1182-P: A Selective Nonpeptide Somatostatin Receptor 5 (sst5) Agonist Effectively Decreases Insulin Secretion in the KATPHI Mouse Model

Inactivating mutations of β-cell K_ATP channels cause the most common and severe form of congenital hyperinsulinism (HI), a β-cell disorder that causes dysregulated insulin secretion and persistent hypoglycemia. Children with K_ATPHI are typically unresponsive to diazoxide, the only FDA-approved drug for HI. Octreotide, a sst2 peptide agonist that inhibits insulin secretion, is used as second line therapy, but poor efficacy and sst2-mediated side effects, such as glucagon suppression and necrotizing enterocolitis, limit its use in infants. Thus, most infants with K_ATPHI require pancreatectomy for intractable hypoglycemia. To address the unmet need for effective and safe therapies, we examined the ability of a selective sst5 nonpeptide agonist CRN02481 (Crinetics Pharmaceuticals) to suppress insulin secretion and prevent fasting hypoglycemia in the SUR1-/- mouse model of K_ATPHI. SUR1-/- mouse islets were treated with CRN02481 (100 nM) or vehicle and then stimulated with a physiologic amino acid mixture (4 mM). CRN02481 significantly decreased baseline (1.5 ± 0.2 vs. 2.4 ± 0.5 ng/uL, p≤0.01) and amino acid-stimulated (2.8 ± 1.5 vs. 4.4 ± 1.1 ng/uL, p≤0.05) insulin secretion. SUR1-/- mice were gavaged with CRN02481 (10 mg/kg/day) or PBS for 7 days (n=7/group) and fasting glucose, glucose tolerance and insulin tolerance tests were assessed. CRN02481 significantly increased fasting glucose and prevented fasting hypoglycemia (98 ± 18 vs. 44 ± 6 mg/dL, p<0.00001). During a glucose tolerance test CRN02481 increased post-glucose load glucose concentrations significantly by 60 and 90 minutes. CRN02481 significantly decreased the slope of decline of glucose concentrations after insulin administration (1 u/kg): -2.8 ± 2.3 vs. -5.7 ± 2.1, p=0.03). Collectively these data show that the sst5 agonist CRN02481 effectively suppresses insulin secretion and prevents fasting hypoglycemia in the K_ATPHI mouse model and is a potentially novel therapy for children with HI.