1619-P: Creation of a Mouse Model That Phenocopies Human MODY8—A Valuable Tool to Interrogate Exocrine–Endocrine Cross Talk

Despite the intimate anatomical relationship between the two compartments of the pancreas, little is known about the biological components mediating the exocrine-endocrine communication in regulating glucose homeostasis. Maturity-onset diabetes of the young, type 8 (MODY8) is a dominantly inherited autosomal form of monogenic diabetes, caused by heterozygous mutations in the carboxy ester lipase (CEL) gene expressed in acinar cells. MODY8 is characterized by chronic pancreatitis (CP) and exocrine dysfunction from childhood, followed by diabetes in adulthood. Heterozygous MODY8 mice develop CP but are normoglycemic. Here, we report a refined mouse model that bears the mutation present in MODY8 patients on one allele, and the humanized normal variable number of tandem repeat (VNTR) of CEL with 16 repeats (16R) on the other, mimicking the genetic make-up seen in MODY8 patients. This mouse model (MODY8/16R) acts as a unique tool to directly interrogate the dynamic communication between the exocrine and endocrine compartments by phenotyping longitudinally from weaning to age 2 yrs. Preliminary histopathological analyses of the pancreata reveal features of CP in some lobes, including inflammation, fibrosis and fat infiltration, mirroring the disease in humans. Moreover, confocal microscopy showed the presence of zymogen granules containing mutant CEL within beta cells. These data argue that the mutant CEL protein is transferred from acinar cells to beta cells in pathological conditions, with implications of directly impacting beta cell viability. Examination of glucose homeostasis revealed that inducing stress (e.g. a high-fat diet) leads to glucose intolerance in MODY8/16R mice compared to their control littermates. In conclusion, the availability of a MODY8/16R mouse model provides a unique opportunity to carefully characterize the endocrine-exocrine communication in the pancreas in a longitudinal manner that is otherwise not possible in humans.