Xiaoying He

Effect of early insulin therapy on nuclear factor κB and cytokine gene expressions in the liver and skeletal muscle of high-fat diet, streptozotocin-treated diabetic rats

To clarify the effect of early insulin therapy on nuclear factor κB (NFκB) pathway and inflammatory cytokine responses in the liver and skeletal muscle in type 2 diabetes. High-fat diet and low dose streptozotocin (STZ) induced diabetic rats were given NPH insulin or gliclazide for 3 weeks initiated at the 3rd day after STZ injection as early treatment and NPH for 3 weeks at 1 month as late treatment. Intraperitoneal glucose tolerance test (IPGTT) was performed at 3rd day after the end of treatment. Early interventions caused a decrease in glucose-insulin index in IPGTT, promoted glucose transporter 4 (Glut4) gene and protein expressions in muscle and reduced phosphoenolpyruvate carboxykinase (PEPCK) protein levels in the liver. There was an increase in inhibitor κB (IκBα) protein and a decrease in NFκB p65 DNA binding activity. A decreased level in mRNAs encoding tumor necrosis factor (TNF)α in the liver and muscle and interleukin (IL)-1β in the liver were observed. Our results suggested that early insulin treatment inhibits NFκB activity and inflammatory cytokine responses in the liver and skeletal muscle that were involved in the amelioration of insulin resistance in type 2 diabetic rats.

Insulin therapy stimulates lipid synthesis and improves endocrine functions of adipocytes in dietary obese C57BL/6 mice.

AbstractAim:To evaluate whether insulin intervention could affect the metabolic and endocrine functions of adipose tissue.Methods:C57BL/6 mice were fed on a high-fat-diet for 12−16 weeks to induce insulin resistance. Insulin intervention was administered in the high-fat-diet mice for 4 weeks at 12 weeks (early insulin treatment) or 16 weeks (late insulin treatment). Intraperitoneal glucose tolerance tests were performed before and after insulin treatment. Expression levels of factors involved in the triglyceride synthesis and endocrine functions of adipose tissue including phosphoenolpyruvate carboxykinase (PEPCK-C), fatty acid synthase (FAS), aquaporin 7 (AQP7), adiponectin, visfatin, and interleukin-6 (IL-6) were determined by Western blot.Results:In the obese mice, glucose tolerance was impaired; triglyceride content was increased in the liver tissue; protein expression of FAS and adiponectin was decreased; expression of visfatin was increased in adipose tissue. After 4-week insulin treatment, glucose tolerance was improved; triglyceride content was decreased in the liver and skeletal muscle; expression of PEPCK-C, FAS, and adiponectin was increased in the adipose tissue; IL-6 and AQP7 expression was reduced in the fat. Early insulin treatment had better effect in increasing the expression of FAS and PEPCK-C and decreasing the expression of IL-6.Conclusion:These results indicate that insulin can target adipocytes for improvement of insulin sensitivity through stimulating triglyceride synthesis and partly improving endocrine functions.

Down-regulation of SOSTDC1 promotes thyroid cancer cell proliferation via regulating cyclin A2 and cyclin E2

Sclerostin domain containing protein 1 (SOSTDC1) is down-regulated and acts as a tumor suppressor in some kinds of cancers. However, the expression pattern and biological significance of SOSTDC1 in thyroid cancer are largely unknown. We demonstrated that SOSTDC1 was significantly down-regulated in thyroid cancer. Ectopic over-expression of SOSTDC1 inhibited proliferation and induced G1/S arrest in thyroid cancer cells. Moreover, SOSTDC1 over-expression suppressed the growth of tumor xenografts in nude mice. We also found that elevated SOSTDC1 led to inhibition of cyclin A2 and cyclin E2. Together, our results demonstrate that SOSTDC1 is down-regulated in thyroid cancer and might be a potential therapeutic target in the treatment of thyroid cancer.

Inhibition of obesity-induced hepatic ER stress by early insulin therapy in obese diabetic rats

To understand the mechanism by which early insulin therapy improves insulin sensitivity in type 2 diabetes, we investigated endoplasmic reticulum (ER) stress in the liver of type 2 diabetic rats. A high fat diet plus a low dose of streptozotocin (STZ) in Sprague–Dawley (SD) rats was implemented to create an animal model mimicking diabetes. After 3xa0weeks of insulin treatment, the rats were examined for insulin sensitivity and ER stress in the liver. To investigate insulin sensitivity within the liver, serine phosphorylation of IRS-1 (Ser307) and Akt (Ser473) and expression of gluconeogenic genes, PEPCK and G6Pase, were tested. Protein levels of ER stress markers, such as immunoglobulin binding protein (Bip), inositol-requiring protein 1 alpha (IRE1α), and unspliced and spliced x-box binding protein-1 (XBP-1), were determined to assess ER stress. In the diabetic (DM) group, IRS-1 phosphorylation was increased (Pxa0<xa00.05), Akt phosphorylation was reduced (Pxa0<xa00.05), expression of PEPCK and G6Pase was elevated (Pxa0<xa00.05), and ER stress markers were up-regulated (Pxa0<xa00.05) relative to the non-diabetic rats. In the insulin (INS) therapy group, all of aforementioned changes were attenuated or reversed (Pxa0<xa00.05). In addition, c-Jun N-terminal kinase (JNK) activity and SREBP-1 expression were decreased (Pxa0<xa00.05). Adipose tissue mass was increased (Pxa0<xa00.05). These data suggest that short-term insulin therapy relieved ER stress and enhanced insulin sensitivity in the liver of diabetic rats. The mechanism is likely related to fat redistribution from liver to adipose tissue. These cellular and molecular responses may represent a mechanism for improvement of insulin sensitivity in type 2 diabetic rats by insulin therapy.

Peroxisome proliferator-activated receptor α agonist-induced down-regulation of hepatic glucocorticoid receptor expression in SD rats

It was reported that glucocorticoid production was inhibited by fenofibrate through suppression of type-1 11beta-hydroxysteroid dehydrogenase gene expression in liver. The inhibition might be a negative-feedback regulation of glucocorticoid receptor (GR) activity by peroxisome proliferator-activated receptor alpha (PPARalpha), which is quickly induced by glucocorticoid in the liver. However, it is not clear if GR expression is changed by fenofibrate-induced PPARalpha activation. In this study, we tested this possibility in the liver of Sprague-Dawley rats. GR expression was reduced by fenofibrate in a time- and does-dependent manner. The inhibition was observed in liver, but not in fat and muscle. The corticosterone level in the blood was increased significantly by fenofibrate. These effects of fenofibrate were abolished by PPARalpha inhibitor MK886, suggesting that fenofibrate activated through PPARalpha. In conclusion, inhibition of GR expression may represent a new molecular mechanism for the negative feedback regulation of GR activity by PPARalpha.

Angiopoietin-like protein 8/betatrophin correlates with hepatocellular lipid content independent of insulin resistance in non-alcoholic fatty liver disease patients

To explore angiopoietin‐like protein 8 (ANGPTL‐8) levels, and its association with hepatocellular lipid content (HCL) and insulin resistance in patients with different extents of non‐alcoholic fatty liver disease (NAFLD).

Exendin-4 promotes pancreatic β-cell proliferation via inhibiting the expression of Wnt5a

Exendin-4, a glucagon-like peptide-1 receptor agonist, is currently regarded as an effective therapeutic strategy for type-2 diabetes. Previous studies indicated that exendin-4 promoted β cell proliferation. However, the underlying mechanisms remain largely unknown. Recently it was reported that exendin-4 promoted pancreatic β cell proliferation by regulating the expression level of Wnt4. The present study was designed to investigate whether other Wnt isoforms take part in accommodation of β-cell proliferation. We found that exendin-4 promotes the proliferation and suppresses the expression of Wnt5a in INS-1 cell line and C57Bl/6 mouse pancreatic β-cells. Further mechanistic study demonstrated that exendin-4 promoted INS-1 cell proliferation partly through down-regulating the expression of Wnt5a. Furthermore, Wnt5a could induce the activation of calmodulin-dependent protein kinase II in INS-1 cells, thereby decreasing the cellular stable β-catenin and its nuclear translocation, and finally reduce the expression of cyclin D1. In addition, we also found that both of the receptors (Frz-2 and Ror-2) mediated the effect of Wnt5a on β cell line INS-1 proliferation. Taken together, this study suggests that Wnt5a plays a critical role in exendin-4-induced β-cell proliferation, indicating that Wnt5a might be a novel regulator in counterbalance of β cell mass.

Glucose metabolism, insulin sensitivity and β-cell function in type A insulin resistance syndrome around puberty: a 9-year follow-up.

Diabetes mellitus is thought to be progressive. Insufficient insulin secretion in compensation for insulin resistance leads to glucose intolerance. A previously reported proband with type A insulin resistance syndrome and her younger twin brothers with and without the R1174W missense mutation in the insulin receptor gene were followed for 9 years to study the progression of glucose metabolism, insulin sensitivity, and β-cell function around puberty. Five-hour OGTT was performed in them at each visit. Areas under the curves of glucose, insulin and C-peptides, insulinogenic index, AIR, and Homa indices were assessed. Intramyocellular lipids (IMCLs) were quantified in the proband and compared to those of 12 nondiabetic subjects, 118 newly diagnosed type 2 diabetic patients. The proband maintained normal HbA1c (27-37u2009mmol/mol) and fasting plasma glucose (3.7-4.5u2009mmol/l), and her glucose tolerance ameliorated over years. The probands Homa-IR decreased into adulthood, while her Homa-B, insulinogenic index, AIR, AUCs of insulin, and C-peptide decreased accordingly. Homa-B to Homa-IR ratios stayed significantly higher than normal. Homa-B, AUCs of insulin, and C-peptide of the twin brothers increased in response to the increment of Homa-IR as they entered middle and late puberty. The changes were more dramatic in the twin brothers carrying the mutation. IMCLs of the proband were lower than those of the nondiabetic counterparts and were disproportional for the degree of insulin resistance. Our longitudinal data of type A insulin resistance syndrome around puberty provide significant information for the study of insulin secretion in compensation for insulin resistance.

Lower mean blood glucose during short‐term intensive insulin therapy is associated with long‐term glycemic remission in patients with newly diagnosed type 2 diabetes: Evidence‐based recommendations for standardization

Optimal glycemic targets during short‐term intensive insulin therapy in patients with newly diagnosed type 2 diabetes are not standardized. The present study was carried out to determine the optimal glycemic targets during therapy by analyzing the impacts of glucose levels on therapeutic outcomes.

Glimepiride treatment in a patient with type A insulin resistance syndrome due to a novel heterozygous missense mutation in the insulin receptor gene

Glimepiride is a sulfonylurea known to have unique insulin mimetic and sensitizing effects. We aimed to study the efficacy of glimepiride in a patient with type A insulin resistance syndrome.