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

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.

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

Frontiers in Endocrinology ◽

10.3389/fendo.2021.697445 ◽

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.

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Distribution of the preferred clothing pressure over the whole body

Textile Research Journal ◽

10.1177/0040517518786272 ◽

2018 ◽

Vol 89 (11) ◽

pp. 2187-2198 ◽

Cited By ~ 1

Author(s):

Tamaki Mitsuno ◽

Ayaka Kai

Keyword(s):

Nervous System ◽

Autonomic Nervous System ◽

Hydrostatic Pressure ◽

Body Part ◽

Whole Body ◽

Elastic Band ◽

Autonomic Nervous ◽

Pressure Load ◽

Calibration Methods ◽

Clothing Pressure

A system for measuring clothing pressure employing a renewed hydrostatic pressure-balancing method was examined using three calibration methods. All methods revealed an almost perfectly linear Y = X relation for the pressure load (X) and the reading of the system (Y). In the application, the distributions of elastic band pressure were examined on 21 planes from head to foot. The preferred elastic band pressures of the leg and arm were significantly higher than those of the neck and abdomen. These results are due to the large presence of the autonomic nervous system at the surfaces of the neck and abdomen. In the area of the abdomen, the preferred elastic band pressure was higher from the mammilla to the shoulder than for the anteroposterior midlines. The development of compression ware must consider appropriate tightening for each body part.

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Abstract P129: Role of the Autonomic Nervous System in Remote Postconditioning in Humans

Circulation ◽

10.1161/circ.118.suppl_18.s_1473-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Rupert P Williams ◽

Michael I Okorie ◽

Harminder Gill ◽

John E Deanfield ◽

Raymond J MacAllister ◽

...

Keyword(s):

Blood Pressure ◽

Nervous System ◽

Autonomic Nervous System ◽

Whole Body ◽

Limb Ischaemia ◽

Protective Effects ◽

Blood Pressure Cuff ◽

Autonomic Nervous ◽

Pressure Cuff ◽

Remote Postconditioning

Brief periods of ischaemia activate systemic mechanisms that induce whole-body tolerance to subsequent prolonged and injurious ischaemia. This phenomenon, remote ischaemic preconditioning (RIPC), is sufficiently acute to reduce ischaemia-reperfusion (IR) injury even when applied simultaneously with injurious ischaemia. This aspect of RIPC is termed remote postconditioning (RPostC). We have previously demonstrated a role for the autonomic nervous system in RIPC. Using an in vivo model of endothelial IR injury, we determined if RPostC is dependent on adrenergic autonomic mechanisms. Vascular ultrasound was used to assess endothelial function in healthy volunteers by measuring dilatation of the brachial artery in response to increased blood flow during reactive hyperaemia (flow-mediated dilatation; FMD). Endothelial IR injury was induced by 20 min of upper limb ischaemia (inflation of a blood pressure cuff to 200 mm Hg) followed by reperfusion. RPostC was induced by applying 2 cycles of 5 minutes ischaemia and 5 minutes reperfusion on the leg during arm ischaemia (via a second blood pressure cuff). In order to determine the dependence of RPostC on autonomic activation, we administered the alpha adrenoceptor blocker phentolamine (0.2– 0.7mg/min, intravenously) during the application of the RPostC stimulus. FMD was determined before ischaemia and at 20 minutes of reperfusion. FMD (percentage change from baseline diameter) was compared statistically by ANOVA. IR alone caused a significant reduction in FMD (5.9±0.7% pre- versus 2.2±0.4% post-IR, n=9, P<0.001). This reduction was prevented by RPostC (5.8±0.4% pre- versus 5.4±0.3% post-IR, n=8, P>0.05). Systemic phentolamine blocked the protective effects of RPostC (FMD 6.1±0.5% pre- versus 2.0±0.3% post-IR, n=7, P<0.001). These data indicate, for the first time in humans, that protection from RPostC depends on preservation of adrenergic signalling. Alpha blockade neutralises one of the endogenous mechanisms of ischemic protection in humans; the clinical consequences of this remain to be determined.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00477.2006 ◽

2007 ◽

Vol 292 (4) ◽

pp. E1069-E1078 ◽

Cited By ~ 16

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.

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Does the autonomic nervous system regulate whole-body lymph flow?

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1983.245.5.r695 ◽

1983 ◽

Vol 245 (5) ◽

pp. R695-R700

Author(s):

G. G. Power ◽

R. A. Brace

Keyword(s):

Heart Rate ◽

Nervous System ◽

Autonomic Nervous System ◽

Isotonic Saline ◽

Lymph Flow ◽

Whole Body ◽

Thoracic Duct Lymph ◽

Ganglionic Blockade ◽

Shed Blood ◽

Autonomic Nervous

We compared whole-body lymph flow responses with and without the autonomic nervous system intact in pentobarbital-anesthetized, acutely nephrectomized dogs. We measured left thoracic duct lymph flow, lymph and plasma protein concentrations, arterial and venous pressures, heart rate, and hematocrit in eight intact and six ganglion-blocked (hexamethonium, 15 mg/kg iv) animals. Ganglionic blockade lowered arterial pressure and heart rate but did not change lymph flow rate or the other variables. In the control and blocked groups at 30-min intervals, isotonic saline, lactated Ringer, and Dextran 70 solutions were serially infused, followed by hemorrhage and reinfusion of shed blood. Infusions or withdrawals were equal to 2% of body weight and were induced over 5-min intervals followed by 25 min of recovery. Lymph flow generally increased to a peak 5–7 min after each infusion was ended and then decayed back toward preinfusion levels; the extent of the rise in lymph flow, the time of the peak flow, and the extent of decay after the peak were unaffected by autonomic blockade. The absolute lymph flow rates in response to the infusions, hemorrhage, or blood infusion were not appreciably altered by ganglionic blockade. Thus the present studies provide little support to the hypothesis that the autonomic nervous system contributes to whole-body lymph flow.

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Effect of whole-body vibration on autonomic nervous system

Autonomic Neuroscience ◽

10.1016/j.autneu.2006.08.023 ◽

2006 ◽

Vol 130 (1-2) ◽

pp. 65

Author(s):

Hiroko Toshima ◽

Yoichi Endo

Keyword(s):

Nervous System ◽

Autonomic Nervous System ◽

Whole Body Vibration ◽

Whole Body ◽

Body Vibration ◽

Autonomic Nervous

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Autonomic Nervous System Function in Newly Diagnosed Multiple Sclerosis: Association With Lipid Levels and Insulin Resistance

Physiological Research ◽

10.33549/physiolres.934695 ◽

2021 ◽

pp. 875-882

Author(s):

M. Hardoňová ◽

P. Šiarnik ◽

M. Siváková ◽

B. Suchá ◽

M. Vlček ◽

...

Keyword(s):

Multiple Sclerosis ◽

Insulin Resistance ◽

Nervous System ◽

Autonomic Nervous System ◽

Sympathetic Activity ◽

Whole Body ◽

Sensitivity Index ◽

Positive Correlation ◽

Autonomic Nervous ◽

Significant Difference

Autonomic nervous system (ANS) disorders are common in multiple sclerosis (MS). Previous studies showed differences in insulin resistance (IR) and lipoprotein levels in MS subjects compared to controls. Lipolysis caused by increased sympathetic activity could be one of the possible linking mechanisms leading to dyslipidemia in MS. Our study aimed to evaluate ANS activity in the context of glucose and lipid metabolism in people with MS. We prospectively measured short-term heart rate variability (HRV), fasting lipoprotein concentrations, and calculated IR indices based on plasma glucose and insulin levels during oral glucose tolerance test (oGTT) in 32 patients with MS and 29 healthy controls matched for age, sex and body mass index in our study. There was no significant difference in HRV parameters and lipoprotein levels between MS and controls. A significant positive correlation was found between low/high-frequency power ratio (LF/HF) and triglycerides (r=0.413, p=0.021) in MS subjects but not in controls. A significantly lower whole-body insulin sensitivity index (ISIMat) was found in patients with MS compared to the control group (7.3±3.7 vs. 9.8±5.6, p=0.041). No significant correlations were found between LF/HF and IR parameters. In MS subjects, the positive correlation of LF/HF with triglycerides could reflect the effects of sympathetic activity on lipolysis. Positive correlations of sympathetic activity with increased lipoprotein levels could rather reflect processes associated with immune system activation/inflammation, than processes involved in glucose homeostasis maintenance.

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Autonomic nervous system activation mediates the increase in whole‐body glucose uptake in response to electroacupuncture

The FASEB Journal ◽

10.1096/fj.201601381r ◽

2017 ◽

Vol 31 (8) ◽

pp. 3288-3297 ◽

Cited By ~ 14

Author(s):

Anna Benrick ◽

Milana Kokosar ◽

Min Hu ◽

Martin Larsson ◽

Manuel Maliqueo ◽

...

Keyword(s):

Nervous System ◽

Autonomic Nervous System ◽

Glucose Uptake ◽

Whole Body ◽

Autonomic Nervous ◽

System Activation

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Diseases of the autonomic nervous system

Oxford Textbook of Medicine ◽

10.1093/med/9780199204854.003.02414_update_002 ◽

2010 ◽

pp. 5055-5068

Author(s):

Christopher J. Mathias ◽

David A. Low

Keyword(s):

Nervous System ◽

Autonomic Nervous System ◽

Autonomic Control ◽

Whole Body ◽

Organ Function ◽

Autonomic Nervous ◽

System P ◽

Efferent Pathways

The autonomic nervous system innervates all organs, producing predominantly involuntary and automatic actions that are mediated by two principal efferent pathways, the sympathetic and parasympathetic, which are neurochemically and anatomically distinct. Numerous synaptic relays and neurotransmitters allow the autonomic control of organ function at local and central levels to be integrated with the requirements of the whole body....

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