New Twist on Neuronal Insulin Receptor Signaling in Health, Disease, and Therapeutics

Abstract

Abstract. 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.

Intranasal Insulin Improves Memory in Humans: Superiority of Insulin Aspart

“…Previous studies have provided clear evidence that declarative memory formation depends on intact hippocampal functioning (Kessels et al, 2001;Bayley et al, 2005). Hippocampal and cortical insulin signaling pathways have been shown to play a pivotal role in enabling long-term memory consolidation by modulating neuronal activity and triggering mechanisms that are required for establishing synaptic plasticity (Gasparini and Xu, 2003;Zhao et al, 2004;Craft and Watson, 2004;Wada et al, 2005). Thus, it is likely that after intranasal administration, insulin improves neuronal processes within these hippocampal and connected structures.…”

Metabolic Alterations Associated to Brain Dysfunction in Diabetes

“…The insulin/IGF-1-mediated activation of complex signalling cascades serves the regulation a plethora of cellular processes including growth, differentiation and metabolism [63]. In the CNS, insulin exerts further control over neurotransmission, synaptic plasticity and cognitive processes, cellular proliferation and antiapoptotic mechanisms, and antioxidant defence [64,65]. Therefore, defects in brain insulin signalling pathways result in altered brain function.…”

Intrahippocampal Transplantation of Transgenic Neural Precursor Cells Overexpressing Interleukin-1 Receptor Antagonist Blocks Chronic Isolation-Induced Impairment in Memory and Neurogenesis

“…However, to our knowledge no previous studies attempted to assess the specific role of the hippocampus in IL-1-mediated anorexia and body weight loss. Nevertheless, it should be noted that the hippocampus has been proposed to participate in body weight regulation (Davidson et al, 2005), possibly via receptors to several feeding and body weightregulating hormones, including leptin, insulin, and glucocorticoids (Wada et al, 2005;Harvey, 2003), which in turn interact with the hippocampal IL-1 system (Hosoi et al, 2002;Dinkel et al, 2003). Moreover, the anorexic response to chronic i.c.v.…”