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2016-02-17 - Colloque/Présentation - poster - Anglais - 1 page(s)

Crombez Déborah , Muller Robert , Burtea Carmen , "Type 2 diabetes and metabolic syndrome : agonist peptides targeted to adiponectin receptors are new therapeutic strategy by activation of AMPK pathway" in Belgian Peptide Group Meeting, Bruxelles, Belgique, 2016

  • Codes CREF : Histologie (DI3212), Sciences biomédicales (DI3200), Endocrinologie (DI3322), Biochimie pharmaceutique (DI3491), Biologie moléculaire (DI3111), Diabétologie (DI3373), Biologie cellulaire (DI311D)
  • Unités de recherche UMONS : Chimie générale, organique et biomédicale (M108)
  • 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)

Abstract(s) :

(Anglais) The incidence of obesity and diabetes is increasing around the world. Type two diabetes can be a consequence of obesity and takes place when the targeted cells become insulin unresponsive, inducing hyperglycemia1. Adiponectin is an adipokine that enhances the insulin sensitivity. Its receptors, AdipoR1 and AdipoR2, are mainly expressed in the skeletal muscle and liver respectively but also in the β cells of the pancreas2,3. When adiponectin binds to AdipoR, it induces the AMPK (AMP activated protein kinase) pathway that leads to an increase of fatty acids’ oxidation, the uptake of glucose into the skeletal muscle, the inhibition of some enzymes involved in hepatic gluconeogenesis and also contributes to the survival of β cells. In obese and diabetic patients, the serum adiponectin concentration is lower than in healthy patients3,4. By using the phage display technology, three peptides (P16, P17 and P18) that are potential agonists of AdipoR have been identified by our group and selected due to their affinity toward these two receptors. The peptides target a C-terminal extracellular domain of AdipoR that is identical in both receptors in humans and mice. The three peptides were synthesized aiming to assess their pharmacologic and therapeutic abilities. The expression of AdipoR and binding of peptides to these receptors in the liver and muscle of NMRI mice but also in human pancreas have been confirmed by immunohistochemistry and immunofluorescence. The concentration of activated AMPK and the rate of glycolysis were evaluated on hepatic cells incubated in a medium supplemented with glucose, fatty acids and the potential therapeutic peptides. The results suggest that peptides present a good affinity and specificity to both adiponectin receptors in all tested mouse tissues, the same as to AdipoR1 expressed by human β cells. P17 presents a higher affinity for AdipoR2 expressed in liver and P18 for AdipoR1 expressed in muscle. Co-localization with AdipoR1 and with insulin proved that peptides (particularly peptide 18) bind to AdipoR1 expressed by β cells. Our results also show that peptides 17 and 18 are able to induce phosphorylation of AMPK and glycolysis in hepatic cells incubated in a medium supplemented with glucose or fatty acids and glucose. They demonstrate that peptides bind specifically to AdipoR2, being able to activate the metabolism. The highest AdipoR2 expression was observed at 15 min in hepatic cells challenged with glucose and at 60 min when cells were challenged with fatty acids and glucose; this high expression was followed by a downregulation, probably by endocytosis and lysosomal proteolysis. This hypothesis is currently under investigation. The pharmacologic activities of peptides are also currently evaluated on skeletal muscle cells in the same conditions as those used for hepatic cells. After in vitro validation, the therapeutic activity of the selected peptides will be evaluated in vivo on a mouse model becoming spontaneously obese and diabetic. 1. Cnop Met al. Diabetes 2005; 54 (Suppl. 2): S97-S107 2. Maury E et al. Mol Cell Endocrinol 2010;314(1): 1-16. 3. Kadowaki T & Yamauchi T. Endocrine Reviews 2005; 26: 439-451. 4. Lee YH, Magkos F, Mantzoros CS, Kang ES. Metabolism. 2011; 60(12): 1664-1672.


Mots-clés :
  • (Anglais) AMPK
  • (Anglais) diabetes
  • (Anglais) peptides
  • (Anglais) therapy
  • (Anglais) phage display