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.

Familial occurrence of neonatal diabetes with duplications in chromosome 6q24: treatment with sulfonylurea and 40-yr follow-up.

We present a Norwegian family, followed since 1967, with a chromosome 6q24 duplication in two siblings with neonatal diabetes, in their non-diabetic father, and in a female (third generation) with adult-onset diabetes. The parents (first generation) were healthy and non-consanguineous. After a miscarriage, the couple had two infants with birth weights of 1780 and 1620 g, respectively, both of whom died on their second day of life. Patient I (male, weight 1840 g at term) had a blood glucose level of 33 mmol/L on day 6. He was treated with insulin for 3 months. In adult life he had permanent diabetes, treated with oral hypoglycemic agents. At 43 yr of age, there were no diabetic late complications. Patient II (female, birth weight 1440 g at term) had an increasing blood glucose of 55 mmol/L on day 13. She received insulin treatment for 12.5 months. Subsequently, she was successfully treated with sulfonylurea (tolbutamide) for 10 yr. At 11 yr of age, insulin was again considered necessary. At 40 yr of age, no diabetic late complications were detected. Patient III had a birth weight of 2630 g at term and no diabetic symptoms as a neonate. She had insulin-requiring diabetes from age 19. We conclude that (i) neonatal diabetes with chromosome 6q24 duplications may become a permanent disease in adult life; (ii) this chromosome anomaly may also be associated with adult-onset diabetes; (iii) sulfonylurea treatment may be attempted, and (iv) late diabetic complications may be absent, even after more than 40 yr.

Studies in 3,523 Norwegians and meta-analysis in 11,571 subjects indicate that variants in the hepatocyte nuclear factor 4 alpha (HNF4A) P2 region are associated with type 2 diabetes in Scandinavians.

OBJECTIVE: Recent publications have found an association between common variants near the hepatocyte nuclear factor 4 alpha (HNF4A) P2 promoter and type 2 diabetes in some populations but not in others, and the role for HNF4A in type 2 diabetes has remained unclear. In an attempt to address these inconsistencies, we investigated HNF4A single nucleotide polymorphisms (SNPs) in a large population-based sample and included a meta-analysis of published studies. RESEARCH DESIGN AND METHODS: We genotyped 12 SNPs in the HNF4A region in a Norwegian population-based sample of 1,644 individuals with type 2 diabetes and 1,879 control subjects (the Nord-Trøndelag Health Study [HUNT] 2). We combined our data with all previously published case/control studies and performed a meta-analysis. RESULTS: Consistent with initial studies, we found a trend toward association for the SNPs rs1884613 (odds ratio [OR] 1.17 [95% CI 1.03-1.35]) and rs2144908 (1.21 [1.05-1.38]) in the P2 region and for rs4812831 (1.21 [1.02-1.44]), located 34 kb downstream of the P2 promoter. Meta-analysis, comprising 12,292 type 2 diabetic case and 15,519 control subjects, revealed a nonsignificant OR of 1.05 (95% CI 0.98-1.12) but with significant heterogeneity between the populations. We therefore performed a subanalysis including only the data for subjects from Scandinavia. Among the 4,000 case and 7,571 control Scandinavian subjects, a pooled OR of 1.14 (1.06-1.23), P = 0.0004, was found for the SNP rs1884613. CONCLUSIONS: Our results suggest that variation in the HNF4A region is associated with type 2 diabetes in Scandinavians, highlighting the importance of exploring small genetic effects in large, homogenous populations.