Design, synthesis and evaluation of phenoxyacetic acid-based PTP1B inhibitors / 药学学报

Protein tyrosine phosphatase (PTP) 1B is a potential therapeutic target for type 2 diabetes. Phosphotyrosine (pTyr) mimetics still dominate the currently available PTP1B inhibitors. The phenoxyacetic acid moiety was taken as a pTyr mimetic herein and phenoxyacetic acid-based compounds 2a-2g and 3a-3c were designed. Among them, compounds 2a-2g exhibited potent inhibition against PTP1B, and compound 2g showed an IC50 of 0.42 μmol·L-1 against PTP1B. Compound 2f exhibited pharmacological profiles similar to that of rosiglitazone, and could improve the insulin sensitivity and the serum total cholesterol level. The results suggest that PTP1B inhibitors might be effective in treating type 2 diabetes as well as associated metabolic syndromes.

PPARγ non-agonist ligand:the structure optimization based on PPARγ partial agonist / 药学学报

Recent studies indicate that insulin-sensitizing activity of TZDs occurs through the inhibition of PPARγ Ser273 phosphorylation mediated by cyclin-dependent kinase 5(Cdk5), which is resulted from the binding activity for PPARγ. While, the side effects of TZDs may be related to the agonistic potency for PPARγ. In this article, 15 target compounds were designed and synthesized based on the structure of PPAR γ partial agonist INT131, with the aim of maintaining the insulin-sensitizing activity and reducing the side effects of INT131. The structures of these compounds were confirmed by 1H NMR and ESI-MS, and their binding activities and agonistic potencies for PPARγ were measured. The binding activity of compound 15 is 88.47% of rosiglitazone, which is similar to INT131 (98.55%), but the agonistic potency of compound 15 is 1.41% of rosiglitazone, obviously lower than INT131 (15.18%).

In silico Studies on Plant Derived Rutin as Potent Agonist of Peroxisome Proliferator-activated Receptor Gamma (PPARγ).

Aims: Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are beneficial in the management of diabetes by increasing insulin sensitivity and inhibiting hepatic gluconeogenesis. The aim of the present study was to investigate PPAR-γ agonist property of rutin, a flavonoid found in many plant species compared to thiazolidenediones (TZDs) using in silico approach. Methodology: Molecular docking of rutin on human PPAR-γ protein was determined by Vina plugin in PYMOL 1.3 and compared with thiazolidinediones, a known agonist of PPARγ. Results: Rutin acts as a potential agonist with binding energy of - 7.8 kcal/mol compared to thiazolidinediones with binding energy of - 4.1 kcal/mol. The molecular interaction of rutin was at residues of GLU 319, ILE 369, LEU 368, MET 362, PHE 321, PHE 310, LEU 497, ALA 320, LYS 289, ILE 354. Conclusion: We conclude that rutin is a better PPARγ agonist than TZDs confirming the capability of rutin for binding at the active site of the PPARγ.

Mitochondrial inhibitor as a new class of insulin sensitizer

Insulin resistance is a major risk factor for type 2 diabetes. AMP-activated protein kinase (AMPK) is a drug target in the improvement of insulin sensitivity. Several insulin-sensitizing medicines are able to activate AMPK through inhibition of mitochondrial functions. These drugs, such as metformin and STZ, inhibit ATP synthesis in mitochondria to raise AMP/ATP ratio in the process of AMPK activation. However, chemicals that activate AMPK directly or by activating its upstream kinases have not been approved for treatment of type 2 diabetes in humans. In an early study, we reported that berberine inhibited oxygen consumption in mitochondria, and increased AMP/ATP ratio in cells. The observation suggests an indirect mechanism for AMPK activation by berberine. Berberine stimulates glycolysis for ATP production that offsets the cell toxicity after mitochondria inhibition. The study suggests that mitochondrial inhibition is an approach for AMPK activation. In this review article, literature is critically reviewed to interpret the role of mitochondria function in the mechanism of insulin resistance, which supports that mitochondria inhibitors represent a new class of AMPK activator. The inhibitors are promising candidates for insulin sensitizers. This review provides a guideline in search for small molecule AMPK activators in the drug discovery for type 2 diabetes.

Polycystic Ovary Syndrome and Insulin Resistance / 대한산부인과학회지

Polycysytic Ovary Syndrome (PCOS) is a common endocrine disorder characterized by chronic anovulation and hyperandrogenism. The etiology of PCOS is complex and incompletely understood. Accumulating data conclude that hyperinsulinemia and hyperandrogenemia may cause hormonal abnormalities that lead to disturbance of ovarian function. Although insulin resistance is not a part of the diagnostic criteria for PCOS, its importance in its pathogenesis can not be ignored. Excess insulin is capable of stimulating steroidogenesis and therefore excessive androgen production occurs from the theca cell system. Recently, the effects of insulin sensitizer in PCOS patients are being reported and they include the improvement of menstrual pattern, improvement in hyperandrogenism, increased response in ovulation induction and prevention of cardiovascular diseases. Understanding the relation of PCOS and insulin resistance will offer an improvement in treatment of PCOS in the future.

Therapeutic Effects of Metformin and Rosiglitazone in Korean Women with Polycystic Ovary Syndrome / 대한내분비학회지

BACKGROUND: Insulin resistance is a central feature of polycystic ovary syndrome (PCOS), and hyperinsulinemia contributes to anovulation, oligo or amenorrhea, hyperandrogenism and infertility in women with PCOS. The use of insulin sensitizers, such as metformin or thiazolidinedione, in PCOS is becoming increasingly accepted. The purpose of our study was to evaluate the therapeutic effects of metformin and rosiglitazone on the metabolic and reproductive derangement, and find parameters predicting their therapeutic efficacy in Korean PCOS women. METHODS: Sixty-two women with PCOS were recruited. The baseline characteristics, including BMI, glucose tolerance test, lipid profiles, sex hormones and hyperinsulinemic euglycemic clamp test, were assessed. After the administration of the insulin sensitizer (metformin 1.5g/day or rosiglitazone 4mg/day) for 3 months, the insulin sensitivity was reassessed. A drug response was defined as menstrual restoration or pregnancy. RESULTS: Of the 62 women with PCOS, 36 gained restored regular menstruation, and a further 5 conceived (a drug response rate of 66.7%). There were no significant clinical differences between responders and nonresponders. Twelve weeks after taking the drugs, the insulin sensitivity was significantly improved (M-value 4.7+/-0.2 vs. 5.5+/-0.4mg/kg/min, P<0.05), and the free testosterone levels(72.5+/-39.9 vs. 45.8 +/-3.8pmol/L, P<0.05) were significantly decreased, without significant weight reduction. CONCLUSION: Metformin and rosiglitazone restored menstruation in 66.1% of women with PCOS. Hyperandrogenemia and insulin sensitivity were significantly improved with the use of the two drugs. However, metabolic or hormonal markers for predicting the drug response could not be found.

Insulin sensitizers in treatment of nonalcoholic fatty liver disease / 中国实用内科杂志

Nonalcoholic fatty liver disease(NAFLD)has become one of the most common liver diseases in the world.Considering the important role of insulin resistance in its pathogenic mechanisms,insulin sensitizers are becoming the promising pharmacological strategies for NAFLD.We collected and analyzed the relevant articles in recent years and found that pioglitazone,rosiglitazone and metformin could improve liver enzymes and insulin sensitivity of NAFLD.However,only pioglitazine was supported in ameliorating liver histology by envidences from randomized,double-blinded,controlled clinical trials.There were no much obvious adverse effects in NAFLD patients who received insulin senitizers.Small or medium samples and no more than 2 years of treatment course may be the major limitation of current studies.Future information derived from well-designed running trials will be useful in defining the clinical implications of insulin sensitizers in the treatment of NAFLD.

Progress in Alzheimer's disease treated with insulin sensitizer / 中华内分泌代谢杂志

In Alzheimer's disease there is obvious evidence of insulin resistance in the brain. Thiazolidinediones,a kind of insulin sensitizer,not only improves insulin sensitivity,but also decreases inflammation,promotes release and clearance of?-amyloid protein,all are beneficial to the improvement of memory.

Preliminary study of insulin resistance induced by neonatal monosodium glutamate treatment in normal Wistar rats / 中国药理学通报

AIM To study the glucose and lipids metabolism and insulin sensitivity of MSG rats during their growing period, and to evaluate the effects of insulin sensitizer pioglitazone on the model rats. METHODS Body weights were measured regularly, and glucose and insulin tolerance tests were taken. In their 3 and 10 months old, rats were given insulin sensitizer pioglitazone orally, then the effects on serum glucose, triglyceride, cholesteral, free fatty acid and insulin concentrations were determined. RESULTS Compared with normal rats, a slight but significant increase of glucose in MSG rats was revealed. The serum triglyceride, cholesteral, free fatty acid and insulin concentrations were significantly higher in model rats. Moreover, gluconeogenesis increased significantly, and insulin tolerance showed abnormal. However, glucose tolerance was nearlly normal. Pioglitazone could ameliorate all these metabolic disorders. CONCLUSION Obesity and insulin resistance were induced by injecting monosodi- um glutamate (MSG) to neonatal Wistar rats. Piogli- tazone can significantly improve the insulin sensitivity of Msc rats. These results suggested that MSG obese rats can be used as an easily accessible and inexpensive insulin resistance animal model for evaluating the efficacy and mechanisms of antidiabetic agents.

The update research on selective PPAR? modulator in anti-diabetic treatment / 中国药理学通报

PPAR? is a kind of nuclear receptors responsible for the regulation of glucose and lipid metabolisim and adipocyte difference,which is related with the pathogenesis of obesity,insulin resistance and type 2 diabetes mellitus.PPAR? agonists as insulin sensitizer have been used in the clinical treatment for type 2 diabetes for more than decades.Recently,with the further research plunging into the PPAR signaling pathway and insulin sensitizer,the recognition of this crucial nuclear receptor has been renewed and developed.The aim of this review is to report the update research outcomes.