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Preclinical Research

Type 1 Diabetes

Insulin-dependent diabetes, known as type 1 diabetes (T1D), is an autoimmune disease that results in progressive destruction, and finally an absolute loss, of insulin-producing beta cells in islets of Langerhans in the pancreas; destruction is preceded by infiltration of immune cells within the islet, a process known as insulitis. Europe has the highest prevalence of T1D per capita diagnosed at childhood. High blood glucose because of diabetes is associated to micro- and macro-vascular complications: atherosclerosis,
increased risk of strokes, heart attacks and heart failure and peripheral vascular disease. In addition, diabetes increases the risk of renal failure, blindness, peripheral neuropathy and premature death. To date no prevention exists for T1D, hence patients require exogenous insulin injections for life.
The endocannabinoid system (ECS) comprises cannabinoid type 1 and 2 receptors (CB1R and CB2R respectively), their endogenous ligands called endocannabinoids (ECs), 2-arachidonoylglycerol and anandamide, and their synthesizing and degradative enzymes. There are also other G protein-coupled receptors, such as GPR55, that are sensitive to cannabinoids. In the last decade the ECS has emerged as key regulator of metabolism and immune action. The EC receptors are potent inflammatory modulators, and cannabinoid-based compounds have resulted in improvements of autoimmune diseases such as multiple sclerosis, Crohn’s disease, fibromyalgia and rheumatoid arthritis. In our research group we are seeking for novel approaches -targeting the ECS- aimed at preventing the initiating underlying pathophysiology, namely insulitis, such that beta cell dysfunction and inflammation, and beta cell death are avoided.

PRINCIPAL INVESTIGATOR

Dra. Isabel González Mariscal
UGC Endocrinología y Nutrición. IBIMA.

ORCID iD: 0000-0003-1186-1212;
53877374500

Contact

Ongoing and finished grants in the last five years

Modulation of the endocannabinoid system in islets of Langerhans as a therapy against the autoimmune destruction occurring in type 1 diabetes

INVESTIGADOR PRINCIPAL: Isabel González Mariscal

DURACIÓN: 2019-2021 PRESUPUESTO: 60,450€

FINANCIADO POR: Consejeria de Salud y Familias de Andalucía

Targeting the Endocannabinoid System within Islets of Langerhans to Protect against Immune Destruction.

INVESTIGADOR PRINCIPAL: Francisco Javier Bermúdez Silva

DURACIÓN: 2018-2020 PRESUPUESTO: 158,121.60€

FINANCIADO POR: European Union Funds – H2020 – Marie Curie Individual Fellowship.

Impact of insulin analogues on oxidative stress and inflammation in people with type 1 diabetes mellitus

INVESTIGADORA PRINCIPAL: María Soledad Ruiz de Aduana

DURACIÓN: 2018-2020 PRESUPUESTO: 99,220€

FINANCIADO POR: Instituto de Salud Carlos III

Study of polyphenols and terpenoids from the extra virgin olive oil for the prevention and treatment of type 2 diabetes. Capacity of this compounds to modulate cannabinoid receptors

INVESTIGADOR PRINCIPAL: Francisco Javier Bermúdez Silva

DURACIÓN: 2018-2020 PRESUPUESTO: 141,570€

FINANCIADO POR: Instituto de Salud Carlos III

Designing Drugs for Treatment of Type 2 Diabetes.

INVESTIGADORA PRINCIPAL: Josephine M. Egan

DURACIÓN: 2012-2018 PRESUPUESTO: 1,500,000$

FINANCIADO POR: Intramural Research Program of the NIA, NIH, USA.

Collaborators

  • Carlos Santos Ocaña.

    Universidad Pablo de Olavide (UPO) / Centro Andaluz de Biología del Desarrollo (CABD)

  • Josephine M. Egan

    National Institute on Aging, NIH

  • Eduardo Muñoz

    Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC) / Emerald Health Pharmaceutics.

  • Stephan Hardivillé

    Université de Lille 2

Relevant publications

González-Mariscal I*, Montoro RA, O’Connell JF, Kim Y, Gonzalez-Freire M, Liu QR, Alfaras I, Carlson OD, Lehrmann E, Zhang Y, Becker KG, Hardivillé S, Ghosh P, Egan JM. Muscle cannabinoid 1 receptor regulates Il-6 and myostatin expression, governing physical performance and whole-body metabolism. FASEB J. 2019 May;33(5):5850-5863. DOI: 10.1096/fj.201801145R. PMID: 30726112.
González-Mariscal I, Martin-Montalvo A, Vazquez-Fonseca L, Pomares-Viciana T, Sánchez-Cuesta A, Fernández-Ayala DJ, Navas P, Santos-Ocana C. The mitochondrial phosphatase PPTC7 orchestrates mitochondrial metabolism regulating coenzyme Q10 biosynthesis. Biochim Biophys Acta Bioenerg. 2018 Nov;1859(11):1235-1248. DOI: 10.1016/j.bbabio.2018.09.369. PMID: 30267671

Liu QR, Huang NS, Qu H, O’Connell JF, Gonzalez-Mariscal I, Santa-Cruz-Calvo S, Doyle ME, Xi ZX, Wang Y, Onaivi ES, Egan JM. Identification of novel mouse and rat CB1R isoforms and in silico modeling of human CB1R for peripheral cannabinoid therapeutics. Acta Pharmacol Sin. 2019 Mar;40(3):387-397. DOI: 10.1038/s41401-018-0152-1. PMID: 30202012
González-Mariscal I*, Egan JM. Endocannabinoids in the Islets of Langerhans: the ugly, the bad, and the good facts. Am J Physiol Endocrinol Metab. 2018 Aug 1;315(2):E174-E179. DOI: 10.1152/ajpendo.00338.2017. Review. PMID: 29631361.
González-Mariscal I, Montoro RA, Doyle ME, Liu QR, Rouse M, O’Connell JF, Santa-Cruz Calvo S, Krzysik-Walker SM, Ghosh S, Carlson OD, Lehrmann E, Zhang Y, Becker KG, Chia CW, Ghosh P, Egan JM. Absence of cannabinoid 1 receptor in beta cells protects against high-fat/high-sugar diet-induced beta cell dysfunction and inflammation in murine islets. Diabetologia. 2018 Jun;61(6):1470-1483. Epub 2018 Mar 1. DOI:10.1007/s00125-018-4576-4. PMID: 29497784
Chia CW, Carlson OD, Liu DD, González-Mariscal I, Santa-Cruz Calvo S, Egan JM. Incretin secretion in humans is under the influence of cannabinoid receptors. Am J Physiol Endocrinol Metab. 2017 Sep 1;313(3):E359-E366. DOI: 10.1152/ajpendo.00080.2017. PMID: 28655715
González-Mariscal I, Krzysik-Walker SM, Doyle ME, Liu QR, Cimbro R, Santa-Cruz Calvo S, Ghosh S, Cieśla Ł, Moaddel R, Carlson OD, Witek RP, O’Connell JF, Egan JM. Human CB1 Receptor Isoforms, present in Hepatocytes and β-cells, are Involved in Regulating Metabolism. Sci Rep. 2016 Sep 19;6:33302. DOI: 10.1038/srep33302. PMID: 27641999
González-Mariscal I, Krzysik-Walker SM, Kim W, Rouse M, Egan JM. Blockade of cannabinoid 1 receptor improves GLP-1R mediated insulin secretion in mice. Mol Cell Endocrinol. 2016 Mar 5;423:1-10. DOI: 10.1016/j.mce.2015.12.015. PMID: 26724516
González-Mariscal I, García-Testón E, Padilla S, Martín-Montalvo A, Pomares-Viciana T, Vazquez-Fonseca L, Gandolfo-Domínguez P, Santos-Ocaña C. Regulation of coenzyme Q biosynthesis in yeast: a new complex in the block. IUBMB Life. 2014 Feb;66(2):63-70. DOI: 10.1002/iub.1243. Review. PMID: 24470391
Paul RK*, Wnorowski A*, Gonzalez-Mariscal I, Nayak SK, Pajak K, Moaddel R, Indig FE, Bernier M, Wainer IW. (R,R’)-4’-methoxy-1-naphthylfenoterol targets GPR55-mediated ligand internalization and impairs cancer cell motility. Biochem Pharmacol. 2014 Feb 15;87(4):547-61. DOI: 10.1016/j.bcp.2013.11.020. PMID: 24355564

Available Techniques

In our laboratory, we are specialized in both human and murine islets of Langerhans handling, including fresh murine islet isolation and study of insulin secretion ex vivo.
In the state-of-the-art vivarium of Malaga University, where we are currently hosting unique mouse models for the study of the cannabinoid type 1 receptor (CB1R). These mouse strains are global CB1R knockout mice and inducible beta cell-specific CB1R knockout mice (MIP-Cre CNR1 LoxP/LoxP ).