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Endocrine Abstracts (2022) 81 OC10.3 | DOI: 10.1530/endoabs.81.OC10.3

1University of Bordeaux, Neurocentre Magendie, INSERM U1215, Team Energy Balance and Obesity, Bordeaux, France; 2Laboratorio de Investigación-Hormonas, Hospital Regional de Málaga – IBIMA, Malaga, Spain; 3Instituto de Neurociencias de Castilla y León (INCyL), Universidad de Salamanca, Salamanca, Spain; 4University of Bordeaux, Neurocentre Magendie, INSERM U1215, Team Endocannabinoids and Neuromodulation, Bordeaux, France

Type 2 diabetes is among the most prevalent chronic diseases worldwide. Further research is needed to identify new mechanisms that may help preserve the function of insulin-secreting pancreatic β-cells. The cannabinoid receptors type 1 (CB1) and their endogenous ligands, endocannabinoids, exert a key role in regulating of glucose homeostasis, β-cells function, and insulin secretion. Intriguingly, CB1 is not only located at the plasma membrane (pmCB1), but also at the mitochondrial membrane component (mtCB1), albeit the relative contribution of subcellular CB1 signaling on β-cell function and glucose control has yet to be determined. This study aimed to uncover the relative role(s) of pmCB1 and mtCB1 in β-cell physiopathology, with a particular focus on the differential impact on insulin secretion and mitochondrial function. For this purpose, we used an animal model expressing a mutant form of CB1 (named DN22-CB1) which lacks in vivo mitochondrial localization and functions but retains pmCB1-related signaling. DN22-CB1 mice present no difference in body weight and insulin sensitivity compared to control littermates, nor when fed chow or a hypercaloric high-fat diet (HFD). However, chow-fed DN22-CB1 mice are hyperglycemic after an overnight fast, and following a glucose load. Hyperglycemia in DN22-CB1 mice is then further worsened under HFD feeding. Regardless the diet, DN22-CB1 mice display reduced in vivo plasma insulin relative to controls. Glucose-stimulated insulin secretion (GSIS) data obtained ex-vivo from isolated islets of chow-fed DN22-CB1, full CB1-KO and control littermates suggest that pmCB1 and mtCB1 act as Ying-Yang partners to influence insulin secretion. Indeed, CB1KO islets display an increased GSIS, whereas GSIS and mitochondrial respiration is blunted in DN22-CB1 islets, with no significant changes in cytosolic calcium signaling. Our work pinpoints a novel molecular mechanism whereby subcellular CB1-dependent signaling orchestrate mitochondrial functions and glucose-dependent insulin secretion in β-cells to influence systemic glucose homeostasis. These findings might have implications for type 2 diabetes pharmacotherapy, thus resurrecting the interest in the use of CB1 receptor modulators in metabolic diseases.

Volume 81

European Congress of Endocrinology 2022

Milan, Italy
21 May 2022 - 24 May 2022

European Society of Endocrinology 

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