NOVEL ANTI-DIABETES MECHANISM – NEXT GENERATION OF IMPROVED THERAPIES
Kambham Venkateswarlu1*, N.Devanna2, R.Venu Priya3, P.Bharath Rathna Kumar4
1M.Pharm Scholar, Department Of Pharmaceutics,
2Faculty Of Pharmacy, Department Of Pharmaceutical Chemistry,
3Faculty Of Pharmacy, Department Of Pharmaceutical Analysis,
4Director Of JNTUA-Otri
JNTUA-Oil Technological Research Institute,
Beside Collector Office, Anantapur,
Anantapur District, Andhra Pradesh, India. Pin Code: 515001
Scientists have uncovered a novel mechanism that dramatically increases insulin sensitivity and reduces the risk of developing type-2 DM and cardio vascular disease. According to American diabetes association, type-2 DM is closely associated to obesity. The new studies on DM focus on controlling a fat-regulating protein known as PPARg. In fact, excess body fat is the most problematic risk factor among all the factors of metabolic syndrome. The formation of fat cells in the body is regulated by a protein called PPARg finding of drugs that can promote increased insulin sensitization but not activate the classical fat cell generating pathway of PPARg is the thrust area for research. Hence targeting the fat regulating ability of this protein in order to treat DM important.
REFERENCE ID: PHARMATUTOR-ART-2097
PPARg is the master gene of fat cell biology. Obesity causes a modification of PPARg that leads to alteration in the expression of a no. of genes including a reduction in the production of an insulin sensitizing protein called adinopectin, and this leads to an increase in insulin resistance.
But unfortunately all the currently available drugs which target PPARg also increase fat while trying to inhibit insulin resistance.
2. ANTI-DIABETIC DRUG MECHANISM:
The process by which reprogramming of genes controlled by PPARγ protein occurs is called phosphorylation. It happens when an enzyme molecule called the cdk5 kinase gets added to this protein. Compounds which activate the enzyme cdk5 kinase are called the agonists. [1, 2]
The scientists discovered that these agonists interact with PPARγ protein in such a manner that it can cause reversed phosphorylation process. This will lead to improved production of adiponectin, which is an insulin-sensitizing protein. [1, 2]
Agonists are either full or partial. The study found that full agonists strongly interacted with a PPARy protein only to generate more fat but be less effective in stopping phosphorylation. When compared to full agonists, partial agonists were better at reversing phosphorylation. A particular partial agonist, MRL-24, interacted with the protein by targeting a potentially critical region of it associated with the phosphorylation process.[1, 2]
It was supposed that during the interaction, partial agonist MRL24 caused mutation in the receptors at the cdk5 kinase site, leading to reverse phosphorylation. As expected, blocking phosphorylation lead to increased production of adiponectin for increased insulin sensitivity, in experimental animals.[1, 2]
Moreover, highfatdiets were found to activate the cdk5 kinase and initiate phosphorylation. The conclusion can be extended on humans too. Drugs similar to MRL24 partial agonist in action, can now be developed to deal with the cdk5 kinase receptor and reverse the phosphorylation process.[1, 2]
3. PROMISING THERAPIES:
Blunting the effects of erythropoietin and anti-vascular endothelia growth factor (anti-VEGR) therapy.
Development of a quick acting insulin analog
Transportation of the pancreas or b-cells.
These findings offer a potent new target in the continuing search for new and improved anti-diabetic treatments. Currently, nearly 24 million children and adults in the United States have some form of the disease, according to the America Diabetes Association.[1, 2]
The new study, which focuses on controlling a fat-regulating protein known as PPARy, was published July 22, 2010, in the journal Nature (Volume 466, Issue 7304).
"The field has become interested in finding drugs that can promote increased insulin sensitization but not activate the classical fat cell generating pathway of PPARγ," said Patrick R. Griffin, chairman of the Department of Molecular Therapeutics at Scripps Florida who headed up the Scripps Research part of the study. "We examined the mechanism of action of compounds that bind to PPARγ that improve insulin sensitivity but have minimal induction of fat. It was clear from the studies that these compounds have a unique but overlapping mechanism with the class of drugs used clinically that target PPARγ." [1, 2]
Adipose or fat tissue lies at the center of the metabolic syndrome, a cluster of risk factors that increases the possibility of type 2 diabetes, as well as stroke, coronary artery disease, even certain cancers. Of those risk factors, excessive body fat is considered the most problematic. PPARγ can be considered the master gene of fat cell biology because it drives the conversion of cellular precursors into fat cells.[1, 2]
The collaborative studies showed obesity causes a modification on PPARγ that leads to alterations in the expression of a number of genes, including a reduction in the production of an insulin-sensitizing protein (adinopectin). This leads to an increase in insulin resistance. The reprogramming of genes controlled by PPARγ occurs when it undergoes phosphorylation (a phosphate group is added to a protein) by the cdk5 kinase, an enzyme that is involved in a number of important sensory pathways and that can be activated by pro-inflammatory proteins.[1, 2]
The scientists were able to use both full and partial agonists (compounds that activate a cellular response) to reverse these phosphorylation effects and improve the production of adinopectin. These results strongly suggest that cdk5-mediated phosphorylation is involved in the development of insulin-resistance and open the door to a novel opportunity for creating an improved generation of anti-diabetic drugs. [1, 2]
4. STUDY AND ASSAY OF DRUGS INFLUENCING INTESTINAL ABSORPTION IN RATS:
The advent of combinatorial synthesis and High throughput Screening has resulted in the rapid identification of potential lead candidates with optimum pharmacodynamics properties. Coincident with the increasing use of these technology, however, has been the greater need for methods that can rapidly and efficiently assess pharmacokinetic properties of lead candidates and in particular the ability to screen for effective bio availability of oral dosage form. [3, 4, 5, 6]
The intestinal drug absorption process is the outcome of a complex interplay of kinetic processes that depends upon physico chemical, physiclogical, anatomical, biochemical, formulation factors among which the drug solubility and intestinal permeability are the key factor impacting drug uptake from GIT. The small intestine is composed of duodenum, jejunum and ileum and is undoubtedly the main site of drug absorption due to its anatomical location just after the stomach. Because of its morphological features, such as its length and large surface area is perfectly designed for solute absorption. [3, 4, 5, 6]
5. MODELS FOR STUDYING INTESTINAL DRUG ABSORPTION:
For absorption evaluation a no.of models have been developed
1. In vitro models:
e.g., Membrane based models
Cell culture based models
Using chamber techniques
2. In situ / in vivo intestinal perfusion models:
e.g., 1. Open loop / closed loop model
2. Intestinal perfusion with venous sampling models
3. Anaesthetized large animal model
4. Cannulated conscious rat models
In situ modelsoffers the advantages over in vitro models. Although the animal has been anaesthetized and surgically manipulated, neural, endocrine, lymphatic, and mesenteric blood supplies are intact and therefore all the transport mechanisms present in a live animal should be functional. As a result absorption rates from these methods may be more realistic in magnitude than those determined from in vitro techniques. [3, 4, 5, 6]
This advance therapy has a promising role in development of future therapies for diabetes.
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4. The study and Assay of substances affecting intestinal absorption in the mouse by J.A. NISSIM British J. Pharamacol (1965) 24, 205-213.
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6. Lin, J.H. 1995 species similarities and differences in pharmacokinetics Drug Metabolism-Dispos 23, 1008-1021.
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