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

Emilie Lobinet, Francois Reichardt, Celine Garret, Laurent Cazals, Aurelie Waget, Sylvie Dejajer, Florence Labrousse, Jean Michel Senard, Jens Juul Holst, Helene Hanaire, Remy Burcelin


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.

Methods: We studied C-peptide negative type 1 diabetic patients (T1D) with (AN+) or without (AN-) autonomic neuropathy. Plasma glucagon, active and total glucagon-like peptide-1 (GLP-1), GIP, pancreatic polypeptide (PP), and glucose concentrations were quantified over 180 minutes following a meal test. Furthermore, to increase the plasma concentration of GLP-1 between groups and study its impact on glucagon secretion, 50 mg of vildagliptin and a second meal test were administered to the same patients.

Results: The plasma concentration of glucagon was higher in AN+ patients than in AN- patients, which was associated with lower PP and active GLP-1 plasma concentrations. This first set of data suggest that AN, presumably involving parasympathetic activity, results in loss of glucose-regulated glucagon secretion. After DPP4i treatment, AN+ patients lost the ability to suppress plasma glucagon, and the low plasma PP responses were not restored.

Conclusions: We here show that a functional autonomic nervous system is required for the proper control of glucagon secretion. The mechanism is insulin-independent. The glucagonostatic action of DPP4i also requires this mechanism.

J Endocrinol Metab. 2015;5(4):229-237


Neuropathy; Gut brain axis; Incretins; GLP-1; Type 1 diabetes

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