European Journal of Clinical Investigation (1999) 29, 842–852 Review Insulin: new roles for an ancient hormone E. Ferrannini * , A. Q. Galvan, A. Gastaldelli, S. Camastra, A. M. Sironi, E. Toschi, S. Baldi, S. Frascerra, F. Monzani, A. Antonelli, M. Nannipieri, A. Mari, G. Seghieri and A. Natali Metabolism Unit of the C N R Institute of Clinical Physiology and Department of Internal Medicine, University of Pisa School of Medicine, Pisa, Italy Abstract Recent research has greatly expanded the domain of insulin action. The classical action of insulin is the control of glucose metabolism through the dual feedback loop linking plasma insulin with plasma glucose concentrations. This canon has been revised to incorporate the impact of insulin resistance or insulin deficiency, both of which alter glucose homeostasis through maladaptive responses (namely, chronic hyperinsulinaemia and glucose toxicity). A large body of knowledge is available on the physiology, cellular biology and molecular genetics of insulin action on glucose production and uptake. More recently, a number of newer actions of insulin have been delineated from in vitro and in vivo studies. In sensitive individuals, insulin inhibits lipolysis and platelet aggregation. In the presence of insulin resistance, dyslipidaemia, hyper-aggregation and anti-fibrinolysis may create a pro-thrombotic milieu. Preliminary evidence indicates that hyperinsulinaemia per se may be pro-oxidant both in vitro and in vivo. Insulin plays a role in mediating diet- induced thermogenesis, and insulin resistance may therefore be implicated in the defective thermogenesis of diabetes. In the kidney, insulin spares sodium and uric acid from excretion; in chronic hyperinsulinaemic states, these effects may contribute to high blood pressure and hyperuricaemia. Insulin hyperpolarises the plasma membranes of both excitable and non- excitable tissues, with consequences ranging from baroreceptor desensitisation to cardiac refractoriness (prolongation of QT interval). Under some circumstances insulin is vaso- dilatory—the mechanism involving both the sodium-potassium pump and intracellular calcium transients. Finally, by crossing the blood–brain barrier insulin exerts a host a central effects (sympatho-excitation, vagal withdrawal, stimulation of corticotropin releasing factor), collectively resembling a stress reaction. Description and understanding of these new roles, their interactions, the interplay between insulin resistance and hyperinsulinaemia, and their implications for cardiovascular disease have only begun. Keywords Insulin, insulin action, insulin resistance. Eur J Clin Invest 1999; 29 (10): 842–852 Introduction Insulin is an unusual hormone in several respects. Firstly, it is a phylogenetically ancient peptide, which has been found to be expressed even in tissues of invertebrates [1]. During evolution, insulin has accu- mulated a plethora of actions, spanning from intermediary metabolism to tissue growth and differentiation. Secondly, unlike most other hormones insulin is not known to be tightly controlled by any ad hoc pituitary or hypothalamic hormone; its release is directly driven by its substrate, with no apparent central integration. Thirdly, insulin is potentially lethal by virtue of its acute control of plasma glucose concentration, and, thereupon, brain function. Finally, insulin action is antagonised by a host of other hormones (growth hormone, cortisol, glucagon, cate- cholamines, thyroid hormones, sex steroids), which col- lectively constitute the fail-safe system that is typical of vital functions. Though insulin acts on all of intermediary metabolism, its chief control is exerted on the glucose system. In fact, the circulating concentration of glucose, unlike those of lipids or amino acids, is a strongly homeostatic variable,  1999 Blackwell Science Ltd * Dr Ele Ferrannini received the G. B. Morgagni Medal for 1998. See Announcement on page 904. Correspondence to: Dr E. Ferrannini, C N R Institute of Clinical Physiology, Via Savi 8, 56100 Pisa, Italy. Tel.: þ39 050 500087; fax: þ39 050 663236; e-mail: ferranni@ifc.pi.cnr.it Received 3 May 1999; accepted 6 June 1999