Mixed Meal and Intravenous L-Arginine Tests Both Stimulate Incretin Release Across Glucose Tolerance in Man: Lack of Correlation with β Cell Function

Abstract

Background: The aims of this study were to 1. define the responses of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, and peptide YY (PYY) to an oral meal and to intravenous L-arginine; and 2. examine correlation of enteroendocrine hormones with insulin secretion. We hypothesized a relationship between circulating incretin concentrations and insulin secretion.

Methods: Subjects with normal glucose tolerance (NGT, n = 23), prediabetes (PDM, n = 17), or with type 2 diabetes (T2DM, n = 22) were studied twice, following a mixed test meal (470 kCal) (mixed meal tolerance test [MMTT]) or intravenous L-arginine (arginine maximal stimulation test [AST], 5 g). GLP-1 (total and active), PYY, GIP, glucagon, and β cell function were measured before and following each stimulus.

Results: Baseline enteroendocrine hormones differed across the glucose tolerance (GT) spectrum, T2DM generally >NGT and PDM. In response to MMTT, total and active GLP-1, GIP, glucagon, and PYY increased in all populations. The incremental area-under-the-curve (0-120 min) of analytes like total GLP-1 were often higher in T2DM compared with NGT and PDM (35-51%; P < 0.05). At baseline glucose, L-arginine increased total and active GLP-1 and glucagon concentrations in all GT populations (all P < 0.05). As expected, the MMTT and AST provoked differential glucose, insulin, and C-peptide responses across GT populations. Baseline or stimulated enteroendocrine hormone concentrations did not consistently correlate with either measure of β cell function.

Conclusions/interpretation: Both MMTT and AST resulted in insulin and enteroendocrine hormone responses across GT populations without consistent correlation between release of incretins and insulin, which is in line with other published research. If a defect is in the enteroendocrine/β cell axis, it is probably reduced response to rather than diminished secretion of enteroendocrine hormones.

Trial registration: ClinicalTrials.gov NCT01454973 NCT01663207 NCT01663220.

Keywords: GLP-1; arginine; incretin; insulin secretion; meal tolerance test; type 2 diabetes.

FIG. 1.

Mean (SEM) for MMTT analyte time profiles by GT population. After baseline samples, the meal was administered at time 0. Glucose, insulin and c-peptide measurements were made out until 240 min postmeal consumption. GLP-1, glucagon, PYY, and GIP were assayed for all subjects until 120 min postmeal after it was determined in a subset of subjects that values stabilized or returned to baseline by 120 min postmeal. GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; GT, glucose tolerance; MMTT, mixed meal tolerance test; PYY; peptide YY; SEM, standard error of mean.

FIG. 2.

MMTT model predicted means (95% CI) for incretin incremental iAUC (0–120 min) Values across GT populations. *P < 0.05, **P < 0.01, ***P < 0.001.

FIG. 3.

Mean (SEM) for AST analyte time profiles by GT population. After baseline samples, L-arginine was injected at time 0 and repeat samples for insulin, glucose, c-peptide, GLP-1, glucagon, PYY, and GIP were drawn. Glucose was then infused after the 10 min sample to raise circulating glucose concentrations. Repeat prearginine samples were drawn followed by an additional injection of L-arginine (5 gm). AST, arginine maximal stimulation test.

FIG. 4.

AST model predicted means (95% CI) for incretin absolute changes from baseline value. Within each GT population, the changes that do not include 0 within the confidence bound reflect a statistically significant change from baseline, at least P < 0.05. For comparisons across GT populations, notation of *P < 0.05 and ***P < 0.001.

FIG. 5.

Model predicted geometric means (asymptotic 95% CI) for MMTT and AST beta cell health parameters. *P < 0.05, **P < 0.01, ***P < 0.001.