ESPEYB19 11. Obesity and Weight Regulation New findings in adipose tissue biology (5 abstracts)
11.3. Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis
Jiang Z , Zhao M , Voilquin L , Jung Y , Aikio MA , Sahai T , Dou FY , Roche AM , Carcamo-Orive I , Knowles JW , Wabitsch M , Appel EA , Maikawa CL , Camporez JP , Shulman GI , Tsai L , Rosen ED , Gardner CD , Spiegelman BM & Svensson KJ
Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA 94305
katrinjs@stanford.edu Cell Metab 2021; 33(9): 1836–1852.e11http://www.ncbi.nlm.nih.gov/pubmed/34348115
Brief Summary: This rodent study identified a novel adipokine in mice which triggers a signaling cascade similar to that of insulin. By acting via an unknown tyrosine kinase, isthmin-1 (ISM1) ameliorates metabolic disturbances associated with type 2 diabetes mellitus, including hyperglycemia and liver steatosis. Interestingly, Ism1 had been discovered some years ago as a gene expressed in the Xenopus midbrain-hindbrain organizer called isthmus and it had been suggested to be important for early brain development [1–3].
Glucose homeostasis is regulated by the interplay of glucose uptake in insulin-sensitive tissues (adipose, muscle, heart) on the one hand, and gluconeogenesis by liver, kidneys, and gut on the other hand [4]. Upon hyperinsulinemic conditions, insulin promotes lipogenesis in the liver contributing to fatty liver disease, which is a side-effect of insulin therapy. According to the data of this paper, ISM1 has a dual role in both activating the PI3K/Akt cascade in adipose tissue, skeletal muscle and liver and inhibiting lipogenesis in the liver at the same time. These properties of ISM1 argue for its potential as a molecule useful in diabetes therapy. Indeed, upon long-term treatment in mice (21 days), ISM1 improved glucose tolerance and insulin sensitivity. In another model of non-alcoholic fatty liver disease, ISM1 treatment was effective on reducing liver lipid accumulation. Further, overexpression of ISM1 prevented DIO-induced insulin resistance and hepatic steatosis.
Some questions remain unanswered so far. To assess its suitability as an anti-diabetes drug, the identification of the ISM1 receptor is crucial. Further, regulation of ISM1 serum levels should be determined under pathological conditions in order to understand if ISM1 treatment would be effective in obese individuals.
References: 1. Osório, L., Wu, X. & Zhou, Z. Distinct spatiotemporal expression of ISM1 during mouse and chick development. Cell Cycle 13, 1571–82 (2014). 2. Venugopal, S. et al. Isthmin is a novel vascular permeability inducer that functions through cell-surface GRP78-mediated Src activation. Cardiovasc. Res. 107, 131–42 (2015). 3. Valle-Rios, R. et al. Isthmin 1 is a secreted protein expressed in skin, mucosal tissues, and NK, NKT, and th17 cells. J. Interferon Cytokine Res. 34, 795–801 (2014). 4. Petersen, M. C. & Shulman, G. I. Mechanisms of Insulin Action and Insulin Resistance. Physiol. Rev. 98, 2133–2223 (2018).
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