Type 2 Diabetes
Type 2 Diabetes
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, reduced glucose uptake in skeletal muscle and increased hepatic glucose production result in an initial combined hyperglycemia and hyperinsulinemia, followed by a decline in β-cell function and insulin secretion.
AMPK and Diabetes: Among many other beneficial effects, activation of AMPK uniquely increases both insulin-dependent and -independent glucose uptake in skeletal muscle. An increasing body of evidence has demonstrated that AMPK activity is repressed during obesity and type 2 diabetes, which has made pharmacological AMPK activation a highly desirable target in diabetes.
As a PAN-AMPK activator, O304 increases glucose uptake in muscle by an insulin-independent mechanism by targeting a key pathway that regulates peripheral glucose uptake in humans. O304 also reduces systemic and age-induced insulin resistance, and potently reduces hyperglycemia, hyperinsulinemia and plasma glucagon in multiple diabetic animal models. Thus, O304 matches the level of insulin secretion to demand and induces β-cell rest that preserves β-cell function and identity. By promoting autophagy O304 also prevents accumulation of toxic IAPP aggregates/amyloid in islet cells. No other anti-diabetic drug can improve glucose homeostasis through this combination of beneficial molecular and physiological mechanisms.
Clinical: In a 28 day phase IIa trial in T2D patients, O304 reduced fasting plasma glucose and insulin resistance/HOMA-IR. Steady-state was reached ~ day 18, and a larger effect of O304 on glucose homeostasis is expected at higher of exposure and by longer duration of treatment.