Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
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.
View: Text | PDF
Research Article Metabolism

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

  • Text
  • PDF
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

×

Figure 3

O304 prevents diabetes in hIAPPtg diet-induced obese mice.

Options: View larger image (or click on image) Download as PowerPoint
O304 prevents diabetes in hIAPPtg diet-induced obese mice.
(A) Timeline ...
(A) Timeline in weeks for hIAPPtg mice fed a high-fat diet (HFD) and oral gavaged with vehicle or O304. (B and C) Fasted blood glucose (B) and insulin (C) levels in hIAPPtg mice on HFD treated with vehicle (n = 25) and O304 (n = 27) for 6w. (D and E) Blood glucose, plasma insulin profiles, and AUC, during i.p. glucose tolerance test (IPGTT) (D) and oral glucose tolerance test (OGTT) (E) in hIAPPtg mice on HFD treated with vehicle (IPGTT, n = 13; OGTT, n = 7) and O304 (IPGTT, n = 16; OGTT, n = 7) for 6w. (F) Plasma insulin profiles and AUC during IPGTT of 16w-old, hIAPPtg mice on HFD treated with O304 for 6w (from D, n = 16) compared with that of 10w-old hIAPPtg mice on regular diet (RD) (n = 7). (G) HOMA-IR calculations from glucose and insulin levels from B and C. (H) Matsuda index calculations from IPGTT (D) and OGTT (E) in vehicle and O304-treated hIAPPtg mice. Data are presented as mean ± SEM, *P < 0.05, **P < 0.01 (Student’s t test).

Copyright © 2021 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts