Bioelectronic modulation of carotid sinus nerve activity in the rat

a potential therapeutic approach for type 2 diabetes

Joana F Sacramento, Daniel J Chew, Bernardete F Melo, Matteo Donegá, Wesley Dopson, Maria P Guarino, Alison Robinson, Jesus Prieto-Lloret, Sonal Patel, Bradley J Holinski, Nishan Ramnarain, Victor Pikov, Kristoffer Famm, Silvia V Conde

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

AIMS/HYPOTHESIS: A new class of treatments termed bioelectronic medicines are now emerging that aim to target individual nerve fibres or specific brain circuits in pathological conditions to repair lost function and reinstate a healthy balance. Carotid sinus nerve (CSN) denervation has been shown to improve glucose homeostasis in insulin-resistant and glucose-intolerant rats; however, these positive effects from surgery appear to diminish over time and are heavily caveated by the severe adverse effects associated with permanent loss of chemosensory function. Herein we characterise the ability of a novel bioelectronic application, classified as kilohertz frequency alternating current (KHFAC) modulation, to suppress neural signals within the CSN of rodents.

METHODS: Rats were fed either a chow or high-fat/high-sucrose (HFHSu) diet (60% lipid-rich diet plus 35% sucrose drinking water) over 14 weeks. Neural interfaces were bilaterally implanted in the CSNs and attached to an external pulse generator. The rats were then randomised to KHFAC or sham modulation groups. KHFAC modulation variables were defined acutely by respiratory and cardiac responses to hypoxia (10% O2 + 90% N2). Insulin sensitivity was evaluated periodically through an ITT and glucose tolerance by an OGTT.

RESULTS: KHFAC modulation of the CSN, applied over 9 weeks, restored insulin sensitivity (constant of the insulin tolerance test [KITT] HFHSu sham, 2.56 ± 0.41% glucose/min; KITT HFHSu KHFAC, 5.01 ± 0.52% glucose/min) and glucose tolerance (AUC HFHSu sham, 1278 ± 20.36 mmol/l × min; AUC HFHSu KHFAC, 1054.15 ± 62.64 mmol/l × min) in rat models of type 2 diabetes. Upon cessation of KHFAC, insulin resistance and glucose intolerance returned to normal values within 5 weeks.

CONCLUSIONS/INTERPRETATION: KHFAC modulation of the CSN improves metabolic control in rat models of type 2 diabetes. These positive outcomes have significant translational potential as a novel therapeutic modality for the purpose of treating metabolic diseases in humans.

Original languageEnglish
Pages (from-to)700-710
Number of pages11
JournalDiabetologia
Volume63
Issue number3
Early online date14 Jan 2018
DOIs
Publication statusPublished - Mar 2018

Fingerprint

Carotid Sinus
Type 2 Diabetes Mellitus
Sucrose
Glucose
Fats
Insulin Resistance
Area Under Curve
Therapeutics
Insulin
Glucose Intolerance
Metabolic Diseases
High Fat Diet
Denervation
Glucose Tolerance Test
Nerve Fibers
Drinking Water
Rodentia
Reference Values
Homeostasis
Diet

Keywords

  • Carotid body
  • Carotid sinus nerve
  • Glucose tolerance
  • Insulin resistance
  • KHFAC modulation
  • Neuromodulation
  • Type 2 diabetes

Cite this

Sacramento, Joana F ; Chew, Daniel J ; Melo, Bernardete F ; Donegá, Matteo ; Dopson, Wesley ; Guarino, Maria P ; Robinson, Alison ; Prieto-Lloret, Jesus ; Patel, Sonal ; Holinski, Bradley J ; Ramnarain, Nishan ; Pikov, Victor ; Famm, Kristoffer ; Conde, Silvia V. / Bioelectronic modulation of carotid sinus nerve activity in the rat : a potential therapeutic approach for type 2 diabetes. In: Diabetologia. 2018 ; Vol. 63, No. 3. pp. 700-710.
@article{8c8388fc4aea4ffd8b731743058260a3,
title = "Bioelectronic modulation of carotid sinus nerve activity in the rat: a potential therapeutic approach for type 2 diabetes",
abstract = "AIMS/HYPOTHESIS: A new class of treatments termed bioelectronic medicines are now emerging that aim to target individual nerve fibres or specific brain circuits in pathological conditions to repair lost function and reinstate a healthy balance. Carotid sinus nerve (CSN) denervation has been shown to improve glucose homeostasis in insulin-resistant and glucose-intolerant rats; however, these positive effects from surgery appear to diminish over time and are heavily caveated by the severe adverse effects associated with permanent loss of chemosensory function. Herein we characterise the ability of a novel bioelectronic application, classified as kilohertz frequency alternating current (KHFAC) modulation, to suppress neural signals within the CSN of rodents.METHODS: Rats were fed either a chow or high-fat/high-sucrose (HFHSu) diet (60{\%} lipid-rich diet plus 35{\%} sucrose drinking water) over 14 weeks. Neural interfaces were bilaterally implanted in the CSNs and attached to an external pulse generator. The rats were then randomised to KHFAC or sham modulation groups. KHFAC modulation variables were defined acutely by respiratory and cardiac responses to hypoxia (10{\%} O2 + 90{\%} N2). Insulin sensitivity was evaluated periodically through an ITT and glucose tolerance by an OGTT.RESULTS: KHFAC modulation of the CSN, applied over 9 weeks, restored insulin sensitivity (constant of the insulin tolerance test [KITT] HFHSu sham, 2.56 ± 0.41{\%} glucose/min; KITT HFHSu KHFAC, 5.01 ± 0.52{\%} glucose/min) and glucose tolerance (AUC HFHSu sham, 1278 ± 20.36 mmol/l × min; AUC HFHSu KHFAC, 1054.15 ± 62.64 mmol/l × min) in rat models of type 2 diabetes. Upon cessation of KHFAC, insulin resistance and glucose intolerance returned to normal values within 5 weeks.CONCLUSIONS/INTERPRETATION: KHFAC modulation of the CSN improves metabolic control in rat models of type 2 diabetes. These positive outcomes have significant translational potential as a novel therapeutic modality for the purpose of treating metabolic diseases in humans.",
keywords = "Carotid body, Carotid sinus nerve, Glucose tolerance, Insulin resistance, KHFAC modulation, Neuromodulation, Type 2 diabetes",
author = "Sacramento, {Joana F} and Chew, {Daniel J} and Melo, {Bernardete F} and Matteo Doneg{\'a} and Wesley Dopson and Guarino, {Maria P} and Alison Robinson and Jesus Prieto-Lloret and Sonal Patel and Holinski, {Bradley J} and Nishan Ramnarain and Victor Pikov and Kristoffer Famm and Conde, {Silvia V}",
year = "2018",
month = "3",
doi = "10.1007/s00125-017-4533-7",
language = "English",
volume = "63",
pages = "700--710",
journal = "Diabetologia",
issn = "0012-186X",
publisher = "Springer-Verlag",
number = "3",

}

Bioelectronic modulation of carotid sinus nerve activity in the rat : a potential therapeutic approach for type 2 diabetes. / Sacramento, Joana F; Chew, Daniel J; Melo, Bernardete F; Donegá, Matteo; Dopson, Wesley; Guarino, Maria P; Robinson, Alison; Prieto-Lloret, Jesus; Patel, Sonal; Holinski, Bradley J; Ramnarain, Nishan; Pikov, Victor; Famm, Kristoffer; Conde, Silvia V.

In: Diabetologia, Vol. 63, No. 3, 03.2018, p. 700-710.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Bioelectronic modulation of carotid sinus nerve activity in the rat

T2 - a potential therapeutic approach for type 2 diabetes

AU - Sacramento, Joana F

AU - Chew, Daniel J

AU - Melo, Bernardete F

AU - Donegá, Matteo

AU - Dopson, Wesley

AU - Guarino, Maria P

AU - Robinson, Alison

AU - Prieto-Lloret, Jesus

AU - Patel, Sonal

AU - Holinski, Bradley J

AU - Ramnarain, Nishan

AU - Pikov, Victor

AU - Famm, Kristoffer

AU - Conde, Silvia V

PY - 2018/3

Y1 - 2018/3

N2 - AIMS/HYPOTHESIS: A new class of treatments termed bioelectronic medicines are now emerging that aim to target individual nerve fibres or specific brain circuits in pathological conditions to repair lost function and reinstate a healthy balance. Carotid sinus nerve (CSN) denervation has been shown to improve glucose homeostasis in insulin-resistant and glucose-intolerant rats; however, these positive effects from surgery appear to diminish over time and are heavily caveated by the severe adverse effects associated with permanent loss of chemosensory function. Herein we characterise the ability of a novel bioelectronic application, classified as kilohertz frequency alternating current (KHFAC) modulation, to suppress neural signals within the CSN of rodents.METHODS: Rats were fed either a chow or high-fat/high-sucrose (HFHSu) diet (60% lipid-rich diet plus 35% sucrose drinking water) over 14 weeks. Neural interfaces were bilaterally implanted in the CSNs and attached to an external pulse generator. The rats were then randomised to KHFAC or sham modulation groups. KHFAC modulation variables were defined acutely by respiratory and cardiac responses to hypoxia (10% O2 + 90% N2). Insulin sensitivity was evaluated periodically through an ITT and glucose tolerance by an OGTT.RESULTS: KHFAC modulation of the CSN, applied over 9 weeks, restored insulin sensitivity (constant of the insulin tolerance test [KITT] HFHSu sham, 2.56 ± 0.41% glucose/min; KITT HFHSu KHFAC, 5.01 ± 0.52% glucose/min) and glucose tolerance (AUC HFHSu sham, 1278 ± 20.36 mmol/l × min; AUC HFHSu KHFAC, 1054.15 ± 62.64 mmol/l × min) in rat models of type 2 diabetes. Upon cessation of KHFAC, insulin resistance and glucose intolerance returned to normal values within 5 weeks.CONCLUSIONS/INTERPRETATION: KHFAC modulation of the CSN improves metabolic control in rat models of type 2 diabetes. These positive outcomes have significant translational potential as a novel therapeutic modality for the purpose of treating metabolic diseases in humans.

AB - AIMS/HYPOTHESIS: A new class of treatments termed bioelectronic medicines are now emerging that aim to target individual nerve fibres or specific brain circuits in pathological conditions to repair lost function and reinstate a healthy balance. Carotid sinus nerve (CSN) denervation has been shown to improve glucose homeostasis in insulin-resistant and glucose-intolerant rats; however, these positive effects from surgery appear to diminish over time and are heavily caveated by the severe adverse effects associated with permanent loss of chemosensory function. Herein we characterise the ability of a novel bioelectronic application, classified as kilohertz frequency alternating current (KHFAC) modulation, to suppress neural signals within the CSN of rodents.METHODS: Rats were fed either a chow or high-fat/high-sucrose (HFHSu) diet (60% lipid-rich diet plus 35% sucrose drinking water) over 14 weeks. Neural interfaces were bilaterally implanted in the CSNs and attached to an external pulse generator. The rats were then randomised to KHFAC or sham modulation groups. KHFAC modulation variables were defined acutely by respiratory and cardiac responses to hypoxia (10% O2 + 90% N2). Insulin sensitivity was evaluated periodically through an ITT and glucose tolerance by an OGTT.RESULTS: KHFAC modulation of the CSN, applied over 9 weeks, restored insulin sensitivity (constant of the insulin tolerance test [KITT] HFHSu sham, 2.56 ± 0.41% glucose/min; KITT HFHSu KHFAC, 5.01 ± 0.52% glucose/min) and glucose tolerance (AUC HFHSu sham, 1278 ± 20.36 mmol/l × min; AUC HFHSu KHFAC, 1054.15 ± 62.64 mmol/l × min) in rat models of type 2 diabetes. Upon cessation of KHFAC, insulin resistance and glucose intolerance returned to normal values within 5 weeks.CONCLUSIONS/INTERPRETATION: KHFAC modulation of the CSN improves metabolic control in rat models of type 2 diabetes. These positive outcomes have significant translational potential as a novel therapeutic modality for the purpose of treating metabolic diseases in humans.

KW - Carotid body

KW - Carotid sinus nerve

KW - Glucose tolerance

KW - Insulin resistance

KW - KHFAC modulation

KW - Neuromodulation

KW - Type 2 diabetes

U2 - 10.1007/s00125-017-4533-7

DO - 10.1007/s00125-017-4533-7

M3 - Article

VL - 63

SP - 700

EP - 710

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 3

ER -