Role of endogenous glucagon‐like peptide‐1 enhanced by vildagliptin in the glycaemic and energy expenditure responses to intraduodenal fat infusion in type 2 diabetes

Abstract

Aim To evaluate the effects of the dipeptidyl peptidase‐4 (DPP‐4) inhibitor vildagliptin on glycaemic and energy expenditure responses during intraduodenal fat infusion, as well as the contribution of endogenous glucagon‐like peptide‐1 (GLP‐1) signalling, in people with type 2 diabetes (T2DM). Methods A total of 15 people with T2DM managed by diet and/or metformin (glycated haemoglobin 49.3 ± 2.1 mmol/mol) were studied on three occasions (two with vildagliptin and one with placebo) in a double‐blind, randomized, crossover fashion. On each day, vildagliptin 50 mg or placebo was given orally, followed by intravenous exendin (9–39) 600 pmol/kg/min, on one of the two vildagliptin treatment days, or 0.9% saline over 180 minutes. At between 0 and 120 minutes, a fat emulsion was infused intraduodenally at 2 kcal/min. Energy expenditure, plasma glucose and glucose‐regulatory hormones were evaluated. Results Intraduodenal fat increased plasma GLP‐1 and glucose‐dependent insulinotropic polypeptide (GIP), insulin and glucagon, and energy expenditure, and decreased plasma glucose (all P < 0.05). On the two intravenous saline days, plasma glucose and glucagon were lower, plasma intact GLP‐1 was higher (all P < 0.05), and energy expenditure tended to be lower after vildagliptin (P = 0.08) than placebo. On the two vildagliptin days, plasma glucose, glucagon and GLP‐1 (both total and intact), and energy expenditure were higher during intravenous exendin (9–39) than saline (all P < 0.05). Conclusions In well‐controlled T2DM during intraduodenal fat infusion, vildagliptin lowered plasma glucose and glucagon, and tended to decrease energy expenditure, effects that were mediated by endogenous GLP‐1.

Dipeptidyl Peptidase-IV Inhibitory Activity and Related Molecular Mechanism of Bovine α-Lactalbumin-Derived Peptides

“…Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones that stimulate 50%−60% of insulin secretion in a glucose-dependent manner [29,30]. However, GLP-1 and GIP have a very short half-life (about 1−2 min) due to the degradation by dipeptidyl-peptidase IV (DPP-IV) [31,32]. Thus, DPP-IV inhibitors (such as sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin), which could inhibit the activity of DPP-IV, have become a novel anti-diabetic approach [29].…”

“…As listed in Table 1, the peptide sequences of the F3-8 and F3-11 were Glu-Leu-Lys-Asp-Leu-Lys-Gly-Tyr (ELKDLKGY) and Ile-Leu-Asp-Lys-Val-Gly-Ile-Asn-Tyr (ILDKVGINY), respectively. Figure 4A showed the LC-MS/MS spectrum of single-charged ion with m/z 483.26996, which matched to sequence ELKDLKGY corresponding to bovine α-lactalbumin f (30)(31)(32)(33)(34)(35)(36)(37). Figure 4B showed the LC-MS/MS spectrum of single-charged ion with m/z 517.79901, which matched to sequence ILDKVGINY corresponding to bovine α-lactalbumin f (114-122).…”

Enteroendocrine Hormone Secretion and Metabolic Control: Importance of the Region of the Gut Stimulation

“…However, a recent meta-analysis suggests that GLP-1 receptor agonists have little, if any, effect on energy expenditure in humans [ 79 ]. Although inhibition of DPP-4 by vildagliptin was found to augment the energy expenditure response to an intraduodenal fat infusion in healthy humans [ 80 ], this effect was not evident in patients with T2DM [ 81 ]. That antagonism of GLP-1 signalling by exendin (9–39) increased energy expenditure in the latter group during treatment with vildagliptin suggests that endogenous GLP-1 signalling may rather be associated with suppression of energy expenditure [ 81 ].…”

Comparative Effects of Intraduodenal Glucose and Fat Infusion on Blood Pressure and Heart Rate in Type 2 Diabetes

“…Forty participants with type 2 diabetes managed by diet or metformin monotherapy (500–2,000 mg/day, stable for > 3 months) were recruited from the community by advertisement for studies evaluating nutritional and/or pharmacological therapies for diabetes in our center. Twenty-six participants received an intraduodenal glucose infusion ( 7 , 8 ) and 14 participants received an intraduodenal lipid infusion ( 9 ) following identical procedures after providing written informed consent ( Table 1 ). We have previously reported the outcomes relating to blood glucose and gut hormones.…”