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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 7

O304 reverts established obesity at thermo-neutral conditions.

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O304 reverts established obesity at thermo-neutral conditions.
(A and B)...
(A and B) Body weight change over time (A) and food intake (B) in CBA mice switched between high-fat diet (HFD) (n = 5) and O304-HFD (2 mg/g) (n = 5) at housing and thermo-neutral conditions as indicated. (C–E) Oxygen consumption (VO2) (C), respiratory exchange ratio (RER) (D), and energy expenditure (EE) rates (E) in CBA mice on HFD (n = 8) and O304-HFD (0.8 mg/g) (n = 8) for 11w. (F) Representative immunoblot analysis and quantification of ATGL and of p-S406 ATGL in inguinal white adipose tissue (iWAT) of CBA mice on HFD (n = 10) and O304-HFD with 0.4 (n = 5), 0.8 (n = 10), and 2 mg/g (n = 10) O304 for 7w. (G) Relative mRNA levels of Atgl, Cpt1b, Ppargc1a, and Cox8b in iWAT of 19w-old CBA mice fed HFD (n = 10) and O304-HFD and 2 mg/g O304 (n = 10) for 7w. (H) Relative mRNA levels of Cd36, Fas, Scd1, Acc1, and Cpt1b in brown adipose tissue (BAT) of 19w-old CBA mice fed HFD (n = 10) and O304-HFD and 2 mg/g O304 (n = 10) for 7w. Data are presented as mean ± SEM, *P < 0.05, **P < 0.01, ***P < 0.001 (Student’s t test).

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