Increased Insulin Secretion and Glucose Tolerance in Mice Lacking Islet Amyloid Polypeptide (Amylin)

doi:10.1006/bbrc.1998.9308

Biochemical and Biophysical Research Communications

Volume 250, Issue 2, 18 September 1998, Pages 271-277

https://doi.org/10.1006/bbrc.1998.9308 Get rights and content

Abstract

Islet amyloid polypeptide (IAPP or amylin) is costored and cosecreted with insulin and may regulate insulin secretion and blood glucose handling. However, the role and importance of endogenous IAPP in the regulation of insulin release and glucose homeostasis have been controversial. Here we report on the generation and phenotypic analysis of IAPP-deficient mice. These mice have normal, or near to normal, basal levels of circulating insulin and glucose. However, following glucose administration, IAPP-deficient males presented increased insulin responses paralleled with a more rapid blood glucose elimination compared to wild-type controls. Blood glucose elimination was also found to be enhanced in IAPP-deficient females, but the insulin response in this gender did not differ from controls. In a transgenic rescue experiment, using an insulin-promoter human-IAPP fusion gene, insulin responses and blood glucose elimination were reversed in IAPP-deficient males, whereas the female phenotype appeared unaffected. Our results provide the first firm evidence of a physiological role for endogenous IAPP and indicate that IAPP, apparently in a gender-dependent manner, limits the degree of glucose-induced insulin secretion and the rate of blood glucose elimination.

References (42)

P. Westermark et al.
Biochem. Biophys. Res. Commun.
(1986)
M.K. Badman et al.
Febs Lett.
(1996)
A. Kanatsuka et al.
Febs Lett.
(1989)
H. Ohsawa et al.
Biochem. Biophys. Res. Commun.
(1989)
R.A. Silvestre et al.
Regul. Pept.
(1994)
T. Tokuyama et al.
Metabolism
(1997)
H.K. Datta et al.
Biochem. Biophys. Res. Commun.
(1989)
J.E. Morley et al.
Peptides
(1991)
A.A. Young et al.
Life Sci.
(1993)
T.A. Lutz et al.
Neurosci. Lett.
(1997)

N. Aiyar et al.

J. Biol. Chem.

(1996)

R.A. Silvestre et al.

Biochem. Pharmacol.

(1993)

M.W. Wang et al.

Febs Lett.

(1991)

C. Betsholtz et al.

Exp. Cell Res.

(1989)

N. Fox et al.

Febs Lett.

(1993)

S. Mosselman et al.

FEBS Lett.

(1988)

L. Christmanson et al.

Febs Lett.

(1990)

E.N. Olson et al.

Cell

(1996)

G.J. Cooper et al.

Proc. Natl. Acad. Sci. USA

(1987)

A. Lukinius et al.

Diabetologia

(1989)

Cited by (141)

Protective roles of adiponectin and molecular signatures of HNF4α and PPARα as downstream targets of adiponectin in pancreatic β cells
2023, Molecular Metabolism
The disease progression of the metabolic syndrome is associated with prolonged hyperlipidemia and insulin resistance, eventually giving rise to impaired insulin secretion, often concomitant with hypoadiponectinemia. As an adipose tissue derived hormone, adiponectin is beneficial for insulin secretion and β cell health and differentiation. However, the down-stream pathway of adiponectin in the pancreatic islets has not been studied extensively. Here, along with the overall reduction of endocrine pancreatic function in islets from adiponectin KO mice, we examine PPARα and HNF4α as additional down-regulated transcription factors during a prolonged metabolic challenge. To elucidate the function of β cell-specific PPARα and HNF4α expression, we developed doxycycline inducible pancreatic β cell-specific PPARα (β-PPARα) and HNF4α (β-HNF4α) overexpression mice. β-PPARα mice exhibited improved protection from lipotoxicity, but elevated β-oxidative damage in the islets, and also displayed lowered phospholipid levels and impaired glucose-stimulated insulin secretion. β-HNF4α mice showed a more severe phenotype when compared to β-PPARα mice, characterized by lower body weight, small islet mass and impaired insulin secretion. RNA-sequencing of the islets of these models highlights overlapping yet unique roles of β-PPARα and β-HNF4α. Given that β-HNF4α potently induces PPARα expression, we define a novel adiponectin-HNF4α-PPARα cascade. We further analyzed downstream genes consistently regulated by this axis. Among them, the islet amyloid polypeptide (IAPP) gene is an important target and accumulates in adiponectin KO mice. We propose a new mechanism of IAPP aggregation in type 2 diabetes through reduced adiponectin action.
Islet amyloid polypeptide does not suppress pancreatic cancer
2023, Molecular Metabolism
Pancreatic cancer risk is elevated approximately two-fold in type 1 and type 2 diabetes. Islet amyloid polypeptide (IAPP) is an abundant beta-cell peptide hormone that declines with diabetes progression. IAPP has been reported to act as a tumour-suppressor in p53-deficient cancers capable of regressing tumour volumes. Given the decline of IAPP during diabetes development, we investigated the actions of IAPP in pancreatic ductal adenocarcinoma (PDAC; the most common form of pancreatic cancer) to determine if IAPP loss in diabetes may increase the risk of pancreatic cancer.
PANC-1, MIA PaCa-2, and H1299 cells were treated with rodent IAPP, and the IAPP analogs pramlintide and davalintide, and assayed for changes in proliferation, death, and glycolysis. An IAPP-deficient mouse model of PDAC (Iapp^−/−; Kras^+/LSL-G12D; Trp53^flox/flox; Ptf1a^+/CreER) was generated for survival analysis.
IAPP did not impact glycolysis in MIA PaCa-2 cells, and did not impact cell death, proliferation, or glycolysis in PANC-1 cells or in H1299 cells, which were previously reported as IAPP-sensitive. Iapp deletion in Kras^+/LSL-G12D; Trp53^flox/flox; Ptf1a^+/CreER mice had no effect on survival time to lethal tumour burden.
In contrast to previous reports, we find that IAPP does not function as a tumour suppressor. This suggests that loss of IAPP signalling likely does not increase the risk of pancreatic cancer in individuals with diabetes.
Understanding the mechanism of amylin aggregation: From identifying crucial segments to tracing dominant sequential events to modeling potential aggregation suppressors
2023, Biochimica et Biophysica Acta - Proteins and Proteomics
One of the most abundant, prevailing, and life-threatening human diseases that are currently baffling the scientific community is type 2 diabetes (T2D). The self-association of human amylin has been implicated in the pathogenesis of T2D, though with an inconclusive understanding of the mechanism. Hence, we focused on the characterization of the conformational ensembles of all the species that are believed to define the structural polymorphism of the aggregation process – the functional monomeric, the initially self-associated oligomeric, and the structured protofibril – by employing near-equilibrium, non-equilibrium, and equilibrium atomistic simulations on the sporadic, two familial variants (S20G and G33R), and their proline-substituted forms (S20P and G33P). The dynamic near-equilibrium assays hint toward – the abundance of helical conformation in the monomeric state, the retainment of the helicity in the initial self-associated oligomeric phase pointing toward the existence of the helix-helix association mechanism, the difference in preference of specific segments to have definite secondary structural features, the phase-dependent variability in the dominance of specific segments and mutation sites, and the simultaneous presence of generic and unique features among various sequences. Furthermore, the non-equilibrium pulling assays exemplify a generic sequential unzipping mechanism of the protofibrils, however, the sequence-dependent uniqueness comes from the difference in location and magnitude of the control of a specific terminus. Importantly, the equilibrium thermodynamic assays efficiently rank order the potential of aggregability among sequences and consequently suggests the probability of designing effective aggregation suppressors against sporadic and familial amylin variants incorporating proline as the mutation.
Noncardiovascular-derived therapeutic peptidomimetics in cardiovascular disease
2022, Peptide and Peptidomimetic Therapeutics: From Bench to Bedside
Cardiovascular diseases (CVDs) make up a group of heart and blood vessel disorders and remain the most common cause of death worldwide. Annually, approximately one in every six US healthcare dollars is spent on CVD, and by 2035 the number of Americans with CVD is anticipated to rise to 131.2 million—45% of the total US population.
Peptides are naturally occurring short chains of amino acids, typically comprising 2–50 amino acids and ubiquitously found in all living organisms, which display a large diversity of biological effects that regulate most physiological processes. Since the isolation of insulin, which later became the first commercially available peptide drug, peptide therapeutics have played important roles in medical practice. Over the years, there has been a constant increase in the number of peptides entering clinical studies. Importantly, peptides demonstrate higher success rates in transitioning from phase 1 to phase 2 trials as compared to small molecules and biological drugs, and in transitioning from phase 3 to regulatory review.
This chapter discusses the therapeutic potential of peptides which primarily affect organ systems other than the cardiovascular system (CVS), but which also play key roles in the CVS. For example, the neurohormones vasopressin and oxytocin, which primarily control endocrine and reproductive processes, were recently found to have cardioprotective properties. The vasodilatory and other cardiovascular effects of calcitonin gene-related protein, vasoactive intestinal peptide, amylin and glucagon-like peptide-1, and the potential cardioprotective effects of ghrelin, salusin, apelin, and urocortin are also reviewed. Together, through their gastrointestinal or neuronal actions, these noncardiovascular peptides play roles in the regulation of normal cardiovascular hemodynamics and may be used to reduce CVD-related morbidity and mortality.
Calcitonin receptor signaling in the medial preoptic area enables risk-taking maternal care
2021, Cell Reports
Maternal mammals exhibit heightened motivation to care for offspring, but the underlying neuromolecular mechanisms have yet to be clarified. Here, we report that the calcitonin receptor (Calcr) and its ligand amylin are expressed in distinct neuronal populations in the medial preoptic area (MPOA) and are upregulated in mothers. Calcr+ MPOA neurons activated by parental care project to somatomotor and monoaminergic brainstem nuclei. Retrograde monosynaptic tracing reveals that significant modification of afferents to Calcr+ neurons occurs in mothers. Knockdown of either Calcr or amylin gene expression hampers risk-taking maternal care, and specific silencing of Calcr+ MPOA neurons inhibits nurturing behaviors, while pharmacogenetic activation prevents infanticide in virgin males. These data indicate that Calcr+ MPOA neurons are required for both maternal and allomaternal nurturing behaviors and that upregulation of amylin-Calcr signaling in the MPOA at least partially mediates risk-taking maternal care, possibly via modified connectomics of Calcr+ neurons postpartum.
Mono and dual agonists of the amylin, calcitonin, and CGRP receptors and their potential in metabolic diseases
2021, Molecular Metabolism
Therapies for metabolic diseases are numerous, yet improving insulin sensitivity beyond that induced by weight loss remains challenging. Therefore, search continues for novel treatment candidates that can stimulate insulin sensitivity and increase weight loss efficacy in combination with current treatment options. Calcitonin gene-related peptide (CGRP) and amylin belong to the same peptide family and have been explored as treatments for metabolic diseases. However, their full potential remains controversial.
In this article, we introduce this rather complex peptide family and its corresponding receptors. We discuss the physiology of the peptides with a focus on metabolism and insulin sensitivity. We also thoroughly review the pharmacological potential of amylin, calcitonin, CGRP, and peptide derivatives as treatments for metabolic diseases, emphasizing their ability to increase insulin sensitivity based on preclinical and clinical studies.
Amylin receptor agonists and dual amylin and calcitonin receptor agonists are relevant treatment candidates, especially because they increase insulin sensitivity while also assisting weight loss, and their unique mode of action complements incretin-based therapies. However, CGRP and its derivatives seem to have only modest if any metabolic effects and are no longer of interest as therapies for metabolic diseases.

View all citing articles on Scopus

^☆: Abbreviations used: CGRP, calcitonin gene-related peptide; IAPP, islet amyloid polypeptide; IVGTT, intravenous glucose tolerance test; OGTT, oral glucose tolerance test;RI1P-hIAPP, rat insulin-I promoter-human IAPP fusion gene

¹: Correspondence: Samuel Gebre-Medhin, Department of Medical Biochemistry, Göteborg University, P.O. Box 440, SE 405 30 Göteborg, Sweden. E-mail:[email protected].

View full text

Regular ArticleIncreased Insulin Secretion and Glucose Tolerance in Mice Lacking Islet Amyloid Polypeptide (Amylin)☆

Abstract

Biochem. Biophys. Res. Commun.

Febs Lett.

Febs Lett.

Biochem. Biophys. Res. Commun.

Regul. Pept.

Metabolism

Biochem. Biophys. Res. Commun.

Peptides

Life Sci.

Neurosci. Lett.

J. Biol. Chem.

Biochem. Pharmacol.

Febs Lett.

Exp. Cell Res.

Febs Lett.

FEBS Lett.

Febs Lett.

Cell

Proc. Natl. Acad. Sci. USA

Diabetologia

Regular Article
Increased Insulin Secretion and Glucose Tolerance in Mice Lacking Islet Amyloid Polypeptide (Amylin)☆