In Vivo and in Vitro Regulation of Hepatic Glucagon Receptor mRNA Concentration by Glucose Metabolism

Abstract

We have recently cloned the murine glucagon receptor (GR) gene and shown that it is expressed mainly in liver. In this organ, the glucagon-GR system is involved in the control of glucose metabolism as it initiates a cascade of events leading to release of glucose into the blood stream, which is a main feature in several physiological and pathological conditions. To better define the metabolic regulators of GR expression in liver we analyzed GR mRNA concentration in physiological conditions associating various glucose metabolic pathways in vivo and in vitro in the rat and in the mouse. First, we report that the concentration of the GR mRNA progressively increased from the first day of life to the adult stage. This effect was abolished when newborn rodents were fasted. Second, under conditions where intrahepatic glucose metabolism was active such as during fasting, diabetes, and hyperglycemic clamp, the concentration of GR mRNA increased independent of the origin of the pathway that generated the glucose flux. These effects were blunted when hyperglycemia was corrected by phlorizin treatment of diabetic rats or not sustained during euglycemic clamp.In accordance with these observations, we demonstrated that the glycolytic substrates glucose, mannose, and fructose, as well as the gluconeognic substrates glycerol and dihydroxyacetone, increased the concentration of GR mRNA in primary cultures of hepatocytes from fed rats. Glucagon blunted the effect of glucose without being dominant. The stimulatory effect of those substrates was not mimicked by the nonmetabolizable carbohydrate L-glucose or the glucokinase inhibitor glucosamine or when hepatocytes were isolated from starved rats. In addition, inhibitors of gluconeogenesis and lipolysis could decrease the concentration of GR mRNA from hepatocytes of starved rats. Combined, these data strongly suggest that glucose flux in the glycolytic and gluconeogenic pathways at the level of triose intermediates could control expression of GR mRNA and participate in controlling its own metabolism. The glucagon receptor (GR)1 is a 63,000-Da plasma membrane protein that belongs to a subfamily of peptide hormone receptors (1, 2). All members of this family contain seven transmembrane domains and are coupled with GTP-binding proteins. Upon binding to its receptor, glucagon initiates its action by activating several GTP-binding proteins which are ratelimiting steps in various signal transduction cascades (3-12).The GR gene is expressed mainly in liver (2,8,13,14) where it initiates a cascade of events leading to synthesis and release of glucose into the blood stream (15). Hepatic glucose production represents a major process in several physiological and pathological conditions. In newborns, glucagon is secreted within an hour of parturition and initiates several processes leading to hepatic glucose production (16) from glycogenolysis and gluconeogenesis (17). Then, during suckling glucagon stimulation ensures hepatic synthesis of glucose, which is otherwise poorly provided by mother's...

Liver Hyperplasia and Paradoxical Regulation of Glycogen Metabolism and Glucose-sensitive Gene Expression in GLUT2-null Hepatocytes

“…Expression of the glucagon receptor mRNA was then assessed. This gene is induced by increased glycolytic and gluconeogenic fluxes (23). Fig.…”

Glucagon receptors

“…Another important mechanism which temporally limits the increase in cAMP concentration induced by glucagon is the ability of this hormone to activate, via cAMP and PKA, cAMP phosphodiesterase 3B [106]. Within the past decade, the cloning of GR gene has made possible studies on the developmental, metabolic and hormonal regulation of expression of the GR gene in vivo [57,58,107] and in cultured cells [107][108][109]. In mice, liver GR mRNA level was shown to progressively increase from the first day of postnatal life to adulthood [107].…”

“…Within the past decade, the cloning of GR gene has made possible studies on the developmental, metabolic and hormonal regulation of expression of the GR gene in vivo [57,58,107] and in cultured cells [107][108][109]. In mice, liver GR mRNA level was shown to progressively increase from the first day of postnatal life to adulthood [107]. In rats rendered hyperglycemic by a glucose infusion or streptozotocin treatment, liver GR mRNA level was increased [107], suggesting that circulating blood glucose, or rather than glucose itself, the glucose flux in liver, is a positive regulator of expression of the GR gene [107].…”

A gene expression network model of type 2 diabetes links cell cycle regulation in islets with diabetes susceptibility

“…Within this module is the glucagon receptor (Gcgr), which shows an age-dependent increase in lean and obese B6 and BTBR mice and an obesitydependent decrease in all mice except 10-wk B6. Hepatic glucagon receptor mRNA expression has been shown to increase in diabetic animals and in fasting conditions, and its expression may be regulated by serum glucose levels via glucokinase (Burcelin et al 1998). Inhibition of glucagon receptor mRNA expression in liver in db/db animals improves glucose tolerance and normalizes serum glucose, so it is clear that hepatic glucagon signaling plays a crucial role in the pathophysiology of diabetes (Liang et al 2004).…”