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Experimental studies have revealed that hypoglycaemia can result in morphological changes in electrocardiographic repolarisation in subjects with type 1 diabetes. However, the influence of spontaneous nocturnal hypoglycaemia on repolarisation morphology in a ‘real life’ situation is not clear. Adults with type 1 diabetes (n = 11) underwent continuous glucose monitoring with a subcutaneous sensor and digital 12-lead ECG recording for three nights. T-wave morphology was analysed with custom-made software during both hypoglycaemia (glucose

Objective: Primary hyperparathyroidism (PHPT), a common endocrine condition, is usually caused by sporadically occurring parathyroid adenoma. A subset of patients carry germline mutations in genes such as MEN1 (multiple endocrine neoplasia type 1), HRPT2 (hyperparathyroidism 2), and CASR (calcium-sensing receptor) predisposing to syndromic forms of PHPT or familial isolated hyperparathyroidism (FIHP). Recently, germline mutations in two novel genes AIP (aryl hydrocarbon receptor-interacting protein) and CDKN1B (cyclin-dependent kinase inhibitor 1B) have been found to be associated with endocrine tumors. The purpose of this study was to evaluate the role of MEN1, HRPT2, CASR, AIP, and CDKN1B genes in PHPT patients with clinical features suggestive of genetic predisposition. Patients and design: Medical records of patients treated for PHPT from 1974 to 2001 at Oulu University Hospital were reviewed. Patients with multiglandular or recurrent/persistent disease, other MEN1-related manifestations, aged 40 yr or younger at onset or with a family history of PHPT/MEN1-related tumor were invited to the study. Twenty patients with previously diagnosed MEN1 were excluded. Participants were interviewed and blood samples obtained for biochemical screening and mutation analysis of MEN1, HRPT2, CASR, AIP, and CDKN1B. Results: Of the 56 invited patients, 29 took part in the study. One patient was found to carry the c. 1356_1367del12 MEN1 founder mutation. Mutations in other genes were not detected. Conclusions: Apart from MEN1, mutations in other genes predisposing to PHPT seem to be rare or non-existing in Northern Finnish PHPT patients. No evidence was found for a role of AIP or CDKN1B in PHPT predisposition.

Nocturnal hypoglycaemia may contribute to sudden death in diabetic patients. However, it is not well known why hypoglycaemia makes these patients prone to death. We assessed the effects of controlled hypoglycaemia on cardiac repolarisation using novel electrocardiographic descriptors of T-wave and QRS complex morphology in 16 type 1 diabetic patients and eight healthy counterparts. Several electrocardiographic variables characterising repolarisation were analysed from digitised 12-lead electrocardiograms during a euglycaemic and a hypoglycaemic clamp. Hypoglycaemia did not result in significant changes either in the QT interval corrected for heart rate by the nomogram method or in QT dispersion. However, the morphology of the T-wave changed significantly during hypoglycaemia. The T-wave amplitude and area in precordial leads decreased significantly in both groups (p

Aims/hypothesis. Inflammation could play a part in insulin resistance. Thiazolidinediones, new antidiabetic drugs, possess anti-inflammatory effects in vitro. We investigated if acute-phase serum proteins are increased in patients with Type II (non-insulindependent) diabetes mellitus who had been treated with insulin and whether troglitazone has anti-inflammatory effects in vivo. Methods. A total of 27 patients (age 63.0 ‐ 1.7 years, HbA 1c 8.8 ‐ 0.3 %, BMI 32.7 ‐ 0.8 kg/m 2 , duration 15.2 ‐ 1.4 years, insulin dose 73.3 ‐ 7.0 U/day) participated in the study. The patients received daily either 400 mg troglitazone or placebo for 16 weeks. Blood samples were taken at baseline, at the end of therapy and after a follow-up time of 23 ‐ 4 days. Results. The concentrations of serum amyloid A (6.2 ‐ 1.1 mg/l) and C-reactive protein (6.1 ‐ 1.1 mg/ l) were increased (p < 0.001) and complement protein C3 (1.69 ‐ 0.05 g/l) was also above the reference range for healthy subjects. Placebo treatment had no effect on glucose or inflammation, whereas troglitazone reduced fasting glucose (from 10.4 ‐ 0.6 mmol/l to 8.1 ‐ 0.5 mmol/l, p < 0.01), HbA 1c (from 8.7 ‐ 0.3 % to 7.5 ‐ 0.3 %, p < 0.01), insulin requirements (from 75 ‐ 10 U/day to 63 ‐ 10 U/day, p < 0.05), serum amyloid A (from 6.3 ‐ 1.5 mg/l to 4.0 ‐ 1.3 mg/l, p = 0.001), a-1-acid glycoprotein (from 906 ‐ 51 mg/l to 729 ‐ 52 mg/l, p = 0.001) and C3 (from 1.72 ‐ 0.07 g/l to 1.66 ‐ 0.06 g/l, p < 0.05) but not a-1-antitrypsin, ceruloplasmin, C-reactive protein or haptoglobin significantly. Concentrations of glucose and acute-phase reactants had returned to those before treatment at the follow-up visit. Conclusion/interpretation. In Type II diabetic patients serum amyloid A and complement protein C3 are raised. Troglitazone exerts a selective reversible action on some acute-phase proteins and C3 but not on others in conjunction with the improvement in glucose metabolism. [Diabetologia (1999) 42: 1433‐ 1438]

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by tumours of the parathyroids, pancreas and anterior pituitary. The MEN1 gene has been localised to a 2-Mb region of chromosome 11q13 by meiotic mapping studies in MEN1 families. Such studies may have a limited resolution of approximately 1 cM (i.e. 1 Mb) and we have therefore investigated 96 MEN1 families (40 British, 17 French, 12 Finnish, 7 Swedish, 7 Dutch, 7 North American, 2 Australian, 1 New Zealand, 1 German, 1 Spanish and 1 Danish) for linkage disequilibrium, in order to facilitate a finer mapping resolution. We have utilised five microsatellite DNA sequence polymorphisms from the candidate region and have accurately determined their allele sizes, which ranged from 161 bp to 272 bp. The heterozygosity and number of alleles (given in brackets), respectively, at the loci were: D11S1883 (76%, 11), D11S457 (55%, 5), PYGM (94%, 18), D11S1783 (10%, 4) and D11S449 (87%, 16). Allelic association was assessed by Chi-square 2 x n contingency tables, by Fisher exact 2 x n contingency tables and by a likelihood-based approach. The results of haplotype analysis revealed 91 different affected haplotypes in the 96 families, an identical affected haplotype being observed in no more than two families. These results indicate the absence of an ancestral affected haplotype. Significant linkage disequilibrium (P < 0.005) could be established amongst the microsatellite loci but not between the loci and MEN1 in either the total population or in any of the geographical sub-populations, The absence of linkage disequilibrium between MEN1 and the polymorphic loci is probably the result of the occurrence of multiple different disease-causing mutations in MEN1.

Familial multiple endocrine neoplasia, type 1 (FMEN1), is an autosomal dominant trait generated by hyperfunction of various endocrine glands. The gene for MEN1 has been mapped to chromosome 11q13 by genetic linkage and deletion mapping in tumors. Eight Finnish families, including 46 individuals carrying the risk haplotype, have been typed for four polymorphic microsatellite DNA markers spanning the MEN1 chromosomal region. Three of the loci concerned, D11S913, D11S987, and D11S1337, displayed maximum lod scores (Zmax) 6.70, 9.88, and 2.54, respectively, with no recombinations with the disease gene, whereas a Zmax of 8.43 was obtained for D11S971 at a recombination fraction of 0.03. Our results indicate that the use of this set of markers considerably improves the diagnostic value of genotyping patients at risk of developing MEN1.