Insulin resistance is the key etiologic defect that defines the metabolic syndrome. Insulin-resistance in combination with reduced β-cell function trigger type 2 diabetes (T2D), which afflicts ~350 million individuals, increases globally and is largely the consequence of obesity and physical inactivity. Obesity also causes an almost epidemic increase in fatty liver; non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steato-hepatitis (NASH), which are correlated to hepatic insulin resistance and increased hepatic glucose output, a major determinant of T2D.

NAFLD independently predicts pre-diabetes and ~70% of diabetics have NAFLD. AMPK regulates both glucose and lipid metabolism and exhibits anti-inflammatory activity and is therefore a suitable target for insulin resistance and NAFLD/NASH.

Around 70% of T2 diabetics exhibit β-cell amyloid deposits of islet amyloid polypeptide (hIAPP). Most studies on β-cell function and integrity have been performed using rodent β-cell lines, isolated islets, and/or animal models. The rodent homolog of hIAPP, does not form toxic oligomers and amyloid, thus the mechanistic role of IAPP amyloidogenesis in β-cell degeneration during T2D development has been difficult to study. Autophagy, a “self-eating” process, occurs at a basal level to ensure cellular homeostasis, including clearance of protein aggregates, and reduced autophagy may lead to accumulation of toxic protein aggregates, such as hIAPP. AMPK induces autophagy in part by repressing the nutrient sensing mTOR complex, which inhibits autophagy. Recent data show that exercise induces AMPK and autophagy in several tissues, including pancreatic β-cells and that AMPK activation and autophagy is regulated by a positive feed-forward mechanism to increase endurance and to mediate the positive effects of exercise on high fat diet-induced diabetes. Thus, autophagy is emerging as an important metabolic mediator that links exercise and AMPK activation.

Moreover, AMPK activity is essential for proper glucose sensing in pancreatic β‐cells. AMPK increases surface levels of KATP channel proteins which  facilitates the decrease in insulin secretion in response to glucose deprivation, and  glucose-stimulated insulin secretion (GSIS) is impaired by AMPKα2 knockout in b-cells.

O304 reduces diet/obesity-induced insulin resistance, fatty liver and plasma IGF-1
Mice given a high fat diet (HFD) develop fatty liver and insulin resistance manifested as hyperinsulinemia and elevated blood glucose levels, which mimic diet/obesity- induced insulin resistance in man.  In mice fed very high fat diet (vHFD), after long-term treatment with O304 fasted glucose levels are lower and fed and fasted insulin, HOMA-IRs, total liver lipids and triglycerides are significantly lower. Thus under these conditions, O304 significantly increases whole-body insulin sensitivity and reduces liver fat content. Elevated plasma IGF-1 levels are associated with increased diabetes mortality, and O304 significantly reduces increased plasma IGF-1 levels in mice fed very high fat diet.

O304 ameliorates β-cell dysfunction
T2D in man develops when peripheral insulin resistance is accompanied by reduced b-cell function, at least in part, mediated by islet amyloid polypeptide (IAPP) deposits in b-cells. O304 induces autophagy in b-cell lines and in isolated mouse and human islets. We have in collaboration with Prof H. Edlund, Umeå University shown that in a humanized animal model of T2D, O304 reduces fatty liver and peripheral insulin resistance and ameliorates impaired β-cell function, the hallmarks of T2D. Moreover, AMPK activity is essential for normal glucose sensing in pancreatic β‐cells. Consistently, O304 increases GSIS in islets derived from a pre-diabetic individual.

Thus, O304 reduces insulin resistance and fatty liver, ameliorates perturbed β-cell function, HOMA-IR, and stimulates GSIS in β-cells. O304 is therefore a putative treatment for NAFLD/NASH and T2D and associated vascular complications.