2-(3,4-Dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), a novel, synthetic small molecule that alleviates insulin resistance and lipid abnormalities.
Type-2 diabetes is growing at epidemic proportions world-wide. This report describes the effect of a novel, synthetic, small molecule 2-(3,4-dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), on metabolic abnormalities in genetic and dietary mouse models of type-2 diabetes. DHPO (20mg/kg/d i.p. for 21 days) attenuated fasting blood glucose, improved glucose disposal and corrected dyslipidemia in genetic (leptin deficient, ob/ob) and dietary (high-fat-fed) mouse models of insulin resistance. In addition, DHPO augmented 2-deoxy-d-glucose (2DG) uptake in gastrocnemius muscles of wild-type mice and in cultured myotubes. The increase in 2DG-uptake was associated with an increase in the phosphorylation of AMPK (thr-172) and its downstream effector acetyl-CoA carboxylase without any changes in the phosphorylation of Akt of insulin receptor. The AMPK inhibitor, compound C attenuated DHPO-induced glucose-uptake whereas the PI3-kinase inhibitor Wortmannin was less effective. In addition, DHPO failed to augment glucose-uptake in the gastrocnemius muscle from AMPK-alpha2-transgenic (kinase-dead) mice. Taken together, these results suggest that DHPO is a novel small molecule that alleviates impaired glucose tolerance and lipid abnormalities associated with type-2 diabetes.
Kandadi
Machender R
MR
University of Wyoming, School of Pharmacy, Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, Department of Animal Sciences, Laramie, WY 82071, USA.
Rajanna
Prabhakar K
PK
Unnikrishnan
Mazhuvancherry K
MK
Boddu
Sai P
SP
Hua
Yinan
Y
Li
Ji
J
Du
Min
M
Ren
Jun
J
Sreejayan
Nair
N
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D015507:Drugs, Investigational / Q000737:chemistry / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D007189:Indans / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D011758:Pyrroles / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use
C546459:2-(3,4-dihydro-2H-pyrrolium-1-yl)-3-oxoindan-1-olate; D001786:Blood Glucose; D015507:Drugs, Investigational; D007004:Hypoglycemic Agents; D007189:Indans; D011758:Pyrroles; C013231:pyrroline