Acute metabolic effects of exenatide in patients with type 1 diabetes with and without residual insulin to oral and intravenous glucose challenges

Abstract

OBJECTIVE Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the gastrointestinal tract. Treatment with GLP-1 analogs has proven to be of clinical use for patients with type 2 diabetes. Patients with type 1 diabetes, particularly those with residual β-cell function, may also respond to treatment, but the acute metabolic effects of GLP-1 analogs on these patients in reaction to both oral and intravenous glucose challenges are not well understood. RESEARCH DESIGN AND METHODS Seventeen patients with type 1 diabetes, half of whom had residual insulin production, underwent two mixed-meal tolerance tests (MMTTs) and two intravenous glucose tolerance tests (IVGTTs), with and without pretreatment with exenatide. No exogenous bolus insulin was administered for the studies. Glucose excursions, insulin secretion rates (ISRs), and levels of glucagon, endogenous GLP-1, and gastric inhibitory polypeptide were measured after the meal or glucose loads. RESULTS During the MMTT, glucose levels were suppressed with exenatide in patients with or without residual insulin production (P = 0.0003). Exenatide treatment did not change the absolute ISR, but the ISR to glucose levels were increased (P = 0.0078). Gastric emptying was delayed (P = 0.0017), and glucagon was suppressed (P = 0.0015). None of these hormonal or glucose changes were detected during the IVGTT with exenatide administration. CONCLUSIONS Exenatide showed a significant antidiabetogenic effect prior to an oral meal in patients with type 1 diabetes involving glucagon suppression and gastric emptying, while preserving increased insulin secretion. GLP-1 analogs may be useful as an adjunctive treatment in type 1 diabetes.

Figure 1

Metabolic effects of exenatide during MMTT: the kinetics of ISRs and glucose, acetaminophen, and glucagon levels are shown in a representative patient with (A–D) or without (E–H) detectable C-peptide levels. +, with; −, without.

Figure 2

Changes in hormonal responses during MMTT and IVGTT with exenatide.A: AUC for glucose (in milligrams per deciliter) during an MMTT without and with administration of exenatide, 5 µg s.c. (P = 0.0003). B: AUC for glucose (in milligrams per deciliter) during IVGTT without and with exenatide (P = 0.8501). C–F: Only patients with detectable C-peptide levels are shown. C: AUC for ISR (in nanomoles per liter) during MMTT without and with subcutaneous injection of exenatide (P = 1.0). D: AUC for ISR during an IVGTT (P = 0.875). E: AUC ISR/AUC glucose during MMTT with and without exenatide (P = 0.0078). F: ISR AUC/glucose AUC at the time of IVGTT with and without pretreatment with exenatide (P = 1.0). G: AUC for glucagon (in picograms per milliliter) during MMTT with and without administration of exenatide (P = 0.0015) in all subjects. H: AUC of the glucagon/glucose ratio in all patients during MMTT, which shows a significant increase with exenatide (P = 0.006). Open circles (○) indicate C-peptide–negative patients, and closed circles (●) indicate C-peptide–positive patients. +, with; −, without.

Figure 3

Changes in incretins with exenatide. A: AUC for GLP-1 during MMTT without exenatide 662.6 ± 270 pmol/L vs. with exenatide 444.2 ± 302.1 pmol/L in eight subjects (P = 0.055). B: AUC for GLP-1 during IVGTT (without exenatide 25.28 ± 12.48 pmol/L vs. with exenatide 46.76 ± 32.83 pmol/L) in six subjects (P = 0.625). C: AUC for GIP during MMTT without and with exenatide in eight subjects. D: AUC for GIP (in picograms per milliliter) during IVGTT (P = 0.875). +, with; −, without.