Diabetes and Metabolic Syndrome
Chromogranin A (ChgA), an index member of the chromogranin/ secretogranin protein family is a pro-protein that gives rise to biologically active peptides such as the dysglycemic hormone pancreastatin (PST: human ChgA250-301), the vasodilator (vascular smooth muscle relaxing) vasostatin (human ChgA1-76) and catestatin (human ChgA352-372) that acts as a potent nicotinic cholinergic receptor antagonist. PST inhibits glucose-stimulated insulin release, inhibits glucose uptake, induces glycogenolysis (glucose release) and prolonged gluconeogenesis (glucose production). The systemic ChgA knockout (KO) mice displayed the following phenotypes: (i) Higher systolic (SBP) and diastolic (DBP) blood pressure (BP), (ii) Increments of plasma catecholamine, (iii) decreased insulin level despite being euglycemic indicating increased insulin sensitivity, and iv) higher insulin sensitivity provides a protection to high fat diet induced insulin resistance. PST and its 33-49 C-terminal fragment inhibit glucagon-stimulated insulin function in-vivo. Pancreastatin activates Gα16 and phospholipase C-β2 by interacting with specific receptors in rat heart membrane. PST binds with GRP78 in liver cells. PST has three naturally occurring genetic variants. The rank order of efficacy to inhibit insulin-stimulated glucose-uptake: PST-G297S>PST-E287K>PST-WT confirm its target validation. PST has role on insulin, glucagon, somatostatin, pancreatic secretion. PST can modulate both endocrine and exocrine pancreatic secretion. PST can suppress insulin signaling by suppressing IRS1/2-phosphatidylinositol 3-kinase-Akt-FOXO-1 signaling and insulin-induced maturation of SREBP1c by PKC and a high level of NO. The rise in blood PST level with age and in diabetes suggests that PST is a negative regulator of insulin sensitivity and glucose homeostasis.
Drug Metabolism and Pharmacokinetic Studies
Analytical & Bioanalytical method development and validation as per the regulatory guidelines using HPLC and LC-MS/MS platform for estimation of molecules (NCEs/Drugs and/or metabolites, etc) in different biological matrices, formulations, extracts, etc. Estimation of pharmacokinetic parameters, bioavailability, dose-proportionality, gender variation, inter-species comparison, tissue distribution, excretion etc. Permeability/absorption characterization studies using PAMPA, Caco-2, MDCK cell line, in situ rat model, protein binding and simulated gastro-intestinal stability for new chemical entities/drugs. In vitro/in vivo metabolism of new chemical entities and/or drugs using animal models, scaling preclinical and in-vitro data to predict events in humans for preliminary assessment of safe exposure levels, determination of the metabolite profiles using liver microsomes/human recombinant CYP450 isozymes, identify Phase I or Phase II enzymes responsible for metabolite formation, predict drug interactions due to inhibition or induction of drug metabolizing enzymes. Drug-drug, herb-drug and food-drug interaction studies in combination therapy.
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