ESPE Abstracts

Inactivating mutations of ß-cell K_ATP channels cause the most common and severe form of congenital hyperinsulinism (HI), a ß-cell disorder that results in dysregulated insulin secretion and persistent hypoglycemia. Children with K_ATPHI are typically unresponsive to diazoxide, the only FDA-approved drug for HI. Octreotide, an SST2-selective agonist peptide that inhibits insulin secretion, is used as second line therapy, but poor efficacy and SST2-mediated side effects limit its use in infants. Crinetics has had ongoing discovery and development efforts aimed at finding a compound to treat HI that have yielded potent and selective nonpeptide SST5 agonists with sub-nanomolar EC_50Sin cell-based assays of receptor activation. We characterized the ability of the selective SST5 nonpeptide agonist CRN02481 to suppress insulin secretion and prevent fasting hypoglycemia in the SUR1^-/- mouse model of K_ATPHI. During batch incubation, SUR1^-/- mouse islets were stimulated with a physiologic amino acid mixture (4mM) after treatment with CRN02481 (100 nM) or buffer control. CRN02481 significantly decreased baseline (2.4 ± 0.5 vs 1.5 ± 0.2 ng/µL) and amino acid-stimulated (4.4 ± 1.1 vs 2.8 ± 1.5 ng/µL) insulin secretion. Insulin secretion was also significantly decreased during perifusion with CRN02481 in primary isolated islets from both wildtype (WT) and SUR1^-/- mice compared to buffer control. In addition, oral administration of CRN02481 (30 mg/kg) significantly increased fasting glucose and prevented fasting hypoglycemia compared to vehicle treatment (98 ± 18 vs 44 ± 6 mg/dl) in SUR1^-/- mice. During a glucose tolerance test, oral administration of CRN02481 significantly increased glucose excursion in both WT and SUR1^-/- mice compared to vehicle treatment. CRN02481 also reduced glucose- and tolbutamide-stimulated insulin secretion from islets isolated from human donors. Moreover, CRN02481 significantly decreased insulin secretion compared to control treatment in human islets isolated from two patients with K_ATPHI and one patient with Beckwith-Wiedemann Syndrome and HI. Collectively, these data show that the selective SST5 agonist CRN02481 prevents fasting hypoglycemia and effectively suppresses insulin secretion not only in the K_ATPHI mouse model, but also in human islets, including those from HI patients. Therefore, compounds like CRN02481 represent a promising potential novel therapy for children with HI.