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2021-12-19 - Article/Dans un journal avec peer-review - Anglais - 49 page(s) (Soumise)

TCHEOUBI Sègbédé Edgard Roméo, AKPOVI Casimir D, Coppée Frédérique , Decleves Anne-Emilie , Laurent Sophie , AGBANGLA Clément, Burtea Carmen , "PCSK9 inhibitors and risk of type 2 diabetes mellitus: Are all PCSK9 cholesterol-lowering genetic variants suitable models for long term impact study?" in Journal of Drug Targeting

  • Edition : Taylor & Francis (United Kingdom)
  • Codes CREF : Sciences biomédicales (DI3200), Endocrinologie (DI3322), Cardiologie et circulation (DI3321), Biochimie pharmaceutique (DI3491), Biologie moléculaire (DI3111), Diabétologie (DI3373), Biologie cellulaire (DI311D)
  • Unités de recherche UMONS : Chimie générale, organique et biomédicale (M108), Biochimie métabolique et moléculaire (M122)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé), Institut des Biosciences (Biosciences)
  • Centres UMONS : Centre de Recherche en Microscopie et Imagerie Médicale (CMMI)
Texte intégral :

Abstract(s) :

(Anglais) Proprotein convertase substilisin/kexin 9 (PCSK9) inhibitors revolutionised the lipid-lowering therapy. However, a risk of type 2 diabetes mellitus (T2DM) is evoked under PCSK9i therapy. In this review, we summarise the current experimental, epidemiological, clinical, and genetic knowledge on the link of PCSK9 with T2DM. Epidemiological and clinical data found significant correlation between PCSK9 and insulin, homeostasis model assessment (HOMA) of insulin resistance and glycated haemoglobin. PCSK9 is also involved in inflammation both at systemic and local level. PCSK9 loss-of-function (LOF) mutations increased T2DM risk by altering insulin secretion but not peripheral insulin sensibility. Local pancreatic low PCSK9 regulates β-cell LDLR expression which in turn promotes intracellular cholesterol accumulation and hampers insulin secretion. Nevertheless, the association of PCSK9 LOF mutations and T2DM is inconsistent. While InsLeu and R46L polymorphisms were more frequent in people with T2DM and were associated with lower HOMA for β-cell function (HOMA-β) and impaired fasting glucose, the C679X polymorphism was associated with low fasting glucose in Black South African people. Regarding the conflicting observations in the above-mentioned LOF mutations, we suggest that genetic variants associated with low pancreatic PCSK9 level would be prone to induce T2DM through disturbing insulin secretion, as depicted by a lower HOMA-β.

Mots-clés :
  • (Anglais) PCSK9
  • (Anglais) type 2 diabetes mellitus
  • (Anglais) insulin
  • (Anglais) cardiovascular diseases
  • (Anglais) PCSK9 inhibitors
  • (Anglais) LDL-cholesterol
  • (Anglais) inflammation