Hepatic β-arrestin 2 is essential for maintaining euglycemia

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

<p class="first" id="d2707668e273">An increase in hepatic glucose production (HGP) represents a key feature of type 2 diabetes. This deficiency in metabolic control of glucose production critically depends on enhanced signaling through hepatic glucagon receptors (GCGRs). Here, we have demonstrated that selective inactivation of the GPCR-associated protein β-arrestin 2 in hepatocytes of adult mice results in greatly increased hepatic GCGR signaling, leading to striking deficits in glucose homeostasis. However, hepatocyte-specific β-arrestin 2 deficiency did not affect hepatic insulin sensitivity or β-adrenergic signaling. Adult mice lacking β-arrestin 1 selectively in hepatocytes did not show any changes in glucose homeostasis. Importantly, hepatocyte-specific overexpression of β-arrestin 2 greatly reduced hepatic GCGR signaling and protected mice against the metabolic deficits caused by the consumption of a high-fat diet. Our data support the concept that strategies aimed at enhancing hepatic β-arrestin 2 activity could prove useful for suppressing HGP for therapeutic purposes. </p>

Related collections

Most cited references 10

Record: found
Abstract: found
Article: not found

Glucagon and regulation of glucose metabolism.

Guoqiang Jiang, B. Zhang (2003)

As a counterregulatory hormone for insulin, glucagon plays a critical role in maintaining glucose homeostasis in vivo in both animals and humans. To increase blood glucose, glucagon promotes hepatic glucose output by increasing glycogenolysis and gluconeogenesis and by decreasing glycogenesis and glycolysis in a concerted fashion via multiple mechanisms. Compared with healthy subjects, diabetic patients and animals have abnormal secretion of not only insulin but also glucagon. Hyperglucagonemia and altered insulin-to-glucagon ratios play important roles in initiating and maintaining pathological hyperglycemic states. Not surprisingly, glucagon and glucagon receptor have been pursued extensively in recent years as potential targets for the therapeutic treatment of diabetes.

0 comments Cited 173 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Emerging paradigms of β-arrestin-dependent seven transmembrane receptor signaling.

Arun Shukla, Kunhong Xiao, Robert Lefkowitz (2011)

β-Arrestins, originally discovered to desensitize activated seven transmembrane receptors (7TMRs; also known as G-protein-coupled receptors, GPCRs), are now well established mediators of receptor endocytosis, ubiquitylation and G protein-independent signaling. Recent global analyses of β-arrestin interactions and β-arrestin-dependent phosphorylation events have uncovered several previously unanticipated roles of β-arrestins in a range of cellular signaling events. These findings strongly suggest that the functional roles of β-arrestins are much broader than currently understood. Biophysical studies aimed at understanding multiple active conformations of the 7TMRs and the β-arrestins have begun to unravel the mechanistic basis for the diverse functional capabilities of β-arrestins in cellular signaling. Copyright © 2011 Elsevier Ltd. All rights reserved.

0 comments Cited 129 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Role of the liver in the control of carbohydrate and lipid homeostasis.

C Postic, R Dentin, J. Girard (2004)

The liver plays a unique role in controlling carbohydrate metabolism by maintaining glucose concentrations in a normal range over both short and long periods of times. In type 2 diabetes, alterations in hepatic glucose metabolism are observed, i.e. increased post-absorptive glucose production and impaired suppression of glucose production together with diminished glucose uptake following carbohydrate ingestion. The simultaneous overproduction of glucose and fatty acids in liver further stimulates the secretion of insulin by the pancreatic B cells, and elicits further peripheral insulin resistance thereby establishing a vicious circle. The present review will focus on some of the genetically-altered mouse models that have helped identify enzymes or transcription factors that are essential for maintaining either glucose or lipid homeostasis in liver. Among these mouse models, we will discuss transgenic mice overexpressing key gluconeogenic enzymes (PEPCK, G6Pase) or transcription factors (Foxo1, Pgc1-alpha) that control de novo glucose synthesis. In addition, since the possibility of controlling hepatic glucose utilization as a treatment of type 2 diabetes has been explored we will review some of the strategies proved to be valuable for improving the hyperglycemic phenotype.