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Our previous studies have implicated genes mainly involved in the activity of pancreatic β cells in type 2 diabetes (T2D) susceptibility in the North Indian population. Recent literature on the role of SIRT1 as a potential master switch modulating insulin secretion and regulating gene expression in pancreatic β cells has warranted an evaluation of SIRT1 promoter region polymorphisms in the North Indian population, which is the main focus of the present study. 1542 samples (692 T2D patients and 850 controls) were sequenced for the 1.46 kb region upstream the translation start site of the SIRT1 gene. We performed a functional characterization of the SIRT1 promoter region polymorphisms using luciferase assay and observed a single-nucleotide polymorphism (SNP), rs12778366, in association with SIRT1 expression. We propose that TT, the high-expressing genotype of SNP rs12778366 in the SIRT1 promoter region and present in >80% of the North Indian population, was favored under conditions of feast-famine cycles in evolution, which has turned out to be a cause of concern in the present sedentary lifestyle under ad libitum conditions. Case-control association analysis did not implicate rs12778366 in T2DM per se in the studied population. However, our earlier reported risk genotype combinations of mt-ND3, PGC1α, and UCP2-866, when compared with the protective genotype combinations, in the background of the high-expressing TT genotype of SIRT1 SNP rs12778366, showed a very high additive risk [corrected odd ratio (OR) = 8.91; p = 6.5×10−11]. The risk level was considerably low in the genotype backgrounds of TX (OR = 6.68; p = 2.71×10−12) and CX (OR = 3.74; p = 4.0×10−3). In addition, we screened other reported T2D-associated polymorphisms: PIK3R1 rs3730089, IRS1 rs1801278, and PPP1R3 rs1799999, which did not show any significant association in North Indian population. The present paper emphasizes the importance of gene interactions in the biological pathways of T2D, a complex lifestyle disease.

Terminalia aquna (T. aduna) stem bark was successively extracted with petroleum ether (A), solvent ether (B), ethanol (C) and water (D). The lipid lowering activity of these four fractions A, B, C, and D was evaluated in vivo in two models viz., triton WR-1339 induced hyperlipemia in rats as well as fructose rich high fat diet (HFD) fed diabetic-dyslipidemic hamsters. Hyperlipidemia induced by triton caused marked increase in the plasma levels of total cholesterol (-Fc), triglyceride (Tg) and phospholipids (PL) in rats. After treatment with T. a~una fractions A, B, C, and D at the doses of 250 mg/kg per oral (p.o.), only the ethanolic fraction (C) exerted significant lipid lowering effect as assessed by reversal of plasma levels of Tc, Tg and PL in hyperlipidemic rats. In another experiment, feeding with HFD produced marked dyslipidemia as observed by increased levels of plasma Tc, Tg, glucose (Glu), glycerol (Gly) and free fatty acids (FFA) in hamsters. After treatment with T. arjuna fractions at the doses of 250 mg/kg p.o. only two fractions (B and C) could exert significant lowering in the plasma levels of lipids and Glu. in dyslipidemic hamsters. In vitro experiment T. arjuna fractions at tested concentrations (50-500 pg/ml) inhibited the oxidative degradation of lipids in human low density lipoprotein and rat liver microsomes induced by metal ions. These fractions when tested against generation of oxygen free radicals at the concentrations (50-500 iglml), counteracted the formation of superoxide anions (0 2) and hydrodyl radicals (OH) in non enzymic test systems. The efficacy of T. a~una fractions as antidysiipidemic and antioxidant agents was found, fraction C> fraction B> fraction A. KEY WORDSAntidyslipidemic activity, antioxidant activity, Terminalia arjuna oxygen free radical, triton model, hamster model.

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Visen, P.K.S., B. Shukla, G.K. Patnaik, S. Kaul, N.K. Kapoor, and B.N. Dhawan: Hepatoprotective activity of picroliv, the active principle of Picrorhiza kurrooa, on rat hepatocytes against paracetamol toxicity. Drug Dev. Res. 22:209-219, 1991. Picroliv, the active principle an iridoid glycoside mixture isolated from the plant Picrorhiza kurrooa, showed dose-dependent (0.75-1 2 mg/kg x 7 days) protective activity on isolated hepatocytes (ex vivo) against paracetamol-induced hepatic damage in rats. It increased the percent viability of the hepatocytes. Picroliv also restored the normal values of enzyme (glutamic oxaloacetic transaminase [GOT], glutamic-pyruvic transaminase [GPT], and alkaline phosphatase) both in the isolated hepatocyte suspension as well as in the serum. Picroliv was found to be more potent than silymarin, a known hepatoprotective agent.