Endocrine Abstracts

The localization of the islets of Langerhans within exocrine pancreatic tissue is suggestive of an interdependency and cross-talk between these two cell populations, in their normal as well as in their abnormal function. Disturbances in glucose metabolism often accompany diseases of the exocrine pancreas, whereas exocrine dysfunction is commonly seen in diabetes patients. Recently, we have described a novel syndrome of exocrine and endocrine pancreatic dysfunction caused by mutations in the carboxyl-ester lipase (CEL) gene (Ræder et al. Nat Genet 2006). CEL is mainly expressed in the pancreatic acinar tissue, and the protein is secreted from the pancreas into the digestive tract. CEL is highly polymorphic due to a VNTR in exon 11. We have described two families with different, single-base deletions in this VNTR. Screening CEL in MODYX materials from the UK and Denmark indicates that CEL mutations may remain a rare cause of monogenic diabetes. Moreover, we have not found any association between VNTR status and type 2 diabetes.

MRI and ultrasound studies of non-diabetic and mutation-positive children suggest that mutation carriers accumulate fat in their pancreata. Moreover, this process seems to occur before the anticipated development of diabetes (Ræder et al. Diabetes 2007). In a treatment trial, nine affected subjects were given pancreatic enzyme substitution therapy. This improved their vitamin E status and increased their blood cholesterol level.

To examine the role of CEL in diabetes development, we have studied CEL knock-out mice. A mild diabetic phenotype was noted in female mice. Moreover, we have made epitope-tagged constructs of the mutated and wild-type CEL genes, expressed these constructs in cell lines and examined protein secretion and subcellular distribution. Preliminary data will be presented.

One possible mechanism of disease could be that lack of O-glycosylation of the mutant CEL causes retention and accumulation of the protein in the ER/Golgi apparatus of the acinar cells, leading to ER stress. Our data may support such a disease model, although impaired secretion or increased degradation of the protein are alternative explanations. Taken together, the molecular and clinical data are consistent with the syndrome starting in the acinar tissue and diabetes being secondary to the exocrine defect.