Increase in DPP-IV in the intestine, liver and kidney of the rat treated with high fat diet and streptozotocin
Introduction
Dipeptidyl peptidase IV (DPP-IV or CD26) is a ubiquitous, Type II cell surface glycoprotein, with the highest levels found in the kidneys and lower levels in: liver, pancreas, placenta, thymus, spleen, epithelial cells, vascular endothelium, and lymphoid and myeloid cells. DPP-IV is the key limited peptidase for glucagon-like peptide-1 (GLP-1). By rapidly cleaving the N-terminal two amino acids, it inactivates GLP-1 within seconds (Mentlein, 1999, Deacon and Holst, 2002, Weber, 2003).
GLP-1 is produced in the small intestine. It is promptly released into circulation upon food ingestion to lower blood glucose mainly by adjusting two major circulating hormones: an increase in insulin and decrease in glucagons (Bell et al., 1983). GLP-1 stimulates insulin biosynthesis (Wang et al., 1997) and β cell proliferation (Li et al., 2003, Farilla et al., 2003) to increase β-cell mass (Abraham et al., 2002, Tourrel et al., 2002). Recent reports have noted that GLP-1 inhibits cytokine and FFA- and STZ-mediated apoptosis (Liu et al., 2004, Bregenholt et al., 2005). Therefore, using DPP-IV inhibitors to extend GLP-1 bioactivity becomes a new class of pharmacological agents for lowing blood glucose and treatment of Type II diabetes (Deacon and Holst, 2002, Weber, 2003).
Inhibition of DPP-IV has enhanced insulin secretion, lowered blood glucose, increased insulin-stimulated muscle glucose uptake, and improved hepatic and peripheral insulin sensitivity in animals (Pospisilik et al., 2002a, Pospisilik et al., 2002b) and oral glucose tolerance in humans (Hoffmann et al., 2001). In patients with Type II diabetes, a DPP-IV inhibitor has significantly reduced blood glucose (Ahren et al., 2002), and even restored glucose homeostasis in Type II diabetics (Mest, 2006). Furthermore, inhibition of DPP-IV has delayed the onset of diabetic development (Sudre et al., 2002).
However, it becomes debatable whether the effects of DPP-IV inhibition on diabetes are mediated solely through GLP-1, because data have shown that i) DPP-IV inhibition causes little increase in endogenous GLP-1; ii) DPP-IV inhibitors have little effect on gastric emptying while GLP-1 does; iii) GLP-1 and incretin mimetics cause nausea/vomiting while DPP-IV inhibitors do not; iv) meal-stimulated levels of GLP-1 fall in response to DPP-IV inhibition (Nauck and El-Ouaghlidi, 2005). Additionally, DPP-IV does not only inactivate GLP-1, but also cleaves other peptides (Mentlein, 1999), suggesting multifunctional properties of DPP-IV that are still not fully understood in diabetes.
In this study, we hypothesize that expression and activity of DPP-IV are increased by a high fat diet or high fat diet plus insulin deficiency, the two major risk factors involved in development of Type II diabetes. We employed combinations of RT-PCR, western blot, immunohistochemistry and DPP-IV enzyme assay to monitor the selected organs' DPP-IV mRNA, protein, enzyme location and activity in the rats treated with high fat diet and STZ for insulin-deficient Type II diabetes.
Section snippets
Animal preparation
The animal preparation was performed according to previously published methodology (Pospisilik et al., 2003, Danda et al., 2005). Male Sprague–Dawley rats, aged 8 weeks, 180–220 g, (maintained at The Experimental Animals Center of Jiangsu, SCXK2001-006, ErMei Rd, Nanjing, China) were individually housed in opaque cages at 22 °C, 30–70% humidity and acclimatized to a 12-hour light cycle (lights on between 7:00AM and 19:00PM). Rats were randomly divided into three groups: control (Ctrl), high fat
Animal body weight, plasma glucose and insulin
During the 12 weeks, the rat body weights increased from 274 to 497 grams for control rats, from 273 to 509 grams for high fat diet (HF) rats, and from 274 to 443 grams for insulin-deficient (ID) rats (Fig. 1A). There was no inferential significance among the three groups on the average weight increases.
The high fat diet (HF) rats had a moderate increase in plasma glucose from 6.9 mmol/L at week 0 to 9.5 mmol/L at week 12 (P < 0.05; Fig. 1B), and increases in plasma insulin from 15.7 mmol/L at
Discussion
Dipeptidyl peptidase IV (DPP-IV) has currently received a great interest as an enzyme that inactivates the incretin hormone glucagon-like peptide 1 (GLP-1) and as a drug target in Type II diabetes mellitus. Its function has been investigated using, among other techniques, including knock-out mice and DPP inhibitors (Deacon and Holst, 2002, Weber, 2003, Conarello et al., 2003). However, the expression of DPP-IV is less well studied in diabetes. By monitoring the rats treated with a high fat diet
Acknowledgments
This study was supported by grant No. 30070881 from the National Natural Science Foundation of China to Dr. Chun Xue and with additional research funding from Nanjing Medical University, China. We also like to thank Cynthia H. Walker for her assistance in editing this paper.
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