Effects of long-term dipeptidyl peptidase-IV inhibition on body composition and glucose tolerance in high fat diet-fed mice
Introduction
Oral glucose administration leads to much greater insulin release than the equivalent intravenous glucose challenge. Gut hormonal substances released in response to glucose include the incretins glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide /glucose-dependent insulinotropic peptide (GIP), which are responsible for ~ 50% of postprandial insulin release. GLP-1 and GIP potentiate glucose-induced insulin secretion from pancreatic β-cells by binding their respective receptors and subsequently increasing the intracellular cAMP concentration. In addition to their action on the enteroinsular axis, GLP-1 inhibits glucagon secretion (Komatsu et al. 1989), delays gastric emptying (Willms et al. 1996), decreases body weight through suppression of appetite (Turton et al. 1996), and suppresses β-cell apoptosis (Toyoda et al. 2008), while GIP enhances energy storage in adipocytes (Miyawaki et al. 2002) and calcium accumulation in bone (Tsukiyama et al. 2006). Thus, the incretins are associated with various systems of metabolic homeostasis, including that of both glucose and body weight.
However, the effects of GLP-1 and GIP are limited by their short half-life of a few minutes, which is primarily due to the action of dipeptidyl peptidase-IV (DPP-IV). DPP-IV is an enzyme distributed throughout the body including plasma and the endothelial lining of several organs, and cleaves two amino acids of biologically active peptides including GLP-1 and GIP by recognizing proline or alanine in the second N-terminal amino acid. The resulting N-terminal-truncated forms of GLP-1 and GIP are devoid of bioactivity. Since DPP-IV-deficient rodents show improved glucose tolerance and increased insulin secretion with elevated plasma active GLP-1 levels after oral glucose loading (Marguet et al., 2000, Nagakura et al., 2001), DPP-IV inhibitor and DPP-IV-resistant GLP-1 receptor agonist are potential targets for the treatment of type 2 diabetes mellitus as a new class of antidiabetic agent. GLP-1 receptor agonist both increases insulin secretion and improves glucose tolerance and decreases body weight in rodents and humans (Szayna et al., 2000, Buse et al., 2004). DPP-IV inhibitor also increases insulin secretion and improves glucose tolerance, but its effect on body weight is controversial (Pospisilik et al., 2002, Lamont and Drucker, 2008, Reimer et al., 2002, Ahrén et al., 2002). It is reported that DPP-IV inhibitor do not increase insulin secretion after glucose loading in GLP-1 receptor (GLP-1R)/GIP receptor (GIPR) double knockout (DIRKO) mice, indicating that both GLP-1 and GIP are critically involved in the insulinotropic action of long-term DPP-IV inhibition (Flock et al. 2007). However, the magnitude of the effects of enhanced GLP-1 and GIP signaling by long-term DPP-IV inhibition on body weight and insulin secretion has not been determined.
In the present study, we investigated the long-term effects of DPP-IV inhibition on body composition and insulin secretion using high fat diet (HFD)-fed wild-type (WT) and GLP-1R knockout (GLP-1R−/−) mice.
Section snippets
Animals
Mice (C57BL/6 background) were housed under a light/dark cycle of 12 h with free access to food and water. As ingestion of a meal rich in fat is a strong stimulus of incretin signaling (Harada et al. 2008), male WT and GLP-1R−/− mice were fed a high fat diet (45% fat, 20% protein and 35% carbohydrate by energy) from 7 weeks of age. Groups of treated HFD-fed WT and GLP-1R−/− mice received DPP-IV inhibitor in drinking water (0.5% W/V), while groups of untreated HFD-fed WT and GLP-1R−/− mice
Body weight and body composition of DPP-IV inhibitor-treated HFD-fed mice
Water intake, food intake, and body weight of HFD-fed WT and GLP-1R−/− mice with or without DPP-IV inhibitor administration were measured. In WT mice, water and food intake in DPP-IV inhibitor-treated and untreated mice were similar during the 8 weeks of the study (Fig. 1A). In GLP-1R−/− mice, water and food intake in DPP-IV inhibitor-treated and untreated mice also were similar (Fig. 1A). A significant difference in body weight between DPP-IV inhibitor-untreated WT and GLP-1R−/− mice appeared
Discussion
In the present study, we evaluated body composition and glucose control in the absence of the GLP-1 signaling using GLP-1R−/− mice treated with DPP-IV inhibitor for 8 weeks to clarify GLP-1 and GIP action under long-term DPP-IV inhibition.
HFD-fed DPP-IV-deficient rodents exhibit reduced food intake and resistance to development of obesity with elevated active GLP-1 levels (Yasuda et al., 2002, Conarello et al., 2003), and DPP-IV inhibitor has been shown to reduce body weight in some previous
Conclusion
Long-term DPP-IV inhibition does not alter body composition, possibly due to the counteracting effects of enhanced GLP-1 and GIP, but does improve glucose tolerance through the synergistic insulinotropic effects of enhanced GLP-1 and GIP, as well as by improved glucose responsiveness in pancreatic islets.
Acknowledgments
We thank Dr. Daniel. J. Drucker (Department of Medicine, The Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Toronto, Canada) for providing the GLP-1R−/− mice.
The funding of this study was supported by Scientific Research Grants from the Ministry of Education, Culture, Sports, Science, and Technology (Japan) and from the Ministry of Health, Labor, and Welfare (Japan).
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