Insulin-Dendrimer Nanocomplex for Multi-Day Glucose-Responsive Insulin Therapy in Ossabaw Miniature Swine with Type 1 Diabetes

Background: Therapy for type 1 diabetes resulting from immunogenic destruction of the insulin-producing pancreatic beta cells has been a challenge for over 100 years. Delivering exogenous insulin to maintain euglycemia is a delicate balance between plasma glucose transport to insulin-responsive tissues, glucose absorption in the gut, and the pharmacodynamics of insulin. The synthesis of short- and long-acting insulins and use of insulin pumps have made great strides in the standard of diabetes care. Despite advances, hypoglycemia is a major limitation. There is no approved therapy that offers glucose-responsive insulin function. Toward this end we engineered a nanoscale complex combining both electrostatic and dynamic-covalent interactions between a synthetic dendrimer carrier and an insulin analogue modified with a high-affnity glucose-binding motif. Hypothesis: This insulin nanocomplex will yield an injectable insulin depot providing both glucose-sensitive and long-lasting insulin availability in a translation preclinical model. Methods: Ossabaw minature swine (41-59 kg; N=6) were made diabetic with alloxan, which was confirmed by stable hyperglycemia (228±43 mg/dL). Oral glucose tolerance tests (OGTT) were conducted at the diabetic baseline and each of the following 6 days after one subcutaneous injection of the insulin nanocomplex. Results: The basline OGTT elicted blood glucose of 350-450 mg/dL for 90 min of the 150 min OGTT, while serum insulin remained at ~5 μU/mL, nearly the detection limit. In contrast, 3 h after injection of insulin nanocomplex (~0.8-0.9 mg/kg) blood glucose decreased to 71±12 mg/dL. Subsequent OGTTs on days 1-6 increased blood glucose from normoglycemia to ~200 mg/dL and serum insulin increased to ~60-220 μU/mL, followed by return to nearly normolgycemia hours after the OGTT. Hypoglycemia was avoided in all pigs. Conclusions: The subcutaneous nanocomplex of a modified insulin and a synthetic dendrimer carrier produced a glucose-responsive insulin depot for week-long glycemic control following a single routine injection. These findings offer great promise for overcoming the hypoglycemia risk of intensive glucose control. Future studies should include additional physiological challenges of exercise and nutritional states. Support: Juvenile Diabetes Research Foundation 5-CDA-2020-947-A-N, Helmsley Charitable Trust 2019PG-T1D016 and 2102-04994, American Diabetes Association Pathway 1-19-ACE-31, National Science Foundation BMAT1944875, European Union-Next Generation EU LX22NPO5104, Czech Academy of Sciences RVO 6138963. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.