Insulin and the insulin receptor in experimental models of learning and memory

Zhao, Weiqin; Hui, Chi Man; Quon, Michael J.; Alkon, Daniel L.

doi:10.1016/j.ejphar.2004.02.045

Cited by 440 publications

(318 citation statements)

References 121 publications

Supporting

Mentioning

304

Contrasting

Unclassified

Order By: Relevance

“…Brain insulin receptor deficiency causes obesity and mild insulin resistance in mice [38], similar to that seen in animals with orexin deficiency. Insulin receptor signalling is mediated by two main pathways: the PI3-kinase/Akt and MAP kinase pathway [20,39]. The hypothalamic PI3-kinase/Akt pathway mediates the effect of insulin on food intake and energy expenditure via forkhead transcription factor Foxo1 [40], whereas insulin-dependent activation of hypothalamic MAP kinase does not have any effect on glucose homeostasis [23].…”

Section: Discussionmentioning

confidence: 99%

Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

et al. 2008

View full text Add to dashboard Cite

Aims/hypothesis Orexin/hypocretin is a hypothalamic neuropeptide that regulates motivated behaviours, such as feeding and arousal, and, importantly, is also involved in energy homeostasis. The aim of this study was to reveal the role of orexin in the regulation of insulin sensitivity for glucose metabolism. Methods Orexin knockout mice fasted overnight underwent oral glucose tolerance testing and insulin tolerance testing. The impact of orexin deficiency on insulin signalling was studied by Western blotting to measure levels of Akt phosphorylation and its upstream and downstream molecules in the hypothalamus, muscle and liver in orexin knockout mice. Results We found that orexin deficiency caused the agerelated development of impaired glucose tolerance and insulin resistance in both male mice without obesity and female mice with mild obesity, fed a normal chow diet. When maintained on a high-fat diet, these abnormalities became more pronounced exclusively in female orexin knockout mice that developed severe obesity. Insulin signalling through Akt was disrupted in peripheral tissues of middle-aged (9-month-old) but not young adult (2-to-3-month-old) orexin knockout mice fed a normal chow diet. Moreover, basal levels of hypothalamic Akt phosphorylation were abnormally elevated in orexin knockout mice at every age studied, and insulin stimulation failed to increase the level of phosphorylation. Similar abnormalities were observed with respect to GSK3β phosphorylation in the hypothalamus and peripheral tissues of middle-aged orexin knockout mice. Conclusions/interpretation Our results demonstrate a novel role for orexin in hypothalamic insulin signalling, which is likely to be responsible for preventing the development of peripheral insulin resistance with age.

show abstract

Section: Discussionmentioning

confidence: 99%

Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

et al. 2008

View full text Add to dashboard Cite

show abstract

“…The neuronal mechanisms underlying the improvement of declarative memory after intranasal insulin administration cannot be derived from our study. Central nervous system insulin is involved in a number of neuronal mechanisms assumed to constitute memory processing (for review, see Zhao et al, 2004). Previous studies have provided clear evidence that declarative memory formation depends on intact hippocampal functioning (Kessels et al, 2001;Bayley et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Discussionmentioning

confidence: 99%

Intranasal Insulin Improves Memory in Humans: Superiority of Insulin Aspart

Benedict

Hallschmid

Schmitz

et al. 2006

Neuropsychopharmacol

261

157

View full text Add to dashboard Cite

There is compelling evidence that intranasal administration of regular human insulin (RH-I) improves memory in humans. Owing to the reduced tendency of its molecules to form hexamers, the rapid-acting insulin analog insulin aspart (ASP-I) is more rapidly absorbed than RH-I after subcutaneous administration. Since after intranasal insulin administration, ASP-I may also be expected to access the brain, we examined whether intranasal ASP-I has stronger beneficial effects on declarative memory than RH-I in humans. Acute (40 IU) and longterm (4 Â 40 IU/day over 8 weeks) effects of intranasally administered ASP-I, RH-I, and placebo on declarative memory (word lists) were assessed in 36 healthy men in a between-subject design. Plasma insulin and glucose levels were not affected. After 8 weeks of treatment, however, word list recall was improved compared to placebo in both the ASP-I (po0.01) and the RH-I groups (po0.05). ASP-I-treated subjects performed even better than those of the RH-I-treated group (po0.05). Our results indicate that insulin-induced memory improvement can be enhanced by using ASP-I. This finding may be especially relevant for a potential clinical administration of intranasal insulin in the treatment of memory disorders like Alzheimer's disease.

show abstract

“…In rats, Morris water maze training stimulates IR signaling involving the recruitment Shc52 at the synaptic membrane to activate Ras-ERK1/2 signaling. Suggesting that training can sensitize the IR; insulin stimulated ERK1/2 phosphorylation in hippoccampal membrane fractions taken from maze-trained but not naive or untrained swimming controls (Zhao et al 2004). It is possible that decreased insulin signaling could contribute to cognitive impairment in AD.…”

Section: Zinc and Insulin Signaling In Diabetes Mellitus And Dementiamentioning

confidence: 99%

Zinc and the aging brain

Nuttall

Oteiza

2013

Genes Nutr

View full text Add to dashboard Cite

Alterations in trace element homeostasis could be involved in the pathology of dementia, and in particular of Alzheimer's disease (AD). Zinc is a structural or functional component of many proteins, being involved in numerous and relevant physiological functions. Zinc homeostasis is affected in the elderly, and current evidence points to alterations in the cellular and systemic distribution of zinc in AD. Although the association of zinc and other metals with AD pathology remains unclear, therapeutic approaches designed to restore trace element homeostasis are being tested in clinical trials. Not only could zinc supplementation potentially benefit individuals with AD, but zinc supplementation also improves glycemic control in the elderly suffering from diabetes mellitus. However, the findings that select genetic polymorphisms may alter an individual's zinc intake requirements should be taken into consideration when planning zinc supplementation. This review will focus on current knowledge regarding pathological and protective mechanisms involving brain zinc in AD to highlight areas where future research may enable development of new and improved therapies.

show abstract

Insulin and the insulin receptor in experimental models of learning and memory

Cited by 440 publications

References 121 publications

Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

Intranasal Insulin Improves Memory in Humans: Superiority of Insulin Aspart

Zinc and the aging brain

Contact Info

Product

Resources

About