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PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients
Pär Steneberg, … , Thomas Edlund, Helena Edlund
Pär Steneberg, … , Thomas Edlund, Helena Edlund
Published June 21, 2018
Citation Information: JCI Insight. 2018;3(12):e99114. https://doi.org/10.1172/jci.insight.99114.
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Research Article Metabolism

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

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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.

Authors

Pär Steneberg, Emma Lindahl, Ulf Dahl, Emmelie Lidh, Jurate Straseviciene, Fredrik Backlund, Elisabet Kjellkvist, Eva Berggren, Ingela Lundberg, Ingela Bergqvist, Madelene Ericsson, Björn Eriksson, Kajsa Linde, Jacob Westman, Thomas Edlund, Helena Edlund

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Figure 9

O304 improves microvascular blood flow and endurance in mice.

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O304 improves microvascular blood flow and endurance in mice.
(A and B) ...
(A and B) Representative laser Doppler image (A) and quantification (B) of peripheral blood fusion in left hind paw in vehicle- (n = 10) and O304-treated (n = 10) B6CBAF1/J (F1) mice on 8w high-fat diet (HFD). (C and D) Endurance test (C) and lactate levels (D) after endurance test in vehicle- (n = 14) and O304-treated (n = 14) aged, lean B6 mice after 30 days of O304 treatment. (E and F) Systolic (E) and diastolic (F) blood pressure in dogs single dosed with vehicle or O304 at indicated concentrations. Data are presented as mean ± SEM, *P < 0.05, #P < 0.05, **P < 0.01, ##P < 0.01, ***P < 0.001, ###P < 0.001 (Student’s t test). In E and F, * refers to vehicle versus 540 mg/kg O304 and # refers to vehicle versus 180 mg/kg O304.

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