Localisation of islet amyloid peptide in lipofuscin bodies and secretory granules of human B-cells and in islets of type-2 diabetic subjects

Clark, Anne; Edwards, C.; Ostle, Lynne R.; Sutton, Robert; Rothbard, Jonathan B.; Morris, John F.; Turner, R. C.

doi:10.1007/bf00221649

Cited by 108 publications

(54 citation statements)

References 27 publications

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“…In ␤-cells and other secretory cells, proteins that are not sorted to granules (e.g., receptors) can be delivered to the plasma membrane and/or secreted via the constitutive pathway. Although the ␤-cell peptide IAPP is colocalized with insulin in secretory granules (4,5) and can be released from ␤-cells by the regulated secretory pathway, our findings demonstrate that a significant proportion (~40%) of glucose-stimulated IAPP release occurs via the constitutive secretory pathway in neonatal rat ␤-cells.…”

Section: Discussionmentioning

confidence: 62%

“…IAPP is synthesized primarily in the pancreatic ␤-cell, where it is colocalized with insulin in secretory granules (4,5) and is released along with insulin in response to stimulation by ␤-cell secretagogues such as glucose (6,7). The physiological function of IAPP has not been determined, although effects on insulin action (8) and secretion (9), gastric emptying (10), and food intake (11) have all been suggested.…”

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confidence: 99%

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The constitutive secretory pathway is a major route for islet amyloid polypeptide secretion in neonatal but not adult rat islet cells.

et al. 2000

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Islet amyloid polypeptide (IAPP or amylin) is a normal secretory product of the pancreatic ␤-cell that is cosecreted with insulin and is the major constituent of islet amyloid deposits in individuals with type 2 diabetes or insulinomas. We have previously reported that glucose stimulates IAPP, but not insulin secretion, from neonatal rat ␤-cells when regulated secretion is prevented by use of calcium-free media, suggesting that IAPP secretion occurs via a constitutive secretory pathway. To directly test this hypothesis, we examined the effects of 2 substances-brefeldin A (BFA) and cycloheximide (CHX)-that are predicted to selectively block constitutive secretion on the release of IAPP-like immunoreactivity (IAPP-LI) and immunoreactive insulin (IRI) from neonatal rat islet cell monolayer cultures. When regulated release was prevented by use of calcium-free media, glucose-stimulated IAPP-LI release was nearly abolished by blocking constitutive release with 10 µg/ml BFA (mean ± SD: 8.7 ± 7.7 vs. 29.3 ± 14.3 pmol/l; n = 5; P < 0.05), an inhibitor of constitutive vesicle formation. Similarly, calcium-independent, glucose-stimulated IAPP-LI secretion was markedly suppressed when new protein synthesis was blocked by administration of 20 µg/ml CHX (4.6 ± 2.1 vs. 29.5 ± 14.0 pmol/l; n = 5; P < 0.005). Secretion of IRI was low in the absence of calcium, and neither BFA nor CHX had any further effect. When calcium was added to the incubation media to allow regulated secretion of both IRI and IAPP-LI, both BFA (47.7 ± 8.7 vs. 80.7 ± 10.3 pmol/l; P < 0.001) and CHX (37.3 ± 5.8 vs. 73.3 ± 6.2 pmol/l; n = 5; P < 0.0001) inhibited glucose-stimulated IAPP-LI secretion by ~40%, but again had no inhibitory effect on IRI secretion. These data indicate that ~40% of glucose-stimulated IAPP-LI release occurs via a constitutive secretory pathway in neonatal rat islet cells. By contrast, in adult rat islets, glucose-stimulated IAPP-LI release was almost abolished in the absence of calcium (86 ± 3% inhibition; P < 0.05) and unaffected by addition of BFA (275 ± 28 vs. 205 ± 89 pmol/l; NS) or CHX (160 ± 20 vs. 205 ± 89 pmol/l; NS), suggesting that constitutive secretion of IAPP does not occur in mature ␤-cells. Collectively, these data suggest that a significant proportion of glucose-stimulated IAPP secretion from neonatal, but not adult, rat islet cells occurs via a constitutive secretory pathway.

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Section: Discussionmentioning

confidence: 62%

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confidence: 99%

The constitutive secretory pathway is a major route for islet amyloid polypeptide secretion in neonatal but not adult rat islet cells.

et al. 2000

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“…It has been suggested that IAPP most probably occurs in the translucent halo [19,20] although in one immune electron microscopy study the strongest IAPP immunoreactivity was found on the granule cores [5]. This latter finding could possibly be due to a preparation artefact but it could not be ruled out that lAPP is stored together with insulin on the granule core surface.…”

Section: Discussionmentioning

confidence: 94%

Effects of beta cell granule components on human islet amyloid polypeptide fibril formation

et al. 1996

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Formation of amyloid-like fibrils in a solution of human islet amyloid polypeptide (hIAPP) with and without the presence of other IS-cell granule components was studied in vitro. Insulin at less than equimolar concentration strongly inhibited hIAPP fibrillogenesis. Proinsulin had a weaker inhibitory effect while C-peptide, Ca 2+ and Zn 2÷ each individually enhanced fibril formation. C-peptide combined with Ca 2+ had an inhibitory effect. Since IAPP was found almost exclusively in the halo fractions of isolated islet secretory granules, primarily the concentrations of C-peptide, Ca 2+ and possibly proinsulin may be crucial for the native state of IAPP. It is concluded that an imbalance between fibril formation enhancers and inhibitors may be of importance in the pathogenesis of amyloid in the islets of Langerhans.Key words: Fibril; Islet amyloid polypeptide; Non-insulindependent diabetes mellitus; In vitro; Granule loid properties in vitro while corresponding rat IAPP peptides do not [10]. This fibril formation of hIAPP occurs rapidly and spontaneously in aqueous solutions.With this knowledge, we hypothesized that there normally may exist a mechanism which hinders the formation of amyloid fibrils from IAPP in fl-cells and in the islets of Langerhans, the only sites where it is expressed at high concentrations. Since IAPP is stored together with insulin, proinsulin and C-peptide in the secretory granules, the influence of these three latter polypeptides on fibril formation was studied in vitro. Both calcium and zinc are present at high concentration in the fl-cell secretory granules and therefore the effect of these ions on fibril formation was included in the investigation. Finally, we determined the concentration of IAPP in the two fl-cell granule compartments. Materials and methods

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“…Under normal conditions, beta-cell granules including intracellular IAPP and insulin which are not targeted for secretion, are degraded in lysosomes [107] and human IAPP accumulates in lysosomes in islets from man and hIAPP transgenic mice [108,109]; however, there was no evidence of IAPP fibril formation in lysosomes indicating that an increased concentration is not sufficient for intracellular fibril formation at this site. A proposal has been made that all amyloid deposits are being degraded continuously [110], possibly by removal by macrophages, and that accumulation of deposits could result from a deficiency in the factors responsible for degradation and/or turnover [111].…”

Section: Iapp Concentrationmentioning

confidence: 99%

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

2004

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The role of islet amyloidosis in the onset and progression of Type 2 diabetes remains obscure. Islet amyloid polypeptide is a 37 amino-acid, beta-cell peptide which is co-stored and co-released with insulin. Human islet amyloid polypeptide refolds to a β-conformation and oligomerises to form insoluble fibrils; proline substitutions in rodent islet amyloid polypeptide prevent this molecular transition. Pro-islet amyloid polypeptide (67 amino acids in man) is processed in secretory granules. Refolding of islet amyloid polypeptide may be prevented by intragranular heterodimer formation with insulin (but not proinsulin). Diabetes-associated abnormal proinsulin processing could contribute to de-stabilisation of granular islet amyloid polypeptide. Increased pro-islet amyloid polypeptide secretion as a consequence of islet dysfunction could promote fibrillogenesis; the propeptide forms fibrils and binds to basement membrane glycosamino-glycans. Islet amyloid polypeptide gene polymorphisms are not universally associated with Type 2 diabetes. Transgenic mice expressing human islet amyloid polypeptide gene have increased islet amyloid polypeptide concentrations but develop islet amyloid only against a background of obesity and/or high fat diet. In transgenic mice, obese monkeys and cats, initially small perivascular deposits progressively increase to occupy 80% islet mass; the severity of amyloidosis in animal models is related to the onset of hyperglycaemia, suggesting that islet amyloid and the associated destruction of islet cells cause diabetes. In human diabetes, islet amyloid can affect less than 1% or up to 80% of islets indicating that islet amyloidosis largely results from diabetes-related pathologies and is not an aetiological factor for hyperglycaemia. However, the associated progressive betacell destruction leads to severe islet dysfunction and insulin requirement. [Diabetologia (2004) 47:157-169]

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Localisation of islet amyloid peptide in lipofuscin bodies and secretory granules of human B-cells and in islets of type-2 diabetic subjects

Cited by 108 publications

References 27 publications

The constitutive secretory pathway is a major route for islet amyloid polypeptide secretion in neonatal but not adult rat islet cells.

The constitutive secretory pathway is a major route for islet amyloid polypeptide secretion in neonatal but not adult rat islet cells.

Effects of beta cell granule components on human islet amyloid polypeptide fibril formation

Islet amyloid: a complication of islet dysfunction or an aetiological factor in Type 2 diabetes?

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