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Title

Current trends in small molecule discovery targeting key cellular signaling events towards the combined management of diabetes and obesity

 

Authors

Kadapakkam Nandabalan Sangeetha1, Sundaresan Sujatha1, Velusamy Shanmuganathan
Muthusamy1, Singaravel Anand1, Kusampudi Shilpa1, Posa Jyothi kumari1, Baskaran
Sarathkumar1, Gopal Thiyagarajan1, Baddireddi Subhadra Lakshmi1, 2*

 

Affiliation

1Department of Biotechnology, Anna University, Chennai Tamilnadu, India 600 025;

2Centre for Food Technology, Department of Biotechnology, Anna University, Chennai Tamilnadu, India 600 025;

 

E-mail

lakshmibs1@gmail.com

 

Article Type

Review

 

Date

Received December 17, 2017; Revised December 19, 2017; Accepted December 19, 2017; Published December 31, 2017;

 

Abstract

Non-insulin dependent diabetes mellitus, also known as Type 2 diabetes is a polygenic disorder leading to abnormalities in the carbohydrate and lipid metabolism. The major contributors in the pathophysiology of type 2 diabetes (T2D) include resistance to insulin action, β cell dysfunction, an abnormality in glucose metabolism and storage, visceral obesity and to some extent inflammation and oxidative stress. Insulin resistance, along with a defect in insulin secretion by the pancreatic β cells is instrumental towards progression to hyperglycemia. Increased incidence of obesity is also a major contributing factor in the escalating rates of type 2 diabetes. Drug discovery efforts are therefore crucially dependent on identifying individual molecular targets and validating their relevance to human disease. The current review discusses bioactive compounds from medicinal plants offering enhanced therapeutic potential for the combined patho-physiology of diabetes and obesity. We have demonstrated that 3β-taraxerol a pentacyclic triterpenoid (14-taraxeren-3-ol) isolated from the ethyl acetate extract of Mangifera indica, chlorogenic acid isolated from the methanol extract of Cichorium intybus, methyl tetracosanoate from the methanol extract of Costus pictus and vitalboside A derived from methanolic extract of Syzygium cumini exhibited significant effects on insulin stimulated glucose uptake causing insulin sensitizing effects on 3T3L1 adipocytes (an in vitro model mimicking adipocytes). Whereas, (3β)-stigmast-5-en-3-ol isolated from Adathoda vasica and Aloe emodin isolated from Cassia fistula showed significant insulin mimetic effects favoring glucose uptake in L6 myotubes (an in vitro model mimicking skeletal muscle cells). These extracts and molecules showed glucose uptake through activation of PI3K, an important insulin signaling intermediate. Interestingly, cinnamic acid isolated from the hydro-alcohol extract of Cinnamomum cassia was found to activate glucose transport in L6 myotubes through the involvement of GLUT4 via the PI3K-independent pathway. However, the activation of glucose storage was effective in the presence of 3β-taraxerol and aloe emodin though inhibition of GSK3β activity. Therefore, the mechanism of improvement of glucose and lipid metabolism exhibited by the small molecules isolated from our lab is discussed. However, Obesity is a major risk factor for type-2 diabetes leading to destruction of insulin receptors causing insulin resistance. Identification of compounds with dual activity (anti-diabetic and antiadipogenic activity) is of current interest. The protein tyrosine phosphatase 1B (PTP1B) is an important negative regulator of the insulin and leptin-signaling pathway is of significance in target definition and discovery.

 

Keywords:

Diabetes, Obesity, PTP1B inhibitors, PPAR modulators, Natural products

 

Citation

Sangeetha et al. Bioinformation 13(12): 394-399 (2017)

 

Edited by

P Kangueane

 

ISSN

0973-2063

 

Publisher

Biomedical Informatics

 

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.