title: Hypothalamic pathogenesis of type 2 diabetes.
abstract: There have recently been increasing experimental and clinical evidences suggesting that hypothalamic dysregulation may be one of the underlying mechanisms of abnormal glucose metabolism. First, increased hypothalamic-pituitary-adrenal axis activity induced by uncontrollable excess stress may cause diabetes mellitus as well as dyslipidemia, visceral obesity, and osteoporosis with some resemblance to Cushing's disease. Second, several molecules are known to be expressed both in pancreas and hypothalamus; adenosine triphosphate-sensitive potassium channels, malonyl-CoA, glucokinase, and AMP-activated protein kinase. Those molecules appear to form an integrated hypothalamic system, which may sense hypothalamic fuel status, especially glucose level, and inhibit action of insulin on hepatic gluconeogenesis, thereby forming a brain-liver circuit. Third, hypothalamic resistance to insulin as an adiposity signal may be involved in pathogenesis of peripheral insulin resistance. The results with mice with a neuron-specific disruption of the insulin receptor gene or those lacking insulin receptor substrate 2 in hypothalamus supported this possibility. Finally, it has very recently been suggested that dysregulation of clock genes in hypothalamus may cause abnormal glucose metabolism. Taken together, it is plausible that some hypothalamic abnormality may underlie at least some portion of type 2 diabetes or insulin resistance in humans, and this viewpoint of hypothalamic pathogenesis of type 2 diabetes may lead to the development of new drugs for type 2 diabetes.
authors.affiliation: Center for Diabetes & Endocrinology, The Tazuke Kofukai Foundation Medical Research Institute, Kitano Hospital, Osaka 530-8480, Japan. h-koshiyama@kitano-hp.or.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koshiyama
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hamamoto
authors.forename: Sachiko
authors.initials: S
authors.lastname: Honjo
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Wada
authors.forename: Hiroki
authors.initials: H
authors.lastname: Lkeda
mesh_terms: D050156:Adipogenesis / Q000235:genetics; D000818:Animals; D056926:CLOCK Proteins; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000235:genetics; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology*; D007031:Hypothalamus / Q000503:physiopathology*; D007333:Insulin Resistance; D051379:Mice; D010913:Pituitary-Adrenal System / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics
chemical_list: D015534:Trans-Activators; D056926:CLOCK Proteins; C538943:CLOCK protein, human; C538944:Clock protein, mouse; D005947:Glucose