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.

 

High risk severe insulin resistant diabetes (SIRD) subgroup

Diagnosis of T2D has been dependent upon measuring one metabolite, glucose. By including additional variables in a clustering analysis, T2D has recently been divided into fivedistinct subgroups, with better prediction of disease progression and outcome. The severe insulin-resistant diabetes (SIRD) cluster was characterized by hyperinsulinemia and severe insulin resistance, obesity, and showed the highest risk of kidney disease and highest prevalence of nonalcoholic fatty liver disease (NAFLD) (Ahlqvist et al., 20181). Since none of the currently approved treatments for T2D reduces insulin resistance the SIRD subgroup of T2D patients lacks effective treatment.

AMPK and T2D

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.

PAN-AMPK activator O304 as treatment for the SIRD subgroup of T2D patients

Consistently, O304 increases glucose uptake in myotubes an insulin-independent mechanism and increases glucose uptake in skeletal muscle in vivo in DIO mice. In addition, O304 reduces systemic insulin resistance, induces β-cell rest and prevents accumulation of toxic IAPP aggregates/amyloid in islet cells in a dose-dependent manner. No other anti-diabetic drug can improve glucose homeostasis through these highly desired mechanisms. In a 28 day phase IIa trial in T2D patients, O304 reduced fasting plasma glucose and insulin resistance/HOMA-IR, and larger effects are expected at higher levels and duration of exposure.

In addition, O304 reduces obesity, fatty liver and shows beneficial effects on renal hemodynamics and cardiac function. Thus, O304 is ideally suited to treat the newly defined severe insulin-resistant diabetes (SIRD) group of T2D patients who have a significantly higher risk of developing kidney disease and increased prevalence of NAFLD compared to other T2D patients and who today lack effective treatment.

1 Ahlqvist et. al., Lancet Diabetes Endocrinol 2018