GLP-1 improves adipose tissue glyoxalase activity and capillarization improving insulin sensitivity in type 2 diabetes

Tiago Rodrigues; Patrícia Borges; Laura Mar; Daniela Marques; Miguel Albano; Hans Eickhoff; Catarina Carrêlo; Bruno Almeida; Salomé Pires; Margarida Abrantes; Beatriz Martins; Cristina Uriarte; Filomena Botelho; Pedro Gomes; Sónia Silva; Raquel Seiça; Paulo Matafome

doi:10.1016/j.phrs.2020.105198

GLP-1 improves adipose tissue glyoxalase activity and capillarization improving insulin sensitivity in type 2 diabetes

Pharmacol Res. 2020 Nov:161:105198. doi: 10.1016/j.phrs.2020.105198. Epub 2020 Sep 14.

Authors

Tiago Rodrigues¹, Patrícia Borges², Laura Mar², Daniela Marques², Miguel Albano³, Hans Eickhoff⁴, Catarina Carrêlo², Bruno Almeida⁵, Salomé Pires⁶, Margarida Abrantes⁶, Beatriz Martins⁷, Cristina Uriarte³, Filomena Botelho⁶, Pedro Gomes³, Sónia Silva⁸, Raquel Seiça¹, Paulo Matafome⁹

Affiliations

¹ Institute of Physiology and Institute of Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra (FMUC), Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal.
² Institute of Physiology and Institute of Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra (FMUC), Portugal.
³ Department of Surgery, Universitary Hospital Center of Coimbra, Portugal.
⁴ Institute of Physiology and Institute of Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra (FMUC), Portugal; Obesity Center, Hospital de Santiago, Setúbal, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal.
⁵ Association for the Protection of Portuguese Diabetic Patients (APDP), Lisbon, Portugal.
⁶ Institute of Biophysics and iCBR, FMUC, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal.
⁷ iCBR, FMUC, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal.
⁸ Obesity Center, Hospital de Santiago, Setúbal, Portugal; Faculty of Farmacy, University of Coimbra, Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal.
⁹ Institute of Physiology and Institute of Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra (FMUC), Portugal; Instituto Politécnico de Coimbra, Coimbra Health School (ESTeSC), Portugal; Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal. Electronic address: paulo.matafome@uc.pt.

PMID: 32942016
DOI: 10.1016/j.phrs.2020.105198

Abstract

Methylglyoxal was shown to impair adipose tissue capillarization and insulin sensitivity in obese models. We hypothesized that glyoxalase-1 (GLO-1) activity could be diminished in the adipose tissue of type 2 diabetic obese patients. Moreover, we assessed whether such activity could be increased by GLP-1-based therapies in order to improve adipose tissue capillarization and insulin sensitivity. GLO-1 activity was assessed in visceral adipose tissue of a cohort of obese patients. The role of GLP-1 in modulating GLO-1 was assessed in type 2 diabetic GK rats submitted to sleeve gastrectomy or Liraglutide treatment, in the adipose tissue angiogenesis assay and in the HUVEC cell line. Glyoxalase-1 activity was decreased in visceral adipose tissue of pre-diabetic and diabetic obese patients, together with other markers of adipose tissue dysfunction and correlated with increased HbA1c levels. Decreased adipose tissue GLO-1 levels in GK rats were increased by sleeve gastrectomy and Liraglutide, being associated with overexpression of angiogenic and vasoactive factors, as well as insulin receptor phosphorylation (Tyr1161). Moreover, GLP-1 increased adipose tissue capillarization and HUVEC proliferation in a glyoxalase-dependent manner. Lower adipose tissue GLO-1 activity was observed in dysmetabolic patients, being a target for GLP-1 in improving adipose tissue capillarization and insulin sensitivity.

Keywords: Adipose tissue; Capillarization; GLP-1; Glyoxalase; Insulin resistance; Liraglutide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue / blood supply*
Adult
Aged
Animals
Capillaries / drug effects*
Capillaries / enzymology
Capillaries / physiopathology
Cells, Cultured
Diabetes Mellitus, Type 2 / drug therapy*
Diabetes Mellitus, Type 2 / enzymology
Diabetes Mellitus, Type 2 / physiopathology
Disease Models, Animal
Female
Gastrectomy
Glucagon-Like Peptide 1 / metabolism
Glucagon-Like Peptide-1 Receptor / agonists*
Glucagon-Like Peptide-1 Receptor / metabolism
Human Umbilical Vein Endothelial Cells / drug effects
Human Umbilical Vein Endothelial Cells / enzymology
Humans
Hypoglycemic Agents / pharmacology*
Incretins / pharmacology*
Insulin Resistance*
Lactoylglutathione Lyase / metabolism*
Liraglutide / pharmacology*
Male
Middle Aged
Neovascularization, Physiologic / drug effects*
Obesity / enzymology
Obesity / physiopathology
Obesity / surgery
Rats, Wistar
Signal Transduction

Substances

Glp1r protein, rat
Glucagon-Like Peptide-1 Receptor
Hypoglycemic Agents
Incretins
Liraglutide
Glucagon-Like Peptide 1
GLO1 protein, human
Glo1 protein, rat
Lactoylglutathione Lyase