Insulin and the CNS: effects on food intake, memory, and endocrine parameters and the role of intranasal insulin administration in humans

Stockhorst, Ursula; Fries, Detlev de; Steingrueber, Hans-Joachim; Scherbaum, Werner A.

doi:10.1016/j.physbeh.2004.07.022

Cited by 115 publications

(94 citation statements)

References 58 publications

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“…The influence of intranasal insulin on the functional state of hormone-regulated signaling pathways in DM has been poorly studied. There is a significant difference in the mechanisms of action of centrally and peripherally administered insulin on organisms, therefore the study of action of intranasal insulin on the hormonal signaling systems in normal subjects and those with DM is an urgent task of molecular endocrinology and practical medicine [16,52]. Insulin in the brain functions as a neuropeptide and binds specifically to brain insulin receptors whose density in the olfactory bulbs, hypothalamus and hippocampus is the highest [53].…”

Section: Discussionmentioning

confidence: 99%

“…In the recent years the method of insulin delivery by intranasal routes has been applied on a large scale. Intranasal insulin improves learning and memory, prevents cognitive decline, cerebral atrophy, and focal cerebral ischemia, and reduces food intake and body weight [15,16]. However, the molecular mechanisms and targets of intranasal insulin action have not been well defined.…”

Section: Introductionmentioning

confidence: 99%

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Intranasal insulin affects adenyl cyclase system in rat tissues in neonatal diabetes

Chistyakova

Derkach

et al. 2011

Open Life Sciences

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Intranasal insulin affects adenyl cyclase system in rat tissues in neonatal diabetes Abbreviations:AC -adenylyl cyclase; AC system -adenylyl cyclase signaling system; DM -diabetes mellitus; EMD-386088 -5 -c h l o r o -2 -m e t h y l -3 -( 1 , 2 , 3 , 6 -tetrahydro-4-pyridinyl)-1H-indole; GppNHp -b,g-imidoguanosine-5'-triphosphate; 5-HT receptor -5-hydroxytryptamine receptor; hCG -human chorionic gonadotropin; PACAP-38 -pituitary adenylyl cyclase-activating peptide-38. IntroductionHypertension, coronary heart diseases, atherosclerosis, nephropathy, retinopathy, neuropathy, cognitive deficit and disorders of the reproductive system are the most common complications of diabetes mellitus (DM) [1][2][3]. Chronic hyperglycemia is quite often an important contributing factor in the development of these complications. Many hormone-and growth factorregulated signaling pathways, such as the adenylyl cyclase (AC) signaling system, phospholipase C/protein kinase C signaling system and the cascade of mitogenactivated protein kinases are implicated in the regulation of the cardiovascular, nervous and reproductive systems and aberration of their functional activity in DM may contribute to complications of this disease [4][5][6][7][8]. It has been shown that in experimental types 1 and 2 DM the functional activity of hormone-sensitive AC system in the skeletal muscles, myocardium, testis, ovaries, uterus and brain of diabetic rats and the sensitivity of this system to hormones regulating AC activity are changed in tissue-and hormone-specific manner [6][7][8][9][10][11][12].The most significant changes of hormonal sensitivity of AC system were found in the myocardium, testis and Abstract:The changes in hormone-regulated adenylyl cyclase (AC) signaling system implicated in control of the nervous, cardiovascular and reproductive systems may contribute to complications of diabetes mellitus (DM). We investigated the functional state of AC system in the brain, myocardium, ovary and uterus of rats with neonatal DM and examined the influence of intranasally administered insulin on the sensitivity of this system to biogenic amines and polypeptide hormones. The regulatory effects of somatostatin and 5-HT 1B R-agonist 5-nonyloxytryptamine acting via G i protein-coupled receptors were significantly decreased in DM and partially restored in insulin-treated rats. The effects of hormones, activators of AC, are changed in tissue-and receptorspecific manner, and intranasal insulin restored the effects rather close to the level in control. In insulin-treated non-diabetic rats, AC stimulating effects of isoproterenol and relaxin in the myocardium and of human chorionic gonadotropin in the ovaries were decreased, while the effects of hormones, inhibitors of AC, were increased. These data indicate that with intranasal insulin, G i protein-mediated signaling pathways continue to gain strength. The obtained data on the influence of hormones on AC system in the brain, myocardium, ovary and uterus allow looking anew into the mechanisms of therapeutic ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intranasal insulin affects adenyl cyclase system in rat tissues in neonatal diabetes

Chistyakova

Derkach

et al. 2011

Open Life Sciences

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“…Concordantly, intranasal insulin failed to acutely suppress food intake in obese men. 35 In rats, the catabolic impact of intracerebroventricular insulin and leptin is curbed in animals with diet-induced obesity, [36][37][38] suggesting that central nervous resistance against both endogenous adiposity signals essentially contributes to obesity. Interestingly, in our previous studies 9,16 normal-weight women displayed memory improvement but did not lose body fat due to intranasal insulin, which is a pattern similar to the effects seen in the obese men of present experiments.…”

Section: Discussionmentioning

confidence: 99%

Obese men respond to cognitive but not to catabolic brain insulin signaling

et al. 2007

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Context and objective: Insulin acts in the brain to reduce food intake and body weight and is considered a major adiposity signal in energy homeostasis. In normal-weight men, intranasal insulin administration reduces body fat and improves declarative memory. The present experiments aimed to generalize these findings to obese patients, with a view to evaluate the therapeutic potential of the compound. Design, subjects and measurements: Insulin and placebo, respectively, were intranasally administered four times a day (amounting to 160 IU day À1 ) over 8 weeks to two groups of 15 obese men each. Results: Contrasting with the catabolic effects in normal-weight men, insulin treatment did not induce any significant reduction of body weight (P40.50) and body fat (P40.44) in the obese subjects. However, in accordance with the effects in normalweight men, declarative memory and mood were improved (Po0.05) and hypothalamic-pituitary-adrenal axis activity as assessed by circulating ACTH (Po0.01) and cortisol levels (Po0.04) was reduced. Conclusions: Our results indicate that in obese men, intranasal insulin is functionally active in the central nervous system but fails to affect the neuronal networks critically involved in body weight regulation. We conclude that obesity in men is associated with central nervous resistance to the adiposity signal insulin. This defect likely contributes to the persistence of obesity in spite of elevated levels of circulating insulin in obese patients.

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“…The main neuronal glucose transporter, GLUT3, is highly expressed at the neutrophil in regions of the central nervous system (CNS) with high synaptic density and metabolic activity, at the hippocampus and frontal and motor cortex (8). Interestingly, evidence suggest that insulin influences cerebral glucose metabolism at the entorhinal cortex and the hippocampus (9). The brain is continuously exposed to free radicals, which may underlie the pathophysiology of neurodegenerative diseases, stroke, and diabetes complications affecting the CNS (10,11).…”

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confidence: 99%

Insulin Restores Metabolic Function in Cultured Cortical Neurons Subjected to Oxidative Stress

et al. 2006

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We previously demonstrated that insulin has a neuroprotective role against oxidative stress, a deleterious condition associated with diabetes, ischemia, and age-related neurodegenerative diseases. In this study, we investigated the effect of insulin on neuronal glucose uptake and metabolism after oxidative stress in rat primary cortical neurons. On oxidative stress, insulin stimulates neuronal glucose uptake and subsequent metabolism into pyruvate, restoring intracellular ATP and phosphocreatine. Insulin also increases intracellular and decreases extracellular adenosine, counteracting the effect of oxidative stress. Insulin effects are apparently mediated by phosphatidylinositol 3-K and extracellular signal-regulated kinase signaling pathways. Extracellular adenosine under oxidative stress is largely inhibited after blockade of ecto-5-nucleotidase, suggesting that extracellular adenosine results preferentially from ATP release and catabolism. Moreover, insulin appears to interfere with the ATP release induced by oxidative stress, regulating extracellular adenosine levels. In conclusion, insulin neuroprotection against oxidative stress-mediated damage involves 1) stimulation of glucose uptake and metabolism, increasing energy levels and intracellular adenosine and, ultimately, uric acid formation and 2) a decrease in extracellular adenosine, which may reduce the facilitatory activity of adenosine receptors.

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Insulin and the CNS: effects on food intake, memory, and endocrine parameters and the role of intranasal insulin administration in humans

Cited by 115 publications

References 58 publications

Intranasal insulin affects adenyl cyclase system in rat tissues in neonatal diabetes

Intranasal insulin affects adenyl cyclase system in rat tissues in neonatal diabetes

Obese men respond to cognitive but not to catabolic brain insulin signaling

Insulin Restores Metabolic Function in Cultured Cortical Neurons Subjected to Oxidative Stress

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