Figure 1.
PF-04991532 regulates glucose metabolism in primary rat hepatocytes.
Structure of PF-04991532 [(S)-6-(3-Cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1yl)propanamido)nicotinic acid] (A) increased glucose uptake (n = 5) (B), decreased glucose production from radiolabeled lactate (n = 4) (C), and increased CO2 production from glucose (n = 6) (D) in primary rat hepatocytes.
Figure 2.
PF-04991532 improves glucose metabolism in rats.
PF-04991532 increased the rate of glucose infusion in order to maintain hyperglycemia in Goto-Kakizaki rats (n = 6/group) (A) which can be attributed to the increased glucose disposal and decreased glucose production (n = 6/group) during steady state (B). PF-04991532 decreased plasma glucose in Goto-Kakizaki rats over 28 days of dosing (n = 6–8/group) [P<0.05 for 30, 60, and 100 mg/kg compared to vehicle] (C) which was accompanied by an increase in plasma triglycerides at the highest dose (n = 6–8/group) [P<0.05 for 100 mg/kg] (D). These plasma changes were not associated with any changes in liver triglycerides compared to vehicle treated animals (E). **P<0.01 One-way ANOVA and Tukey’s Multiple Comparison Test were used for A,C,D, & E. Student’s t-test was used for B.
Figure 3.
PF-04991532 effects on lipid metabolism and downstream hepatic metabolites.
Expression of key lipid, carbohydrate, and cholesterol metabolism genes in rats treated with an acute 100/kg dose of PF-04991532 relative to vehicle (A). The increase in expression of the lipogenic genes can be explained by the increased nuclear ChREBP (n = 3/4/group) (B). Lastly, a metabolic profile of key metabolites using 31P-NMR and 1H-NMR in rats treated with an acute dose of PF-04991532 (n = 5–6/group) (C). *P<0.05; #P<0.1 for Vehicle vs. 100 mg/kg PF-04991532. Student’s t-test was used.
Figure 4.
PF-04991532 increased hepatic futile cycling.
The effect of hepatic glucokinase activation on G6Pase (A) and the loss of positional labeling (B) in primary rat hepatocytes. PF-04991532 increased total hepatic substrate cycling due to increased substrate cycling between glucose and glucose-6-phosphate (n = 5–7/group) (C). The increased substrate cycling decreased hepatic ATP concentrations as assessed by NMR (n = 6/group) (D) which in turn increased hepatic pAMPK/AMPK ratio (E) (n = 5/group). *P<0.05, **P<0.01, ***P<0.005 for Vehicle vs. 100 mg/kg PF-04991532. Student’s t-test was used.