The amylin superfamily: A novel grouping of biologically active polypeptides related to the insulin A-chain

doi:10.1016/0955-2235(89)90004-5

Progress in Growth Factor Research

Volume 1, Issue 2, 1989, Pages 99-105

Progress in Growth F...

https://doi.org/10.1016/0955-2235(89)90004-5 Get rights and content

Abstract

The peptide amylin (previously termed Diabetes Associated Peptide) has recently been isolated and characterised from the amyloid of the pancreatic islets of Langerhans from human type 2 diabetics [1]. Amylin shows about 46% identity in amino acid sequence on comparison with the calcitonin gene-related peptides (CGRPs) and also shows some similarity to insulin [1]. Recent studies have also shown that both amylin and CGRP are potent inhibitors of insulin-stimulated glycogen synthesis in skeletal muscle in vitro [2,3]. Hormones may be arranged into families, therefore a degree of order exists even though hormone-mediated effects are complex [4]. The polypeptides insulin, insulin-like growth factors (IGFs) and relaxins have been grouped into such a family with similarities both at the protein-structural and genetic levels [4,5]. We now demonstrate that this insulin-related family, along with amylin and the CGRPs, are members of a peptide superfamily defined by structural similarity in the region corresponding to the A-chain of insulin. In order to distinguish this grouping of small biologically active peptides from the previous one, we have designated it the amylin superfamily. All the members of the previously defined insulin family have a region homologous to the insulin B-chain. Insulin, the IGFs, the relaxins, the CGRPs and amylin are all involved in carbohydrate metabolism and therefore these peptides are functionally as well as structurally related. This grouping of peptides may have important implications for the study of human metabolic disease.

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Cited by (21)

Historical Background
2005, Advances in Pharmacology
Citation Excerpt :
A distant homology is reported between amylin and the insulin/relaxin/IGF superfamily (Cooper et al., 1989b). No statistically significant homology between amylin and calcitonins was noted on Dayhoff analysis (Cooper et al., 1989b), but sequence similarity is clearly apparent between rat amylin and salmon and rat calcitonins, particularly at functionally important segments at N and C termini (Young et al., 1995). The C‐terminal portion of adrenomedullin, a 52‐amino‐acid peptide, shows some (∼20%) homology with amylin and CGRPs (Kitamura et al., 1993).
This chapter explains a hyaline (homogeneous glassy) appearance within the islets of Langerhans from diabetic patients. The hyaline material present in pancreata from diabetic patients has been histologically identified to be amyloid, an extracellular proteinaceous material with characteristic staining properties. Westermark and coworkers, while working with amyloid obtained from resected insulinoma tissue, reported a partial sequence of a material that they designated as “insulinoma amyloid peptide” (IAP). There may be utility in using the term “IAPP” in its original context (i.e., when referring to a material derived from insulinoma tissue) because it is not clear that such material is post-translationally modified or bioactive. Several studies have addressed the possibility that type 2 diabetes mellitus is associated with a mutation of the amylin gene. Homology has been noted among amylin from pancreatic islets, amyloid material from insulinoma, and CGRP—a product of alternate splicing of the calcitonin gene.
Amyloidogenicity and cytotoxicity of recombinant mature human islet amyloid polypeptide (rhIAPP)
2004, Journal of Biological Chemistry
Citation Excerpt :
IAPP belongs to the calcitonin-gene related peptides (CGRPs) family. Two characteristics of members of this family are the presence of a disulfide bond in the N-terminal domain of the protein and an amidated C-terminal (34–36). In order to determine the state of oxidation of the disulfide bond between cysteine residues 2 and 7 of rhIAPP, we have carried out DTNB (5,5′-dithiobis-(2-nitrobenzoic) acid) titrations of thiol reactive groups in the recombinant protein according to previously described procedures (37, 38).
Pancreatic amyloid plaques formed by the pancreatic islet amyloid polypeptide (IAPP) are present in more than 95% of type II diabetes mellitus patients, and their abundance correlates with the severity of the disease. IAPP is currently considered the most amyloidogenic peptide known, but the molecular bases of its aggregation are still incompletely understood. Detailed characterization of the mechanisms of amyloid formation requires large quantities of pure material. Thus, availability of recombinant IAPP in sufficient amounts for such studies constitutes an important step toward elucidation of the mechanisms of amyloidogenicity. Here, we report, for the first time, the successful expression, purification and characterization of the amyloidogenicity and cytotoxicity of recombinant human mature IAPP. This approach is likely to be useful for the production of other amyloidogenic peptides or proteins that are difficult to obtain by chemical synthesis.
Pharmacological characterization of receptor-activity-modifying proteins (RAMPs) and the human calcitonin receptor
1999, Journal of Pharmacological and Toxicological Methods
Receptor-activity-modifying proteins (RAMPs) are a family of single transmembrane domain proteins shown to be important for the transport and ligand specificity of the calcitonin gene-related peptide (CGRP) receptor. In this report, we describe the analysis of pharmacological properties of the human calcitonin receptor (hCTR) coexpressed with different RAMPs with the use of the Xenopus laevis melanophore expression system. We show that coexpression of RAMP3 with human calcitonin receptor changed the relative potency of hCTR to human calcitonin (hCAL) and rat amylin. RAMP1 and RAMP2, in contrast, had little effect on the change of hCTR potency to hCAL or rat amylin. When coexpressed with RAMP3, hCTR reversed the relative potency by a 3.5-fold loss in sensitivity to hCAL and a 19-fold increase in sensitivity to rat amylin. AC66, an inverse agonist, produced apparent simple competitive antagonism of hCAL and rat amylin, as indicated by linear Schild regressions. The potency of AC66 was changed in the blockade of rat amylin but not hCAL responses with RAMP3 coexpression. The mean pK_B for AC66 to hCAL was 9.4 ± 0.3 without RAMP3 and 9.45 ± 0.07 with RAMP3. For the antagonism of AC66 to rat amylin, the pK_B was 9.25 ± 0.15 without RAMP3 and 8.2 ± 0.35 with RAMP3. The finding suggests that RAMP3 might modify the active states of calcitonin receptor in such a way as to create a new receptor phenotype that is “amylin-like.” Irrespective of the physiological association of the new receptor species, the finding that a coexpressed membrane protein can completely change agonist and antagonist affinities for a receptor raises implications for screening in recombinant receptor systems.
Alpha<inf>2</inf>-adrenoceptors and the regulation of glucose, insulin and amylin levels in diabetic rats
1995, Life Sciences
The effects of the selective alpha₂-adrenoceptor agonist UK 14.304 on glucose, insulin and amylin levels were examined in neonatal streptozotocin-induced diabetic rats. UK 14.304 (0.03 to 0.3 mg/kg i.p.) induced a dose-dependent reduction of both insulin and amylin levels in normal rats while UK 14.304 at 0.03 mg/kg had already a maximal effect in diabetic rats. Amylin/insulin molar ratios rose after UK 14.304 administration in diabetic rats but remainded constant in normal rats. The alpha₂-adrenoceptor antagonist deriglidole (3 mg/kg i.p.) slightly increased insulin and amylin levels in the two groups of rats but glucose levels were more markedly decreased in diabetic rats. Deriglidole completely antagonized UK 14.304 (0.1 mg/kg i.p.)-induced changes thereby normalizing amylin/insulin molar ratios in diabetic rats. These results suggest that insulin and amylin are both under inhibitory control via alpha₂-adrenoceptor though the responses may be differentially regulated. It is further suggested that diabetes in the neonatal streptozotocin-induced rat model is associated with a hypersensitivity of the pancreas to alpha₂-adrenoceptor stimulation.
Anti-inflammatory activity of amylin and CGRP in different experimental models of inflammation
1995, Life Sciences
The anti-inflammatory activity of amylin was studied in different models of inflammation, and compared to that of CGRP. Both peptides were active against mouse ear oedema induced by croton oil and acetic acid-induced peritonitis in the rat. CGRP was more potent than amylin in both models. Pretreatment with CGRP 8–37 fragment blocked the anti-inflammatory activity of both peptides in croton oil ear oedema. No anti-inflammatory activity was evidenced against serotonin-induced rat paw oedema and plasma protein extravasation induced by dextran in rat skin. Our results suggest that amylin exerts anti-inflammatory activity only in inflammatory models characterized by a vascular component. This effect appears to be mediated by the involvement of CGRP receptors.
Does amylin have a pathophysiological endocrine role in diabetes mellitus in man?
1994, Journal of Diabetes and Its Complications

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View full text

The amylin superfamily: A novel grouping of biologically active polypeptides related to the insulin A-chain

Abstract

J Biol Chem.

FEBS Lett.

Prog Growth Factor Res.

Gastroenterology

Methods Enzymol.

Immunol. Today

FEBS Lett.

Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients

Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle in vitro

Nature

Amylin found in amyloid deposits in human type 2 diabetes mellitus may be a hormone that regulates glycogen metabolism in skeletal muscle

Hormone families: pancreatic hormones and homologous growth factors

Nature

Isolation of the human insulin-like growth factors genes: Insulin-like growth factor II and insulin genes are contiguous

Relaxin gene expression in human ovaries and the predicted structure of a human preprorelaxin by analysis of cDNA clones

EMBO J.

Insulin and insulin-like growth factor receptors and responses in cultured human muscle cells

Am J Physiol.

Effects and binding of insulin-like growth factor I in the isolated soleus muscle of lean and obese mice

Endocrinology

Effect of relaxin on uterine glycogen and protein in the rat

Demonstration of some of the physiological properties of rat relaxin

J Reprod Fert.

Relaxin affects the release of oxytocin and vasopressin from the neurohypothysis

Nature

Amylin and non-insulin-dependent (type 2) diabetes mellitus