Type II (non-insulin-dependent) diabetes mellitus is a common, age-related, multifactorial disease [1,2]. Although still debated, it seems that the primary defect in most subjects developing Type II diabetes involves resistance to insulin action in muscle or liver or in both which initially is compensated for by increased insulin secretion. When in addition insulin production becomes impaired (ªbeta-cell exhaustionº), however, glucose intolerance or overt diabetes may develop [3±5]. Therefore, factors inhibiting insulin production might promote progression to overt diabetes in subjects with insulin resistance. Islet amy- Diabetologia (1999) Abstract Aims/hypothesis. Type II (non-insulin-dependent) diabetes mellitus is a multifactorial disease in which pancreatic islet amyloid is a characteristic histopathological finding. Islet amyloid fibrils consist of the beta-cell protein ªislet amyloid polypeptideº (IAPP)/ªamylinº. Unlike human IAPP (hIAPP), mouse IAPP cannot form amyloid. In previously generated transgenic mice, high expression of hIAPP as such did not induce islet amyloid formation. To further explore the potential diabetogenic role of amyloidogenic IAPP, we introduced a diabetogenic trait (ªobº mutation) in hIAPP transgenic mice. Methods. Plasma concentrations of IAPP, insulin and glucose were determined at 3.5 (t1), 6 (t2), and 16±19 months of age (t3). At t3, the mice were killed and the pancreas was analysed (immuno)histochemically.Results. In non-transgenic ob/ob mice, insulin resistance caused a compensatory increase in insulin production, normalizing the initial hyperglycaemia. In transgenic ob/ob mice, concurrent increase in hIAPP production resulted in extensive islet amyloid formation (more often and more extensive than in transgenic non-ob/ob mice), insulin insufficiency and persistent hyperglycaemia: At t3, plasma insulin levels in transgenic ob/ob mice with amyloid were fourfold lower than in non-transgenic ob/ob mice (p < 0.05), and plasma glucose concentrations in transgenic ob/ ob mice were almost twofold higher (p < 0.05). In addition, the degree of islet amyloid formation in ob/ob mice was positively correlated to the glucose:insulin ratio (r s = 0.53, p < 0.05). Conclusion/interpretation. Islet amyloid is a secondary diabetogenic factor which can be both a consequence of insulin resistance and a cause of insulin insufficiency. [Diabetologia (1999)
Abstract. Two patients with hyponatraemia resulting from an inappropriate ADH secretion syndrome had low serum values and elevated clearances of uric acid. All the values returned to normal after fluid restriction. The same changes in uric acid clearance and serum level were seen when this syndrome was experimentally induced in five normal subjects.
We describe an improved method for the determination of islet amyloid polypeptide (IAPP) levels in plasma. Plasma is first extracted with acid-acetone, followed by a specific and sensitive radioimmunoassay (RIA) for IAPP using rabbit-anti-human-IAPP serum. Recovery of synthetic IAPP from plasma was 82 +/- 6% (n = 16). Standard samples, prepared in 'hormone-free' serum, were also extracted with acid-acetone. Displacement curves of serially diluted acid-acetone extracted plasma samples were parallel to the standard curve. The lower detection limit of the RIA was 2.3 +/- 0.1 fmol/sample (n = 5). Intra-assay variations for IAPP concentrations of 4, 17 and 32 pM were 16.3% (n = 10), 9.2% (n = 10) and 6.2% (n = 10); interassay variations were 35.9% (n = 14), 19.9% (n = 15) and 15.4% (n = 15), respectively. Non-stimulated IAPP levels ranged from 2.4 to 12 pM (mean 6 +/- 4 pM, n = 10) in healthy control subjects. IAPP was not detectable in type 1 (insulin-dependent) diabetic patients before and after glucagon administration. In type 2 (non-insulin-dependent) diabetic patients basal levels ranged from 2.2 to 14.5 pM and glucagon-stimulated levels ranged from 2.2 to 38.9 pM. The increase in IAPP varied from 0 to 24.4 pM. The anti-human-IAPP serum had full cross-reactivity with rat IAPP (= mouse IAPP). Transgenic mice overexpressing the human IAPP gene showed elevated plasma IAPP levels as compared to (non-transgenic) control mice. It is concluded that the method presented for the determination of IAPP in plasma is reliable and easy to perform, yielding reproducible results.(ABSTRACT TRUNCATED AT 250 WORDS)
Objective: Islet amyloid polypeptide (IAPP), also named amylin, is the predominant protein component of amyloid deposits in human islet b cell tumours of the pancreas (insulinomas). IAPP is co-produced with insulin by islet b cells. We investigated IAPP expression in relation to insulin expression and to amyloid formation in eleven insulinomas. Design and methods: RNA and protein extracts were prepared from the same pieces of tumour tissue, and from specimens of two normal human pancreata. IAPP and insulin mRNA and peptide content were quantified using Northern blot analysis and radioimmunoassay (RIA) respectively. Molecular forms of IAPP immunoreactivity were analysed by reversed-phase high-performance liquid chromatography (HPLC). The presence of islet hormones and of amyloid was assessed by (immuno)histochemical staining of paraffin sections. Plasma levels of IAPP and insulin prior to tumour resection were determined by RIA. Results: IAPP and insulin mRNA and peptide content varied widely between the tumour specimens, and there was considerable intratumour heterogeneity of peptide content. HPLC analysis indicated correct proteolytic processing of the IAPP precursor protein. Amyloid deposits were detected only in the three tumours with the highest IAPP content. In contrast to insulin, plasma levels of IAPP were not elevated in the insulinoma patients. Conclusions: The spectrum of hormone production by insulinomas cannot be inferred from only a few tissue sections due to intratumour heterogeneity. Expression of the IAPP and insulin genes is not coupled in insulinomas, which produce properly processed mature IAPP. In addition to IAPP overproduction, additional factors such as intracellular accumulation of IAPP are involved in amyloidogenesis in insulinomas.
Abstract. Sera from 96 hypertensive patients and an equal number of matched controls have been studied for autoantibodies. Significantly higher frequencies were found of antibodies to gastric parietal cells (14%) and antinuclear factors (A.N.F.) (14%). The direct anti‐human globulin (A.H.G.) test was positive in 5% of the hypertensive patients. No increase was found in the incidence of other autoantibodies. The occurrence of A.N.F. appeared to be related to treatment with chlorthalidone, and the incidence of a positive direct A.H.G. test to α‐methyldopa therapy. A possible combined effect of these drugs on serological aberrations was observed. These aberrations appeared to be unrelated to the possible cause and severity of hypertension and to age and sex. No relation was found between treatment and antibodies to gastric parietal cells.
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