SGLT2-i improves markers of islet endothelial cell function in db/db diabetic mice

Islet endothelial cells produce paracrine factors important for islet beta-cell function and survival. Under conditions of type 2 diabetes, islet endothelial cells exhibit a dysfunctional phenotype including increased expression of genes involved in cellular adhesion and inflammation. We sought to determine wheth er treatment of hyperglycemia with the sodium glucose co-transporter 2 inhibito r empagliflozin, either alone or in combination with metformin, would improve markers o f endothelial cell function in islets, assessed ex vivo, and if such an improvement is associated with improved insulin secretion in a mouse model of diabetes in vivo. For these studies, db/db diabetic mice and non-diabetic littermate controls were treated for 6 we eks with empagliflozin or metformin, either alone or in combination. For each treatment group, expression of genes indicative of islet endothelial dysfunction was quantified. Islet endothelial and beta-cell area was assessed by morphometry of i mmunochemically stained pancreas sections. Measurements of plasma glucose and insulin secretion during an intravenous glucose tolerance test were performed on vehicle and drug treated diabetic animals. We found that expression of endotheli al dysfunction marker genes is markedly increased in diabetic mice. Treatment with either empagliflozin or metformin lowered expression of the dysfunction marker genes ex vivo, which correlated with improved glycemic control, and increased insulin release in vivo. Empagliflozin treatment was more effective than metformin alone, with a combin ation of the two drugs demonstrating the greatest effects. Improving islet endoth elial function through strategies such as empagliflozin/metformin treatment may provide an effective approach for improving insulin release in human type 2 diabetes.