Pancreatic islet amyloid formation in patients with noninsulin-dependent diabetes mellitus

Oosterwijk, Cor; Höppener, Jo W.M.; Hulst, Karen L. van; Lips, Cornelis J.M.

doi:10.1007/bf02825416

Cited by 8 publications

(5 citation statements)

References 69 publications

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“…Our data indicate that islet amyloid is a ªsecondary diabetogenic factorº which is both induced by and involved in the pathogenesis of Type II diabetes [27]. Thus, a gene encoding an amyloidogenic IAPP molecule constitutes an ªendogenous diabetogenic traitº and, like e. g. the ªobº gene, the hIAPP gene can be considered a ªdia-betogeneº [28].…”

Section: Discussionmentioning

confidence: 82%

Extensive islet amyloid formation is induced by development of Type II diabetes mellitus and contributes to its progression: pathogenesis of diabetes in a mouse model

et al. 1999

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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)

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Section: Discussionmentioning

confidence: 82%

Extensive islet amyloid formation is induced by development of Type II diabetes mellitus and contributes to its progression: pathogenesis of diabetes in a mouse model

et al. 1999

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“…Both in islet b cell tumours and in type-2 diabetes patients, impaired IAPP secretion is probabaly involved in amyloidogenesis, associated with b cell destruction (36,37).…”

Section: Discussionmentioning

confidence: 99%

Islet amyloid polypeptide/amylin messenger RNA and protein expression in human insulinomas in relation to amyloid formation

Hulst¹,

Oosterwijk²,

Born

et al. 1999

European Journal of Endocrinology

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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.

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“…Long-term exposure of isolated human islets to high glucose concentrations enhanced IAPP synthesis but lowered IAPP secretion (31). As a consequence, hIAPP accumulates intracellularly and islet amyloid formation may be initiated (14,15,32). This notion is supported by IAPP accumulation observed in ß cell lysosomes of the present transgenic mice in vivo (17,33), When pancreatic islets of these hIAPP transgenic mice were cultured in high glucose medium, intra-and extra¬ cellular amyloid fibrils were formed, whereas no fibril formation was observed after culture in low glucose medium (34).…”

Section: Discussionmentioning

confidence: 99%

“…Multiple potential physiological functions of IAPP have been reported, in particular inhibition of insulin secretion from ß cells (6)(7)(8)(9), and hyperglycémie actions on skeletal muscle and liver (10)(11)(12)(13). Islet amyloid, insulin resistance (often accompanied by obesity) and hyperglycemia are characteristic features of type 2 diabetes mellitus (14,15).…”

Section: Introductionmentioning

confidence: 99%

Biologically active human islet amyloid polypeptide/amylin in transgenic mice

Hulst

Born²,

Muff³

et al. 1997

European Journal of Endocrinology

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Pancreatic islet amyloid formation in patients with noninsulin-dependent diabetes mellitus

Cited by 8 publications

References 69 publications

Extensive islet amyloid formation is induced by development of Type II diabetes mellitus and contributes to its progression: pathogenesis of diabetes in a mouse model

Extensive islet amyloid formation is induced by development of Type II diabetes mellitus and contributes to its progression: pathogenesis of diabetes in a mouse model

Islet amyloid polypeptide/amylin messenger RNA and protein expression in human insulinomas in relation to amyloid formation

Biologically active human islet amyloid polypeptide/amylin in transgenic mice

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