Insulin Action: Molecular Basis of Diabetes

Abstract

Unbalanced regulation of the signalling cascades that mediate insulin action in the cell leads to diabetes mellitus. Thus, identification of the basic mechanism of insulin action promotes our understanding of the molecular basis of diabetes and the development of better therapeutic interventions.

Keywords: insulin receptor; tyrosine kinase; autophosphorylation; substrates; synthesis; secretion; clearance

Figure 1.

The insulin promoter. The genomic sequence elements are shown in boxes. Hepatic nuclear factors (HNF) regulate the expression of binding proteins (shown at an angle) that regulate the transcription of insulin in the β cell of the pancreas. TX denotes the transcription initiation site, and HNF the hepatic nuclear factors that regulate the expression of the binding proteins in a tissue‐specific manner. CREB, cAMP regulatory element (binding protein); IDX, islet duodenum homeobox.

Figure 2.

The proinsulin molecule, which consists of a C‐peptide bridge linking the A and B chains. Cleavage of the C‐peptide bridge by endopeptidases produces mature and active insulin. S–S denotes the disulfide bonds.

Figure 3.

Insulin action in the cell. Insulin exerts multiple effects in the cell. Insulin action is mediated by the binding of insulin to its receptor, and the subsequent phosphorylation of the receptor and other substrates by the receptor tyrosine kinase.

Figure 4.

The insulin receptor, a heterotetrameric structure containing two α and two β subunits. The α subunit contains the insulin‐binding domain and the β subunit contains the catalytic tyrosine kinase domain. Binding of insulin (ligand) to its receptor activates the kinase to phosphorylate the receptor on tyrosine (Tyr) residues in the intracellular domain of the receptor. ATP, adenosine triphosphate.

Figure 5.

Intracellular insulin signalling pathways. Insulin binding to its receptor activates different signalling pathways. Two main limbs propagate insulin signals: the insulin receptor substrate (IRS)/phosphatidylinositol 3‐kinase (PI3‐K) pathway, and the Ras/mitogen‐activated protein kinase (MAPK) pathway. The IRS/PI3‐K pathway mediates glycogen synthesis and the translocation of glucose transporters (Glut) to the cell surface. The Ras/MAPK pathway, which is activated by coupling of growth factor receptor‐binding protein 2 (GRB‐2) to the receptor either by IRS proteins or by SHC, mediates the effects of insulin on cell growth and proliferation. GS(K), glycogen synthase (kinase); G‐6‐P, glucose‐6‐phosphate; MAPKK, MAPK kinase; Ras, a GTPase protooncogene product; Raf, a serine/threonine kinase protoconcogene product; RSK, ribosomal S6 kinase; PP1‐G, glycogen‐associated protein phosphatase‐1; UDP‐G, uridine diphosphate‐glucose.

Figure 6.

The docking function of proteins of the insulin receptor substrate family. Phosphorylated tyrosine residues of insulin receptor substrate (IRS) proteins at signature Y‐x‐x‐M motifs (where Y is tyrosine, x is any amino acid, and M is methionine) become binding sites for src homology 2 (SH2) domains of the p85α subunit of phosphatidylinositol 3‐kinase (PI3‐kinase). This leads to the activation of the p110 catalytic subunit of PI3‐kinase and the propagation of insulin signal through the IRS/PI3‐kinase pathway.

Figure 7.

Alignment of the members of the insulin receptor substrate (IRS) family of proteins, showing the four clones of IRS proteins. The length of the polypeptide chain is shown to the right of each bar. Conserved phosphorylation sites are indicated by small red boxes. The figure also includes the pleckstrin homology (PH) domain, the phosphotyrosine‐binding (PTB) domain and the kinase regulatory loop‐binding (KRLB) domain, which is found only in IRS‐2.

Figure 8.

Interaction of insulin receptors and proteins from the insulin receptor substrates family. Association between the insulin receptor substrate (IRS) proteins and the insulin receptor occurs mainly between the phosphotyrosine‐binding (PTB) domain of IRS proteins and the juxtamembrane region of the insulin receptor. It requires phosphorylation of tyrosine 972 in the juxtamembrane domain of the receptor. The pleckstrin homology (PH) domain appears to stabilize this conformation, perhaps by binding to the phospholipids of the surface membrane bilayer. Association of IRS‐2 with the receptor also involves the binding of its kinase regulatory loop‐binding (KRLB) domain to the receptor. This requires phosphorylation on tyrosines 1158, 1162 and 1163 in the catalytic domain of the receptor.

Figure 9.

Substrates of the insulin receptor kinase. Various substrates undergo phosphorylation by the insulin receptor kinase. Whereas most substrates are cytoplasmic, pp120 is a plasma membrane protein that undergoes insulin‐stimulated tryosine phosphorylation in its cytoplasmic tail. AKT, product of the AKT proto‐oncogene; GSK, glycogen synthase kinase; PDK, phosphatidylinositol‐dependent kinase; PH, pleckstrin homology domain; PI3‐K, phosphatidylinositol 3‐kinase; PIP3, phosphatidylinositol triphosphate; PKC, protein kinase C.

Figure 10.

Downstream effectors of insulin signalling: the AKT serine/threonine kinase. In response to insulin, phosphatidylinositol 3‐kinase (PI3‐K) is activated, and subsequently the intracellular concentration of PI 3‐phosphate is increased. This activates the PI‐dependent kinases (PDK) 1 and 2 which, in turn, activate AKT kinase by phosphorylating its threonine 308 and serine 473 residues, respectively. Active AKT kinase mediates the effect of insulin on glycogen synthesis and glucose transport. GAP, GTPase‐activator protein; GRB‐IR, growth factor receptor‐binding protein‐insulin receptor; IRS, insulin receptor substrate; c‐CBL, an adaptor protooncogene product; SHP‐2, src homology domain containing phosphatase‐2; Ras, a GTPase protooncogene product.

close

References

Di Guglielmo GM, Drake PG, Baass PC et al. (1998) Insulin receptor internalization and signalling. Molecular and Cellular Biochemistry 182: 59–63.

Duckworth WC, Bennett RG and Hamel FG (1998) Insulin degradation: progress and potential. Endocrine Reviews 19: 608–624.

Habener JF and Stoffers DA (1998) A newly discovered role of transcriptional factors involved in pancreas development and the pathogenesis of diabetes mellitus. Proceedings of the Association of American Physicians 110: 12–21.

Hotamisligil GS, Peraldi P, Budavari A et al. (1996) IRS‐1‐mediated inhibition of insulin receptor tyrosine kinase activity in TNFα‐ and obesity‐induced insulin resistance. Science 271: 665–668.

Kahn CR, Vicent D and Doria A (1996) Genetics of non‐insulin‐dependent (type‐II) diabetes mellitus. Annual Review of Medicine 47: 509–531.

Matozaki T and Kasuga M (1996) Roles of protein‐tyrosine phosphatases in growth factor‐signalling. Cellular Signaling 8: 13–19.

Najjar SM, Blakesley VA, Calzi SL et al. (1997) Differential phosphorylation of pp120 by insulin and insulin‐like growth factor‐1 receptors: role for the C‐terminal domain of the β‐subunit. Biochemistry 36: 6827–6834.

Ogawa W, Matozaki T and Kasuga M (1998) Role of binding proteins to IRS‐1 in insulin signalling. Molecular and Cellular Biochemistry 182: 13–22.

Taylor SI (1999) Deconstructing type 2 diabetes. Cell 97: 9–12.

Taylor SI, Accili D, Haft CR et al. (1994) Mechanisms of hormone resistance: lessons from insulin‐resistant patients. Acta Paediatrica 399: 95–104 [Supplement].

van den Ouweland JM, Lemkes HH, Trembath RC et al. (1994) Maternally inherited diabetes and deafness is a distinct subtype of diabetes and associates with a single point mutation in the mitochondrial tRNA(Leu(UUR)) gene. Diabetes 43: 746–751.

White MF (1998) The IRS‐signalling system: a network of docking proteins that mediate. Molecular and Cellular Biochemistry 182: 3–11.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Najjar, Sonia(Jan 2003) Insulin Action: Molecular Basis of Diabetes. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0001402]