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

Cardin, Sylvain; Jackson, Patricia A.; Edgerton, Dale S.; Neal, Doss W.; Coffey, Christopher S.; Cherrington, Alan D.

doi:10.2337/diabetes.50.3.558

Cited by 20 publications

(15 citation statements)

References 33 publications

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“…[41][42][43][44] In contrast, the activation of glucagon secretion by insulin-induced hypoglycemia was not inhibited by inactivating the hepatic vagal nerve, suggesting that this sensor did not participate in the induction of counterregulation. [45][46][47] However, more recent data showed that celiac-superior mesenteric ganglionectomy, but not vagotomy, suppressed the response to insulin-induced hypoglycemia, suggesting that the hepatoportal sensor may indeed participate in triggering glucagon secretion. 48,49 In the central nervous system, sites of glucose detection for the control of counter-regulation are present in the hypothalamus and different brainstem nuclei.…”

Section: Counter-regulationmentioning

confidence: 99%

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

Thorens

2008

Int J Obes

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The control of body weight and of blood glucose concentrations depends on the exquisite coordination of the function of several organs and tissues, in particular the liver, muscle and fat. These organs and tissues have major roles in the use and storage of nutrients in the form of glycogen or triglycerides and in the release of glucose or free fatty acids into the blood, in periods of metabolic needs. These mechanisms are tightly regulated by hormonal and nervous signals, which are generated by specialized cells that detect variations in blood glucose or lipid concentrations. The hormones insulin and glucagon not only regulate glycemic levels through their action on these organs and the sympathetic and parasympathetic branches of the autonomic nervous system, which are activated by glucose or lipid sensors, but also modulate pancreatic hormone secretion and liver, muscle and fat glucose and lipid metabolism. Other signaling molecules, such as the adipocyte hormones leptin and adiponectin, have circulating plasma concentrations that reflect the level of fat stored in adipocytes. These signals are integrated at the level of the hypothalamus by the melanocortin pathway, which produces orexigenic and anorexigenic neuropeptides to control feeding behavior, energy expenditure and glucose homeostasis. Work from several laboratories, including ours, has explored the physiological role of glucose as a signal that regulates these homeostatic processes and has tested the hypothesis that the mechanism of glucose sensing that controls insulin secretion by the pancreatic beta-cells is also used by other cell types. I discuss here evidence for these mechanisms, how they integrate signals from other nutrients such as lipids and how their deregulation may initiate metabolic diseases.

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Section: Counter-regulationmentioning

confidence: 99%

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

Thorens

2008

Int J Obes

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“…Stainless steel cooling coils, with Silastic extension tubing attached, were placed around the vagus nerves in the neck in all dogs, as described previously (1,10). The effectiveness of the cooling-induced blockade of parasympathetic signaling was verified by measuring the heart rate (which is under vagal control).…”

Section: Methodsmentioning

confidence: 99%

Involvement of the vagus nerves in the regulation of basal hepatic glucose production in conscious dogs

Cardin

Walmsley

Neal

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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. Involvement of the vagus nerves in the regulation of basal hepatic glucose production in conscious dogs. Am J Physiol Endocrinol Metab 283: E958-E964, 2002; 10.1152/ajpendo.00566. 2001.-We determined if blocking transmission in the fibers of the vagus nerves would affect basal hepatic glucose metabolism in the 18-h-fasted conscious dog. A pancreatic clamp (somatostatin, basal portal insulin, and glucagon) was employed. A 40-min control period was followed by a 90-min test period. In one group, stainless steel cooling coils (Sham, n ϭ 5) were perfused with a 37°C solution, while in the other (Cool, n ϭ 6), the coils were perfused with Ϫ20°C solution. Vagal blockade was verified by heart rate change (80 Ϯ 9 to 84 Ϯ 14 beats/min in Sham; 98 Ϯ 12 to 193 Ϯ 22 beats/min in Cool). The arterial glucose level was kept euglycemic by glucose infusion. No change in tracer-determined glucose production occurred in Sham, whereas in Cool it dropped significantly (2.4 Ϯ 0.4 to 1.9 Ϯ 0.4 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Net hepatic glucose output did not change in Sham but decreased from 1.9 Ϯ 0.3 to 1.3 Ϯ 0.3 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 in the Cool group. Hepatic gluconeogenesis did not change in either group. These data suggest that vagal blockade acutely modulates hepatic glucose production by inhibiting glycogenolysis. vagal cooling; liver nerves; parasympathetic blockade; gluconeogenesis; glycogenolysis THE AUTONOMIC NERVOUS SYSTEM is involved in the regulation of hepatic glucose metabolism. It has been demonstrated, for example, that electrical stimulation of the vagus nerves induces activation of the liver enzyme glycogen synthase, which in turn increases glycogen synthesis and reduces glucose output (19). Conversely, electrical stimulation of the splanchnic nerve induces activation of the liver enzyme glycogen phosphorylase, which in turn increases glycogenolysis and glucose output (20). Taken together, these data have been interpreted to suggest that activation of the parasympathetic nervous system promotes glucose uptake and hepatic glycogen deposition while activation of the sympathetic nervous system promotes glycogenolysis and glucose output.It is also known that glucosensors within the hepatoportal region have the ability to sense glucose and inform the brain of its concentration via afferent fibers traveling, at least in part, along the hepatic vagus nerves (16). It has been hypothesized that the brain uses this information to minimize fluctuations in the plasma glucose level after feeding (18). The efferent responses of this feedback loop involve the pancreas, adrenal glands, adipocytes, skeletal muscles, and the liver (2). Although it is known that the autonomic nervous system is vital to the regulation of glucose metabolism in times of stress, evidence is accumulating to support a role for it in the postprandial state. Nevertheless, its role in regulating hepatic glucose metabolism after an overnight fast is not clear.Our aim, therefore, was to cool the vagus nerves, in the presence of a pancreatic clamp, to study the involve...

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“…Free fatty acids (FFAs), cortisol, lactate, and glycerol were measured as previously described (4,17).…”

Section: Methodsmentioning

confidence: 99%

Simulated first-phase insulin release using Humulin or insulin analog HIM2 is associated with prolonged improvement in postprandial glycemia

DiCostanzo

Moore²,

Lautz³

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

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We examined the extent to which priming the liver with a pulse of Humulin or the insulin analog hexyl-insulin monoconjugate 2 (HIM2) reduces postprandial hyperglycemia. Somatostatin (0.5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was given with basal intraportal insulin and glucagon for 4.5 h into three groups of 42-h-fasted conscious dogs. From 0 -5 min, group 1 (BI, n ϭ 6) received saline, group 2 (HI, n ϭ 6) received a Humulin pulse (10 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ), and group 3 (HIM2, n ϭ 6) received a HIM2 pulse (10 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ). Duodenal glucose was infused (5.0 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) from 15 to 270 min. Arterial insulin in BI remained basal (6 Ϯ 1 U/ml) and peaked at 52 Ϯ 15 (HI) and 164 Ϯ 44 U/ml (HIM2) and returned to baseline by 30 and 60 min, respectively. Arterial plasma glucose plateaued at 265 Ϯ 20, 214 Ϯ 15, and 193 Ϯ 14 mg/dl in BI, HI, and HIM2. Glucose absorption was similar in all groups. Significant net hepatic glucose uptake occurred at 85, 55, and 25 min in BI, HI, and HIM2, respectively. Nonhepatic glucose clearance at 270 min differed among groups (BI, HI, HIM2): 0.62 Ϯ 0.11, 0.76 Ϯ 0.26, and 1.61 Ϯ 0.29 ml ⅐ kg Ϫ1 ⅐ min Ϫ1 (P Ͻ 0.05). A brief (5-min) insulin pulse improved postprandial glycemia, stimulating hepatic glucose uptake and prolonging enhancement of nonhepatic glucose clearance. HIM2 was more effective than Humulin, perhaps because its lowered clearance caused higher levels at the liver and periphery and its biological activity was not reduced proportionally to its decreased clearance.hexyl-insulin monoconjugate 2; insulin action SUBCUTANEOUSLY ADMINISTERED INSULIN is initially absorbed into the peripheral circulation of individuals with diabetes, resulting in fat and muscle being exposed to higher insulin levels than the liver. This peripheral hyperinsulinemia predisposes to hypoglycemia and is thought to be linked to weight gain and other metabolic abnormalities, which in turn lead to microvascular and macrovascular disease (15). If insulin could be given orally, the normal portal vein/arterial insulin distribution would be restored. It has been shown that agents capable of rapidly increasing the insulin concentration in response to a glucose challenge are good regulators of hepatic glucose metabolism and are more effective controllers of postprandial glucose concentrations than peripherally delivered insulin (3). An oral insulin would eliminate the disproportionately high peripheral insulin levels while still delivering adequate amounts of insulin to the liver, thereby potentially being useful as a new therapeutic agent.The release of insulin in response to a glucose challenge is biphasic in nature, with an early phase and a late phase. The early phase consists of two parts: a cephalic phase and a first phase. The cephalic phase is rapid (Յ2 min after a meal) yet very small, increasing arterial plasma insulin levels by only ϳ5 U/ml. The more pronounced first phase occurs 5-10 min postprandially and is dependent on the amount of glucose present. The liver responds quickly, such that the first-phas...

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

Cited by 20 publications

References 33 publications

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

Involvement of the vagus nerves in the regulation of basal hepatic glucose production in conscious dogs

Simulated first-phase insulin release using Humulin or insulin analog HIM2 is associated with prolonged improvement in postprandial glycemia

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