Role of insulin as a negative regulator of plasma endocannabinoid levels in obese and nonobese subjects.
OBJECTIVE
Endocannabinoids (ECs) control metabolism via cannabinoid receptors type 1 (CB1). Their plasma levels are elevated in overweight type 2 diabetes (T2D) and in obese patients, and decrease postprandially in normoweight individuals. We investigated in two different cohorts of nonobese or obese volunteers whether oral glucose in glucose tolerance tests (OGTT) or acute insulin infusion during euglycemic hyperinsulinemic clamp affect plasma EC levels.


METHODS
OGTT was performed in ten obese hyperinsulinemic patients (body mass index (BMI)=35.8 kg/m2, fasting insulin=14.83 mU/l), and ten normoweight normoinsulinemic volunteers (BMI=21.9 kg/m2, fasting insulin=7.2 mU/l). Insulin clamp was performed in 19 mostly nonobese men (BMI=25.8 kg/m2) with varying degrees of liver fat and plasma triglycerides (TGs), with (n=7) or without T2D. Plasma levels of ECs (anandamide and 2-arachidonoylglycerol (2-AG)) were measured by liquid chromatography-mass spectrometry, before and 60 and 180 min after OGTT, and before and 240 and 480 min after insulin or saline infusion.


RESULTS
Oral glucose load decreased anandamide plasma levels to an extent inversely correlated with BMI, waist circumference, subcutaneous fat, fasting insulin and total glucose, and insulin areas under the curve during the OGTT, and nonsignificantly in obese volunteers. Insulin infusion decreased anandamide levels to an extent that weakly, but significantly, correlated negatively with TGs, liver fat and fasting insulin, and positively with high density lipoprotein cholesterol. OGTT decreased 2-AG levels to a lower extent and in a way weakly inversely correlated with fasting insulin.


CONCLUSIONS
We suggest that insulin reduces EC levels in a way inversely related to anthropometric and metabolic predictors of insulin resistance and dyslipidemia.
Di Marzo
Vincenzo
V
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei, 34, Comprensorio Olivetti, 80078 Pozzuoli (NA), Italy. vdimarzo@icmib.na.cnr.it
Verrijken
An
A
Hakkarainen
Antti
A
Petrosino
Stefania
S
Mertens
Ilse
I
Lundbom
Nina
N
Piscitelli
Fabiana
F
Westerbacka
Jukka
J
Soro-Paavonen
Aino
A
Matias
Isabel
I
Van Gaal
Luc
L
Taskinen
Marja-Riitta
MR
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood; D000886:Anthropometry; D001055:Apolipoproteins B / Q000097:blood; D001095:Arachidonic Acids / Q000097:blood / Q000378:metabolism*; D001784:Blood Gas Analysis; D001823:Body Composition / Q000502:physiology; D063385:Cannabinoid Receptor Modulators / Q000097:blood / Q000378:metabolism*; D002784:Cholesterol / Q000097:blood; D015331:Cohort Studies; D063388:Endocannabinoids; D005260:Female; D005947:Glucose / Q000032:analysis / Q000378:metabolism*; D005989:Glycerides / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000097:blood* / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000097:blood / Q000378:metabolism*; D018709:Statistics, Nonparametric; D014280:Triglycerides / Q000097:blood
D001055:Apolipoproteins B; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D007328:Insulin; D053284:Polyunsaturated Alkamides; D014280:Triglycerides; C094503:glyceryl 2-arachidonate; D002784:Cholesterol; D000410:Alanine Transaminase; D005947:Glucose; C078814:anandamide