The metabolic role of vagal afferent innervation

Waise, T.M. Zaved; Dranse, Helen J.; Lam, Tony K.T.

doi:10.1038/s41575-018-0062-1

Cited by 86 publications

(69 citation statements)

References 226 publications

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“…As such, the infusion of glucose into the upper small intestine stimulates intestinal GLP1 release, as revealed by increased portal vein active GLP1 levels, however, there is no effect on peripheral circulating GLP1 levels. These findings suggest that GLP1 acts locally in the gut by activating GLP1R on vagal afferent nerves that innervate the gut mucosa 153,177 .…”

Section: Metformin Action On the Gut-brain Neuronal Axis Emerging Evmentioning

confidence: 88%

“…The glucoregulatory role of duodenal AMPK activation was also demonstrated in response to intraduodenal infusion of resveratrol (a natural polyphenolic compound known for its many beneficial effects to human health) or the AMPK activator A-769662, indicating the therapeutic relevance of targeting duodenal AMPK for gut-mediated antidiabetic therapies 155,181,182 . In a recent 2018 study, it was reported that inhibition of mTOR signalling is also required for the glucose-lowering effect of intraduodenal metformin but that mTOR acts independently of AMPK signalling 177 , thereby adding a novel potential gut target to potently lower glucose levels in patients with T2DM.…”

Section: Metformin Action On the Gut-brain Neuronal Axis Emerging Evmentioning

confidence: 99%

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Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

2019

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Despite its position as the first-line treatment for type 2 diabetes mellitus, the mechanisms underlying the plasma glucose level-lowering effects of metformin (1,1dimethylbiguanide) still remain incompletely understood. Metformin is thought to exert its primary antidiabetic action through the suppression of hepatic glucose production. Furthermore, the discovery that metformin inhibits the mitochondrial respiratory-chain complex 1 has placed energy metabolism and activation of AMP-activated protein kinase (AMPK) at the center of its mechanism of action. However, the role of AMPK has been challenged and might only account for indirect changes in hepatic insulin sensitivity. Various mechanisms involving alterations of cellular energy charge, AMP-mediated inhibition of adenylate cyclase or fructose-1,6-bisphosphatase-1 (FBP1) and modulation of the cellular redox state through direct inhibition of mitochondrial glycerol-3phosphate dehydrogenase (mG3PDH) are proposed for the acute inhibition of gluconeogenesis by metformin. Emerging evidence suggests that metformin could improve obesity-induced meta-inflammation via direct and indirect effects on tissueresident immune cells in metabolic organs (that is, adipose tissue, the gastrointestinal tract and the liver). Furthermore, the gastrointestinal tract also has a major role in metformin action through modulation of glucose-lowering hormone glucagon-like peptide-1 (GLP-1) and intestinal bile acid pool and alterations in gut microbiota composition. 3 Key points • Metformin is the first-line drug for treatment of type 2 diabetes mellitus, with an excellent safety profile, high efficacy on glycaemic control and clear but incompletely understood cardioprotective benefits. • The pleiotropic properties of metformin suggest that the drug acts on multiple tissues through various underlying mechanisms rather than on a single organ via an unifying mode of action. • The mitochondrial respiratory-chain complex 1 is a key cellular target of metformin and its mild and transient inhibition is involved in the AMPK-independent regulation of hepatic gluconeogenesis by triggering alterations in the cellular energy charge and redox state. • Metformin might contribute to improvements in obesity-associated metainflammation and tissue-specific insulin sensitivity through direct and indirect effects on various resident immune cells in metabolic organs. • The gastrointestinal tract has an important role in the action of metformin, which modulates bile acid recirculation and enhances the secretion of the glucose-lowering gut incretin hormone glucagon-like peptide-1 (GLP1). • The gut microbiota represents a novel target in the mechanisms of metformin action and is involved in both the therapeutic and adverse effects of the drug.

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Section: Metformin Action On the Gut-brain Neuronal Axis Emerging Evmentioning

confidence: 88%

Section: Metformin Action On the Gut-brain Neuronal Axis Emerging Evmentioning

confidence: 99%

Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

2019

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“…Sensory signaling through the vagus nerve has a critical role in the maintenance of bodily homeostasis in diverse functions relating to digestion, satiety, respiration, blood pressure, and heart rate control ( Mazzone and Undem, 2016 , Waise et al., 2018 , Wehrwein and Joyner, 2013 ). Its profound role is illustrated by abnormalities that can lead to far-reaching consequences, including gastroesophageal reflux disease, heart failure, failure of respiratory control, gastroparesis, vasovagal syncope, and chronic pain.…”

Section: Introductionmentioning

confidence: 99%

An Atlas of Vagal Sensory Neurons and Their Molecular Specialization

Kupari¹,

Häring²,

Agirre³

et al. 2019

Cell Reports

289

328

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“…The system is divided into the sympathetic nervous system, which controls "fight-or-flight" responses, and the parasympathetic nervous system, which regulates "rest-and-digest" functions 1 . A main parasympathetic nerve is the vagus nerve, which innervates many visceral organs, such as the heart, lungs, stomach, liver, pancreas and intestines 2,3 , and contributes to the regulation of numerous autonomic functions, which include breathing, immune responses, digestion, glucose metabolism and others [4][5][6][7][8] . The vagus nerve at the cervical level is partially composed of myelinated Aδ and B fibers 9,10 , but the great majority of axons (over 80%) are unmyelinated C-fibers 2,11,12 .…”

Section: Introductionmentioning

confidence: 99%

“…Autonomic nerves are typically dominated by hundreds to thousands of unmyelinated fibers 27,28,38,39 . The fibers of the vagus nerve in particular innervate multiple critical organs and contribute to the regulation of many autonomic functions [2][3][4][5][6][7][8] . Therefore, a need remains for an intraneural electrode array that can record physiological single-neuron activity at multiple sampling locations within small autonomic nerves.…”

Section: Introductionmentioning

confidence: 99%

Multi-channel intraneural vagus nerve recordings with a novel high-density carbon fiber microelectrode array

Jiman

Ratze

Welle

et al. 2020

Preprint

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25Autonomic nerves convey essential neural signals that regulate vital body functions. Recording 26 clearly distinctive physiological neural signals from autonomic nerves will help develop new 27 treatments for restoring regulatory functions. However, this is very challenging due to the small 28 nature of autonomic nerves and the low-amplitude signals from their small axons. We developed 29 a multi-channel, high-density, intraneural carbon fiber microelectrode array (CFMA) with ultra-30 small electrodes (8-9 µm in diameter, 150-250 µm in length) for recording physiological action 31 potentials from small autonomic nerves. In this study, we inserted CFMA with up to 16 32 recording carbon fibers in the cervical vagus nerve of 22 isoflurane-anesthetized rats. We 33 recorded action potentials with peak-to-peak amplitudes of 15.1-91.7 µV and signal-to-noise 34 ratios of 2.0-8.3 on multiple carbon fibers per experiment, determined conduction velocities of 35 some vagal signals in the afferent (0.7-1.0 m/sec) and efferent (0.7-8.8 m/sec) directions, and 36 monitored firing rate changes in breathing and blood glucose modulated conditions. Overall, 37 these experiments demonstrated that CFMAs are a novel interface for in-vivo intraneural action 38 potential recordings from autonomic nerves. This work is a milestone towards the 39 comprehensive understanding of physiological neural signaling and the development of 40 innovative treatment modalities for restoring vital functions controlled by autonomic nerves. 41 42

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The metabolic role of vagal afferent innervation

Cited by 86 publications

References 226 publications

Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus

An Atlas of Vagal Sensory Neurons and Their Molecular Specialization

Multi-channel intraneural vagus nerve recordings with a novel high-density carbon fiber microelectrode array

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