Role of the autonomic nervous system in the development of hyperinsulinemia by high-carbohydrate formula feeding to neonatal rats

2007 ◽  
Vol 292 (4) ◽  
pp. E1069-E1078 ◽  
Author(s):  
Paul Mitrani ◽  
Malathi Srinivasan ◽  
Catherine Dodds ◽  
Mulchand S. Patel
Keyword(s):  
Nervous System ◽  
Insulin Secretion ◽  
Autonomic Nervous System ◽  
Dietary Intervention ◽  
Neonatal Rat ◽  
Milk Formula ◽  
Autonomic Nervous ◽  
High Carbohydrate

An early dietary intervention in the form of a high-carbohydrate (HC) milk formula in neonatal rat pups results in immediate onset of hyperinsulinemia. While increased insulin secretion in HC rats has been shown to be related to hypersensitivity to glucose, the immediate onset of hyperinsulinemia and its persistence throughout the suckling period suggest involvement of multiple systems that enhance insulin secretion in response to increased demand. Evidence presented here in 12-day-old HC rats indicates that altered activity of the autonomic nervous system contributes to enhanced insulin secretory responses to glucose stimulation through increased parasympathetic and decreased sympathetic signaling. Both in vivo and in vitro studies have shown that HC rats secrete significantly higher levels of insulin in response to glucose in the presence of acetylcholine, a cholinergic agonist, while sensitivity to inhibition of insulin secretion by oxymetazoline, an α2a-adrenergic receptor (α2aAR) agonist, was reduced. In addition, HC rats showed increased sensitivity to blockade of cholinergic-induced insulin secretion by the muscarinic type 3 receptor (M3R) antagonist 4-diphenylacetoxy- N-methylpiperidine methobromide, as well as increased potentiation of glucose-stimulated insulin secretion by treatment with yohimbine. Increases in islets levels of M3R, phospholipase C-β1, and protein kinase Cα mRNAs, as well as decreased α2aAR mRNA, in 12-day-old HC rats provide a mechanistic connection to the changes in insulin secretion seen in HC rats. In conclusion, altered autonomic regulation of insulin secretion, due to the HC nutritional intervention, contributes to the development of hyperinsulinemia in 12-day-old HC rats.

Autonomic involvement in the permanent metabolic programming of hyperinsulinemia in the high-carbohydrate rat model

2007 ◽  
Vol 292 (5) ◽  
pp. E1364-E1377 ◽  
Author(s):  
Paul Mitrani ◽  
Malathi Srinivasan ◽  
Catherine Dodds ◽  
Mulchand S. Patel
Keyword(s):  
Insulin Secretion ◽  
Dietary Intervention ◽  
Metabolic Programming ◽  
Milk Formula ◽  
Mrna Levels ◽  
Autonomic Activity ◽  
Suckling Period ◽  
High Carbohydrate ◽  
Type 3

Exposure to a high-carbohydrate (HC) milk formula during the suckling period results in permanent metabolic programming of hyperinsulinemia in HC rats. Previous studies have shown that hyperinsulinemia in HC rats involves a programmed hyperresponsiveness to glucose. However, the immediate onset and persistence of enhanced insulin secretion throughout life suggests a role for numerous factors that control insulin secretion. Present in vivo and in vitro studies have shown a role for altered autonomic activity, including increased parasympathetic and decreased sympathetic activities, in the maintenance of hyperinsulinemia in 100-day-old HC rats. HC rats were shown to be more sensitive to cholinergic-induced potentiation of glucose-stimulated insulin secretion (GSIS) in response to acetylcholine and showed increased sensitivity to blockade of cholinergic-induced insulin secretion by the muscarinic-type 3 receptor-specific antagonist 4-diphenylacetoxy- N-methylpiperidine. In addition, HC rats were less sensitive to adrenergic-induced inhibition of insulin secretion by oxymetazoline, whereas treatment with yohimbine resulted in increased GSIS. Furthermore, HC rats showed greater reductions in plasma insulin levels after vagotomy, as well as an attenuation of yohimbine-induced potentiation of GSIS, suggesting that yohimbine-mediated changes are mediated by parasympathetic activity. Changes in autonomic regulation of GSIS are supported by increased mRNA levels of the parasympathetic signaling molecules muscarinic-type 3 receptor, phospholipase Cβ1, and protein kinase C-α and decreased levels of α2a-adrenergic receptors in islets from adult HC rats. In conclusion, metabolic programming of hyperinsulinemia throughout adulthood of HC rats involves changes in autonomic activity in response to the HC dietary intervention in the suckling period.

scholarly journals Brain permeable AMPK activator R481 raises glycemia by autonomic nervous system activation and amplifies the counterregulatory response to hypoglycemia in rats

2019 ◽  
Author(s):  
Ana M. Cruz ◽  
Yasaman Malekizadeh ◽  
Julia M. Vlachaki Walker ◽  
Paul G. Weightman Potter ◽  
Katherine Pye ◽  
...  
Keyword(s):  
Nervous System ◽  
Autonomic Nervous System ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Ventromedial Hypothalamus ◽  
Whole Body ◽  
Ampk Activation ◽  
Autonomic Nervous ◽  
Glucose Levels

ABSTRACTAMP-activated protein kinase (AMPK) is a critical cellular and whole body energy sensor activated by energy stress, including hypoglycemia, which is frequently experienced by people with diabetes. Previous studies using direct delivery of an AMPK activator to the ventromedial hypothalamus (VMH) in rodents increased hepatic glucose production. Moreover, recurrent glucoprivation in the hypothalamus leads to blunted AMPK activation and defective hormonal responses to subsequent hypoglycemia. These data suggest that amplifying AMPK activation may prevent or reduce frequency hypoglycemia in diabetes. We used a novel brain-permeable AMPK activator, R481, which potently increased AMPK phosphorylation in vitro. R481 significantly increased peak glucose levels during glucose tolerance tests in rats, which were attenuated by treatment with AMPK inhibitor SBI-0206965 and completely abolished by blockade of the autonomic nervous system. This occurred without altering insulin sensitivity measured by hyperinsulinemic-euglycemic clamps. Endogenous insulin secretion was not altered by R481 treatment. During hyperinsulinemic-hypoglycemic clamp studies, R481 treatment reduced exogenous glucose requirements and amplified peak glucagon levels during hypoglycemia. These data demonstrate that peripheral administration of the brain permeable AMPK activator R481 amplifies the counterregulatory response to hypoglycemia in rats, which could have clinical relevance for prevention of hypoglycemia.

scholarly journals Chronic neural activity recorded within breast tumors

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Grant A. McCallum ◽  
Jay Shiralkar ◽  
Diana Suciu ◽  
Gil Covarrubias ◽  
Jennifer S. Yu ◽  
...  
Keyword(s):  
Nervous System ◽  
Autonomic Nervous System ◽  
Tumor Growth ◽  
Neural Activity ◽  
Malignant Tumors ◽  
Nerve Fibers ◽  
Autonomic Nervous ◽  
Tumor Growth And Metastasis ◽  
Worse Prognosis

Abstract Nerve fibers are known to reside within malignant tumors and the greater the neuronal density the worse prognosis for the patient. Recent discoveries using tumor bearing animal models have eluded to the autonomic nervous system having a direct effect on tumor growth and metastasis. We report the first direct and chronic in vivo measurements of neural activity within tumors. Using a triple-negative mammary cancer mouse model and chronic neural interface techniques, we have recorded neural activity directly within the tumor mass while the tumor grows and metastasizes. The results indicate that there is a strong connection between the autonomic nervous system and the tumor and could help uncover the mechanisms of tumor growth and metastasis.

scholarly journals Brain Permeable AMP-Activated Protein Kinase Activator R481 Raises Glycaemia by Autonomic Nervous System Activation and Amplifies the Counterregulatory Response to Hypoglycaemia in Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Ana M. Cruz ◽  
Katie M. Partridge ◽  
Yasaman Malekizadeh ◽  
Julia M. Vlachaki Walker ◽  
Paul G. Weightman Potter ◽  
...  
Keyword(s):  
Nervous System ◽  
Autonomic Nervous System ◽  
Protein Kinase ◽  
Glucose Tolerance ◽  
Sprague Dawley ◽  
Autonomic Nervous ◽  
Glucose Levels ◽  
Sprague Dawley Rats ◽  
Amp Activated Protein Kinase

AimWe evaluated the efficacy of a novel brain permeable “metformin-like” AMP-activated protein kinase activator, R481, in regulating glucose homeostasis.Materials and MethodsWe used glucose sensing hypothalamic GT1-7 neuronal cells and pancreatic αTC1.9 α-cells to examine the effect of R481 on AMPK pathway activation and cellular metabolism. Glucose tolerance tests and hyperinsulinemic-euglycemic and hypoglycemic clamps were used in Sprague-Dawley rats to assess insulin sensitivity and hypoglycemia counterregulation, respectively.ResultsIn vitro, we demonstrate that R481 increased AMPK phosphorylation in GT1-7 and αTC1.9 cells. In Sprague-Dawley rats, R481 increased peak glucose levels during a glucose tolerance test, without altering insulin levels or glucose clearance. The effect of R481 to raise peak glucose levels was attenuated by allosteric brain permeable AMPK inhibitor SBI-0206965. This effect was also completely abolished by blockade of the autonomic nervous system using hexamethonium. During hypoglycemic clamp studies, R481 treated animals had a significantly lower glucose infusion rate compared to vehicle treated controls. Peak plasma glucagon levels were significantly higher in R481 treated rats with no change to plasma adrenaline levels. In vitro, R481 did not alter glucagon release from αTC1.9 cells, but increased glycolysis. Non brain permeable AMPK activator R419 enhanced AMPK activity in vitro in neuronal cells but did not alter glucose excursion in vivo.ConclusionsThese data demonstrate that peripheral administration of the brain permeable “metformin-like” AMPK activator R481 increases blood glucose by activation of the autonomic nervous system and amplifies the glucagon response to hypoglycemia in rats. Taken together, our data suggest that R481 amplifies the counterregulatory response to hypoglycemia by a central rather than a direct effect on the pancreatic α-cell. These data provide proof-of-concept that central AMPK could be a target for future drug development for prevention of hypoglycemia in diabetes.

scholarly journals Involvement of the autonomic nervous system in the in vivo memory to glucose of pancreatic beta cell in rats.

1994 ◽  
Vol 94 (4) ◽  
pp. 1456-1462 ◽  
Author(s):  
J M N'Guyen ◽  
C Magnan ◽  
M C Laury ◽  
C Thibault ◽  
J Leveteau ◽  
...  
Keyword(s):  
Nervous System ◽  
Autonomic Nervous System ◽  
Beta Cell ◽  
Pancreatic Beta Cell ◽  
Autonomic Nervous
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