Evidence that the brain of the conscious dog is insulin sensitive.

Colburn, Christopher A.; Dobbins, Robert L.; Nadeau, Sylvain; Neal, Doss W.; Williams, Phillip E.; Cherrington, Alan D.

doi:10.1172/jci117703

Cited by 70 publications

(49 citation statements)

References 64 publications

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“…Circulating insulin appears to have no direct effect on glucose utilisation in the brain, despite recent observations in hypoglycaemic dogs and humans that the brain is sensitive to insulin [22,23]. In agreement with previous findings in dogs [24], brain glucose utilisation was of similar magnitude irrespective of the fall in circulating glucose from 4.8 to 2.4 mmol/l ( Table 1).…”

Section: Discussionsupporting

confidence: 88%

Brain substrate utilisation during acute hypoglycaemia

et al. 1999

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It is now clearly established that tight blood glucose control substantially reduces or delays most of the chronic complications in patients with Type I (insulin-dependent) diabetes mellitus [1]. A tight blood glucose control, however, is accompanied by increased hypoglycaemic episodes [1]. These recurrent hypoglycaemic episodes are major impediments in achieving ideal blood glucose control in a substantial number of Type I diabetic patients. In studies where alternative fuels, such as b-hydroxybutyrate and lactate [2] were provided in attempts to alleviate hypoglycaemic symptoms, the response of the autonomic system to hypoglycaemia was diminished or prevented [3]. Based on this indirect evidence, it was concluded that the brain uses these alternative fuels during hypoglycaemia. The brain contains the enzyme systems that are required for the metabolism of a range of different carbohydrate and lipid substrates [4]. There is thus, no immediate reason why the brain Diabetologia (1999) AbstractAims/hypothesis. Our study was undertaken to examine directly the utilisation of glucose and alternative substrates, in particular amino acids, during hypoglycaemia.Methods. Catheters were positioned in the jugular venous bulb and an artery in six healthy subjects in the overnight fasted state. Arterio-venous differences for glucose, amino acids, lactate and pyruvate were measured in the basal state, during hyperinsulinaemic euglycaemia and during hyperinsulinaemic hypoglycaemia. The subjects were studied on two different occasions, once during intravenous infusion of amino acids and once during infusion of saline.Results. In the basal state the fractional extraction of glucose across the brain was 10 ± 2 %, glucose uptake accounted for 106 ± 5 % of the brain's oxidative metabolism. There was a small release of lactate and pyruvate. During hyperinsulinaemia glucose uptake continued to account for the entire fuel requirement

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Section: Discussionsupporting

confidence: 88%

Brain substrate utilisation during acute hypoglycaemia

et al. 1999

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“…In our earlier experiments, we used high levels of insulin to create hypoglycemia and showed that complete vagal blockade failed to alter the counterregulatory response. Davis et al (9), however, have shown, using their head insulin infusion model, that in the presence of the same systemic glycemia (ϳ57 mg/dl) and insulinemia (ϳ85 U/ml), a selective increase in the insulin level in the head (85 vs. 195 U/ml) was associated with a marked increase in the sympathetic response to hypoglycemia. They subsequently concluded that the brain can directly sense the circulating insulin level.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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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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“…12 Although during hypoglycemia different insulin infusion rates had no effect on the ACTH and cortisol response in the present study, previous studies 13 -15 provided evidence for a dose-dependent amplifying effect of insulin on HPA response to hypoglycemia. Moreover, Davis et al 16 demonstrated that a selective increase in the level of insulin in the blood perfusing the brain amplified the cortisol response to hypoglycemia in dogs, indicating that insulin directly acts on the brain. Taken together, the previous and present results provide strong evidence that hyperinsulinemia increases basal as well as hypoglycemia-stimulated HPA secretory activity.…”

Section: Discussionmentioning

confidence: 99%

Hyperinsulinemia causes activation of the hypothalamus-pituitary-adrenal axis in humans

et al. 2001

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OBJECTIVE: Hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis is frequently found in hyperinsulinemic subjects, such as patients with diabetes or abdominal obesity. Here, the question has been posed as to whether hyperinsulinemia increases HPA secretory activity. METHODS: We performed paired -euglycemic and stepwise hypoglycemic (76 -66 -56 -46 mg=dl) -clamp experiments in two groups (each of 15 healthy men) at different insulin infusions rates, ie, 1.5 mU=min=kg (low-insulin condition) and 15.0 mU=min=kg (high-insulin condition). RESULTS: During the euglycemic clamp, the high rate insulin infusion increased plasma ACTH levels, whereas plasma ACTH levels remained essentially unchanged during the low-insulin condition (condition by time interaction, P ¼ 0.008). Likewise, serum cortisol levels were higher during the high-vs low-insulin condition (condition by time interaction, P ¼ 0.004). During the hypoglycemic clamp, plasma ACTH levels did not differ between the low-vs high-insulin condition, while serum cortisol levels were higher during the high-vs low-insulin condition at the beginning of the clamp (plasma glucose $ 76 mg=dl; P ¼ 0.032). CONCLUSION: Data indicate that hyperinsulinemia acutely increases HPA secretory activity in healthy men. This finding appears to be relevant to the pathogenesis of many clinical abnormalities associated which diabetes and abdominal adiposity, often referred to as the metabolic syndrome.

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Evidence that the brain of the conscious dog is insulin sensitive.

Cited by 70 publications

References 64 publications

Brain substrate utilisation during acute hypoglycaemia

Brain substrate utilisation during acute hypoglycaemia

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

Hyperinsulinemia causes activation of the hypothalamus-pituitary-adrenal axis in humans

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