ArticleMolecular metabolism2025
Peptidylglycine alpha-amidating monooxygenase is important in mice for beta-cell cilia formation and insulin secretion but promotes diabetes risk through beta-cell independent mechanisms.
Article in Molecular metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed.
- Primary Cilia as Integrative Hubs of Metabolic Signaling in Type 2 Diabetes: Inter-Organ Evidence From Central, Peripheral, and Pancreatic Islet Tissues.Journal of cellular physiology · 2026Review
- A surviving beta cell subpopulation enriched in patients with T1D.bioRxiv : the preprint server for biology · 2026Article
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10 authors.
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Abstract
objectivesCarriers of PAM (peptidylglycine alpha-amidating monooxygenase) coding variant alleles have reduced insulinogenic index, higher risk of developing type 2 diabetes (T2D), and islets from heterozygous carriers of the PAM p.Asp563Gly variant display reduced insulin secretion. Exactly how global PAM deficiency contributes to hyperglycemia remains unclear. PAM is the only enzyme capable of converting glycine-extended peptide hormones into amidated products. Like neuropeptide Y (NPY), α-melanocyte stimulating hormone (αMSH), and glucagon-like peptide 1 (GLP-1), islet amyloid polypeptide (IAPP), a beta cell peptide that forms islet amyloid in type 2 diabetes, is a PAM substrate. We hypothesized that Pam deficiency limited to beta cells would lead to reduced insulin secretion, prevent the production of amidated IAPP, and reveal the extent to which loss of Pam in β-cells could accelerate the onset of hyperglycemia in mice.
methodsPAM activity was assessed in human islets from donors based on their PAM genotype. We generated beta cell-specific Pam knockout (Ins1
resultsPAM enzyme activity was significantly reduced in islets from donors with the PAM p. Asp563Gly T2D-risk allele. Islets from βPamKO mice had impaired second-phase glucose- and KCl-induced insulin secretion. Beta cells from βPamKO mice had larger dense-core granules and fewer and shorter cilia. Interestingly, non-amidated hIAPP was less fibrillogenic in vitro, and high glucose-treated hIAPP
conclusionsEliminating Pam expression only in beta cells leads to morphological changes in insulin granules, reduced insulin secretion, reduced hIAPP amyloid burden and altered ciliogenesis. However, in mice beta-cell Pam deficiency has no impact on the development of diet- or hIAPP-induced hyperglycemia. Our data are consistent with current studies revealing ancient, highly conserved roles for peptidergic signaling in the coordination of the diverse signals needed to regulate fundamental processes such as glucose homeostasis.
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