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. During development of T2D, insulin resistance, and reduced glucose uptake in skeletal muscle result in an initial combined hyperglycemia and hyperinsulinemia. β-cells progressively fail to match the increasing demand for insulin, which leads to the development of severe hyperglycemia and diabetes.
No currently used anti-glycemic drug increases glucose uptake in skeletal muscle and/or reduces insulin resistance. Exercise appears more effective than insulin treatment to promote glucose uptake in insulin resistant skeletal muscle of T2D patients, an effect that, at least in part, is mediated by activation of AMP-activated protein kinase (AMPK), which is activated in response to energy shortage imposed by physical activity and caloric restriction.
By increasing glucose uptake in skeletal muscle AMPK indirectly preserves/restores β-cell function. AMPK appears also to ensure both normal β-cell glucose sensing and glucose stimulated insulin secretion to promote β-cell rest. AMPK also stimulates macroautophagy that is important for β-cell function and survival, and that may prevent accumulation of toxic IAPP aggregates/amyloid in β-cells.
O304 and T2D
In diet induced obesity (DIO) mice, O304 increased glucose uptake in skeletal muscle and reduced insulin resistance. O304 also reduced b-cell stress and promoted b-cell rest. Consistently, in a 28 day proof-of-concept phase IIa clinical trial in T2D patients treated with Metformin, O304 reduced fasting plasma glucose and HOMA-IR, and was well tolerated. O304 also improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but 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.