Autonomic Diabetic Neuropathy Impairs Glucose and Dipeptidyl Peptidase 4 Inhibitor-Regulated Glucagon Concentration in Type 1 Diabetic Patients

Lobinet, Emilie; Reichardt, François; Garret, Céline; Cazals, L.; Waget, Aurélie; Dejajer, Sylvie; Labrousse, F.; Senard, Jean‐Michel; Holst, Jens J.; Hanaire, H.; Burcelin, Rémy

doi:10.14740/jem289w

Cited by 3 publications

(2 citation statements)

References 57 publications

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“…Furthermore, some of them, due to lack of efficacy, even have to discontinue their treatment, defining a state of GLP-1 resistance (Knop et al, 2012;Muscelli et al, 2008). The mechanisms responsible for GLP-1 unresponsiveness could be related to lipo-glucotoxicity (Duca et al, 2013;Hodson et al, 2013;Ten Kulve et al, 2016;Xu et al, 2007), autonomic neuropathy (Lee et al, 2012;Lobinet et al, 2015), and gut microbiota dysbiosis (B€ ackhed et al, 2004;Gill et al, 2006;Ley et al, 2005). Regarding the latter hypothesis, we and others notably demonstrated the role played by the proinflammatory bacterial determinant lipopolysaccharides (LPSs) and peptidoglycans on inflammation-induced insulin resistance (Amar et al, 2011;Cani et al, 2007a;Denou et al, 2015;Schertzer et al, 2011).…”

Section: Introductionmentioning

confidence: 89%

A Specific Gut Microbiota Dysbiosis of Type 2 Diabetic Mice Induces GLP-1 Resistance through an Enteric NO-Dependent and Gut-Brain Axis Mechanism

et al. 2017

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Glucagon-like peptide-1 (GLP-1)-based therapies control glycemia in type 2 diabetic (T2D) patients. However, in some patients the treatment must be discontinued, defining a state of GLP-1 resistance. In animal models we identified a specific set of ileum bacteria impairing the GLP-1-activated gut-brain axis for the control of insulin secretion and gastric emptying. Using prediction algorithms, we identified bacterial pathways related to amino acid metabolism and transport system modules associated to GLP-1 resistance. The conventionalization of germ-free mice demonstrated their role in enteric neuron biology and the gut-brain-periphery axis. Altogether, insulin secretion and gastric emptying require functional GLP-1 receptor and neuronal nitric oxide synthase in the enteric nervous system within a eubiotic gut microbiota environment. Our data open a novel route to improve GLP-1-based therapies.

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Section: Introductionmentioning

confidence: 89%

A Specific Gut Microbiota Dysbiosis of Type 2 Diabetic Mice Induces GLP-1 Resistance through an Enteric NO-Dependent and Gut-Brain Axis Mechanism

et al. 2017

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“…Those results suggest that the local/enteric action of GLP-1 on the intestinal vagus nerve and enteric nervous system is more important than the endocrine action of the peptide. In support of the neural mode of action of GLP-1, an impaired autonomic nervous system reduces DPP4i efficacy in humans (35) and favors the early onset of metabolism alterations (28). The identification of this physiological mode of action endogenous GLP-1 raises the possibility that a similar mechanism might explain the pharmacological effects of systemically administered long-acting GLP-1 receptor agonists such as exendin 4, lixisenatide, and liraglutide for the treatment of type 2 diabetes.…”

Section: Discussionmentioning

confidence: 98%

Lixisenatide requires a functional gut-vagus nerve-brain axis to trigger insulin secretion in controls and type 2 diabetic mice

Charpentier

Waget

Klopp

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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Endogenous glucagon-like peptide-1 (GLP-1) regulates glucose-induced insulin secretion through both direct β-cell-dependent and indirect gut-brain axis-dependent pathways. However, little is known about the mode of action of the GLP-1 receptor agonist lixisenatide. We studied the effects of lixisenatide (intraperitoneal injection) on insulin secretion, gastric emptying, vagus nerve activity, and brain c-Fos activation in naive, chronically vagotomized, GLP-1 receptor knockout (KO), high-fat diet-fed diabetic mice, or db/db mice. Lixisenatide dose-dependently increased oral glucose-induced insulin secretion that is correlated with a decrease of glycemia. In addition, lixisenatide inhibited gastric emptying. These effects of lixisenatide were abolished in vagotomized mice, characterized by a delay of gastric emptying and in GLP-1 receptor KO mice. Intraperitoneal administration of lixisenatide also increased the vagus nerve firing rate and the number of c-Fos-labeled neurons in the nucleus tractus solitarius (NTS) of the brainstem. In diabetic mouse models, lixisenatide increased the firing rate of the vagus nerve when administrated simultaneously to an intraduodenal glucose. It increased also insulin secretion and c-Fos activation in the NTS. Altogether, our findings show that lixisenatide requires a functional vagus nerve and neuronal gut-brain-islets axis as well as the GLP-1 receptor to regulate glucose-induced insulin secretion in healthy and diabetic mice. NEW & NOTEWORTHY Lixisenatide is an agonist of the glucagon-like protein (GLP)-1 receptor, modified from exendin 4, used to treat type 2 diabetic patients. However, whereas the mode of action of endogenous GLP-1 is extensively studied, the mode of action of the GLP-1 analog lixisenatide is poorly understood. Here, we demonstrated that lixisenatide activates the vagus nerve and recruits the gut-brain axis through the GLP-1 receptor to decrease gastric emptying and stimulate insulin secretion to improve glycemia.

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Efficacy and tolerability of DPP4 inhibitor, teneligliptin, on autonomic and peripheral neuropathy in type 2 diabetes: an open label, pilot study

2020

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Autonomic Diabetic Neuropathy Impairs Glucose and Dipeptidyl Peptidase 4 Inhibitor-Regulated Glucagon Concentration in Type 1 Diabetic Patients

Abstract: Background: Dipeptidyl peptidase 4 inhibitors (DPP4i) could exert their glucagonostatic action through a functional autonomic nervous system independently from insulin secretion. We explored this hypothesis.

Cited by 3 publications

References 57 publications

A Specific Gut Microbiota Dysbiosis of Type 2 Diabetic Mice Induces GLP-1 Resistance through an Enteric NO-Dependent and Gut-Brain Axis Mechanism

A Specific Gut Microbiota Dysbiosis of Type 2 Diabetic Mice Induces GLP-1 Resistance through an Enteric NO-Dependent and Gut-Brain Axis Mechanism

Lixisenatide requires a functional gut-vagus nerve-brain axis to trigger insulin secretion in controls and type 2 diabetic mice

Efficacy and tolerability of DPP4 inhibitor, teneligliptin, on autonomic and peripheral neuropathy in type 2 diabetes: an open label, pilot study

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