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  • ion transport  (5)
  • insulin  (4)
  • linkage analysis  (4)
  • 1
    Electronic Resource
    Electronic Resource
    Plasma proinsulin, C-peptide and insulin in diagnostic suppression tests for insulinomas (1977)
    Springer
    Diabetologia 13 (1977), S. 571-577 
    Details
    ISSN: 1432-0428
    Keywords: Insulinoma ; malignant insulinoma ; proinsulin ; C-peptide ; insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The value of plasma insulin, human C-peptide and proinsulin estimation in the diagnosis of 15 insulinomas has been investigated. Measurement of plasma proinsulin in an overnight fasting sample diagnosed all the insulinomas studied, irrespective of the plasma glucose. Patients with insulinomas had plasma proinsulin in the range 0.04–4.2 pmol/l and normal values were less than 0.01 pmol/ml. If hypoglycaemia was present, an inappropriately raised plasma immunoreactive insulin (including proinsulin) was diagnostic, but this assay was of little assistance if the plasma glucose was normal. Hypoglycaemia was induced with fish insulin in twelve patients with insulinomas and eight normal subjects. Using an antiserum which did not detect fish insulin, but cross-reacted with human proinsulin, the endogenous immunoreactive insulin was suppressed in the normal subjects, but all insulinoma patients had impaired suppression. Assay of plasma human C-peptide, or of the combined immunoreactive C-peptide and proinsulin, discriminated less well and did not clearly diagnose three insulinomas which secreted proinsulin rather than insulin and C-peptide. Plasma human proinsulin values during induced hypoglycaemia gave excellent discrimination and should detect insulinomas irrespective of their degree of histological differentiation. The assay of plasma human proinsulin allows a suppression test to be performed with hypoglycaemia induced by any type of insulin. A raised plasma proinsulin in proportion to C-peptide suggests an undifferentiated insulinoma, which may be more likely to be malignant.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01236309
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  • 2
    Electronic Resource
    Electronic Resource
    Non-linkage of the glucagon-like peptide 1 receptor gene with maturity onset diabetes of the young (1994)
    Springer
    Diabetologia 37 (1994), S. 721-724 
    Details
    ISSN: 1432-0428
    Keywords: Glucagon-like peptide-1 receptor ; non-insulin-dependent diabetes mellitus ; maturity onset diabetes of the young ; polymerase chain reaction ; linkage analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Glucagon-like peptide-1 (GLP-1) is a hormone derived from the preproglucagon molecule that is secreted by intestinal L cells and stimulates insulin secretion from betacells. The GLP-1 receptor is a candidate gene for diabetes mellitus, as mutations may induce the impaired insulin response that is a characteristic feature of NIDDM. To study the relationship between the GLP-1 receptor gene and NIDDM, linkage of a microsatellite polymorphism flanking the GLP-1 receptor gene with diabetes was investigated in three Caucasian families with MODY and in the nuclear families of 12 NIDDM probands. A cumulative LOD score −8.50 excludes linkage in these MODY pedigrees. A LOD score of −1.24 in the NIDDM nuclear pedigrees makes linkage improbable. Mutations in or near the GLP-1 receptor gene are unlikely to be the major cause of the inherited predisposition to NIDDM in Caucasian pedigrees, but we cannot exclude a role for this locus in a polygenic model or a major role in some pedigrees.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00417698
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  • 3
    Electronic Resource
    Electronic Resource
    Twenty-four hour profiles of plasma C-peptide in Type 1 (insulin-dependent) diabetic children (1982)
    Springer
    Diabetologia 22 (1982), S. 245-249 
    Details
    ISSN: 1432-0428
    Keywords: Type 1 diabetes ; diabetic children ; blood glucose profiles ; insulin ; C-peptide ; B cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Twenty-four hour profiles of plasma C-peptide an index of endogenous insulin secretion, were performed in 15 Type 1 (insulin-dependent) diabetic children. Plasma C-peptide was detectable in six children, of whom four (‘C-peptide producers’) had peak values above normal fasting levels. In each of the six children with residual B cell function, there was a close correlation between plasma C-peptide and simultaneous blood glucose (r〉 0.50, p〈 0.05). Post-breakfast peak blood glucose was 10.2 ± 1.7 mmol/l (mean ±SEM) in the ‘C-peptide producers’ and 18.7 ± 1.7 mmol/l in the 11 children with low or no detectable C-peptide. Mean M-value, an index of deviation from an ideal blood glucose, was lower in the ‘C-peptide producers’ (p〈0.05). It is concluded that residual functioning B cells in diabetic children behave physiologically in that insulin secretion fluctuates in accordance with the prevailing blood glucose; and that the pattern of action of injected insulin is more critical in non-C-peptide producers who lack the post-prandial dampening effect provided by residual endogenous insulin secretion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00281299
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  • 4
    Electronic Resource
    Electronic Resource
    Type 2 (non-insulin-dependent) diabetes mellitus new genetics for old nightmares (1988)
    Springer
    Diabetologia 31 (1988), S. 407-414 
    Details
    ISSN: 1432-0428
    Keywords: Genetics ; Type 2 (non-insulin-dependent) diabetes ; linkage analysis ; restriction fragment length polymorphism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the last five years, genetic markers for a large number of diseases have been localised using linkage analysis of DNA polymorphisms in affected families. The site of the genetic defect or defects leading to Type 2 (non-insulin-dependent) diabetes mellitus, a common illness with a major genetic component, remains unknown. This is due, at least in part, to the lack of large well-defined Type 2 diabetic pedigrees suitable for linkage analysis. There are several features of the disease which make large pedigrees difficult to find. The late age of onset of most probands means that informative older generations are often dead, while there is difficulty in detecting disease in younger generations. The diagnostic criteria for diabetes are, as yet, dependent on an arbitrary cut-off along a continuum of plasma glucose. The high prevalence of the disease may also produce problems as, in any given family, diabetogenic genes may be contributed by more than one parent. Varieties of the disease with a well-defined inheritance, such as maturity onset diabetes of youth, are more suitable for linkage analysis but might be due to defects at a different gene locus. Despite these difficulties, once large well-defined pedigrees have been found, linkage analysis using both candidate genes and random highly polymorphic markers is the strategy most likely to find genetic markers for the disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00271584
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  • 5
    Electronic Resource
    Electronic Resource
    Linkage analysis of the human insulin receptor gene in Type 2 (non-insulin-dependent) diabetic families and a family with maturity onset diabetes of the young (1988)
    Springer
    Diabetologia 31 (1988), S. 792-797 
    Details
    ISSN: 1432-0428
    Keywords: Genetics ; Type 2 (non-insulin-dependent) diabetes ; insulin receptor ; linkage analysis ; maturity onset diabetes of the young
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The possibility of linkage between the human insulin receptor gene locus and diabetes was examined in three Type 2 (non-insulin-dependent) diabetic families and one family with maturity onset diabetes of the young. Insulin receptor gene haplotypes were established using BglII, Rsal and Sstl restriction enzyme digests of genomic DNA from all available family members. The digested DNA was subjected to agarose gel electrophoresis, Southern blotted, and hybridised to 32P-labelled human insulin receptor gene cDNA. In the pedigree with maturity onset diabetes of the young, formal linkage analysis allowed exclusion of close linkage between the insulin receptor locus and diabetes (logarithm of the odds for linkage versus non-linkage was −5.35 at recombination fraction of 0.01). This confirms the absence of linkage between insulin receptor and diabetes which has been reported in two similar pedigrees. In the three Type 2 diabetic families there were a minimum of 4 recombinants between the insulin receptor locus and diabetes, which makes a direct role for insulin receptor defects unlikely. The importance of using realistic estimates of penetrance when performing linkage analysis in a disease with a late age of onset is emphasised. In contrast to the one previous linkage analysis study of the insulin receptor gene, no specific association of diabetes with the rare Sstl Sl(-) allele was observed in either the maturity onset diabetes of the young or the Type 2 diabetic families.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00277479
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  • 6
    Electronic Resource
    Electronic Resource
    Candidate gene studies in pedigrees with maturity-onset diabetes of the young not linked with glucokinase (1995)
    Springer
    Diabetologia 38 (1995), S. 1055-1060 
    Details
    ISSN: 1432-0428
    Keywords: Maturity-onset diabetes of the young ; glucokinase ; adenosine deaminase ; pituitary adenylate cyclase-activation polypeptide receptor ; hexokinase II ; glucagon-like peptide-1 receptor ; polymerase chain reaction ; linkage analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Maturity-onset diabetes of the young (MODY) is a form of non-insulin-dependent diabetes mellitus characterised by an early age of onset and an autosomal dominant mode of inheritance. Only a proportion of cases are due to mutations in the glucokinase gene. We have studied five Caucasian MODY families, including the first MODY family to be described, with five candidate genes implicated in regulation of insulin secretion. The affected subjects showed more marked hyperglycaemia than that found in subjects with glucokinase mutations. We assessed polymorphic markers close to the genes for glucokinase, hexokinase II, adenosine deaminase, pituitary adenylate cyclase-activating polypeptide receptor, and glucagon-like peptide-1 receptor. Linkage analysis with diabetes gave cumulative log of the odds (LOD) scores of less than -3, implying that mutations in these genes are unlikely to provide a major genetic contribution to this form of MODY.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00402175
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  • 7
    Electronic Resource
    Electronic Resource
    Sulphonylurea therapy doubles B-cell response to glucose in Type 2 diabetic patients (1985)
    Springer
    Diabetologia 28 (1985), S. 809-814 
    Details
    ISSN: 1432-0428
    Keywords: Sulphonylureas ; insulin ; C-peptide ; insulin resistance ; hyperglycaemic clamp
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The effect of sulphonylurea therapy for 3 weeks on glucose-stimulated insulin secretion and insulin resistance was studied in Type 2 diabetic patients. The fasting plasma insulin and C-peptide concentrations on diet alone were compared with each subject's fasting concentrations on sulphonylurea treatment at a lower fasting plasma glucose and at the original diet-alone glycaemic level obtained by the hyperglycaemic clamp technique. At this isoglycaemic level (mean 11 mmol/l), plasma insulin levels increased from 6.9 mU/l on diet alone to 12.1 mU/l on sulphonylurea treatment (p〈0.01). The subjects were also studied by the hyperglycaemic clamp technique at mean glycaemic levels of 13 mmol/l before and after sulphonylurea treatment; the incremental insulin response was similarly enhanced from 7.6±3.5 to 13.7±6.9 mU/l (p〈0.02) respectively. Sulphonylureas appear to reduce glycaemia by enhancing B-cell function two-fold. In the patients studied this was from approximately 21% to 37% of a normal response. Insulin resistance assessed by the same hyperglycaemic clamps as endogenous plasma insulin concentrations divided by glucose infusion rates was unchanged by sulphonylurea therapy (mean 4.37 compared to 4.40 mU. 1−1·mg−1·kg·min on diet alone).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00291069
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  • 8
    Electronic Resource
    Electronic Resource
    Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man (1985)
    Springer
    Diabetologia 28 (1985), S. 412-419 
    Details
    ISSN: 1432-0428
    Keywords: β-cell function ; insulin resistance ; mathematical model ; intravenous glucose tolerance test ; glucose clamp ; insulin receptors ; Type 2 diabetes ; insulin ; glucose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The steady-state basal plasma glucose and insulin concentrations are determined by their interaction in a feedback loop. A computer-solved model has been used to predict the homeostatic concentrations which arise from varying degrees of β-cell deficiency and insulin resistance. Comparison of a patient's fasting values with the model's predictions allows a quantitative assessment of the contributions of insulin resistance and deficient β-cell function to the fasting hyperglycaemia (homeostasis model assessment, HOMA). The accuracy and precision of the estimate have been determined by comparison with independent measures of insulin resistance and β-cell function using hyperglycaemic and euglycaemic clamps and an intravenous glucose tolerance test. The estimate of insulin resistance obtained by homeostasis model assessment correlated with estimates obtained by use of the euglycaemic clamp (Rs = 0.88, p 〈 0.0001), the fasting insulin concentration (Rs = 0.81, p 〈 0.0001), and the hyperglycaemic clamp, (Rs = 0.69, p 〈 0.01). There was no correlation with any aspect of insulin-receptor binding. The estimate of deficient β-cell function obtained by homeostasis model assessment correlated with that derived using the hyperglycaemic clamp (Rs = 0.61, p 〈 0.01) and with the estimate from the intravenous glucose tolerance test (Rs = 0.64, p 〈 0.05). The low precision of the estimates from the model (coefficients of variation: 31% for insulin resistance and 32% for β-cell deficit) limits its use, but the correlation of the model's estimates with patient data accords with the hypothesis that basal glucose and insulin interactions are largely determined by a simple feed back loop.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00280883
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  • 9
    Electronic Resource
    Electronic Resource
    Inactivation of the rabbit parotid Na/K/Cl cotransporter by N-ethylmaleimide (1989)
    Springer
    The journal of membrane biology 112 (1989), S. 51-58 
    Details
    ISSN: 1432-1424
    Keywords: loop diuretics ; exocrine gland ; fluid secretion ; parotid ; acinar cell ; ion transport ; chloride secretion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Summary The inactivation of the rabbit parotid Na/K/Cl cotransporter by the irreversible sulfhydryl reagent N-ethylmaleimide (NEM) is studied by monitoring its effect on high affinity bumetanide binding to the carrier. NEM reduces the number of bumetanide binding sites with no significant change in the affinity of those remaining. NEM also reduces KCl-dependent22Na flux via the cotransporter by the same factor as the reduction in bumetanide binding sites. Both bumetanide and its analogue furosemide can protect against the effect of NEM. The concentration range over which this protection occurs is in good agreement with affinities of these two compounds for the high affinity bumetanide binding site (2.6 and 85 μm, respectively), indicating an association of this site with the site of action of NEM. Also consistent with this hypothesis are the observations that (i) sodium and potassium, both of which are required for high affinity bumetanide binding, increase the rate of inactivation of binding by NEM and (ii) chloride, at concentrations previously shown to competitively inhibit bumetanide binding, protects the cotransporter against NEM. The effects of NEM on bumetanide binding are mimicked by another highly specific sulfhydryl reagent, methyl methanethiolsulfonate. The apparent rate constant for inactivation of high affinity bumetanide binding by NEM is a hyperbolic function of NEM concentration consistent with a model in which the inactivation reaction is first order in [NEM] and proceeds through an intermediate adsorptive complex. The data indicate that the presence of a reduced sulfhydryl group at or closely related to the bumetanide binding site is essential for the operation of the parotid Na/K/Cl cotransporter.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01871163
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  • 10
    Electronic Resource
    Electronic Resource
    Solubilization and partial purification of the rabbit parotid Na/K/Cl-dependent bumetanide binding site (1990)
    Springer
    The journal of membrane biology 113 (1990), S. 203-210 
    Details
    ISSN: 1432-1424
    Keywords: loop diuretics ; exocrine gland ; fluid secretion ; parotid ; acinar cell ; ion transport ; chloride secretion ; detergent
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology
    Notes: Summary We demonstrate that the high affinity bumetanide binding site of the rabbit parotid acinar cell can be extracted from a basolateral membrane fraction using relatively low concentrations (0.07%, wt/vol; 1 mg membrane protein/ml) of the nonionic detergent Triton X-100. This extracted site cannot be sedimented by ultracentrifugation at 100,000 ×g × 1 hr. Bumetanide binding to this site retains the ionic characteristics of bumetanide binding to native membranes but shows a fivefold increase in binding affinity (K d=0.57±0.15 μm vs.K d=3.3±0.7 μm for native membranes). Inactivation of the extracted bumetanide binding site observed at detergent/protein ratios〉1 can be prevented or (partially) reversed by the addition of exogenous lipid (0.2% soybean phosphatidylcholine). When the 0.07% Triton extract is fractionated by sucrose density gradient centrifugation in 0.24% Triton X-100, 0.2% exogenous lipid and 200mm salt, the high affinity bumetanide binding site sediments as a single band withS 20,w =8.8±0.8 S. This corresponds to a molecular weight ∼200 kDa for the bumetanide binding protein-detergent-lipid complex and represents a sevenfold purification of this site relative to the starting membrane fraction. In contrast to previous attempts to purify Na/K/Cl cotransport proteins and their associated bumetanide binding sites, the present method avoids harsh detergent treatment as well as direct covalent modification (inactivation) of the transporter itself. As a consequence, one can follow the still active protein through a series of extraction and purification steps by directly monitoring its bumetanide binding properties.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01870072
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