O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function

In Type 2 diabetes, insulin resistance elicits compensatory insulin hypersecretion, provoking β-cell stress and eventually compensatory failure. In insulin deficient STZ treated diabetic mice the dual AMPK activator and mitochondrial uncoupler O304 stimulates insulin independent glucose uptake and utilization in skeletal muscle and heart in vivo, thus improving glucose homeostasis. In obese In type 2 diabetic db/db mice, O304 additionally preserves β-cell function by preventing decline in insulin secretion, β-cell mass, and pancreatic insulin content. It remains however unclear whether these effects of O304 is mediated by a direct protective effect on β-cells, or indirectly by improving glucose homeostasis thereby inducing β-cell rest. To investigate the ability of O304 to directly mitigate the detrimental effect of hyperglycemia on β-cell function, we exposed isolated islets ex vivo to normoglycemic and hyperglycemic comdition in the abscence or prescene of O304. Islets of langerhans were isolated from the pancreas of wildtype mice and exposed to normoglycemic (11mM Glucose) or hyperglycemic (22mM Glucose) conditions with or without the addition of 5uM O304 for 48h (i.e 4 conditions). Five (5) independent replicates were analysed for each experimental condition (i.e total 20 samples)