During development of T2D, insulin resistance and reduced glucose uptake in skeletal muscle result in an initial combined hyperglycemia and hyperinsulinemia, which are key metabolic abnormalities associated with the development of T2D ( 1– 3) as well as key risk factors for cardiovascular diseases ( 4, 5). The increase in type 2 diabetes (T2D) is strongly linked to the global increase in obesity, caused by physical inactivity and a Western diet, as well as an aging population. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications. 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. 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. 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.
#STRONGEST AMPK ACTIVATOR ACTIVATOR#
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. 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.