Bioelectronic modulation of carotid sinus nerve activity in the rat: a potential therapeutic approach for type 2 diabetes

Autor: Sonal Patel, Matteo Donegà, Victor Pikov, Bernardete F. Melo, Bradley J. Holinski, Joana F. Sacramento, Daniel J. Chew, Silvia V. Conde, Jesus Prieto-Lloret, Wesley Dopson, Alison Robinson, Nishan Ramnarain, Maria P. Guarino, Kristoffer Famm
Přispěvatelé: GlaxoSmithKline, Fundação para a Ciência e a Tecnologia (Portugal)
Rok vydání: 2018
Předmět:
Blood Glucose
Male
0301 basic medicine
medicine.medical_specialty
Endocrinology
Diabetes and Metabolism
medicine.medical_treatment
Type 2 diabetes
Nitric Oxide
Article
Carotid sinus nerve
03 medical and health sciences
0302 clinical medicine
Insulin resistance
Metabolic Diseases
Internal medicine
Internal Medicine
medicine
Humans
Animals
Insulin
Glucose homeostasis
Peripheral Nerves
Denervation
C-Peptide
KHFAC modulation
Neuromodulation
Electromyography
business.industry
Insulin tolerance test
Carotid sinus
Glucose tolerance
medicine.disease
Rats
3. Good health
Plethysmography
Carotid body
Diabetes Mellitus
Type 1
Carotid Sinus
030104 developmental biology
medicine.anatomical_structure
Endocrinology
Diabetes Mellitus
Type 2
Insulin Resistance
Corticosterone
business
030217 neurology & neurosurgery
Zdroj: Diabetologia
Digital.CSIC. Repositorio Institucional del CSIC
instname
ISSN: 1432-0428
0012-186X
DOI: 10.1007/s00125-017-4533-7
Popis: [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.
This study was supported financially by Galvani Bioelectronics (formerly the Bioelectronics R&D unit at GlaxoSmithKline). JFS and BFM are supported by PhD Grants from the Portuguese Foundation for Science and Technology (reference PD/BD/105890/2014 and PD/BD/128336/2017, respectively). Data in the present manuscript has been filed with the International Bureau WO/2016/72875. International application no. PCT/PT2015/000047.
Databáze: OpenAIRE
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