SAT-217 - Dulaglutide Treatment Improves Body Composition and Glucose Tolerance without Compromising Growth in a Mouse Model of Youth-Onset Type 2 Diabetes

Background: Youth-onset type 2 diabetes (YO-T2D) is an aggressive chronic condition that often coincides with puberty, complicating treatment. First line therapies in YO-T2D have high failure rates because the loss of beta cells is accelerated compared to adults with T2D, partially related to peripheral insulin resistance being greater in adolescents during the pubertal transition. Currently approved GLP-1 receptor agonist therapies should be evaluated as a first line option for YO-T2D because of their incretin effect, insulin sensitization, and potential pro-proliferative properties. To evaluate the molecular effects of using GLP-1 therapies as a first line in early diabetes development in adolescents, model systems must be used.

Methods: We recapitulated YO-T2D in young mice by exposing three-week old male and female C57BL/6J mice to a 60% high fat diet (HFD). One week after diet initiation, repeated, low-dose streptozotocin (STZ; 50mg/kg) injections were administered for five days. One week after STZ, diabetes status was confirmed by glucometer and mice were randomized to either saline or dulaglutide (0.3mg/kg) subcutaneous injection every other day from five to eight weeks of age. During treatment, metabolic phenotyping by oral and intraperitoneal glucose tolerance testing, insulin tolerance testing, and body composition through EchoMRI scanning was completed. Tissues were collected after three weeks of treatment for molecular analysis.

Results: Using a combined HFD and STZ approach, we successfully induced diabetes in adolescent mice. After three weeks of treatment, dulaglutide-treated diabetic animals experienced improvements in body composition without growth restriction in developing mice. Dulaglutide-treated mice had 6.3% lower body weight and 22% lower fat mass compared to saline-treated animals. Glucose tolerance, measured by area under the curve (AUC), was improved significantly in oral and intraperitoneal glucose tolerance tests (59.7% and 46.9% lower, respectively) in the dulaglutide group. Insulin tolerance also improved, but only in males (68.6% lower AUC). Further evaluation of the molecular effect of dulaglutide in pancreas, muscle, and adipose tissues are underway.

Conclusion: Modeling of YO-T2D in mice is possible with a combination of overnutrition and beta-cell toxins in mouse models. Dulaglutide treatment improves glucose tolerance and body composition in both sexes. Insulin sensitivity improved in males. Further study is underway to evaluate the beta-cell proliferative capacity between treatments