (odds ratio [OR] 17.677, 95% confidence interval [CI] 5.205-60.027; P  < 0.001) and the 2 h-PCP/FCP ratio (OR 0.241, 95% CI 0.058-0.679; P  = 0.007) had predictive value. CONCLUSIONS: A higher 2 h-PCP/FCP ratio and a lack of previous insulin treatment increase the likelihood of BOT success.

Downregulation of Cavin-1 Expression via Increasing Caveolin-1 Degradation Prompts the Proliferation and Migration of Vascular Smooth Muscle Cells in Balloon Injury-Induced Neointimal Hyperplasia.

BACKGROUND: Percutaneous coronary intervention has been widely used in the treatment of ischemic heart disease, but vascular restenosis is a main limitation of percutaneous coronary intervention. Our previous work reported that caveolin-1 had a key functional role in intimal hyperplasia, whereas whether Cavin-1 (another important caveolae-related protein) was involved is still unknown. Therefore, we will investigate the effect of Cavin-1 on neointimal formation. METHODS AND RESULTS: Balloon injury markedly reduced Cavin-1 protein and enhanced ubiquitin protein expression accompanied with neointimal hyperplasia in injured carotid arteries, whereas Cavin-1 mRNA had no change. In cultured vascular smooth muscle cells (VSMCs), Cavin-1 was downregulated after inhibition of protein synthesis by cycloheximide, which was distinctly prevented by pretreatment with proteasome inhibitor MG132 but not by lysosomal inhibitor chloroquine, suggesting that proteasomal degradation resulted in Cavin-1 downregulation. Knockdown of Cavin-1 by local injection of Cavin-1 short hairpin RNA (shRNA) into balloon-injured carotid arteries in vivo promoted neointimal formation. In addition, inhibition or overexpression of Cavin-1 in cultured VSMCs in vitro prompted or suppressed VSMC proliferation and migration via increasing or decreasing extracellular signal-regulated kinase phosphorylation and matrix-degrading metalloproteinases-9 activity, respectively. However, under basic conditions, the effect of Cavin-1 on VSMC migration was stronger than on proliferation. Moreover, our results indicated that Cavin-1 regulated caveolin-1 expression via lysosomal degradation pathway. CONCLUSIONS: Our study revealed the role and the mechanisms of Cavin-1 downregulation in neointimal formation by promoting VSMC proliferation, migration, and synchronously enhancing caveolin-1 lysosomal degradation. Cavin-1 may be a potential therapeutic target for the treatment of postinjury vascular remodeling.

Glycemic variability evaluated by continuous glucose monitoring system is associated with the 10-y cardiovascular risk of diabetic patients with well-controlled HbA1c.

BACKGROUND: The present study aimed to identify the relationship between glycemic variability (GV) and the 10-y risk of cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM) patients with good glycemic control. METHODS: Two-hundred forty consecutive T2DM patients (HbA1c≤7.0%) without CVD were included to calculate the 10-y CVD risk by Framingham risk score (FRS), and divided into 3 groups: low-risk group (FRS≤10%), intermediate-risk group (>10%, ≤20%) and high-risk group (>20%). Inter-group differences of GV were determined by comparing the SD of blood glucose (SDBG), mean amplitudes of glycemic excursion (MAGE), and mean of daily differences (MODD) gathered from 72-h continuous glucose monitoring system. RESULTS: The levels of SDBG and MAGE significantly increased along with the raises of 10-y CVD risk of T2DM patients (p<0.01). FRS was positively correlated with age, systolic blood pressure, SDBG and MAGE (r=0.717, 0.525, 0.509 and 0.485 respectively, p<0.01), while negatively correlated with the level of HDL-C (r=-0.348, p<0.01). Furthermore, multivariate logistic regression analysis confirmed that increased MAGE [OR: 1.623(1.198-2.316), p<0.001] and patients with high urine albumin excretion rates [OR: 1.743(1.247-2.793), p<0.001] were independent predictors for high 10-y CVD risk. CONCLUSION: GV predicts independently the 10-y CVD risk of T2DM patients with well-controlled HbA1c.

Oestrogen exerts anti-inflammation via p38 MAPK/NF-κB cascade in adipocytes.

BACKGROUND: Oestrogen has anti-inflammatory property in obesity. However, the mechanism is still not defined. OBJECTIVE: To investigate the effect of oestrogen on LPS-induced monocyte chemoattractant protein-1 (MCP-1) production in adipocytes. METHODS: Lipopolysaccharides (LPS) was used to imitate inflammatory responses and monocyte chemotactic protein-1 (MCP-1) was selected as an inflammatory marker to observe. 17ß-Estradiol (E2), SB203580 (SB), pyrrolidine dithiocarbamate (PDTC), pertussis toxin (PTX), wortmannin (WM), p65 siRNA and p38 MAPK siRNA were pre-treated respectively or together in LPS-induced MCP-1. Then p38 MAPK and NF-κB cascade were silenced successively to observe the change of each other. Lastly, oestrogen receptor (ER) α agonist, ERß agonist and ER antagonist were utilised. RESULTS: LPS-induced MCP-1 largely impaired by pre-treatment with E2, SB, PDTC or silencing NF-κB subunit. E2 inhibited LPS-induced MCP-1 in a time- and dose-dependent manner, which was related to the suppression of p65 translocation to nucleus. Furthermore, LPS rapidly activated p38 MAPK, while E2 markedly inhibited this activation. It markedly attenuated LPS-stimulated p65 translocation to nucleus and MCP-1 production by transfecting with p38 MAPK siRNA or using p38 MAPK inhibitor. The oestrogen's inhibitory effect was mimicked by the ERα agonist, but not by the ERß agonist. The inhibition of E2 on p38 MAPK phosphorylation was prevented by ER antagonist. CONCLUSIONS: E2 inhibits LPS-stimulated MCP-1 in adipocytes. This effect is related to the inhibition of p38 MAPK/NF-κB cascade, and ERα appears to be the dominant ER subtype in these events.

Dickkopf-1 promotes the differentiation and adipocytokines secretion via canonical Wnt signaling pathway in primary cultured human preadipocytes.

OBJECTIVE: Dickkopf-1, a newly recognized antagonist for canonical Wnt signaling, is secreted in the early stage of human adipose-derived stem cells (ASCs) adipogenic differentiation. This study was aimed to investigate whether human recombinant DKK-1 (rhDKK-1) could affect the differentiation and metabolism as well as adipocytokines secretion in primary cultured human ASCs. METHODS: Human ASCs were isolated from omental adipose tissue and induced to adipogenic differentiation in the absence or presence of Wnt signaling antagonist rhDKK-1 and agonist SB216763, respectively. mRNA and protein expression profiles of adipogenic factors during the differentiation process were analyzed using quantitative RT-PCR and Western blotting. Adipocytokines secretion levels in the culture medium were measured by ELISA method. RESULTS: Our results showed that DKK-1 was already expressed during the early stage of adipogenesis and reached the peak on the 9th day. Exogenous rhDKK-1 exposure accelerated the differentiation by up-regulating PPAR-γ and C/EBP-α, down-regulating Wnt3a, Wnt10b and ß-catenin, without affecting non-canonical Wnt signaling marker (Wnt5a). In addition, rhDKK-1 treatment increased the secretion of leptin, RBP4, TNF-α and adiponectin during differentiation. rhDKK-1 treatment also significantly increased the intracellular accumulation of lipids and lipolysis. Thus, Wnt signal pathway agonist SB216763 down-regulated DKK-1 transcriptional and secretion levels during adipogenic process. CONCLUSIONS: Our results suggest that rhDKK-1 could promote ASCs differentiation and increase adipocytokines secretion via canonical Wnt signaling pathway.

Saxagliptin is similar in glycaemic variability more effective in metabolic control than acarbose in aged type 2 diabetes inadequately controlled with metformin.

This study compared the effects on glycaemic variability and glucose control between saxagliptin and acarbose as add-on therapies for aged T2DM inadequately controlled with metformin alone. The results showed that compared with acarbose-metformin, saxagliptin-metformin was more effective in glucose control with similar glycaemic variability.

Glycated haemoglobin A1c for diagnosing diabetes in Chinese subjects over 50 years old: a community-based cross-sectional study.

OBJECTIVE: Little is known about using glycated haemoglobin A1c (HbA1c) to diagnose diabetes in Chinese subjects over 50 years old. This study aims to evaluate HbA1c in diagnosing diabetes and identify the optimal threshold to be used in Chinese community subjects aged over 50 years. METHODS: A community-based cross-sectional survey was conducted from October 2010 to January 2011 in Shipai community of Guangzhou, Guangdong, China. A total of 1494 subjects (72·8%) aged over 50 years were investigated. Fasting plasma glucose (FPG1st ) and HbA1c were assayed in each participant. Diabetic candidates with FPG1st ≥ 5·6 mmol/l or HbA1c ≥ 39 mmol/mol (5·7%) were informed to undergo a 75-g oral glucose tolerance test (OGTT). Diagnosis of diabetes was made by 1999 World Health Organization criteria. Sensitivity and specificity of HbA1 c for diagnosing diabetes were calculated by receiver operating characteristics (ROC) curve. RESULTS: Among 1494 subjects, 161 subjects (10·8%) with previously diagnosed diabetes and 21 with missing data were excluded. Among the remaining 1312 subjects (87·8%), 861 subjects (65·6%) with either FPG1st ≥ 5·6 mmol/l or HbA1c ≥ 39 mmol/mol (5·7%) were invited to perform OGTT. Finally, 453 subjects (52·6%) performed OGTT (FPG2nd and 2-h plasma glucose were measured) and 54 subjects (11·9%) were identified as being diabetes. The area under ROC curve was 0·916 (0·887-0·940) for HbA1c and 0·972 (0·953-0·985) for FPG2nd in diagnosing diabetes (P = 0·045). An HbA1c threshold of 48 mmol/mol (6·5%) yielded the highest combination of sensitivity (75·9%) and specificity (95·5%) for diagnosing diabetes. CONCLUSION: An HbA1 c threshold of 48 mmol/mol (6·5%) was highly specific and had a good sensitivity for diagnosing diabetes among Chinese subjects aged over 50 years with FPG ≥ 5·6 mmol/l or HbA1c ≥ 39 mmol/mol (5·7%). This threshold may be suitable for diagnosing diabetes in Chinese subjects over 50 years old.

[Primary culturing and effects of insulin glargine on proliferation, differentiation of human preadipocytes from subcutaneous and omental adipose tissue].

OBJECTIVE: To compare the morphological and functional differences of human primary preadipocytes from different fat depots and explore the effects of insulin glargine on their proliferation and differentiation. METHODS: Primary preadipocytes isolated from human subcutaneous and omental adipose tissue by collagenase I were passaged in vitro.Inverted phase contrast microscope was used to observe the morphological differences of two kinds of preadipocytes. Then two kinds of preadipocytes were cultured or induced to differentiation with different doses of insulin glargine. The methyl thiazolyl tetrazolium (MTT) assay was used to detect their proliferative differences.Reverse transcription-polymerase chain reaction (RT-PCR) was used to observe the effects of insulin on adipogenic gene expression. RESULTS: (1) Both preadipocytes could be successfully cultured from adipose tissue and amplified in vitro.Subcutaneous preadipocytes were more slender and proliferated more quickly while omental preadipocytes were polygonal and aged easily.(2) MTT results showed that insulin glargine could inhibit the proliferation of omental preadipocytes in a dose-dependent fashion. After 72 h incubation, compared with negative control, the absorbance (A) value of 1000 nmol/L insulin glargine group decreased greatly (0.144 ± 0.021 vs 0.267 ± 0.040, P < 0.01). But it had no effect on subcutaneous preadipocytes (0.305 ± 0.045 vs 0.350 ± 0.037, P > 0.05). (3) Insulin at 500 nmol/L was a suitable concentration for inducing differentiation.RT-PCR analysis showed that, for subcutaneous adipocytes, adipogenic genes such as peroxisome proliferator-activated receptor gamma (PPARγ) (F = 31.31, P < 0.01) and CCAAT enhancer binding protein α (C/EBPα) (F = 9.86, P < 0.05) had the highest mRNA expression while preadipocytes gene Pref-1 had the lowest expression at this concentration. But insulin dose had no obvious effect on PPARγ or C/EBPα mRNA (P > 0.05) for omental adipocytes. CONCLUSION: Insulin glargine could inhibit the proliferation of omental preadipocytes, and enhance the differentiation of subcutaneous and omental preadipocytes.

Gly482Ser mutation impairs the effects of peroxisome proliferator-activated receptor γ coactivator-1α on decreasing fat deposition and stimulating phosphoenolpyruvate carboxykinase expression in hepatocytes.

Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a transcriptional coactivator of nuclear receptor peroxisome proliferator-activated receptor γ that critically regulates glucose and fat metabolism. Although clinical evidence suggests that Gly482Ser polymorphism of PGC-1α is associated with an increased incidence of nonalcoholic fatty liver disease, a direct role for Gly482Ser mutation in altering PGC-1α actions on hepatocyte fat deposition remains to be explored. We hypothesized that Gly482Ser mutation impairs the abilities of PGC-1α in ameliorating overnutrition-induced hepatocyte fat deposition and in stimulating hepatocyte expression of cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C; encoded by a key PGC-1α target gene). In the present study, treatment of cultured hepatocytes with palmitate induced fat deposition, serving as a cell model of hepatic steatosis. Upon overexpression of wild-type PGC-1α, H4IIE cells exhibited a significant decrease in palmitate-induced hepatocyte fat deposition compared with control cells and/or cells upon overexpression of mutant PGC-1α (Gly482Ser). Overexpression of wild-type PGC-1α, but not mutant PGC-1α, also caused a significant increase in hepatocyte expression of carnitine palmitoyl transferase 1a, a rate-determining enzyme that transfers long-chain fatty acids into mitochondria for oxidation. In addition, overexpression of mutant PGC-1α did not stimulate PEPCK-C expression as overexpression of wild-type PGC-1α did, likely due to a decrease in the ability of mutant PGC-1α in increasing PEPCK promoter transcription activity. Together, these results suggest that Gly482Ser mutation impairs the abilities of PGC-1α in decreasing fat deposition and in stimulating PEPCK-C expression in cultured hepatocytes.

Caveolin-3 is involved in the protection of resveratrol against high-fat-diet-induced insulin resistance by promoting GLUT4 translocation to the plasma membrane in skeletal muscle of ovariectomized rats.

Insulin resistance is recognized as a common metabolic factor which predicts the future development of both type 2 diabetes and atherosclerotic disease. Resveratrol (RSV), an agonist of estrogen receptor (ER), is known to affect insulin sensitivity, but the mechanism is unclear. Evidence suggests that caveolin-3 (CAV-3), a member of the caveolin family, is involved in insulin-stimulated glucose uptake. Our recent work indicated that estrogen via ER improves glucose uptake by up-regulation of CAV-3 expression. Here, we investigated the role of CAV-3 in the effect of RSV on insulin resistance in skeletal muscle both in vivo and in vitro. The results demonstrated that RSV ameliorated high-fat-diet (HFD)-induced glucose intolerance and insulin resistance in ovariectomized rats. RSV elevated insulin-stimulated glucose uptake in isolated soleus muscle in vivo and in C2C12 myotubes in vitro by enhancing GLUT4 translocation to the plasma membrane rather than increasing GLUT4 protein expression. Through ERα-mediated transcription, RSV increased CAV-3 protein expression, which contributed to GLUT4 translocation. Moreover, after knockdown of CAV-3 gene, the effects of RSV on glucose uptake and the translocation of GLUT4 to the plasma membrane, as well as the association of CAV-3 and GLUT4 in the membrane, were significantly attenuated. Our findings demonstrated that RSV via ERα elevated CAV-3 expression and then enhanced GLUT4 translocation to the plasma membrane to promote glucose uptake in skeletal muscle, exerting its protective effects against HFD-induced insulin resistance. It suggests that this pathway could represent an effective therapeutic target to fight against insulin resistance syndrome induced by HFD.

Effects of a combination of oral anti-diabetes drugs with basal insulin therapy on ß-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes.

BACKGROUND: Oral anti-diabetes drugs plus basal insulin (OAD + insulin) therapy in patients with newly diagnosed type 2 diabetes might improve ß-cell function and result in extended glycaemic remission. This randomised trial compared the effect on ß-cell function and diabetes remission rate between oral drug alone or with addition of basal insulin. METHODS: One hundred and twenty-nine patients, aged 35-50 years, were enrolled between June 2005 and June 2009. For initial correction of hyperglycaemia, patients with fasting plasma glucose ≥9.0 mmol/L and HbA(1c) ≥ 9.0%, were randomly assigned to therapy with oral drugs + insulin or oral drugs alone. Treatment was stopped after normoglycaemia was maintained for 3 months. Patients were then followed-up with diet and physical exercise. Blood glucose, HbA(1c) and insulin were measured prior to treatment and at 1-year follow-up. RESULTS: More patients achieved target glycaemic control in the oral drugs + insulin group [98.3% (58 of 59)] in less time [(10.4 ± 2.5) days] than those in the oral drug group [95.7% (67 of 70) and (12.4 ± 3.4) days]. At 1-year follow-up, more patients maintained target glycaemia without any drugs in the oral drug + insulin group than in the oral drug group [37.9% (22 of 58) vs 20.9% (14 of 67)]. Both treatments improved homeostasis model assessment-ß (HOMA-ß) and homeostasis model assessment-insulin resistance (HOMA-IR) significantly. They had similar effects on insulin resistance [lg(HOMA-IR): (0.50 ± 0.09) vs (0.48 ± 0.09), p = 0.23]. However, oral drugs + insulin could recover ß-cell function much more than OAD alone could [lg(HOMA-ß): (2.17 ± 0.14) vs (2.11 ± 0.13), p = 0.03]. CONCLUSION: In newly diagnosed type 2 diabetes, therapy with oral drugs + insulin has had favourable outcomes on recovery and maintenance of ß-cell function and protracted glycaemic remission compared with treatment with oral drugs alone.