The combination of loss of glyoxalase1 and obesity results in hyperglycemia.
Animals
CRISPR-Cas Systems
Diabetes Mellitus, Experimental
Diabetes Mellitus, Type 2
/ genetics
Diet
Disease Models, Animal
Gene Knockout Techniques
Genetic Predisposition to Disease
Glucose
/ metabolism
Hyperglycemia
/ etiology
Insulin Resistance
Lactoylglutathione Lyase
/ genetics
Liver
/ metabolism
Male
Obesity
/ complications
Pyruvaldehyde
/ metabolism
Retina
/ pathology
Zebrafish
/ growth & development
Diabetes
Endocrinology
Metabolism
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
20 06 2019
20 06 2019
Historique:
received:
12
11
2018
accepted:
16
05
2019
entrez:
21
6
2019
pubmed:
21
6
2019
medline:
25
8
2020
Statut:
epublish
Résumé
The increased formation of methylglyoxal (MG) under hyperglycemia is associated with the development of microvascular complications in patients with diabetes mellitus; however, the effects of elevated MG levels in vivo are poorly understood. In zebrafish, a transient knockdown of glyoxalase 1, the main MG detoxifying system, led to the elevation of endogenous MG levels and blood vessel alterations. To evaluate effects of a permanent knockout of glyoxalase 1 in vivo, glo1-/- zebrafish mutants were generated using CRISPR/Cas9. In addition, a diet-induced-obesity zebrafish model was used to analyze glo1-/- zebrafish under high nutrient intake. Glo1-/- zebrafish survived until adulthood without growth deficit and showed increased tissue MG concentrations. Impaired glucose tolerance developed in adult glo1-/- zebrafish and was indicated by increased postprandial blood glucose levels and postprandial S6 kinase activation. Challenged by an overfeeding period, fasting blood glucose levels in glo1-/- zebrafish were increased which translated into retinal blood vessel alterations. Thus, the data have identified a defective MG detoxification as a metabolic prerequisite and glyoxalase 1 alterations as a genetic susceptibility to the development of type 2 diabetes mellitus under high nutrition intake.
Identifiants
pubmed: 31217350
pii: 126154
doi: 10.1172/jci.insight.126154
pmc: PMC6629122
doi:
pii:
Substances chimiques
Pyruvaldehyde
722KLD7415
Lactoylglutathione Lyase
EC 4.4.1.5
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
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