GLP-1 released to the mesenteric lymph duct in mice: Effects of glucose and fat

Abstract

Using a newly developed in vivo model measuring glucagon-like peptide-1 (GLP-1) in gut lymphatics in mice, we quantified GLP-1 secretion in vivo after glucose versus fat ingestion with and without concomitant DPP-4 inhibition. The mesenteric lymphatic duct was cannulated in anesthetized C57BL6/J mice and lymph was collected in 30 min intervals. Glucose or fat emulsion (IntralipidR) (0.03, 0.1 or 0.3 kcal) with or without DPP-4-inhibition (NVP DPP728; 10 μmol/kg) was administered by gastric gavage. Basal intact GLP-1 levels were 0.37 ± 0.04 pmol/l (n = 61) in lymph compared to 0.07 ± 0.03 in plasma (n = 6; P = 0.04) and basal DPP-4 activity was 4.7 ± 0.3 pmol/min/μl in lymph (n = 23) compared to 22.3 ± 0.9 pmol/min/μl in plasma (n = 8; P < 0.001). Lymph flow increased from 1.2 ± 0.1 μl/min to 2.3 ± 02 μl/min at 30 min after glucose and fat administration, with no difference between type of challenge or dose (n = 81). Lymph GLP-1 levels increased calorie-dependently after both glucose and fat but with different time courses in that glucose induced a transient increase which had returned to baseline after 90 min whereas the lipid induced a sustained increase which was still elevated above baseline after 210 min. Lymph GLP-1 appearance during 210 min was two to three-fold higher after glucose (7.4 ± 2.3 fmol at 0.3 kcal) than after isocaloric fat (2.9 ± 0.8 fmol at 0.3 kcal; P < 0.001). The slope between caloric load and lymph GLP-1 appearance was, however, identical after glucose and fat. We conclude that lymph GLP-1 is higher than plasma GLP-1 whereas lymph DPP-4 activity is lower than plasma DPP-4 activity and that both glucose and fat clearly stimulate GLP-1 secretion calorie-dependently in vivo but with different time courses.

Important species differences regarding lymph contribution to gut hormone responses

“…It has been reported that intestinal lymph flow may be reduced by anesthesia; but to mitigate this we used an anesthetic (␣-chloralose), which is mainly a hypnotic with minimal effect on gastrointestinal motility and secretion and enteric reflexes in pigs [9]. While our findings with respect to GLP-1 levels in lymph clearly contrast to the cited studies [1,3,17], D'Alessio et al reported, similar to our findings, lower DPP-4 activity in lymph when compared activity levels in plasma [3]. Thus, despite stimulating the secretion of GLP-1 to a similar extent as in the rodent studies (as evidenced from the prompt and robust increases in plasma concentrations), we were unable to demonstrate a corresponding increase in lymph levels, which remained low and relatively unchanged throughout the study.…”

“…This could explain that much lower concentrations are found in the central core [7]. Tso et al previously found food stimulated GLP-1 levels in lymph from rats to be 10-fold higher than plasma (v.portae) levels increasing from about 15 (basal levels) to 300 pmol/l (total GLP-1), and Ohlsson et al recently reported increases in intact GLP-1 during glucose or fat stimulation from 0.5 to around 40 pmol/l in lymph from anaesthetized mice [1,3,17]. In the present study, NC resulted in robust increases in arterial GLP-1 concentrations (reaching 50 pmol/l), indicating that we achieved a similar degree of stimulation of secretion as in the rodent studies.…”

“…However, it has also been suggested that GLP-1 might enter the lymphatic capillaries (lacteals) together with other nutrients e.g. chylomicrons [17], with the lymph system acting as a conduit for transporting high levels of GLP-1 from the intestinal mucosa to the systemic circulation [17], Moreover, since DPP-4 activity was reported to be less in lymph compared to plasma [17], measurement of intact GLP-1 in lymph has also been suggested as a novel model for studying the effects of GLP-1 secretagogues [15].…”

Insulin Regulates Retinol Dehydrogenase Expression and All-trans-retinoic Acid Biosynthesis through FoxO1

“…A comparison of oral glucose dosing to infusion via the portal vein revealed similar enhancement in hepatic glucose uptake relative to peripheral presentation, which excludes a contribution from a gut-secreted factor, such as Glp-1 (54). Yet, secretion of Glp-1 upon feeding contributes to reduced glucose production in liver by augmenting glucose-stimulated insulin secretion from pancreas (55). Our data of oral but not peripheral glucose dosing reducing Rdh mRNA are consistent with these observations and support the physiological significance of the observation.…”

Lipid transport in cholecystokinin knockout mice

“…Duodenal lipids have been reported to enhance BAT thermogenesis via a CCK-1R in the small intestine [23]. In response to dietary lipids, gut peptides such as CCK, peptide YY, glucose-dependent insulinotropic peptide and glucagon-like peptide-1 are released from small intestine [3, 44, 75, 76]. The involvement of these gut peptides in the activation of BAT thermogenesis via intestinal CCK-1R requires further experiments.…”