Insulin Resistance and Its Relevance to Treatment

F. Belfiore, S. Iannello

Institute of Internal Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy

Insulin Action

Introduction

Insulin exerts its metabolic effects on the insulin-sensitive tissues, i.e. on liver, muscle and adipose tissue. In these tissues, insulin action is the result of complex mechanisms. We can distinguish (1) insulin binding to specific receptors and the following sequence of events along the insulin signalling pathway, which ultimately lead to (2) the insulin metabolic effects at postreceptor level.

The Insulin Receptor

The insulin receptor is a heterodimer composed of two chains or subunits, the a- and the P-chain, linked by disulfide bridges. The a-subunit is extracellular in location and is the site of insulin binding. The P-subunit is transmembrane in location and originates from the signal transduction.

Normally there is a large surplus in the number of receptors (i.e. there is a large amount of spare receptors). Nevertheless, considering that insulin binding to its receptors is a random phenomenon, it follows that the higher the number of insulin molecules or receptor units, the higher the number of insulin molecules which will bind to the receptor units. An increase in the insulin level causes a decrease in the receptor number on the plasma membrane (downregulation of insulin receptors), a phenomenon that may occur in conditions of persistent hyperinsulinemia (insulin-resistant states, including obesity).

Dose Response Curve Insulin

Insulin concentration

Fig. 1. Schematic representation of dose-response curves of insulin action in the normal state and in conditions of impaired insulin action. For explanation, see the text.

Insulin concentration

Fig. 1. Schematic representation of dose-response curves of insulin action in the normal state and in conditions of impaired insulin action. For explanation, see the text.

When the receptor number is decreased, the number of insulin molecules that bind to the receptors at a given insulin level will be reduced, and therefore the insulin effects will be diminished, i.e. there is insulin resistance. However, by increasing the insulin level, the number of insulin molecules that bind to the receptors can be increased toward the normal and therefore the insulin effects can be restored; moreover, by increasing further the insulin level, the maximum effect can be reached. This condition is called decreased insulin sensitivity. By plotting the insulin concentrations (on the abscissa) against the insulin effect (on the ordinate), the insulin dose-response curve is obtained. This curve, in the case of insulin resistance due to reduced receptor number, will be shifted to the right, as the maximum effect is reached at very high insulin levels. On the other hand, when the insulin resistance is due to defects in postreceptor steps of insulin action (see below), the dose-response curve is flattened and the maximum insulin effect is not reached even at very high insulin concentrations. When the two conditions coexist, the insulin dose-response curve will be shifted to the right and flattened (fig. 1).

Concerning the fate of the insulin-receptor complexes, several data suggest that they are internalized and delivered to endosomes, the acidic pH of which induces the dissociation of insulin molecules from insulin receptors and their sorting in different directions: insulin molecules are targeted to late endosomes and lysosomes where they are degraded whereas receptors are recycled back to the cell surface in order to be reused.

To understand the function of insulin receptors, it should be recalled that protein kinases that directly phosphorylate proteins are divided into two major classes: those that phosphorylate tyrosine (tyrosine-specific protein kinases) and those that phosphorylate serine and threonine (the serine/threonine-spe-cific protein kinases). The receptor P-subunit can be phosphorylated on serine, threonine and tyrosine residues and possesses intrinsic protein-tyrosine kinase activity. Insulin stimulates this activity (i.e. the insulin receptor is itself an insulin-sensitive enzyme) which is responsible for both autophosphorylation of the receptor itself and phosphorylation of tyrosine residues of various cellular substrates, including the insulin receptor substrates (IRS-1 and IRS-2). The latter, through a mechanism not yet fully understood, trigger a sequence of events which include phosphorylation/dephosphorylation of several cyto-plasmatic proteins which, in turn, will induce the spectrum of insulin effects (fig. 2). Two insulin receptor isoforms have been identified, the A and the B form, which, however, revealed no difference in their tyrosine kinase activity in vivo.

Protein-tyrosine phosphatases (PTPases) play an essential role in the regulation of reversible tyrosine phosphorylation of cellular proteins that mediate insulin action. In particular, some data suggest a possible role of the transmembrane PTPase in insulin receptor signal transduction.

Recent studies suggest that the insulin receptor tyrosine kinase inhibitor, the membrane glycoprotein PC-1, may modulate insulin activity (and may play a role in insulin resistance - see the second part of this chapter).

Metabolic Effects of Insulin (Postreceptor Effects)

The mechanisms of postreceptor insulin effects can be distinguished into: (a) translocation (and activation) of glucose transporters (the GLUT-4 isoform) from the intracellular pool to the cell membrane; (b) activation/inhibition of several enzymes of intermediary metabolism through either changes in concentrations of ions or regulatory compounds which bind to the enzyme at sites distinct from the substrate-binding site (allosteric effectors), or covalent modifications of the enzyme molecules often consisting of phosphorylation/ dephosphorylation processes; (c) induction/repression mechanisms leading to changes in enzyme concentration through regulation of the synthesis of the enzyme proteins. Translocation and activation/inhibition processes are short-term mechanisms (occurring within seconds or minutes), the induction/repression processes are long-term mechanisms (hours).

Stimulation of glucose transport across the cell membrane is one of the main effects of insulin in muscle and adipose tissue, and is the result of the translocation of glucose transporter (the GLUT-4 isoform)-containing vesicles from an intracellular storage pool to the surface membrane. This event is mediated through IRSs, which in turn activate PI-3-kinase isoforms (fig. 2). Translocation and activation of GLUT-4 is favored by its dephos-phorylation. In addition to glucose transport, insulin also stimulates the transport across the cell membrane of amino acids and ions, mainly potassium and phosphate.

Insulin regulates several key metabolic steps (fig. 1). In doing so, insulin is opposed by the four counterregulatory hormones (the rapid-acting glucagon and catecholamines, and the slow-acting growth hormone and cortisol). Insulin affects the pathways of glucose utilization as well as the synthesis and degradation of macromolecules (glycogen, triglycerides and proteins) by regulating the activity of 'key enzymes'. Indeed, along each metabolic pathway, there is one or more key step(s) catalyzed by key enzymes. These are enzymes which, because of their low activity and sensitivity to regulatory factors (including hormones), regulate the overall rate of the pathway to which they belong. In particular, insulin (or, better, its prevalence over the counterregulatory hormones) exerts the following effects (fig. 1):

(a) favors glucose utilization by activating the three key glycolytic kinases, namely hexokinase (and GK in the liver), phosphofructokinase and pyruvate kinase; in the liver, this is associated with repression of the opposing key gluconeogenic enzymes: glucose-6-phosphatase, fructose bisphosphatase and phosphoenolpyruvate carboxykinase plus pyruvate carboxylase;

(b) stimulates glucose oxidation, by activating the key enzyme pyruvate dehydrogenase in the mitochondria;

(c) lowers FFA level by inhibiting lipolysis in the adipose tissue and reduces ketogenesis from FFA in the liver (see chapter VII on ketoacidosis for further explanation);

(d) favors glycogen synthesis and depresses glycogenolysis by activating the enzyme glycogen synthase while inhibiting glycogen phosphorylase;

(e) enhances triglyceride synthesis and refrains triglyceride hydrolysis (lipolysis) by inhibiting the hormone sensitive lipase;

(f) finally, insulin stimulates protein synthesis and opposes protein degradation (or proteolysis). The main insulin actions are summarized in table 1.

Thus, the overall action of insulin is (1) to increase glucose utilization in muscle, liver and adipose tissue while depressing glucose production in the liver, which results in blood glucose lowering; (2) to lower FFA level by refraining lipolysis, and (3) to prevent ketone formation in the liver by opposing ketogenesis.

Catecholamines And Insulin Resistance

Fig. 2. Simplified representation of the mechanisms of action of insulin, glucagon, catecholamines (sympathetic activation) and acetylcholine (parasympathetic activation). (Continuous lines ending with black arrows indicate transformation or translocation of substrates or ions; dotted lines ending with white arrows indicate stimulation; dotted lines ending with filled circles indicate inhibition.)

Insulin: Insulin receptors, with their tyrosine kinase activity, phosphorylate several protein substrates (IRS1, IRS2, Shc, etc.) which in turn phosphorylate (activate) several protein kinases (PI3-K, MAP-K, PKB, PKCz, PKCl, etc.) and these, through a complex cascade of phosphorylation/dephosphorylation, produce the various insulin effects (glucose transport, enzyme activation/inhibition, induction/repression of enzymes and other proteins).

Other hormones: Glucagon and catecholamines (P-receptors) activate adenylate cyclase (with the participation of Gs proteins), thus producing cAMP and stimulating PKA. Catecholamines (a2-receptors) inhibit adenylate cyclase (with the participation of Gi proteins) and therefore exert opposite effects. Acetylcholine (parasympathetic stimulation) activate PLC (with the participation of Gp proteins) which split PIP3 thus producing IP3 and DAG. IP3 favors the increase in cytosolic Ca (release of Ca from the endoplasmic reticulum stores or Ca influx from outside the cell) thus activating the CaCalm PK. DAG activates PKC. The activation of these protein kinases will eventually result in enzyme activation-inhibition.

Note that protein kinases may activate (through phosphorylation) some protein phosphatases, resulting in dephosphorylation of some key enzymes. Most key enzymes of anabolic pathways are active in the dephosphorylated form (example: glycogen synthase), and are activated by insulin and inhibited by glucagon and catecholamines. Most key enzymes of catabolic pathways are active in the phosphorylated form (example: glycogen phosphorylase, hormonesensitive lipase) and are activated by glucagon or catecholamines and inhibited by insulin.

Abbreviations (alphabetic order): a2 = a2-adrenergic receptor; AC = adenylate cyclase; P = P-adrenergic receptor; cAMP = cyclic AMP; DAG= 1,2-diacylglycerol; G-4 = isoform 4

Table l. Metabolic effects of insulin

Stimulation

Inhibition

Synthesis of macromolecules

Degradation of macromolecules

(and allied processes):

(and allied processes):

Glycogen

Glycogen

Glucose transport

Proteins

Glucose phosphorylation

Amino acid oxidation

Triglycerides

Gluconeogenesis

Lipoprotein lipase

Lipolysis

Proteins

FFA oxidation

Amino acid transport

Ketogenesis

Nucleic acids

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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