Insulin, secreted by the β-cells of the pancreas, is directly infused via the portal vein to the liver, where it exerts profound metabolic effects. These effects are the response of the activation of the insulin receptor which belongs to the class of cell surface receptors that exhibit intrinsic tyrosine kinase activity (see Signal Transduction). The insulin receptor is a heterotetramer of 2 extracellular α-subunits disulfide bonded to 2 transmembrane β-subunits. With respect to hepatic glucose homeostasis, the effects of insulin receptor activation are specific phosphorylation events that lead to an increase in the storage of glucose with a concomitant decrease in hepatic glucose release to the circulation as diagrammed below (only those responses at the level of glycogen synthase and glycogen phosphorylase are represented).
Insulin receptor actions. Insulin receptor interactions at the level of insulin receptor substrate-1 (IRS1) and activation of the kinase cascade leading to altered activities of glycogen phosphorylase and glycogen synthase are depicted. PI3K: posphatidylinositol-3-kinase; PIP2: phosphatidylinositol-4,5-bisphosphate; PIP3: phosphatidylinositol-3,4,5-bisphosphate; PDK1: PIP3-dependent protein kinase; Tsc1 and Tsc2: Tuberous sclerosis tumor suppressors 1 (hamartin) and 2 (tuberin); Rheb: Ras homolog enriched in brain; mTOR: mechanistic target of rapamycin. PKB/AKT: protein kinase B/AKT2; GSK3: glycogen synthase kinase-3; S6K: 70kDa ribosomal protein S6 kinase, also called p70S6K. The insulin-mediated activation of mTOR also leads to changes in protein synthesis (see below). Arrows denote either direction of flow or positive effects. T lines represent inhibitory effects.
In most nonhepatic tissues, particularly in adipose tissue and skeletal muscle, insulin increases glucose uptake by stimulating an increase in the number of plasma membrane glucose transporters: GLUTs. Glucose transporters are in a continuous state of turnover. Increases in the plasma membrane content of GLUTs stem from an increase in the rate of recruitment of the transporters into the plasma membrane, deriving from a special pool of preformed transporters localized in the cytoplasm. GLUT1 is present in most tissues, GLUT2 is found primarily in intestine, pancreatic β-cells, kidney and liver, GLUT3 is found primarily in neurons but also found in the intestine, GLUT4 is found in insulin-responsive tissues such as heart, adipose tissue and skeletal muscle and GLUT5 is expressed in intestine, kidney, testes, skeletal muscle, adipose tissue and brain.
In the liver, glucose uptake is dramatically increased because of increased activity of the enzymes glucokinase, phosphofructokinase-1 (PFK-1), and pyruvate kinase (PK), the key regulatory enzymes of glycolysis. The latter effects are induced by insulin-dependent activation of phosphodiesterase (PDE3B) which hydrolyzes cAMP to AMP. Insulin triggers activation of PDE3B via the insulin receptorsignaltransduciton cascade that activates the kinase, PKB/AKT. Active PKB/AKT in turn phosphorylates and activates PDE3B. The resultant reduction in cAMP leads to decreased PKA activity and diminished phosphorylation of pyruvate kinase and phosphofructokinase-2, PFK-2. Dephosphorylation of pyruvate kinase increases its' activity while dephosphorylation of PFK-2 renders it active as a kinase. The kinase activity of PFK-2 converts fructose-6-phosphate into fructose-2,6-bisphosphate (F2,6BP). F2,6BP is a potent allosteric activator of the rate limiting enzyme of glycolysis, PFK-1, and an inhibitor of the gluconeogenic enzyme, fructose-1,6-bisphosphatase. In addition, phosphatases specific for the phosphorylated forms of the glycolytic enzymes increase in activity under the influence of insulin. All these events lead to conversion of the glycolytic enzymes to their active forms and consequently a significant increase in glycolysis. In addition, glucose-6-phosphatase activity is down-regulated. The net effect is an increase in the content of hepatocyte glucose and its phosphorylated derivatives, with diminished blood glucose. In addition to the above described events, diminished cAMP and elevated protein phosphatase activity combine to convert glycogen phosphorylase to its inactive form and glycogen synthase to its active form, with the result that not only is glucose funneled to glycolytic products, but glycogen content is increased as well.
Insulin-mediated effects on glycogen homeostasis: Insulin activates the synthesis of glycogen, while smultaneously inhibiting glycogenolysis, through the concerted effects of several insulin receptor activated pathways. Shown in this Figure are the major insulin-regulated activities and how they can rapidly exert their effects since all the activities are closely associated through interactions with protein targeting to glycogen (PTG). PTG is actually a regulatory subunit of the heterotetrameric PP1. There is a muscle-specific PTG (PPP1R3A) and a liver-specific PTG (PPP1R3B). Also diagrammed is the response to insulin at the level of glucose transport into cells via GLUT4 translocation to the plasma membrane. PDK1: PIP3-dependent protein kinase 1. GS/GP kinase: glycogen synthase: gycogen phosphorylase kinase (PHK). PP1: protein phosphatase-1. PDE: phosphodiesterase. Arrows denote either direction of flow or positive effects, red T lines represent inhibitory effects.
Epinephrine, the fight-or-flight hormone, diminishes insulin secretion by a cAMP-coupled regulatory path. In addition, epinephrine counters the effect of insulin in liver and peripheral tissue, where it binds to β-adrenergic receptors, induces adenylate cycles activity, increases cAMP, and activates PKA similarly to that of glucagon. The latter events induce glycogenolysis and gluconeogenesis, both of which are hyperglycemic and which thus counter insulin's effect on blood glucose levels. In addition, epinephrine influences glucose homeostasis through interaction with α-adrenergic receptors.
Pathways involved in the regulation of glycogen phosphorylase by epinephrine activation of α1-adrenergic receptors. See Glycogen Metabolism for details of the epinephrine action in glycogen homeostasis. PLC-β is phospholipase C-β. The substrate for PLC-β is phosphatidylinositol-4,5-bisphosphate, (PIP2) and the products are inositol trisphosphate, IP3 and diacylglycerol, DAG. Gs-GP kinase is glycogen synthase-glycogen phosphorylase kinase. More commonly called phosphorylase kinase (PHK). Similar calmodulin-mediated activation of PHK phosphorylations lead to inhibition of glycogen synthase.
With respect to insulin responses and metabolism, activation of PKB/AKT and PKC-λ lead to translocation of GLUT4 molecules to the cell surface resulting in increased glucose uptake which is significant in skeletal muscle. Activation of PKB/AKT also leads to the phosphorylation and inhibition of glycogen synthase kinase-3 (GSK3), which is a major regulatory kinase of glycogen homeostasis. In addition, PKB/AKT phosphorylates and inhibits the activity of a transcription factor (FOXO3; originally called FKHRL1) that has pro-apoptotic activity. This results in reduced apoptosis in response to insulin action.back to the top