Familial hyperinsulinism caused by an activating glucokinase mutation.
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Adult↗
Biomedical subjects
B Glaser
Publications and source records attributed to B Glaser.
Familial hyperinsulinism with apparent autosomal dominant inheritance: clinical and genetic differences from the autosomal recessive variant.
We describe three families with hypoglycemia caused by familial hyperinsulinism (HI) in whom vertical transmission of the disorder occurred, suggesting autosomal dominant (AD) inheritance. We therefore examined the relationship between the apparent AD disorder and the more common autosomal recessive (AR) form of HI, which has recently been linked to the sulfonylurea receptor on chromosome 11p15.1. The clinical features of the 11 patients with AD HI were milder than those seen in 14 patients with AR HI. Hypoglycemia was readily controlled with either diet alone or with diazoxide in 10 of 11 patients with AD HI but in none of those with the AR form. In one large pedigree, analysis of genomic DNA with polymorphic simple sequence repeat markers excluded linkage of AD HI to the SUR locus in a dominant manner. The possibility of linkage to the SUR locus could not be absolutely excluded in the two smaller pedigrees. None of the published mutations of the SUR gene identified in patients with AR HI were detected in the patients with the AD form. We conclude that the AD form of hyperinsulinism is phenotypically different from the AR variant. The identification of more families with this form of HI may make it possible to locate the responsible gene by the use of linkage analysis.
Adolescent↗
Genetic heterogeneity in familial hyperinsulinism.
Familial hyperinsulinism (HI) is a disorder characterized by dysregulation of insulin secretion and profound hypoglycemia. Mutations in both the Kir6.2 and sulfonylurea receptor (SUR1) genes have been associated with the autosomal recessive form of this disorder. In this study, the spectrum and frequency of SUR1 mutations in HI and their significance to clinical manifestations of the disease were investigated by screening 45 HI probands of various ethnic origins for mutations in the SUR1 gene. Single-strand conformation polymorphism (SSCP) and nucleotide sequence analyses of genomic DNA revealed a total of 17 novel and three previously described mutations in SUR1 . The novel mutations comprised one nonsense and 10 missense mutations, two deletions, three mutations in consensus splice-site sequences and an in-frame insertion of six nucleotides. One mutation occurred in the first nucleotide binding domain (NBF-1) of the SUR1 molecule and another eight mutations were located in the second nucleotide binding domain (NBF-2), including two at highly conserved amino acid residues within the Walker A sequence motif. The majority of the remaining mutations was distributed throughout the three putative transmembrane domains of the SUR1 protein. With the exception of the 3993-9G-->A mutation, which was detected on 4.5% (4/88) disease chromosomes, allelic frequencies for the identified mutations varied between 1.1 and 2.3% for HI chromosomes, indicating that each mutation was rare within the patient cohort. The clinical manifestations of HI in those patients homozygous for mutations in the SUR1 gene are described. In contrast with the allelic homogeneity of HI previously described in Ashkenazi Jewish patients, these findings suggest that a large degree of allelic heterogeneity at the SUR1 locus exists in non-Ashkenazi HI patients. These data have important implications for genetic counseling and prenatal diagnosis of HI, and also provide a basis to further elucidate the molecular mechanisms underlying the pathophysiology of this disease.
ATP-Binding Cassette Transporters↗
Somatostatin-receptor scintigraphy in the management of gastroenteropancreatic tumors.
OBJECTIVE: This study evaluates the diagnostic and therapeutic implications of somatostatin-receptor scintigraphy in the management of patients with proven or high clinical suspicion of gastroenteropancreatic endocrine tumors. METHODS: Forty-one patients were studied by planar and tomographic imaging at 4 h and 24 h after 111In-pentetreotide injection. Scintigraphic findings were compared with computed tomography, and in several patients also with ultrasound, angiography, biopsy, and/or surgery, when performed. RESULTS: Among 23 patients with carcinoid tumor, three of nine primary tumors were initially identified by scintigraphy. Unsuspected mesenteric metastases found on scintigraphy in three patients led to octreotide treatment. Scintigraphic detection of multiple metastases in a patient with thyroid metastasis of bronchial carcinoid spared her an unnecessary total thyroidectomy. Among 18 patients with 19 islet-cell tumors, scintigraphy detected three of five insulinomas, whereas computed tomography identified only one. Receptor positivity in an islet-cell tumor (vipoma?) with no metastases on the scan led to surgical removal of the primary tumor. Receptor-positive metastases of gastrinoma (two of three patients), glucagonoma (two of three patients), and parathyroid hormone-related peptide-producing tumor (one patient) led to octreotide treatment. Nonvisualization of metastases of a glucovipoma led to chemotherapy. CONCLUSIONS: Somatostatin-receptor scintigraphy contributes to the management of patients with gastroenteropancreatic tumors in the following ways: 1) localization of a primary occult tumor, allowing surgical removal; 2) staging of the disease for optimal therapy-surgical excision or systemic treatment; and 3) identification of receptor status of the metastases for octreotide treatment or chemotherapy.
Adenoma, Islet Cell↗
Isolation and characterization of the human PAX4 gene.
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Amino Acid Sequence↗
Pancreatic beta-cell glucokinase: closing the gap between theoretical concepts and experimental realities.
There remains a wide gap between theoretical concepts and experimental realities in the enzyme kinetics and biochemical genetics of the pancreatic beta-cell glucokinase-glucose sensor. It is the goal of present efforts in many laboratories to bridge this gap. This perspective intends to provide a timely review of this crucial aspect of research in glucose homeostasis. It deals briefly with some fundamentals of glucokinase enzyme kinetics, offers some pertinent biochemical genetic considerations, takes stock of the current experimental database of the field by emphasizing human studies and referring to recent mouse studies, and ventures a few extrapolations into the future of this endeavor.
Animals↗
Hepatocyte nuclear factor 1alpha coding mutations are an uncommon contributor to early-onset type 2 diabetes in Ashkenazi Jews.
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Adult↗
Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy.
The ATP-sensitive potassium channel, K(ATP) channel, a functional complex of the sulfonylurea receptor 1, SUR1, and an inward rectifier potassium channel subunit, Kir6.2, regulates insulin secretion in the pancreas. Mutations in both the Kir6.2 and SUR1 genes are associated with persistent hyperinsulinemic hypoglycemia of infancy (PHHI), a disorder of pancreatic beta-cell function characterized by excess insulin secretion and hypoglycemia. We have studied the functional properties of novel SUR1 mutations identified in PHHI patients, including H125Q, N188S, F591L, T1139M, R1215Q, G1382S, and R1394H. R1394H and deltaF1388 SUR1, a previously identified PHHI mutation, resulted in no functional channels when coexpressed with Kir6.2 in COS cells, while H125Q, N188S, F591L, T1139M, R1215Q, and G1382S SUR1 generated functional channels in the absence of ATP. With the exception of N188S and H125Q, all mutants had reduced response to stimulation by MgADP. These results indicate that lack of, or reduction of, K(ATP) channel sensitivity to MgADP is a common molecular defect associated with the disease. The mutant channels also showed varied response to activation by the potassium channel opener diazoxide. Because these mutations are distributed throughout the molecule, our data have new implications for structure-function relationships of the K(ATP) channel, suggesting that structural elements in SUR1 outside of the two nucleotide-binding folds are also important in regulating channel activity.
ATP-Binding Cassette Transporters↗
Psychiatry and paedophilia: a major public health issue.
OBJECTIVE: The aim of this study was to provide a brief review of current perspectives on paedophilia as well as some suggestions regarding the place of psychiatry in dealing with the problem. METHOD: A literature survey was conducted. RESULTS: Child sexual abuse has unfortunately been ignored and minimised by psychiatry until recently. The current evidence strongly indicates that it is a common event which is highly likely to cause both short- and long-term harm to its victims. The perpetrators generally are psychiatrically otherwise 'normal' men who are skilled at both planning their offending behaviours and denying their existence. CONCLUSIONS: Psychiatrists have an important role to play in assessment and treatment of both offenders and victims, although they may have to learn new clinical skills. Their preventative role is also important, particularly in the field of public education.
Adult↗
[Imported arthropod-borne parasites and parasitic arthropods in dogs. Species spectrum and epidemiologic analysis of the cases diagnosed in 1995/96].
Between January 1995 and December 1996 nonendemic or only regionally occurring arthropodborne parasites including ehrlichiae and parasitic arthropods in Germany were detected in 484 dogs, whereby at least 15 species were involved. Listed in decreasing order, Leishmania infections occurred most frequently, followed by infections/infestations with Babesia canis, Ehrlichia canis, Rhipicephalus sanguineus, Dirofilaria immitis and Dermacentor reticulatus. The other species, namely Babesia gibsoni, Trypanosoma congolense, Hepatozoon canis, Ehrlichia platys, Dirofilaria repens, Dipetalonema reconditum, Dermacentor marginatus, Boophilus microplus and Cordylobia anthropophaga were demonstrated in a few or single dogs. Irrespective of the pathogen-species, most of the dogs had travelled with their owners to Mediterranean countries or to Portugal or had been imported from there. Infections with B. canis were diagnosed very frequently in dogs returning from Hungary. Of the 28 dogs with previous residence in Germany only, twelve and four animals were infected with B. canis and E. canis, respectively, and seven and five dogs were infested with R. sanguineus and D. marginatus, respectively.
Animals↗
[Dog tourism and import: an inquiry in Germany on the extent as well as on the spectrum and preference of countries of residence and origin respectively].
A survey was conducted among practicing veterinarians and at pet clinics in Germany in order to estimate the extent of tourism with dogs and import of dogs and to determine the range and preference of the foreign countries involved. The survey covered the years from 1985 to 1995 and included 5240 dogs, of which 4567 (87.2%) were born in Germany and 673 (12.8%) were born abroad. Among the latter, 263 (39.1%) originated from Mediterranean countries and Portugal, 344 (51.1%) were born in other European countries and 66 (9.8%) were from non-European countries. Of all 5240 dogs surveyed, 2894 (55.2%) had been taken abroad at least once between 1985 and 1995. Of these, 2424 (53.1%) were born in Germany, 470 (69.8%) were born abroad. Of the 2894 dogs taken abroad, 1929 (66.7%) travelled to Mediterranean countries or Portugal and 1152 of these had additional travels to other countries as well. The spectrum of all countries travelled to was very broad, but numerous dogs were taken regularly, repeatedly and exclusively to Austria, Switzerland, Italy, Spain or France. Other countries were visited only once for the majority of dogs. The analysis of the annual survey data revealed a steady increase of dogs along on trips from Germany to other countries, rising from 31.1% in 1990 to 40.8% in 1994. In any of these years, always more than 56% of these dogs were taken to Mediterranean countries.
Africa↗
Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS).
Pendred syndrome is a recessively inherited disorder with the hallmark features of congenital deafness and thyroid goitre. By some estimates, the disorder may account for upwards of 10% of hereditary deafness. Previous genetic linkage studies localized the gene to a broad interval on human chromosome 7q22-31.1. Using a positional cloning strategy, we have identified the gene (PDS) mutated in Pendred syndrome and found three apparently deleterious mutations, each segregating with the disease in the respective families in which they occur. PDS produces a transcript of approximately 5 kb that was found to be expressed at significant levels only in the thyroid. The predicted protein, pendrin, is closely related to a number of known sulphate transporters. These studies provide compelling evidence that defects in pendrin cause Pendred syndrome thereby launching a new area of investigation into thyroid physiology, the pathogenesis of congenital deafness and the role of altered sulphate transport in human disease.
Amino Acid Sequence↗
A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism.
ATP-sensitive potassium (K[ATP]) channels are an essential component of glucose-dependent insulin secretion in pancreatic islet beta-cells. These channels comprise the sulfonylurea receptor (SUR1) and Kir6.2, a member of the inward rectifier K+ channel family. Mutations in the SUR1 subunit are associated with familial hyperinsulinism (HI) (MIM:256450), an inherited disorder characterized by hyperinsulinism in the neonate. Since the Kir6.2 gene maps to human chromosome 11p15.1 (1,2), which also encompasses a locus for HI, we screened the Kir6.2 gene for the presence of mutations in 78 HI probands by single-strand conformation polymorphism (SSCP) and nucleotide sequence analyses. A nonsense mutation, Tyr-->Stop at codon 12 (designated Y12X) was observed in the homozygous state in a single proband. 86Rb+ efflux measurements and single-channel recordings of COS-1 cells co-expressing SUR1 and either wild-type or Y12X mutant Kir6.2 proteins confirmed that K(ATP) channel activity was abolished by this nonsense mutation. The identification of an HI patient homozygous for the Kir6.2/Y12X allele affords an opportunity to observe clinical features associated with mutations resulting in an absence of Kir6.2. These data provide evidence that mutations in the Kir6.2 subunit of the islet beta-cell K(ATP) channel are associated with the HI phenotype and also suggest that the majority of HI cases are not attributable to mutations in the coding region of the Kir6.2 gene.
Animals↗
Genetics of NIDDM in France: studies with 19 candidate genes in affected sib pairs.
As part of an ongoing search for susceptibility loci for NIDDM, we tested 19 genes whose products are implicated in insulin secretion or action for linkage with NIDDM. Loci included the G-protein-coupled inwardly rectifying potassium channels expressed in beta-cells (KCNJ3 and KCNJ7), glucagon (GCG), glucokinase regulatory protein (GCKR), glucagon-like peptide I receptor (GLP1R), LIM/homeodomain islet-1 (ISL1), caudal-type homeodomain 3 (CDX3), proprotein convertase 2 (PCSK2), cholecystokinin B receptor (CCKBR), hexokinase 1 (HK1), hexokinase 2 (HK2), mitochondrial FAD-glycerophosphate dehydrogenase (GPD2), liver and muscle forms of pyruvate kinase (PKL, PKM), fatty acid-binding protein 2 (FABP2), hepatic phosphofructokinase (PFKL), protein serine/threonine phosphatase 1 beta (PPP1CB), and low-density lipoprotein receptor (LDLR). Additionally, we tested the histidine-rich calcium locus (HRC) on chromosome 19q. All regions were tested for linkage with microsatellite markers in 751 individuals from 172 families with at least two patients with overt NIDDM (according to World Health Organization criteria) in the sibship, using nonparametric methods. These 172 families comprise 352 possible affected sib pairs with overt NIDDM or 621 possible affected sib pairs defined as having a fasting plasma glucose value of >6.1 mmol/l or a glucose value of >7.8 mmol/l 2 h after oral glucose load. No evidence for linkage was found with any of the 19 candidate genes and NIDDM in our population by nonparametric methods, suggesting that those genes are not major contributors to the pathogenesis of NIDDM. However, some evidence for suggestive linkage was found between a more severe form of NIDDM, defined as overt NIDDM diagnosed before 45 years of age, and the CCKBR locus (11p15.4; P = 0.004). Analyses of six additional markers spanning 27 cM on chromosome 11p confirmed the suggestive linkage in this region. Whether an NIDDM susceptibility gene lies on chromosome 11p in our population must be determined by further analyses.
Age Factors↗
Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment.
OBJECTIVE: Type 2 diabetes is a slowly progressive disease, in which the gradual deterioration of glucose tolerance is associated with the progressive decrease in beta-cell function. Hyperglycemia per se has deleterious effects on both beta-cell function and insulin action, which are partially reversible by the short-term control of blood glucose levels. We hypothesized that the induction of euglycemia, using intensive insulin therapy at the time of clinical diagnosis, could lead to a significant improvement in insulin secretion and action and thus alter the clinical course of the disease. RESEARCH DESIGN AND METHODS: Thirteen newly diagnosed diet-unresponsive type 2 diabetic patients were treated with continuous subcutaneous insulin infusion (CSII) for 2 weeks and followed longitudinally while being treated with diet alone. RESULTS: Four patients were considered therapeutic failures since CSII failed to induce euglycemia (n = 1) or glucose control deteriorated within 6 months after CSII (n = 3). The remaining nine patients were maintained on diet alone with adequate control from 9 to > 50 months (median +/- SE, 26 +/- 4.8 months). In five patients, glycemic control deteriorated after 9-36 months, but a repeat 2-week CSII treatment reestablished control in four patients. One of these patients underwent a third CSII treatment 13 months later. At the time this article was written, six patients of the initial group were still controlled without medication 16-59 months (median +/- SE, 45.5 +/- 6.6 months) after the initiation of treatment. Body weight remained unchanged in all patients. CONCLUSIONS: These findings suggest that in a significant proportion of type 2 diabetic patients who fail to respond to dietary measures, short-term intensive insulin treatment can effectively establish responsiveness, allowing long-term glycemic control without medication. Further studies are required to establish whether simpler treatment regimens could be equally effective. If the hypothesis offered here finds support, present approaches to the management of newly diagnosed type 2 diabetes may need to be revised.
Adult↗
[Imported parasites in dogs: Dirofilaria repens and Dipetalonema reconditum].
Between June 1993 and May 1996 infections with filariae were diagnosed in 80 dogs. Five animals were infected with Dirofilaria repens and three other dogs with Dipetalonema reconditum. One of the D. reconditum positive dogs was also infected with Dirofilaria immitis. An epidemiological analysis of the cases was possible for three D. repens and two D. reconditum infected dogs. Two of the dogs with D. repens infections had been imported from Italy or Greece, the third dog had been taken by its owner to Hungary and former Yugoslavia. The dogs infected with D. reconditum were imported from Corse or Spain. Regarding the other 72 dogs with filariae, 45 animals were infected with D. immitis. For 27 dogs being negative in the D. immitis ELISA, microfilariae have been demonstrated. However, a histochemical species differentiation of the microfilariae was not possible because fresh blood smears were not available.
Animals↗
Adenosine diphosphate as an intracellular regulator of insulin secretion.
Adenosine triphosphate (ATP)-sensitive potassium (KATP) channels couple the cellular metabolic state to electrical activity and are a critical link between blood glucose concentration and pancreatic insulin secretion. A mutation in the second nucleotide-binding fold (NBF2) of the sulfonylurea receptor (SUR) of an individual diagnosed with persistent hyperinsulinemic hypoglycemia of infancy generated KATP channels that could be opened by diazoxide but not in response to metabolic inhibition. The hamster SUR, containing the analogous mutation, had normal ATP sensitivity, but unlike wild-type channels, inhibition by ATP was not antagonized by adenosine diphosphate (ADP). Additional mutations in NBF2 resulted in the same phenotype, whereas an equivalent mutation in NBF1 showed normal sensitivity to MgADP. Thus, by binding to SUR NBF2 and antagonizing ATP inhibition of KATP++ channels, intracellular MgADP may regulate insulin secretion.
ATP-Binding Cassette Transporters↗
Normal proinsulin processing despite beta-cell dysfunction in persistent hyperinsulinaemic hypoglycaemia of infancy (nesidioblastosis).
Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a genetic disorder which causes severe hypoglycaemia in the neonate. The beta cells fail to respond to changes in blood glucose levels in all the stages of the disease, which often ends with NIDDM. Fasting insulin, intact proinsulin and des 31,32 split proinsulin levels were measured in PHHI patients with active disease, patients after partial pancreatectomy, and those in clinical remission. All but one of the pancreatectomized patients developed diabetes and were hyperglycaemic on evaluation. Fasting insulin was comparable in pancreatectomized and medically treated patients. Des 31,32 split proinsulin levels were much higher in pancreatectomized compared to non-pancreatectomized patients (10.7 +/- 2.5 vs 3.4 +/- 0.8 pmol/l, p = 0.001) and age-matched control subjects (3.8 +/- 1.4 pmol/l, p = 0.018). Also the ratio of des 31,32 split proinsulin to total insulin plus proinsulin-like peptides was higher in pancreatectomized patients (18.7 +/- 2.8 vs 7.2 +/- 0.8% in non-pancreatectomized patients, p = 0.001, and 6.8 +/- 2.1% in normal control subjects, p = 0.004). Furthermore, des 31,32 split proinsulin was the dominating species of proinsulin-like molecules in the pancreatectomized patients (62.7 +/- 1.6% vs 45.5 +/- 3.8%, and 49.0 +/- 3.2% in non-pancreatectomized patients and control subjects, respectively, p = 0.001 and p = 0.0002). Intact proinsulin levels, and the proinsulin percentage, tended to be higher in pancreatectomized patients; however, the differences did not reach statistical significance. All parameters were similar in non-pancreatectomized patients and age-matched control subjects. Subgroup analysis showed comparable proinsulin-like peptide levels in patients with active disease and those in apparent clinical remission. Fasting levels of insulin and proinsulin-like peptides were also measured in a larger group of healthy children and young adults. Insulin and des 31,32 split proinsulin increased with age, the differences being most prominent when the young age group (0-8 years) was compared to the older groups (8-16 and > 16 years). The fasting levels of plasma insulin were correlated with those of intact proinsulin and des 31,32 split proinsulin (r = 0.82 and 0.81, respectively). Fasting insulin, intact proinsulin and des 31,32 split proinsulin were correlated with BMI (r = 0.55, 0.56 and 0.53, respectively). In summary, relative hyperproinsulinaemia was noted only in PHHI patients with increased secretory demand following pancreatectomy, but not in patients with active disease or those in spontaneous clinical remission. These findings suggest that abnormal proinsulin processing is not an intrinsic feature of PHHI despite the severe beta-cell dysfunction.
Adolescent↗