Grant: Proof of Principle Program Phase I - Drug Development

Hypoglycemia (low blood sugar) is a serious side effect of insulin treatment in type 1 diabetes. It is also the major barrier to good glycemic control since patients "relax" intensive insulin treatment for fear of hypoglycemia. The risk of hypoglycemia increases with time because counteregulatory responses (glucagon, cortisol, growth hormone and catecholamines) diminish as the disease progresses. Currently, no prophylactic treatment exists for the prevention of hypoglycemia, other than relaxing insulin treatment. One treatment may be to lower somatostatin action, which is known to be elevated in type 1 diabetes; in turn this will restore counterregulatory hormone responses to hypoglycemia. Somatostatin is an inhibitory hormone with defined actions in the brain, pituitary, pancreas gut and elsewhere, so global inhibition may have side effects. Our work, for which we now hold a granted patent, indicates that a selective antagonist of the somatostatin receptor type 2 fully normalizes glucagon responses and other counterregulatory hormone responses to hypoglycemia and improves blood glucose homeostasis in diabetic rodents. However, as part of the commercial development of this technology, we now need to determine if the selective inhibitor can be used subcutaneously with insulin delivery, the likely route for patient administration. We also need to examine whether there are safety issues related to any non specific off target effects of somatostatin receptor type 2 inhibition. To do this, we propose to conduct both in vitro and in vivo toxicology/dose safety studies and biodistribution studies.. This project provides a basis for novel preventative treatments to decrease the threat of hypoglycemia, improve glycemic control, and thus diminish the threat of diabetic complications, and addressing these dosing and safety issues will allow us to present data that will be of significant interest to pharmaceutical licensing partners.