title: Effects of acutely inhibiting PI3K isoforms and mTOR on regulation of glucose metabolism in vivo.
abstract: In in vitro studies class-I PI3Ks (phosphoinositide 3-kinases), class-II PI3Ks and mTOR (mammalian target of rapamycin) have all been described as having roles in the regulation of glucose metabolism. The relative role each plays in the normal signalling processes regulating glucose metabolism in vivo is less clear. Knockout and knockin mouse models have provided some evidence that the class-I PI3K isoforms p110α, p110β, and to a lesser extent p110γ, are necessary for processes regulating glucose metabolism and appetite. However, in these models the PI3K activity is chronically reduced. Therefore we analysed the effects of acutely inhibiting PI3K isoforms alone, or PI3K and mTOR, on glucose metabolism and food intake. In the present study impairments in glucose tolerance, insulin tolerance and increased hepatic glucose output were observed in mice treated with the pan-PI3K/mTOR inhibitors PI-103 and NVP-BEZ235. The finding that ZSTK474 has similar effects indicates that these effects are due to inhibition of PI3K rather than mTOR. The p110α-selective inhibitors PIK75 and A66 also induced these phenotypes, but inhibitors of p110β, p110δ or p110γ induced only minor effects. These drugs caused no significant effects on BMR (basal metabolic rate), O2 consumption or water intake, but BEZ235, PI-103 and PIK75 did cause a small reduction in food consumption. Surprisingly, pan-PI3K inhibitors or p110α inhibitors caused reductions in animal movement, although the cause of this is not clear. Taken together these studies provide pharmacological evidence to support a pre-eminent role for the p110α isoform of PI3K in pathways acutely regulating glucose metabolism.
authors.affiliation: Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
authors.forename: Greg C
authors.initials: GC
authors.lastname: Smith
authors.forename: Wee Kiat
authors.initials: WK
authors.lastname: Ong
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Rewcastle
authors.forename: Jackie D
authors.initials: JD
authors.lastname: Kendall
authors.forename: Weiping
authors.initials: W
authors.lastname: Han
authors.forename: Peter R
authors.initials: PR
authors.lastname: Shepherd
mesh_terms: D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005663:Furans / Q000493:pharmacokinetics / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006835:Hydrazones / Q000493:pharmacokinetics / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D005663:Furans; D006835:Hydrazones; D007093:Imidazoles; D007527:Isoenzymes; C522973:PI103; C549211:PIK 75; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011804:Quinolines; D013449:Sulfonamides; C546843:mTOR protein, mouse; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; D005947:Glucose; C531198:dactolisib