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Diabetologia (2009) 52:22642269 DOI 10.1007/s00125-009-1501-x
FOR DEBATE
Central nervous insulin resistance: a promisingtarget in the treatment of metabolic and cognitive disorders?
M. Hallschmid & B. Schultes
Received: 11 June 2009 /Accepted: 24 July 2009 /Published online: 25 August 2009 # Springer-Verlag 2009
Abstract Research on functions and signalling pathways of insulin has traditionally focused on peripheral tissues such as muscle, fat and liver, while the brain was commonly believed to be insensitive to the effects of this hormone secreted by pancreatic beta cells. However, since the discovery some 30 years ago that insulin receptors are ubiquitously found in the central nervous system, an ever-growing research effort has conclusively shown that circulating insulin accesses the brain, which itself does not synthesise insulin, and exerts pivotal functions in central nervous networks. As an adiposity signal reflecting the amount of body fat, insulin provides direct negative feedback to hypothalamic nuclei that control whole-body energy and glucose homeostasis. Moreover, insulin affects distinct cognitive processes, e.g. by triggering the formation of psychological memory contents. Accordingly, metabolic and cognitive disorders such as obesity, type 2 diabetes mellitus and Alzheimers disease are associated with resistance of central nervous structures to the effects of insulin, which may derive from genetic polymorphisms as well as from long-term exposure to excess amounts of circulating insulin due to peripheral insulin resistance. Thus, overcoming central nervous insulin resistance, e.g. by pharmacological interventions, appears to be an attractive strategy in the treatment and prevention of these disorders. Enhancement of central nervous insulin signal-
ling by administration of intranasal insulin, insulin analogues and insulin sensitisers in basic research approaches has yielded encouraging results that bode well for the successful translation of these effects into future clinical practice.
Keywords Alzheimers disease . Brain . Central nervous system . Cognition . Dementia . Energy homeostasis . Food intake . Insulin . Insulin resistance . Obesity
AbbreviationsBBB Bloodbrain barrierCSF Cerebrospinal fluidHPA Hypothalamicpituitaryadrenal
Introduction
The brain has traditionally been assumed not to be sensitive to the effects of insulin. However, 30 years ago it was shown that insulin receptors are ubiquitously expressed in the central nervous system [1] and solid evidence indicates that insulin accesses the brain from the circulation by crossing the bloodbrain barrier (BBB) via an active, receptor-mediated transport system located...