Shiying Shao

Circulating Betatrophin Levels Are Increased in Patients With Type 2 Diabetes and Associated With Insulin Resistance

CONTEXT Betatrophin has recently attracted increasing interests as a potential β-cell regenerative therapy in diabetes. However, differences in betatrophin profiles in patients with type 2 diabetes mellitus (T2DM) remain unclear. OBJECTIVE The objective of the study was to examine circulating betatrophin levels in subjects with different glucose tolerance status and its correlation with insulin resistance. DESIGN, SETTING, AND PARTICIPANTS Serum betatrophin levels were measured using an ELISA in age-, sex-, body mass index-, and blood lipid-matched subjects with normal glucose tolerance (n = 137), isolated impaired fasting glucose (n = 69), isolated impaired glucose tolerance (n = 120), and newly diagnosed T2DM (n = 112) from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal study. RESULTS Serum betatrophin levels were elevated in patients with T2DM compared with subjects with normal glucose tolerance, isolated impaired fasting glucose, or isolated impaired glucose tolerance (798.6 ± 42.5 vs 692.7 ± 29.0, P < .05, vs 682.7 ± 43.0, P < .05, vs 646.8 ± 34.3 pg/mL, P < .01). Betatrophin levels positively correlated with the index of homeostasis model assessment of insulin resistance (partial r = 0.11); inversely correlated with quantitative insulin sensitivity check index (partial r = -0.11), the Gutt insulin sensitivity index (partial r = -0.12), and the Matsuda insulin sensitivity index (partial r = -0.11) after controlling for age, sex, body mass index, and blood lipid in all participants (all values of P < .05). CONCLUSION Circulating betatrophin levels are increased in patients with T2DM and associated with indexes of insulin resistance.

Th17 cells in type 1 diabetes

T1D is an autoimmune disorder, which involves the CD4(+) as well as CD8(+) T-cell-mediated destruction of β cells. Recently, another population of T cells (Th17) is found to be involved in T1D pathology. This review will discuss the characteristics of Th17 cells and the mechanism of Th17-mediated T1D development. Th17 cell expansion is unstrained under T1D condition. Certain Treg cells are defective in T1D and lose the control of Th17 expansion. In addition, the altered function of APCs and a subset of monocytes which spontaneously secrete IL-1β and IL-6 in T1D determine the abnormal expansion of Th17 as well. The pathogenic Th17 cells can cause the imbalance between Teff and Treg cells. Conversion from Th17 to Th1 phenotype and Th17 stimulated CTL responses may play an accessory role in T1D as well. Due to the effects of Th17 on T1D, therapeutic strategies designed to inhibit these cells are applicable and the positive effects are obvious. Taken together, Th17 may exert essential effects on the development of T1D. Identification of the underlying mechanism may inspire new viewpoints for the therapy of this disease.

Transcription factors involved in glucose-stimulated insulin secretion of pancreatic beta cells

GSIS, the most important function of pancreatic beta cell, is essential for maintaining the glucose homeostasis. Transcription factors are known to control different biological processes such as differentiation, proliferation and apoptosis. In pancreas, some transcription factors are involved in regulating the function of beta cells. In this review, the role of these transcription factors including Pdx-1, FoxO1, SREBP-1c, and MafA in GSIS is highlighted. The related molecular mechanisms are analyzed as well. Furthermore, the association between the role of transcription factors in GSIS and the development of T2DM is discussed.

Subcutaneous Administration of Liraglutide Ameliorates Alzheimer-Associated Tau Hyperphosphorylation in Rats with Type 2 Diabetes

BACKGROUND/OBJECTIVE Type 2 diabetes increases the risk for developing Alzheimers disease (AD), a progressive neurodegenerative disorder. Brain insulin resistance contributes to the pathogenesis of AD, and abnormal hyperphosphorylation of tau protein is crucial to neurodegeneration. Here we studied whether liraglutide, an agonist of glucagon-like peptide-1 (GLP-1) and a new anti-diabetic drug, can promote brain insulin signaling and inhibit tau hyperphosphorylation in the brains of type 2 diabetic rats. METHODS Type 2 diabetic rats were treated with subcutaneous administration of liraglutide (0.2 mg/kg body weight) or, as a control, saline twice a day for up to four weeks. Blood, cerebrospinal fluid (CSF), and brain tissue (n = 7 each group) were collected for analyses after liraglutide or saline administration for one, two, three, and four weeks. RESULTS We found decreased CSF insulin, hyperphosphorylation of tau at AD-relevant phosphorylation sites, and decreased phosphorylation of protein kinase B (AKT) and glycogen synthase kinase-3β (GSK-3β) in the brain, which indicated decreased insulin signaling leading to overactivation of GSK-3β, a major tau kinase, in type 2 diabetic rats. Liraglutide treatment not only ameliorated hyperglycemia and peripheral insulin resistance, but also reversed these brain abnormalities in a time-dependent manner. CONCLUSION Our results indicated that subcutaneous administration of liraglutide restores both peripheral and brain insulin sensitivity and ameliorates tau hyperphosphorylation in rats with type 2 diabetes. These findings support the potential use of liraglutide for the prevention and treatment of AD in individuals with type 2 diabetes.

Signaling molecules involved in lipid-induced pancreatic beta-cell dysfunction.

The increasing incidence of type 2 diabetes mellitus is partially due to the rising obesity rates and the elevated levels of free fatty acids (FFAs). It is known that FFAs are putative mediators of beta-cell dysfunction, which is characterized with impaired glucose-stimulated insulin secretion and increased apoptosis, being defined as lipotoxicity. To date, many factors and their related signal pathways have been reported to be involved in FFA-induced beta-cell dysfunction. However, the entire blueprint is still not obtained. Some essential and newfound effectors, including the sterol regulatory element-binding protein (SREBP)-1c, farnesoid X receptor (FXR), forkhead box-containing protein O (FoxO) 1, ubiquitin C-terminal hydrolase L (UCHL) 1, N-myc downstream-regulated gene (NDRG) 2, perilipin family proteins, silent information regulator 2 protein 1 (Sirt1), pituitary adenylate cyclase-activating polypeptide (PACAP), and ghrelin are described in this review, which may help to further understand the molecular network for lipotoxicity.

Effects of Omega-3 Fatty Acid Supplementation on Glucose Control and Lipid Levels in Type 2 Diabetes: A Meta-Analysis

Background Many studies assessed the impact of marine omega-3 fatty acids on glycemic homeostasis and lipid profiles in patients with type 2 diabetes (T2DM), but reported controversial results. Our goal was to systematically evaluate the effects of omega-3 on glucose control and lipid levels. Methods Medline, Pubmed, Cochrane Library, Embase, the National Research Register, and SIGLE were searched to identify eligible randomized clinical trials (RCTs). Extracted data from RCTs were analyzed using STATA 11.0 statistical software with fixed or random effects model. Effect sizes were presented as weighted mean differences (WMD) with 95% confidence intervals (95% CI). Heterogeneity was assessed using the Chi-square test with significance level set at p < 0.1. Results 20 RCT trials were included into this meta-analysis. Among patients with omega-3 supplementation, triglyceride (TG) levels were significantly decreased by 0.24 mmol/L. No marked change in total cholesterol (TC), HbA1c, fasting plasma glucose, postprandial plasma glucose, BMI or body weight was observed. High ratio of EPA/DHA contributed to a greater decreasing tendency in plasma insulin, HbAc1, TC, TG, and BMI measures, although no statistical significance was identified (except TG). FPG levels were increased by 0.42 mmol/L in Asians. No evidence of publication bias was observed in this meta-analysis. Conclusions The ratio of EPA/DHA and early intervention with omega 3 fatty acids may affect their effects on glucose control and lipid levels, which may serve as a dietary reference for clinicians or nutritionists who manage diabetic patients.

SREBP‐1c, Pdx‐1, and GLP‐1R involved in palmitate–EPA regulated glucose‐stimulated insulin secretion in INS‐1 cells

Impairment of glucose‐stimulated insulin secretion (GSIS) caused by glucolipotoxicity is an essential feature in type 2 diabetes mellitus (T2DM). Palmitate and eicosapentaenoate (EPA), because of their lipotoxicity and protection effect, were found to impair or restore the GSIS in beta cells. Furthermore, palmitate was found to up‐regulate the expression level of sterol regulatory element‐binding protein (SREBP)‐1c and down‐regulate the levels of pancreatic and duodenal homeobox (Pdx)‐1 and glucagon‐like peptide (GLP)‐1 receptor (GLP‐1R) in INS‐1 cells. To investigate the underlying mechanism, the lentiviral system was used to knock‐down or over‐express SREBP‐1c and Pdx‐1, respectively. It was found that palmitate failed to suppress the expression of Pdx‐1 and GLP‐1R in SREBP‐1c‐deficient INS‐1 cells. Moreover, down‐regulation of Pdx‐1 could cause the low expression of GLP‐1R with/without palmitate treatment. Additionally, either SREBP‐1c down‐regulation or Pdx‐1 over‐expression could partially alleviate palmitate‐induced GSIS impairment. These results suggested that sequent SREBP‐1c‐Pdx‐1‐GLP‐1R signal pathway was involved in the palmitate‐caused GSIS impairment in beta cells. J. Cell. Biochem. 111: 634–642, 2010.

Protective Action of Liraglutide in Beta Cells Under Lipotoxic Stress Via PI3K/Akt/FoxO1 Pathway

Liraglutide, a modified form of glucagon‐like peptide‐1 (GLP‐1), has been found to improve beta cell function in type 2 diabetes (T2DM). However, the effect of liraglutide on beta cell function under lipotoxic stress and the underlying molecular mechanisms remain unclear. In the present study, we investigated the role of PI3K/Akt/FoxO1 signaling in liraglutide‑involved beta cell protection in high free fatty acids (FFAs) condition. The apoptosis, proliferation, and insulin secretion capability of MIN6 cells and islets from C57BL/6J mice were evaluated when exposed to FFAs with/without liraglutide. The expression of effectors involved in PI3K/Akt/FoxO1signalling pathway was detected by real‐time PCR and western blotting in MIN6 cells and islets from C57BL/6J mice. Liraglutide substantially inhibited the lipoapoptosis and improved the proliferation and insulin secretion of beta cells in high FFAs condition. Western blot revealed that the phosphorylation of Akt and FoxO1 was markedly decreased under lipid stress but was elevated when treated with liraglutide. Moreover, FFAs could up‐regulate the expression levels of p27, Bax, Cidea but down‐regulate the expression levels of Pdx‐1, MafA, and NeuroD in beta cells, which was canceled by the addition of liraglutide. Moreover, LY294002, a PI3K inhibitor, could significantly abrogate all the protective actions of liraglutide against lipotoxicity. We concluded that liraglutide markedly improved beta cell function under lipid stress and that the protective action of liraglutide was mediated by activation of PI3K/Akt, which resulted in inactivation of FoxO1 along with the down‐regulation of p27, Bax, Cidea and up‐regulation of Pdx‐1, MafA, and NeuroD expressions. J. Cell. Biochem. 115: 1166–1175, 2014.

Effect and cardiovascular safety of adding rosiglitazone to insulin therapy in type 2 diabetes: A meta-analysis.

Recently, the use of rosiglitazone has been limited or withdrawn from the market as a result of cardiovascular risk. However, theoretically adding rosiglitazone to insulin could help insulin to decrease the glucose level. The present meta‐analysis was designed to investigate the effect and safety of adding rosiglitazone to insulin therapy in type 2 diabetes.

Short-Term Effects of Continuous Subcutaneous Insulin Infusion Therapy in Perioperative Patients with Diabetes Mellitus

BACKGROUND Hyperglycemia is common and hard to control in surgical patients with diabetes. We retrospectively investigated short-term effects of continuous subcutaneous insulin infusion (CSII) in perioperative patients with diabetes. PATIENTS AND METHODS Perioperative patients with diabetes discharged between January 1, 2006 and January 1, 2012 were included. Glucose control and postoperative outcomes were compared between the patients using CSII or non-CSII insulin therapy. RESULTS We identified 108 pairs of patients matched by propensity and surgical category who were using CSII therapy (CSII group) or non-CSII insulin therapy (control group). The CSII group had significantly lower fasting glucose levels (on the first postoperative day, 9.06±3.09 mmol/L vs. 11.05±4.19 mmol/L; P=0.003) and lower mean glucose levels (on the operation day, 9.93±2.65 mmol/L vs. 12.05±3.86 mmol/L; P=0.001). The CSII group also had a lower incidence of fever (on the first postoperative day, 30.4% vs. 53.2%; P=0.005). Furthermore, patients in the CSII group experienced significantly shorter postoperative intervals for suture removal (P=0.02) and hospital discharge (P=0.03). No significant difference in the total medical expenditure was observed between the two groups (P=0.47). We also made a comparison between the 30 pairs of patients who were using CSII or multiple daily insulin injection therapy but observed no significant difference between these two therapies in glucose control or postoperative outcomes. CONCLUSIONS Compared with non-CSII insulin therapy, even short-term implementation of CSII can improve the postoperative control of glucose, reduce the incidence of postoperative fever, and shorten the time for suture removal and discharge in surgical patients with diabetes.