Treating insulin resistance: future prospects.
Insulin resistance typically reflects multiple defects of insulin receptor and post-receptor signalling that impair a diverse range of metabolic and vascular actions. Many potential intervention targets and compounds with therapeutic activity have been described. Proof of principle for a non-peptide insulin mimetic has been demonstrated by specific activation of the intracellular B-subunit of the insulin receptor. Potentiation of insulin action has been achieved with agents that enhance phosphorylation and prolong the tyrosine kinase activity of the insulin receptor and its protein substrates after activation by insulin. These include inhibitors of phosphatases and serine kinases that normally prevent or terminate tyrosine kinase signalling. Additional approaches involve increasing the activity of phosphatidylinositol 3-kinase and other downstream components of the insulin signalling pathways. Experimental interventions to remove signalling defects caused by cytokines, certain adipocyte hormones, excess fatty acids, glucotoxicity and negative feedback by distal signalling steps have also indicated therapeutic possibilities. Several hormones, metabolic enzymes, minerals, co-factors and transcription co-activators have shown insulin-sensitising potential. Since insulin resistance affects many metabolic and cardiovascular diseases, it provides an opportunity for simultaneous therapeutic attack on a broad front.
Bailey
Clifford J
CJ
Deabetes Research Group, School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK. c.j.bailey@aston.ac.uk
D000263:Adenylate Kinase / Q000627:therapeutic use; D017667:Adipocytes / Q000378:metabolism; D019440:Anti-Obesity Agents / Q000494:pharmacology; D016207:Cytokines / Q000187:drug effects; D005938:Glucocorticoids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000188:drug therapy* / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D008903:Minerals / Q000627:therapeutic use; D047495:PPAR gamma / Q000819:agonists; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects; D011972:Receptor, Insulin / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D014815:Vitamins / Q000627:therapeutic use
D019440:Anti-Obesity Agents; D016207:Cytokines; D005938:Glucocorticoids; D008903:Minerals; D047495:PPAR gamma; D014815:Vitamins; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D000263:Adenylate Kinase; D005947:Glucose