Background: Nonalcoholic fatty liver disease (NAFLD) is a major factor in the pathogenesis of type-2 diabetes (T2D). Liver pyruvate kinase (PK) inactivating mutations are associated with diabetes in human subjects and PK deficiency associated with severe liver dysfunction and fat accumulation.
Aim: To determine whether small molecule activators of PK (PKa) could improve liver metabolism in rats fed a high fat diet.
Methods: Sprague Dawley regular chow (RC) or high fat diet (HFD) rats were either treated acutely (IV bolus 11mg/kg/min then primed continuous 0.06 mg/kg/min) or chronically (50 mg/kg/day x 3 weeks). Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp studies.
Results: PKa dose dependently suppressed glucose production from primary rat hepatocytes. Acute PKa infusion suppressed endogenous glucose production (EGP) by 20% in RC rats. Chronic PKa exposure did not affect body weight in HFD-fed rats. Three-week PKa treatment did not change activity, food intake, whole-body energy expenditure, or body weight in HFD-fed mice. Nevertheless, PKa improved whole-body insulin sensitivity compared with control HFD-fed rats (glucose infusion rate: control 11.8±1.4 vs. PKa 15.3±0.7 mg/(kg-min),P<0.05). Differences in whole-body insulin sensitivity were accounted for by a 15% reduction in EGP and increased insulin-stimulated peripheral glucose uptake (21.2±0.6 vs. 26.4±1.7 mg/(kg-min), P<0.05). Insulin-stimulated hepatic AKT phosphorylation was also significantly improved. Consistent with improving of peripheral insulin sensitivity, liver and muscle triglyceride content (liver: 27.2±2.6 vs. 16.9±1.5 mg/g, P<0.05. muscle: 9.8 ±1.4 vs. 6.7±1.0 mg/g, P<0.05) were improved in PKa-treated rats.
In conclusion, activation of pyruvate kinase in rodents protects against HFD-induced insulin resistance. By reducing EGP and insulin resistance, activation of PK may be an exciting potential therapeutic target for T2D.
A. Abulizi: None. R.L. Cardone: None. S. Siebel: None. C. Kung: Employee; Self; Agios Pharmaceuticals. Stock/Shareholder; Self; Agios Pharmaceuticals. R. Kibbey: None.
American Diabetes Association (1-16-IBS-158 to R.K.); National Institutes of Health (R01DK108283-01A1)