BBB seminar: Pål Rasmus Njølstad

Pål Rasmus Njølstad
Department of Clinical Medicine, University of Bergen

The pancreas serves both endocrine and exocrine functions. The endocrine cells are found in the islets of Langerhans, they synthesize insulin and other hormones, and are involved in the pathogenesis of diabetes mellitus. The exocrine cells produce bicarbonate and digestive enzymes and are involved in the pathogenesis of pancreatic malabsorption . The localization of the islets 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. Diabetes has been proposed to be both the cause and the consequence of exocrine pancreatic disease. In other cases a common factor has been considered to lead to both exocrine pancreas dysfunction and diabetes, reflecting that exocrine and endocrine pancreatic cells originate from the same pool of endodermal cells . A recent report indicates a prevalence of 15-30 % of severe exocrine pancreas dysfunction in patients with type 1 (T1D) and type 2 diabetes (T2D) .

We have studied two families with diabetes and exocrine pancreatic dysfunction by genetic, physiological, and in vitro functional studies (Ræder et al ., Nature Genetics, 2006, 38:54). A genome-wide screen in Family 1 linked diabetes to chromosome 9q34 (lod score 5.07). Using fecal elastase deficiency as a marker of exocrine pancreatic dysfunction refined the critical chromosomal region to 1.16 Mb (lod score 11.6). Here, we identified a single-base deletion in the VNTR-containing exon 11 of the carboxyl-ester lipase ( CEL ) gene, a major component of pancreatic juice and responsible for the duodenal hydrolysis of cholesterol esters. Screening subjects with maturity-onset diabetes of the young identified Family 2, with another single-base deletion in CEL and a similar phenotype with beta-cell failure and pancreatic exocrine disease. The in vitro catalytic activities of wild-type and mutant CEL were comparable. The mutant enzyme was, however, less stable and secreted at a lower rate. Furthermore, we found some evidence for an association between common insertions in the CEL VNTR and exocrine dysfunction in a material of 182 unrelated subjects with diabetes (odds ratio 4.2 [1.6, 11.5]). Our findings link diabetes to the disrupted function of a lipase in the pancreatic acinar cells which was unexpected since most diabetes genes are expressed in the beta-cells.