Characterisation of oral and i.v. glucose handling in truncally vagotomised subjects with pyloroplasty

Astrid Plamboeck, Simon Veedfald, Carolyn F Deacon, Bolette Hartmann, André Wettergren, Lars B Svendsen, Søren Meisner, Claus Hovendal, Filip K Knop, Tina Vilsbøll, Jens J Holst, Astrid Plamboeck, Simon Veedfald, Carolyn F Deacon, Bolette Hartmann, André Wettergren, Lars B Svendsen, Søren Meisner, Claus Hovendal, Filip K Knop, Tina Vilsbøll, Jens J Holst

Abstract

Objective: Glucagon-like peptide 1 (GLP1) is rapidly inactivated by dipeptidyl peptidase 4 (DPP4), but may interact with vagal neurons at its site of secretion. We investigated the role of vagal innervation for handling of oral and i.v. glucose.

Design and methods: Truncally vagotomised subjects (n=16) and matched controls (n=10) underwent 50 g-oral glucose tolerance test (OGTT)±vildagliptin, a DPP4 inhibitor (DPP4i) and isoglycaemic i.v. glucose infusion (IIGI), copying the OGTT without DPP4i.

Results: Isoglycaemia was obtained with 25±2 g glucose in vagotomised subjects and 18±2 g in controls (P<0.03); thus, gastrointestinal-mediated glucose disposal (GIGD) - a measure of glucose handling (100%×(glucoseOGTT-glucoseIIGI/glucoseOGTT)) - was reduced in the vagotomised compared with the control group. Peak intact GLP1 concentrations were higher in the vagotomised group. Gastric emptying was faster in vagotomised subjects after OGTT and was unaffected by DPP4i. The early glucose-dependent insulinotropic polypeptide response was higher in vagotomised subjects. Despite this, the incretin effect was equal in both groups. DPP4i enhanced insulin secretion in controls, but had no effect in the vagotomised subjects. Controls suppressed glucagon concentrations similarly, irrespective of the route of glucose administration, whereas vagotomised subjects showed suppression only during IIGI and exhibited hyperglucagonaemia following OGTT. DPP4i further suppressed glucagon secretion in controls and tended to normalise glucagon responses in vagotomised subjects.

Conclusions: GIGD is diminished, but the incretin effect is unaffected in vagotomised subjects despite higher GLP1 levels. This, together with the small effect of DPP4i, is compatible with the notion that part of the physiological effects of GLP1 involves vagal transmission.

Trial registration: ClinicalTrials.gov NCT01176760.

Figures

Figure 1
Figure 1
(A) Time course of changes in pancreatic polypeptide (PP) secretion before and after ‘sham-feeding’ in vagotomised (circles) and control (squares) subjects. (B) Changes in PP secretion immediately after ‘sham-feeding’ in vagotomised (black bar) and control (white bar) subjects. (C) Plasma glucose before and after ‘sham-feeding’ in vagotomised (circles) and control (squares) subjects. (D) Total GLP1 before and after ‘sham-feeding’ in vagotomised (circles) and control (squares) subjects. Data are shown as means±s.e.m. *Significantly reduced PP secretion in the first 15 min after ‘sham-feeding’ in the vagotomised subjects (P<0.03).
Figure 2
Figure 2
Time course of plasma glucose (A) during 50 g-oral glucose tolerance test (OGTT) (filled symbols) with (broken line) and without (solid line) DPP4 inhibition and isoglycaemic i.v. glucose infusion (IIGI) (open symbols) and paracetamol (B) during 50 g-OGTT (filled symbols) with (broken line) and without (solid line) DPP4 inhibition in vagotomised (left panel, circle) and control (right panel, square) subjects. Data are shown as means±s.e.m.
Figure 3
Figure 3
Time course of total GLP1 (A), intact GLP1 (B) and intact GIP (C) during 50 g-oral glucose tolerance test (OGTT) (filled symbols) with (broken line) and without (solid line) DPP4 inhibition and isoglycaemic i.v. glucose infusion (IIGI) (open symbols) in vagotomised (left panel, circles) and control (right panel, squares) subjects. Data are shown as means±s.e.m.
Figure 4
Figure 4
Time course of insulin (A), C-peptide (B) and ISR (C) during 50 g-oral glucose tolerance test (OGTT) (filled symbols) with (broken line) and without (solid line) DPP4 inhibition and isoglycaemic i.v. glucose infusion (IIGI) (open symbols) in vagotomised (left panel, circles) and control (right panel, squares) subjects and β cell glucose sensitivity (βGS) (D), insulinogenic index (IGI; E) during 50 g-OGTT with (checked bars) and without (black bars) DPP4 inhibition and IIGI (white bars) in vagotomised (left panel) and control (right panel) subjects, disposition index (DI) using βGS (F) and DI using IGI (G) during 50 g-OGTT in vagotomised (black) and control (white) subjects. Data are shown as means±s.e.m. *Significantly reduced βGS and IGI after i.v. compared with oral glucose load in both vagotomised and control subjects (P<0.002).
Figure 5
Figure 5
(A) Time course of glucagon during 50 g-oral glucose tolerance test (OGTT) (filled symbols) with (broken line) and without (solid line) DPP4 inhibition and isoglycaemic i.v. glucose infusion (IIGI) (open symbols) in vagotomised (left panel, circles) and control (right panel, squares) subjects. (B) Incremental area under the curve (AUC) values for glucagon during 50 g-OGTT with (checked bars) and without (black bars) DPP4 inhibition and IIGI (white bars) in vagotomised (left panel) and control (right panel) subjects. Data are shown as means±s.e.m. *Significantly reduced glucagon secretion after i.v. compared with oral glucose load in vagotomised subjects (P<0.005, left panel) and *significantly reduced glucagon secretion during DPP4 inhibition in control subjects (P<0.05, right panel).

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