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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Categories: Research Article Metabolism

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.

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 6

O304 reduces amyloid formation in hIAPPtg diet-induced obese mice and improves arginine-induced insulin secretion in diet-induced obese mice.

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O304 reduces amyloid formation in hIAPPtg diet-induced obese mice and im...
Representative images (A) and quantification (B) of Thio-S+ amyloid deposits in hIAPPtg mice on high-fat diet (HFD) for 16w (n = 9) and in mice on HFD for 9w and then switched to O304-HFD (2 mg/g) for an additional 7w (n = 9). (C) Representative immunoblot analysis and quantification of O304 stimulation of p-T172 AMPK in INS-1 insulinoma cells (vehicle, 2.5 μM and 5 μM O304, n = 9; 10 μM O304, n = 6, per condition, respectively), mouse primary islets (n = 6 per condition), hIAPPtg mouse primary islets (n = 6 per condition), and human islets (n = 8 per condition). (D and E) Representative images (D) and quantification (E) of Thio-S+ amyloid deposits in hIAPPtg islets ex vivo cultured for 96 hours in 11 mM glucose (n = 36 islets), 22 mM glucose (n = 45 islets), and 22 mM glucose with 2.5 μM (n = 42 islets), 5.0 μM (n = 41 islets), and 10 μM O304 (n = 36 islets) as indicated (n = 3 experiments for each ). (F and G) Representative images (F) and quantification (G) of Thio-S+ amyloid deposits in hIAPPtg islets ex vivo cultured for 96 hours in 11 mM glucose (n = 43 islets), 11 mM glucose with 5.0 μM 3-MA (n = 59 islets), 22 mM glucose (n = 54 islets), 22 mM glucose with 5.0 μM O304 (35 islets), and 22 mM glucose with 5.0 μM O304 and 5.0 μM 3-MA (n = 44 islets) as indicated (n = 3 experiments for each). (H) Plasma insulin profiles and AUC following i.p. injection of arginine (1 g/kg) in CBA mice fed a HFD (n = 10) and O304-HFD (0.8 mg/g) (n = 10) for 11w. Data are presented as mean ± SEM, *P < 0.05, **P < 0.01, ***P < 0.001 (Student’s t test).