PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients

Abstract

AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which - in diet-induced obese mice - increased glucose uptake in skeletal muscle, reduced β cell stress, and promoted β cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro- and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.

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“…Furthermore, many studies suggest that AMPK is a potential therapeutic target for in ammation, cancer, diabetes, and other diseases [34][35][36][37]. We proposed that FMN, an activator of AMPK, could not only serve as a candidate drug for the treatment of IL-6-mediated diseases but might also be a novel therapeutic agent against other diseases in which AMPK activity represents a potential therapeutic strategy.…”

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“…One of the pathways affected by caloric restriction is the AMPK one. AMPK controls glucose disposal by inhibiting liver gluconeogenesis and increasing muscle glucose uptake [22][23][24][25] . Targeting hepatic AMPK with an AMPK-specific small-molecule activator reduces liver steatosis and improves glucose disposal in obese mice 26,27 .…”

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“…Using US Food and Drug Administration (FDA) allometric scaling, the 200 mg/kg mouse dose is equivalent to 1000 mg/day in humans, which is a typical starting dose for the use of metformin in type 2 diabetes. 18 In Steneberg et al, 10 the dose of O304 used in the phase IIa clinical trial was 1000 mg/day. Using US FDA allometric scaling, that is equivalent to 200 mg/kg daily O304 dose in mice.…”

“…9 O304 is a new direct AMPK activator that has concluded a phase IIa clinical trial in Europe for glucose homeostasis in patients with type 2 diabetes (metformin being the gold standard drug for treatment of type two diabetes) and for microvascular perfusion in skeletal muscle. 10 O304 suppresses the dephosphorylation of the Thr172 in the α-subunit of AMPK by protein phosphatase 2C (PP2C) without inhibiting PP2C activity, a key regulatory mechanism to increase AMPK activity. 2 10 With a known mechanism of action, it is more likely that a successful O304 treatment in rodents will correspond to a therapeutic effect in humans.…”

“…One pharmacokinetic difference between metformin and O304 is that metformin can cross the blood-brain barrier, 11 12 while O304 is orally available but does not cross the blood-brain barrier. 10 Therefore, the dorsal root ganglion (DRG) would be a common site to compare the activity of the two drugs on the AMPK pathway.…”