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PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
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2018 (English)In: JCI INSIGHT, ISSN 2379-3708, Vol. 3, no 12, article id e99114Article in journal (Refereed) Published
Abstract [en]

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 beta cell stress, and promoted beta 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.

Place, publisher, year, edition, pages
American Society for Clinical Investigation , 2018. Vol. 3, no 12, article id e99114
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Endocrinology and Diabetes Physiology
Identifiers
URN: urn:nbn:se:umu:diva-150778DOI: 10.1172/jci.insight.99114ISI: 000436144100013PubMedID: 29925691OAI: oai:DiVA.org:umu-150778DiVA, id: diva2:1244372
Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2019-05-10Bibliographically approved

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Steneberg, PärLindahl, EmmaDahl, UlfLidh, EmmelieStraseviciene, JurateBacklund, FredrikKjellkvist, ElisabetEricsson, MadeleneEdlund, ThomasEdlund, Helena

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Steneberg, PärLindahl, EmmaDahl, UlfLidh, EmmelieStraseviciene, JurateBacklund, FredrikKjellkvist, ElisabetEricsson, MadeleneEdlund, ThomasEdlund, Helena
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Umeå Centre for Molecular Medicine (UCMM)Physiological chemistry
Endocrinology and DiabetesPhysiology

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