Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis.
Adipokines
Animals
Diabetes Mellitus, Type 2
/ drug therapy
Diet, High-Fat
Fatty Liver
/ drug therapy
Glucose
/ metabolism
Insulin Resistance
Intercellular Signaling Peptides and Proteins
Lipid Metabolism
/ physiology
Lipogenesis
Liver
/ metabolism
Mice
Mice, Inbred C57BL
Phosphatidylinositol 3-Kinases
/ metabolism
adipokine
cellular signaling
diabetes
glucose uptake
hepatic steatosis
lipogenesis
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
07 09 2021
07 09 2021
Historique:
received:
29
09
2020
revised:
02
06
2021
accepted:
09
07
2021
pubmed:
5
8
2021
medline:
8
4
2022
entrez:
4
8
2021
Statut:
ppublish
Résumé
With the increasing prevalence of type 2 diabetes and fatty liver disease, there is still an unmet need to better treat hyperglycemia and hyperlipidemia. Here, we identify isthmin-1 (Ism1) as an adipokine and one that has a dual role in increasing adipose glucose uptake while suppressing hepatic lipid synthesis. Ism1 ablation results in impaired glucose tolerance, reduced adipose glucose uptake, and reduced insulin sensitivity, demonstrating an endogenous function for Ism1 in glucose regulation. Mechanistically, Ism1 activates a PI3K-AKT signaling pathway independently of the insulin and insulin-like growth factor receptors. Notably, while the glucoregulatory function is shared with insulin, Ism1 counteracts lipid accumulation in the liver by switching hepatocytes from a lipogenic to a protein synthesis state. Furthermore, therapeutic dosing of recombinant Ism1 improves diabetes in diet-induced obese mice and ameliorates hepatic steatosis in a diet-induced fatty liver mouse model. These findings uncover an unexpected, bioactive protein hormone that might have simultaneous therapeutic potential for diabetes and fatty liver disease.
Identifiants
pubmed: 34348115
pii: S1550-4131(21)00326-0
doi: 10.1016/j.cmet.2021.07.010
pmc: PMC8429235
mid: NIHMS1726602
pii:
doi:
Substances chimiques
Adipokines
0
Intercellular Signaling Peptides and Proteins
0
isthmin protein, mouse
0
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1836-1852.e11Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK120565
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK045735
Pays : United States
Organisme : NIDDK NIH HHS
ID : K99 DK111916
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK116750
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK031405
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA124435
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK119254
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK087092
Pays : United States
Organisme : NIDDK NIH HHS
ID : R00 DK111916
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK061562
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK125260
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK102173
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK046200
Pays : United States
Organisme : NIDDK NIH HHS
ID : R37 DK031405
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK057521
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK034989
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK116074
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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