Brain of the conscious dog is sensitive to physiological changes in circulating insulin

Dunham, Bruce; Walmsley, Konstantin; Shavers, C.; Neal, Doss W.; Williams, Phillip E.; Cherrington, Alan D.

doi:10.1152/ajpendo.1997.272.4.e567

Cited by 24 publications

(29 citation statements)

References 9 publications

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“…However, with long-term intranasal treatment we did not find any hints towards an elevating effect of insulin on blood pressure in humans [35]. These findings fit well with animal studies indicating that long-term in contrast to immediate central nervous insulin administration does not affect arterial blood pressure [34,36,37,38]. On this background, our data point to a gradual activation of counterregulatory mechanisms during prolonged treatment with insulin.…”

Section: Intranasal Administration Of Insulinsupporting

confidence: 86%

“…Accordingly, circulating insulin and glucose levels also do not change during prolonged (8 weeks) of intranasal treatment with insulin (160 IU/day) [32, 33]. Since animal experiments have indicated that central nervous insulin can induce acute sympathoexcitation via central nervous autonomous centers [34], the possible therapeutic use of intranasal insulin administration might be hampered by elevating effects on blood pressure. However, with long-term intranasal treatment we did not find any hints towards an elevating effect of insulin on blood pressure in humans [35].…”

Section: Intranasal Administration Of Insulinmentioning

confidence: 99%

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Intranasal Insulin to Improve Memory Function in Humans

Benedict¹,

Hallschmid²,

Schultes

et al. 2007

Neuroendocrinology

152

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Background: Compelling evidence indicates that central nervous insulin enhances learning and memory and in particular benefits hippocampus-dependent (i.e., declarative) memory. Intranasal administration of insulin provides an effective way of delivering the compound to the central nervous system, bypassing the blood-brain barrier and avoiding systemic side effects. Methods: Here we review a series of recent studies on the effects of intranasally administered insulin on memory functions in humans. In accordance with the beneficial effects of intravenously administered insulin on hippocampus-dependent declarative memory observed in hyperinsulinemic-euglycemic clamp studies, intranasal insulin administration similarly improves this type of memory, but in the absence of adverse peripheral side effects. Result andConclusion: Considering that cerebrospinal fluid insulin levels are reduced in patients suffering from Alzheimer’s disease, these results may be of considerable relevance for future clinical applications of insulin in the treatment of memory disorders.

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Section: Intranasal Administration Of Insulinsupporting

confidence: 86%

Section: Intranasal Administration Of Insulinmentioning

confidence: 99%

Intranasal Insulin to Improve Memory Function in Humans

Benedict¹,

Hallschmid²,

Schultes

et al. 2007

Neuroendocrinology

152

View full text Add to dashboard Cite

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“…Finally, neural pathways stimulated by hypoglycemia induce feeding behavior [2]. Hormone responses and symptoms of hypoglycemia tend to be blunted in DM patients treated with insulin, and it is likely that deficient responses to hypoglycemia result from recurrent severe hypoglycemia sustained over many years of insulin replacement [1] CNS mechanisms of autonomic and endocrine responses to hypoglycemia have been studied in dogs and in rodents, and these studies indicate participation of structures in brainstem as well as hypothalamus [3][4][5][6][7][8][9][10][11][12]. Although these animal studies have proven useful in elucidating aspects of neural circuitry underlying counterregulatory hormone secretion, symptom thresholds, per se, cannot be directly assessed in an animal model.…”

Section: Introductionmentioning

confidence: 99%

Hypoglycemia activates arousal-related neurons and increases wake time in adult rats

Tkacs

Pan

Sawhney

et al. 2007

Physiology & Behavior

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Hypoglycemia resulting from excess of exogenous or endogenous insulin elicits central nervous system activation that contributes to counterregulatory hormone secretion. In adult humans without diabetes, hypoglycemia occurring during sleep usually produces cortical activation with awakening. However, in adult humans with type 1 diabetes, hypoglycemic arousal appears blunted or absent. We hypothesized that insulin injection sufficient to produce hypoglycemia would induce awakening in adult male rats. Polysomnographic studies were carried out to characterize the effect of insulin injection on measures of sleep and waking during a circadian time of increased sleep. Compared to a baseline day, insulin treatment more than doubled the time spent awake, from 18.4 ± 2.6% after saline injection to 48.0 ± 5.5% after insulin. Insulin injection also reduced rapid eye movement sleep (REMS) from 27.3 ± 1.8% to 5.6 ± 1.3%. The percent of time in non-REM sleep (NREMS) sleep was not different between saline and insulin days, however, NREMS after insulin was fragmented, with increased number and decreased duration of episodes. These electrophysiological data indicate that insulin-induced hypoglycemia is an arousing stimulus in rats, as in nondiabetic adult humans. We also studied the effect of insulin on activation of selected arousal-related neurons using immunohistochemical detection of Fos. Fos-immunoreactivity increased in orexin (OX) neurons after insulin, from 8.7 ± 4.9% after saline injection to 37 ± 9% after insulin. Basal forebrain cholinergic nuclei also showed increased Fos-immunoreactivity after insulin. These correlated behavioral and histological data provide targets for future studies of the neural pathways underlying hypoglycemic arousal.

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“…The results of our experiments argue against a role for vagal afferents in the initiation of the counterregulatory response to insulin-induced hypoglycemia. On the other hand, Davis et al (9,10) demonstrated that during insulin-induced hypoglycemia in conscious dogs, the brain insulin level is a key determinant of the magnitude of the counterregulatory response, such that higher insulin levels markedly augment the sympathetic response to hypoglycemia. The concept that the insulin concentration can modify the counterregulatorry response to hypoglycemia has also been demonstrated in nondiabetic (11,12) and diabetic humans (13,14).…”

mentioning

confidence: 99%

Effect of Vagal Cooling on the Counterregulatory Response to Hypoglycemia Induced by a Low Dose of Insulin in the Conscious Dog

Cardin¹,

Jackson²,

Edgerton³

et al. 2001

Diabetes

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We previously demonstrated, using a nerve-cooling technique, that the vagus nerves are not essential for the counterregulatory response to hypoglycemia caused by high levels of insulin. Because high insulin levels per se augment the central nervous system response to hypoglycemia, the question arises whether afferent nerve fibers traveling along the vagus nerves would play a role in the defense of hypoglycemia in the presence of a more moderate insulin level. To address this issue, we studied two groups of conscious 18-h-fasted dogs with cooling coils previously placed on both vagus nerves. Each study consisted of a 100-min equilibration period, a 40-min basal period, and a 150-min hypoglycemic period. Glucose was lowered using a glycogen phosphorylase inhibitor and a low dose of insulin infused into the portal vein (0.7 mU ⅐ kg ؊1 ⅐ min ؊1 ). The arterial plasma insulin level increased to 15 ؎ 2 U/ml and the plasma glucose level fell to a plateau of 57 ؎ 3 mg/dl in both groups. The vagal cooling coils were perfused with a 37°C (SHAM COOL; n ‫؍‬ 7) or a ؊20°C (COOL; n ‫؍‬ 7) ethanol solution for the last 90 min of the study to block parasympathetic afferent fibers. Vagal cooling caused a marked increase in the heart rate and blocked the hypoglycemia-induced increase in the arterial pancreatic polypeptide level. The average increments in glucagon (pg/ml), epinephrine (pg/ml), norepinephrine (pg/ ml), cortisol (g/dl), glucose production (mg ⅐ kg -1 ⅐ min -1 ), and glycerol (mol/l) in the SHAM COOL group were 53 ؎ 9, 625 ؎ 186, 131 ؎ 48, 4.63 ؎ 1.05, ؊0.79 ؎ 0.24, and 101 ؎ 18, respectively, and in the COOL group, the increments were 39 ؎ 7, 837 ؎ 235, 93 ؎ 39, 6.28 ؎ 1.03 (P < 0.05), ؊0.80 ؎ 0.20, and 73 ؎ 29, respectively. Based on these data, we conclude that, even in the absence of high insulin concentrations, afferent signaling via the vagus nerves is not required for a normal counterregulatory response to hypoglycemia. Diabetes 50: 558 -564, 2001 H ypoglycemia is a serious condition that can lead to death if the organism does not respond properly. The physiological response to hypoglycemia involves an increase in the plasma levels of a variety of counterregulatory hormones, including glucagon, cortisol, epinephrine, norepinephrine, and growth hormone. This hormonal response results in an increase in glucose production and a decrease in glucose utilization, thereby defending the organism against the hypoglycemia. Individuals with type 1 diabetes have a blunted counterregulatory response to hypoglycemia, making them more vulnerable to low blood glucose. It is of clinical importance, therefore, to understand which areas of the body are responsible for sensing a decrease in blood glucose. The site of hypoglycemic sensing is controversial. Until recently, the brain was generally accepted as the site of detection of hypoglycemia. In accordance with this, Borg et al.(1) demonstrated in rats that ablation of the ventromedial hypothalamus abolished the counterregulatory response to hypoglycemia. In the conscious dog, ...

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Brain of the conscious dog is sensitive to physiological changes in circulating insulin

Cited by 24 publications

References 9 publications

Intranasal Insulin to Improve Memory Function in Humans

Intranasal Insulin to Improve Memory Function in Humans

Hypoglycemia activates arousal-related neurons and increases wake time in adult rats

Effect of Vagal Cooling on the Counterregulatory Response to Hypoglycemia Induced by a Low Dose of Insulin in the Conscious Dog

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