Episodes of insulin-induced hypoglycemia are frequent in type 1 and advanced type 2 diabetes, but pharmaceutical approaches to prevent these are lacking. Cellular stresses such as low blood sugar activate AMPK, which has emerged as a whole body and cellular energy sensor. Direct delivery of AMPK activator to the ventromedial hypothalamus of rodents leads to increased hepatic glucose-production, observed during hyperinsulinemic-hypoglycemic clamp studies, and genetic activation of AMPK in the pancreatic alpha cell increases glucagon release. It may therefore be suitable to target AMPK for hypoglycemia prevention. Here, R481, a novel metformin-like brain permeable AMPK activator, was used to assess the impact of AMPK pathway activation on the counterregulatory response to hypoglycemia.

Hypothalamic glucose sensing GT1-7 cells were treated with R481 and activation of AMPK pathway by phosphorylation assessed using Western Blotting. R481 was administered orally to male Sprague Dawley rats prior to insulin-induced hypoglycemia, following which blood glucose and feeding were measured. A separate cohort of rats underwent a hyperinsulinemic-hypoglycemic clamp study where glucose infusion rates and counterregulatory hormones levels were determined.

Nanomolar concentrations of R481 increased AMPK pathway phosphorylation in GT1-7 neurons. Administration of R481 (5-20 mg/kg) to rats attenuated insulin-mediated drop in blood glucose during acute insulin-induced hypoglycemia, without altering fast-induced refeeding. R481 decreased the glucose infusion rate during hyperinsulinemic-hypoglycemic clamps, by amplifying plasma glucagon secretion, without altering epinephrine.

Peripheral administration of AMPK activator R481 amplified glucagon release to improve counterregulatory response to hypoglycemia in healthy rats.


A.M.L. Cruz: None. Y. Malekizadeh: None. J.M. Vlachaki Walker: None. S.J. Shaw: Employee; Self; Rigel Pharmaceuticals. K.L. Ellacott: None. C. Beall: None.


JDRF; Diabetes UK

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