Sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy. This pharmacogenetic response to sulfonylureas may result from the closing of mutant K(ATP) channels, thereby increasing insulin secretion in response to incretins and glucose metabolism. (ClinicalTrials.gov number, NCT00334711 [ClinicalTrials.gov].).

OBJECTIVE -It is unclear whether the demands of good metabolic control or the consequences of poor control have a greater influence on quality of life (QOL) for adolescents with diabetes. This study aimed to assess these relations in a large international cohort of adolescents with diabetes and their families.RESEARCH DESIGN AND METHODS -The study involved 2,101 adolescents, aged 10 -18 years, from 21 centers in 17 countries in Europe, Japan, and North America. Clinical and demographic data were collected from March through August 1998. HbA 1c was analyzed centrally (normal range 4.4 -6.3%; mean 5.4%). Adolescent QOL was assessed by a previously developed Diabetes Quality of Life (DQOL) questionnaire for adolescents, measuring the impact of diabetes, worries about diabetes, satisfaction with life, and health perception. Parents and health professionals assessed family burden using newly constructed questionnaires.RESULTS -Mean HbA 1c was 8.7% (range 4.8 -17.4). Lower HbA 1c was associated with lower impact (P Ͻ 0.0001), fewer worries (P Ͻ 0.05), greater satisfaction (P Ͻ 0.0001), and better health perception (P Ͻ 0.0001) for adolescents. Girls showed increased worries (P Ͻ 0.01), less satisfaction, and poorer health perception (P Ͻ 0.01) earlier than boys. Parent and health professional perceptions of burden decreased with age of adolescent (P Ͻ 0.0001).Patients from ethnic minorities had poorer scores for impact (P Ͻ 0.0001), worries (P Ͻ 0.05), and health perception (P Ͻ 0.01). There was no correlation between adolescent and parent or between adolescent and professional scores.CONCLUSIONS -In a multiple regression model, lower HbA 1c was significantly associated with better adolescent-rated QOL on all four subscales and with lower perceived family burden as assessed by parents and health professionals.

Permanent neonatal diabetes (PND) can be caused by mutations in the transcription factors insulin promoter factor (IPF)-1, eukaryotic translation initiation factor-2␣ kinase 3 (EIF2AK3), and forkhead box-P3 and in key components of insulin secretion: glucokinase (GCK) and the ATP-sensitive K؉ channel subunit Kir6.2. We sequenced the gene encoding Kir6.2 (KCNJ11) in 11 probands with GCK-negative PND. Heterozygous mutations were identified in seven probands, causing three novel (F35V, Y330C, and F333I) and two known (V59M and R201H) Kir6.2 amino acid substitutions. Only two probands had a family history of diabetes. Subjects with the V59M mutation had neurological features including motor delay. Three mutation carriers tested had an insulin secretory response to tolbutamide, but not to glucose or glucagon. Glibenclamide was introduced in increasing doses to investigate whether sulfonylurea could replace insulin. At a glibenclamide dose of 0.3-0.4 mg ⅐ kg ؊1 ⅐ day ؊1 , insulin was discontinued. Blood glucose did not deteriorate, and HbA 1c was stable or fell during 2-6 months of follow-up. An oral glucose tolerance test performed in one subject revealed that glucose-stimulated insulin release was restored. Mutations in Kir6.2 were the most frequent cause of PND in our cohort. Apparently insulin-dependent patients with mutations in Kir6.2 may be managed on an oral sulfonylurea with sustained metabolic control rather than insulin injections, illustrating the principle of pharmacogenetics applied in diabetes treatment. Diabetes 53: [2713][2714][2715][2716][2717][2718] 2004 N eonatal diabetes may be defined as hyperglycemia diagnosed within the first 3 months of life (1). Transient neonatal diabetes is associated with abnormalities in chromosome 6 (2), whereas the permanent form may be caused by mutations in the genes encoding the transcription factors insulin promoter factor (IPF)-1 (3,4), eukaryotic translation initiation factor-2␣ kinase 3 (EIF2AK3) (5), forkhead box-P3 (6), and the glucose-sensing enzyme glucokinase (GCK) (7,8). Gloyn et al. (9) recently identified that the ATPsensitive K ϩ channel subunit Kir6.2 can cause PND. We here report nine new cases of PND associated with mutations in the gene KCNJ11 encoding Kir6.2. In addition, we also show that oral therapy with a sulfonylurea drug should be considered in patients with mutations in Kir6.2. RESEARCH DESIGN AND METHODSThe neither systematic nor population-based screening included 16 referred probands with PND from Norway, Israel, Italy, Turkey, and the U.S. (8,10). Informed consent was obtained from the subjects or their parents. The studies were performed according to the Declaration of Helsinki and approved by ethics committees. Genetic studies. KCNJ11 encoding Kir6.2 was sequenced as previously described (9). Microsatellite markers localized to four different chromosomes were used to confirm family relationships. Clinical studies. A common protocol was carried out for all participating centers. The medical records of mutation carriers were reviewed ...

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.

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