New twist on neuronal insulin receptor signaling in health, disease, and therapeutics.
Long after the pioneering studies documenting the existence of insulin (year 1967) and insulin receptor (year 1978) in brain, the last decade has witnessed extraordinary progress in the understanding of brain region-specific multiple roles of insulin receptor signalings in health and disease. In the hypothalamus, insulin regulates food intake, body weight, peripheral fat deposition, hepatic gluconeogenesis, reproductive endocrine axis, and compensatory secretion of counter-regulatory hormones to hypoglycemia. In the hippocampus, insulin promotes learning and memory, independent of the glucoregulatory effect of insulin. Defective insulin receptor signalings are associated with the dementia in normal aging and patients with age-related neurodegenerative diseases (e.g., Alzheimer's disease); the cognitive impairment can be reversed with systemic administration of insulin in the euglycemic condition. Intranasal administration of insulin enhances memory and mood and decreases body weight in healthy humans, without causing hypoglycemia. In the hypothalamus, insulin-induced activation of the phosphoinositide 3-kinase pathway followed by opening of ATP-sensitive K+ channel has been shown to be related to multiple effects of insulin. However, the precise molecular mechanisms of insulin's pleiotropic effects still remain obscure. More importantly, much remains unknown about the quality control mechanisms ensuring correct conformational maturation of the insulin receptor, and the cellular mechanisms regulating density of cell surface functional insulin receptors.
Wada
Akihiko
A
Department of Pharmacology, Miyazaki Medical College, University of Miyazaki, Miyazaki 889-1692, Japan. akihiko@fc.miyazaki-u.ac.jp
Yokoo
Hiroki
H
Yanagita
Toshihiko
T
Kobayashi
Hideyuki
H
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D019439:Chromaffin Cells / Q000187:drug effects / Q000378:metabolism; D025461:Feedback, Physiological; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology / Q000502:physiology* / Q000627:therapeutic use; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology / Q000627:therapeutic use; D008568:Memory / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000188:drug therapy; D017526:Receptor, IGF Type 1 / Q000187:drug effects; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology*
D007328:Insulin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin