Modulation of insulin action

Abstract

Insulin is a key hormone regulating the control of metabolism and the maintenance of normoglycaemia and normolipidaemia. Insulin acts by binding to its cell surface receptor, thus activating the receptor's intrinsic tyrosine kinase activity, resulting in receptor autophosphorylation and phosphorylation of several substrates. Tyrosine phosphorylated residues on the receptor itself and on subsequently bound receptor substrates provide docking sites for downstream signalling molecules, including adapters, protein serine/threonine kinases, phosphoinositide kinases and exchange factors. Collectively, those molecules orchestrate the numerous insulin-mediated physiological responses.A clear picture is emerging of the way in which insulin elicits several intracellular signalling pathways to mediate its physiologic functions. A further challenge, being pursued by several laboratories, is to understand the molecular mechanisms that underlie insulin action at the peripheral level, deregulation of which ultimately leads to hyperglycaemia and Type 2 diabetes.We review how circulating factors such as insulin itself, TNF-α, interleukins, fatty acids and glycation products influence insulin action through insulin signalling molecules themselves or through other pathways ultimately impinging on the insulin-signalling pathway. Understanding how the mechanism by which molecular insulin action is modulated by these factors will potentially provide new targets for pharmacological agents, to enable the control of altered glucose and lipid metabolism and diabetes. [Diabetologia (2004) 47:170-184]

Tissue selectivity of insulin detemir action in vivo

“…In peripheral tissue, activation of this pathway is involved in processes like glucose transport, suppression of hepatic gluconeogenesis, protein synthesis and gene transcription [7,16]. However, in the brain, intact insulin signalling via the Irs-PI 3-kinase pathway is essential for nutrient homeostasis and appetite regulation as pharmacological inhibition of insulin signalling, especially in the hypothalamus, leads to obesityinduced diabetes [17,18].…”

Specificity of insulin signalling in human skeletal muscle as revealed by small interfering RNA

“…Further complexity is built into the system by the expression of multiple isoforms of substrates and protein kinases at each of these nodes. Negative regulation of insulin signalling can be conferred through activation of cell-surface receptor signalling pathways that are responsive to cytokines such as TNF-α or IL-6, which are produced by macrophages that infiltrate adipose tissue in obesity, as well as to elevated levels of glucose or lipids [3,4]. Negative regulation of the insulin cascade occurs through serine phosphorylation events at the level of the insulin receptor [4] and IRS isoforms [5].…”

“…Negative regulation of insulin signalling can be conferred through activation of cell-surface receptor signalling pathways that are responsive to cytokines such as TNF-α or IL-6, which are produced by macrophages that infiltrate adipose tissue in obesity, as well as to elevated levels of glucose or lipids [3,4]. Negative regulation of the insulin cascade occurs through serine phosphorylation events at the level of the insulin receptor [4] and IRS isoforms [5]. Several serine/threonine protein kinases have been implicated in the negative regulation of insulin signalling, including protein kinase C isoforms, MAPK isoforms, mammalian target of rapamycin (mTOR) and p70 ribosomal S6 kinase (p70S6K) [1].…”

“…Targeting insulin signalling cascades using siRNA Several reviews have highlighted the critical components of the canonical insulin signalling cascade in health and metabolic disease [1,2,4,8,9]. Major nodes, or points of convergence, for insulin signalling include the insulin receptor/IRS1-4, PI3K and its regulatory and catalytic subunits, and AKT/protein kinase B isoforms 1-3 [1].…”

“…Experimentally, skeletal muscle insulin resistance can be induced by exposure to elevated levels of glucose, insulin, NEFA or cytokines such as TNF-α. Although these factors induce insulin resistance via different mechanisms and signalling pathways (reviewed in [4]), several of these factors co-exist in vivo and may collectively contribute to the overall clinical phenotype in diabetic patients. For example, an acute infusion of TNF-α into healthy volunteers impairs insulin-mediated skeletal muscle glucose uptake without altering endogenous glucose production [50].…”