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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 10

O304 reduces fasting plasma glucose and blood pressure and increases microvascular perfusion in type 2 diabetes (T2D) patients on Metformin.

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O304 reduces fasting plasma glucose and blood pressure and increases mic...
(A–C) Fasting plasma blood glucose (FPG) (A and B) and HOMA-IR (C) at day 1 and day 28 in placebo- (n = 24) and O304-treated (n = 25) T2D patients on Metformin with the FPG range >7 to <13.3 mmol/l (>126 to <240 mg/dl) at day 1. (D) Hyperemic microvascular perfusion assessed by dynamic T2*-quantification monitored by MRI at screening (MRI1) and at day 27–29 (MRI2) in calf muscle of the T2D patients. The O304 group and the placebo group were split in half based on the time-to-peak (TTP) at baseline, where short TTP (placebo A [n = 14], O304 A [n = 14]) and long TTP (placebo B [n = 13], O304 B [n = 14]) represent a relative higher and lower rate of hyperemic perfusion, respectively. A significant shortening of TTP (P = 0.043) and increase in Δ-T2* (P = 0.034) was observed in subjects with relative lower rate of perfusion at baseline (long TTP) in the O304 group (i.e., comparing O304 B MRI1 with O304 B MRI2) but not in subjects with short TTP, and there was no difference in subjects with either short or long TTP at baseline in the placebo group. (E) Absolute and relative change in systolic and diastolic blood pressure from day 1–28 in T2D patients on Metformin treated with placebo (n = 27) or O304 (n = 30). Data are presented as mean ± SEM, *P < 0.05, **P < 0.01, ***P < 0.001 (Signed Wilcoxon’s rank sum test).

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