Inhibition of Insulin Secretion

I. Summary_

Reports of the effects of amylin and amylin agonists on insulin secretion have varied widely. Some confusion can be attributed to the use of human amylin, which has been shown to readily fall out of solution resulting in low estimates of bioactivity. Some confusion can be resolved by assessing the probability that this had happened. The view taken here, supported by authors using reliable and well-characterized ligands (representing the preponderance of recent studies), is that exogenously administered amylin agonists inhibit insulin secretion, at least partly via activation of an amylin-like receptor linked to Gi-mediated inhibition of cAMP in islets. There may additionally be autonomic extrapancreatic effects of amylin on insulin secretion that derive from its action at the area postrema. Studies with amylin receptor antagonists, including human studies, indicate that endogenously secreted amylin may physiologically inhibit b-cell secretion

Advances in Pharmacology, Volume 52 Copyright 2005, Elsevier Inc. All rights reserved.

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(insulin and amylin) via feedback inhibition that is characteristic of many other hormones. Part of this inhibition may be local (paracrine), as indicated by the amylin sensitivity of isolated preparations and the fact that the concentration of secreted products in the islet interstitium can be over 100-fold higher than in the circulation (Bendayan, 1993).

II. Background_

Initial reports of the effect of amylin on insulin secretion conflict with more recent reports. This may be a good illustration of how scientific knowledge evolves.

Prior to 1992, most (15/24, 63%) reports (Ahren and Pettersson, 1990; Ar'Rajab and Ahren, 1991; Bretherton-Watt et al., 1990; Broderick and Gold, 1991; Broderick et al., 1991; Fehmann et al., 1990; Ghatei et al., 1990; Gilbey et al., 1989; Gold et al., 1990; Nagamatsu et al., 1990a,b; O'Brien et al., 1990; Pettersson and Ahren, 1990; Tedstone et al., 1989, 1990) concluded that amylin had no impact on insulin secretion. A minority reported an insulinostatic effect (Degano et al., 1991; Johnson et al., 1990; Kogire et al., 1991; Marco et al., 1990; Murakami et al., 1990; Ohsawa et al., 1989; Peiro et al., 1991; Silvestre et al., 1990a,b). After 1992, when most studies used rat amylin instead of human amylin (Rodriguez-Gallardo et al., 1995; Young et al., 1992a), 45/49 (92%) of reports described an insulinostatic effect (Ahren et al., 1998; Bennet et al., 1994; Bloom, 1994; Bretherton-Watt et al., 1992a,b; Chuang et al., 1992; Degano et al., 1992, 1993; Furnsinn et al., 1992, 1994; Gebre-Medhin et al., 1998; Gedulin et al., 1992, 1993; Goke et al., 1993, 1993; Inoue et al., 1993; Kulkarni et al., 1996; Leaming et al., 1995; Lewis et al., 1988; Marco and Silvestre, 1997; O'Harte et al., 1998; Rodriguez-Gallardo et al., 1995; Salas et al., 1994, 1995; Sandler and Stridsberg, 1994; Silvestre et al.,

1992, 1993a,b, 1994, 1996, 1997; Smith and Bloom, 1995; Stridsberg et al., 1993; Suzuki et al., 1992; Wagoner et al., 1992, 1993; Wang et al., 1993, 1997; Young and Gedulin, unpublished; Young et al., 1992a,

1993, 1994, 1995), with four reporting no effect (Barakat et al., 1994; Nagamatsu et al., 1992; Panagiotidis et al., 1992; Wang et al., 1997).

The reasons for the highly significant switch in preponderance of conclusions (P < 0.0001, Fischer's exact test) are not fully clear, but they are likely to include initial use of human amylin. The adverse physicochemical properties of human amylin resulted in commercial batches with highly variable purity (as low as 5%) and biological activity (as low as 1% of native amylin) (Lehman-deGaeta et al., 1991). Compared to rat amylin, human amylin produced very inconsistent results (Rodriguez-Gallardo et al., 1995). Reasons for a heterogeneous literature on amylin's pancreatic effects may also include nonmethodological phenomena, such as biases in the processes by which scientific findings are audited, peer-reviewed, and accepted for publication. Of the nine reports that initially described an insulinostatic effect, five came from the laboratory of Marco et al. in Madrid, whose group has published 17 communications that all report an insulinostatic action. Amylin Pharmaceuticals, Inc. and corporate collaborators have published 10 reports that described an insulinostatic action. Other groups with access to commercial batches of material have observed insulinostatic effects only sporadically. For example, Steven Bloom's lab produced three studies that did not observe an insulinostatic effect and seven that did. And the five publications from Per Westermark's group comprise three against and two for an insulinostatic effect.

Effects of amylin and amylin agonists have been studied in isolated b-cells and b-cell-like cell lines (14 reports), in isolated pancreatic islets (14 reports), in isolated perfused pancreas (20 reports), in vivo in animals (18 reports), and in humans (five reports). Most recent studies have used rat amylin. Some further insights may be obtained from the literature on the effects of salmon calcitonin, which is an amylin agonist.

III. Effects of Amylin on Insulin Secretion_

A. Isolated b'Cells and b-Cell-like Lines

The first indication that amylin might directly inhibit secretion from its cells of origin came from the discovery that calcitonin gene-related peptide (CGRP), an amylin agonist, inhibited insulin secretion from dissociated rat b-cells, as measured in a hemolytic plaque assay (Lewis et al., 1988). Some authors, applying high concentrations of amyloidogenic (fibril-forming) amylin species, such as human amylin, have proposed a cytotoxic effect on isolated b-cells and neurons (Lorenzo and Yankner, 1994; Lorenzo et al., 1994; May et al., 1993), but not with rat amylin or non-amyloidogenic molecular species (May et al., 1993). Some have proposed that the cytotoxic effect of human amylin may adversely affect insulin secretion in metabolic disease (Lorenzo et al., 1994).

In dissociated b-cells from mice, Wagoner and others at Glaxo showed that rodent amylin directly inhibited glucose-stimulated electrical activity, although this occurred at ambient concentrations of amylin that exceeded those measured in plasma (Wagoner et al., 1993). Importantly, they also showed that this effect of amylin could be blocked with the amylin receptor antagonist AC253 (Wagoner and Dukes, unpublished), indicating that the inhibitory effect of amylin was likely to be receptor mediated, rather than a non-specific ''cytotoxic'' effect that would require mechanical (disruptive) contact of fibrils with the cell surface (Lorenzo et al., 1994). A receptor-mediated action was supported by observations that minor changes in

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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