Abstract
Objectives
Administration of Δ9-tetrahydrocannabinol (Δ9-THC) to pregnant rats results in glucose intolerance, insulin resistance and reduced
islet mass in female, but not male, offspring. The effects of Δ9-THC on other islet hormones is not known. One downstream target of the cannabinoid
receptor, stathmin-2 (Stmn2), has recently been shown to suppress glucagon secretion,
thereby suggesting Δ9-THC may also affect alpha-cell function. The aim of the present study was to determine
the effects of in-utero Δ9-THC exposure on the profile of glucagon, insulin and Stmn2 in the rat offspring islet
and serum.
Methods
Pregnant Wistar rat dams were injected with Δ9-THC (3 mg/kg per day, intraperitoneally) or vehicle from gestational day 6 to birth.
Offspring were euthanized at postnatal day 21 (PND21) or at 5 months (adult) to collect
blood and pancreata.
Results
At PND21, control and Δ9-THC–exposed offspring showed that Stmn2 had a strong colocalization with glucagon
(Pearson’s correlation coefficient ≥0.6), and a weak colocalization with insulin (Pearson’s
correlation coefficient <0.4) in both males and females, with no changes by either
treatment or sex. In adult female offspring in the Δ9-THC group, intensity analysis indicated an increased insulin-to-glucagon (I/G; p<0.05)
ratio and a decreased glucagon-to-Stmn2 (G/S; p<0.01) ratio, and no changes in these
ratios in adult males. Furthermore, Δ9-THC did not alter fasting blood glucose and serum insulin levels in either male or
female adult offspring. However, female Δ9-THC–exposed offspring exhibited an increased I/G ratio (p<0.05) and decreased G/S
ratio in serum by adulthood (p<0.05).
Conclusion
Collectively, the reduced G/S ratio in both islet and serum in association with an
increased serum I/G ratio has direct correlations with early glucose intolerance and
insulin resistance observed exclusively in females’ offspring in this prenatal cannabinoid
model.
Résumé
Objectifs
L’administration de Δ9-tétrahydrocannabinol (Δ9-THC) aux rates gestantes entraîne une intolérance au glucose, une résistance à l’insuline
et contribue à réduire la masse d’îlots de la progéniture femelle, mais non de la
progéniture mâle. On ignore les effets du Δ9-THC sur les autres hormones produites par les îlots. Il a été récemment démontré
que l’une des cibles en aval des récepteurs cannabinoïdes, la stathmine-2 (STMN2),
supprime la sécrétion de glucagon, ce qui laisse ainsi croire que le Δ9-THC peut aussi avoir une incidence sur le fonctionnement des cellules alpha. L’objectif
de la présente étude était de déterminer les effets de l’exposition in utero au Δ9-THC sur le profil du glucagon, de l’insuline et de la STMN2 dans les îlots et le
sérum de la progéniture des rates.
Méthodes
Nous avons injecté du Δ9-THC (3 mg/kg par jour, par voie intrapéritonéale) ou un véhicule aux mères rates
gestantes Wistar du 6e jour de la gestation à la naissance. Nous avons euthanasié la progéniture au 21e jour après la naissance (21JAN) ou à 5 mois (adultes) pour prélever le sang et les
pancréas.
Résultats
Au 21JAN, les témoins et la progéniture exposée au Δ9-THC montraient que la STMN2 avait une forte colocalisation avec le glucagon (coefficient
de corrélation de Pearson ≥ 0,6) et une faible colocalisation avec l’insuline (coefficient
de corrélation de Pearson < 0,4) chez les mâles et les femelles, sans aucun changement
selon le traitement ou le sexe. Chez la progéniture femelle adulte du groupe de Δ9-THC, l’analyse de l’intensité montrait une élévation du ratio insuline/glucagon (I/G;
p < 0,05) et une diminution du ratio glucagon/STMN2 (G/S; p < 0,01), mais aucun changement
dans ces ratios chez la progéniture mâle adulte. De plus, le Δ9-THC ne contribuait pas à la modification des concentrations de la glycémie à jeun
et des concentrations sériques de l’insuline, quelle que soit la progéniture adulte,
mâle ou femelle. Toutefois, la progéniture femelle exposée au Δ9-THC montrait une élévation du ratio I/G (p < 0,05) et une diminution du ratio G/S
dans le sérum à l’âge adulte (p < 0,05).
Conclusion
En association, la réduction du ratio G/S dans les îlots et le sérum, et l’augmentation
du ratio I/G dans le sérum ont des corrélations directes avec l’intolérance au glucose
et la résistance à l’insuline de survenue précoce observées exclusivement chez la
progéniture femelle dans ce modèle sur l’exposition prénatale aux cannabinoïdes.
Keywords
Mots clés
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References
- Metabolic syndrome among marijuana users in the United States: An analysis of national health and nutrition examination survey data.Am J Med. 2017; 129: 173-179
- Cannabis, the pregnant woman and her child: Weeding out the myths.J Perinatol. 2014; 34: 417-424
- Metabolic consequences of gestational cannabinoid exposure.Int J Mol Sci. 2021; 22: 9528
- Cannabis use and obesity and young adults.Am J Drug Alcohol Abuse. 2010; 36: 350-356
- Fetal exposure to cannabis and childhood metabolic outcomes: The Healthy Start study.J Clin Endocrinol Metab. 2022; 107: e2862-e2869
- Maternal exposure to Δ9-tetrahydrocannabinol impairs female offspring glucose homeostasis and endocrine pancreatic development in the rat.Reprod Toxicol. 2020; 94: 84-91
- Δ9-Tetrahydrocannabinol exposure during rat pregnancy leads to symmetrical fetal growth restriction and labyrinth-specific vascular defects in the placenta.Sci Rep. 2020; 10: 544
- In utero exposure to Δ9-tetrahydrocannabinol leads to postnatal catch-up growth and dysmetabolism in the adult rat liver.Int J Mol Sci. 2021; 22: 7502
- Exposure to Δ9-tetrahydrocannabinol during rat pregnancy leads to impaired cardiac dysfunction in postnatal life.Pediatr Res. 2021; 90: 532-539
- Gestational exposure to Δ9-THC impacts ovarian follicular dynamics and angiogenesis in adulthood in Wistar rats.J Dev Orig Heal Dis. 2021; 12: 865-869
- Glucagonocentric restructuring of diabetes: A pathophysiologic and therapeutic makeover.J Clin Invest. 2012; 122: 4-12
- Plasticity in the glucagon interactome reveals proteins that regulate glucagon secretion in alpha TC1-6 cells.Front Endocrinol. 2019; 9: 792
- Stathmin-2 mediates glucagon secretion from pancreatic α-cells.Front Endocrinol. 2020; 11: 29
- Misrouting of glucagon and stathmin-2 towards lysosomal system of α-cells in glucagon hypersecretion of diabetes.Islets. 2022; 14: 40-57
- Two separate motifs cooperate to target stathmin-related proteins to the Golgi complex.J Cell Sci. 2005; 118: 2313-2323
- What is the role of stathmin-2 in axonal biology and degeneration?.Neurology. 2021; 97: 330-333
- The trans-Golgi proteins SCLIP and SCG10 interact with chromogranin A to regulate neuroendocrine secretion.Biochemistry. 2008; 47: 7167-7178
- Epigenomic plasticity enables human pancreatic alpha to beta cell reprogramming.J Clin Invest. 2013; 123: 1275-1284
- Single-cell transcriptomes identify human islet cell signatures and reveal cell-type–specific expression changes in type 2 diabetes.Genome Res. 2017; 27: 208-222
- Alpha TC1 and beta-TC-6 genomic profiling uncovers both shared and distinct transcriptional regulatory features with their primary islet counterparts.Sci Rep. 2017; 7: 1-14
- Miswiring the brain: D9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10 / stathmin-2 degradation pathway.EMBO J. 2014; 33 (65): 668
- Presence of functional cannabinoid receptors in human endocrine pancreas.Diabetologia. 2008; 51: 476-487
- Fetal endocannabinoids orchestrate the organization of pancreatic islet microarchitecture.Proc Natl Acad Sci USA. 2015; 112: E6185-E6194
- Identification of recent cannabis use: Whole-blood and plasma free and glucuronidated cannabinoid pharmacokinetics following controlled smoked cannabis administration.Clin Chem. 2011; 57: 1406-1414
- Maternal hair testing for the assessment of fetal exposure to drug of abuse during early pregnancy: Comparison with testing in placental and fetal remains.Forensic Sci Int. 2011; 218: 92-96
- Cannabidiol potentiates Δ9-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats.Psychopharmacology (Berl). 2011; 218: 443-457
- Prenatal toxicity, maternal distribution and placental transfer of tetrahydrocannabinol.J Pharmacol Exp Ther. 1972; 180: 446-453
- Bridging the gap between qualitative and quantitative colocalization results in fluorescence microscopy studies.Sci Rep. 2013; 3: 1-5
- Exposure of the pregnant rat to low protein diet causes impaired glucose homeostasis in the young adult offspring by different mechanisms in males and females.Exp Biol Med (Maywood). 2009; 234: 1425-1436
- Isoxazole alters metabolites and gene expression, decreasing proliferation and promoting a neuroendocrine phenotype in β-cells.ACS Chem Biol. 2016; 11: 1128-1136
- EphA4 receptor forward signaling inhibits glucagon secretion from α-cells.Diabetes. 2015; 64: 3839-3851
- Impact of uteroplacental insufficiency on ovarian follicular pool in the rat.Reprod Biol Endocrinol. 2019; 17: 10
- Plasma concentrations of delta-9-tetrahydrocannabinol in dams and fetuses following acute or multiple prenatal dosing in rats.Life Sci. 1989; 44: 697-701
- Cannabinoids inhibit insulin receptor signaling in pancreatic β-cells.Diabetes. 2011; 60: 1198-1209
- Cannabinoids regulate Bcl-2 and cyclin D2 expression in pancreatic β cells.PLoS One. 2016; 11e0150981
- Presence of functional cannabinoid receptors in human endocrine pancreas.Diabetologia. 2008; 51: 476-487
- Endocannabinoid crosstalk between placenta and maternal fat in a baboon model (Papio spp.) of obesity.Placenta. 2013; 34: 983-989
- Analysis of cannabinoid receptor binding and mRNA expression and endogenous cannabinoid contents in the developing rat brain during late gestation and early postnatal period.Synapse. 1999; 33: 181-191
- The cannabinoid receptors.Prostagland Other Lipid Mediat. 2002; 68-69: 619-631
- The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders.Cell Metab. 2013; 17: 475-490
- Pathways of glucagon secretion and trafficking in the pancreatic alpha cell: Novel pathways, proteins, and targets for hyperglucagonemia.Front Endocrinol. 2021; 12726368
- Marijuana use during pregnancy and breastfeeding: Implications for neonatal and childhood outcomes.Pediatrics. 2018; 142e20181889
- Association of glucagon-to-insulin ratio and nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus.Diabetes Vasc Dis Res. 2019; 16: 186-195
- Neuronal stathmins: A family of phosphoproteins cooperating for neuronal development, plasticity and regeneration.Prog Neurobiol. 2015; 126: 1-18
- Cannabis in the treatment of traumatic brain injury: A primer for clinicians.Can J Neurol Sci. 2020; 47: 11-17
- Cannabinoids and neuronal damage: Differential effects of THC, AEA and 2-AG on activated microglial cells and degenerating neurons in excitotoxically lesioned rat organotypic hippocampal slice cultures.Exp Neurol. 2007; 203: 246-257
- Marijuana: Neurotoxic or neuroprotective?.Glob J Med Res. 2015; 15: 7-10
Article Info
Publication History
Published online: July 04, 2022
Accepted:
June 27,
2022
Received in revised form:
June 15,
2022
Received:
March 24,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
Crown Copyright © 2022 Published on behalf of the Canadian Diabetes Association.
