Perturbation of glucose flux in the liver by decreasing F26P2 levels causes hepatic insulin resistance and hyperglycemia

American Journal of Physiology. Endocrinology and Metabolism
Chaodong WuAlex J Lange

Abstract

Hepatic insulin resistance is one of the characteristics of type 2 diabetes and contributes to the development of hyperglycemia. How changes in hepatic glucose flux lead to insulin resistance is not clearly defined. We determined the effects of decreasing the levels of hepatic fructose 2,6-bisphosphate (F26P(2)), a key regulator of glucose metabolism, on hepatic glucose flux in the normal 129J mice. Upon adenoviral overexpression of a kinase activity-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, the enzyme that determines F26P(2) level, hepatic F26P(2) levels were decreased twofold compared with those of control virus-treated mice in basal state. In addition, under hyperinsulinemic conditions, hepatic F26P(2) levels were much lower than those of the control. The decrease in F26P(2) leads to the elevation of basal and insulin-suppressed hepatic glucose production. Also, the efficiency of insulin to suppress hepatic glucose production was decreased (63.3 vs. 95.5% suppression of the control). At the molecular level, a decrease in insulin-stimulated Akt phosphorylation was consistent with hepatic insulin resistance. In the low hepatic F26P(2) states, increases in both gluconeogenesis and glycogenolysis in the liv...Continue Reading

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Citations

Oct 29, 2014·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Johan H van HeerdenBas Teusink
Jul 5, 2011·Cell Metabolism·Hua V Lin, Domenico Accili
Jun 7, 2016·Trends in Biotechnology·Bhanu Chandra MulukutlaWei-Shou Hu
Jul 22, 2017·Nature Reviews. Endocrinology·Max C PetersenGerald I Shulman
Jun 1, 2017·Journal of Molecular Endocrinology·Ting QiChaodong Wu
Oct 5, 2018·Free Radical Research·Ji GengZheng-Hong Qin
Aug 2, 2018·Physiological Reviews·Max C Petersen, Gerald I Shulman
Feb 6, 2008·Metabolism: Clinical and Experimental·Satish C KalhanDavid E Kelley
Dec 19, 2012·The Journal of Nutritional Biochemistry·Honggui LiChaodong Wu

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