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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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.