Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction.

Dysfunction of the exocrine pancreas is observed in diabetes, but links between concurrent exocrine and endocrine pancreatic disease and contributing genetic factors are poorly characterized. We studied two families with diabetes and exocrine pancreatic dysfunction by genetic, physiological and in vitro functional studies. A genome-wide screen in Family 1 linked diabetes to chromosome 9q34 (maximal lod score 5.07). Using fecal elastase deficiency as a marker of exocrine pancreatic dysfunction refined the critical chromosomal region to 1.16 Mb (maximal lod score 11.6). Here, we identified a single-base deletion in the variable number of tandem repeats (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 protein 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 group 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.

Diagnostic screening of MODY2/GCK mutations in the Norwegian MODY Registry.

BACKGROUND: Maturity-onset diabetes of the young, type 2 (MODY2) is caused by mutations in the glucokinase gene (GCK). The aim of our study was to determine the prevalence of GCK mutations in the Norwegian MODY Registry and to delineate the clinical phenotype of identified GCK mutation carriers. METHODS: We screened 122 probands referred to the MODY Registry for mutations in GCK and studied extended families with MODY2. RESULTS: We found 2 novel (S76Y and N231S) and 13 previously reported (V62A, G72R, L146R, R191W, A208T, M210K, Y215X, M235T, R275C, E339G, R377C, S453L, and IVS5+1G>C) GCK mutations in 23 probands and in their 33 family members. The prevalence of MODY2 was 12% in the Norwegian MODY Registry. The subjects with GCK mutations had features of mild diabetes. Yet, 15 of 56 MODY2 subjects were treated with oral drugs or insulin. Three subjects had retinopathy and one had macrovascular disease. Also, a limited number of cases had elevated fasting serum triglyceride values. Moreover, two GCK mutation carriers were diagnosed with type 1 diabetes. CONCLUSIONS: According to our diagnostic screening of GCK in the MODY Registry, MODY2 is less prevalent than MODY3 in Norway but is likely to be underreported. Recognizing MODY2 in diabetic patients is important in order to prevent overtreatment. Finally, our study demonstrates the co-occurrence of MODY2 in families with type 1 or type 2 diabetes.