Elsevier

Life Sciences

Volume 81, Issue 4, 4 July 2007, Pages 272-279
Life Sciences

Increase in DPP-IV in the intestine, liver and kidney of the rat treated with high fat diet and streptozotocin

https://doi.org/10.1016/j.lfs.2007.04.040Get rights and content

Abstract

High fat diet or insulin deficiency is commonly seen in Type II diabetes, while the mechanism remains unclear. To test our hypothesis that DPP-IV contributes to Type II diabetes, we examined the expression and activity of DPP-IV in rats (n = 8 to each group) treated for 12 weeks with 3 separate diets: a) normal control; b) a high fat diet; and c) a high fat diet plus streptozotocin, a chemical for induction of insulin-deficient diabetes. Compared to rats on the normal diet, the rats with a high fat diet significantly increased DPP-IV's expression and activity about 142–152% in the intestine (P < 0.05) and 153–240% in kidneys (P < 0.05), but there was no change in the liver. Administration of streptozotocin to the rats treated with the high fat diet showed an insufficient insulin secretion and higher blood glucose in response to glucose/insulin tolerance test, and an increase in expression of DPP-IV and activity by 188–242% in the intestine (P < 0.01); 191–225% in liver (P < 0.01); and 211–321% in the kidneys (P < 0.01). Immunohistochemistry studies confirmed the above results, showing increased DPP-IV immunostaining localized primarily in intestinal epithelium, hepatocytes and renal tubular cells. This study, for the first time reports an increase in DPP-IV associated with a high fat diet, as well as in the combination of a high fat diet with an insulin deficiency. Since both high fat diet and insulin deficiency are closely linked with etiology of Type II diabetes, the evidence in this study suggests a role of DPP-IV in development of Type II diabetes.

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.

References (45)

  • C.C.G. Adriana et al.

    Role of dipeptidyl peptidase IV in regulating activity of Na+/H+ exchanger isoform NHE3 in proximal tubule cells

    American Journal of Physiology Cell Physiology

    (2004)
  • B. Ahren et al.

    Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in Type 2 diabetes

    Diabetes Care

    (2002)
  • American Diabetes Association

    Postprandial blood glucose

    Diabetes Care

    (2001)
  • American Diabetes Association

    Standards of medical care in diabetes

    Diabetes Care

    (2004)
  • G.I. Bell et al.

    Hamster preproglucagon contains the sequence of glucagons and two related peptides

    Nature

    (1983)
  • S. Bregenholt et al.

    The long-acting glucagons-like peptide-1 alalogue, liraglutid inhibits beta-cell apoptosis in vitro

    Biochemical and Biophysical Research Communications

    (2005)
  • S.L. Conarello et al.

    Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance

    Proceedings of the National Academy of Science of United States of America

    (2003)
  • T.P. DiLorezo et al.

    The good turned ugly: immunopathogenic basis for diabetogenic CD8+ T cells in NOD mice

    Immunological Review

    (2005)
  • L. Farilla et al.

    Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets

    Endocrinology

    (2003)
  • X.H. Guo et al.

    A novel rat model of Type 2 diabetes mellitus

    Chinese Journal Nephrology Dialysis & Transplantation

    (2000)
  • I.S. Hoffmann et al.

    Urinary albumin excretion in lean, overweight and obese glucose tolerant individuals: its relationship with dyslipidaemia, hyperinsulinaemia and blood pressure

    Journal of Human Hypertension

    (2001)
  • J.J. Holst

    Implementation of GLP-1 based therapy of Type 2 diabetes mellitus using DPP-IV inhibitors

    Advance Experimental Medical Biology

    (2003)
  • Cited by (74)

    • DPP4/CD32b/NF-κB Circuit: A Novel Druggable Target for Inhibiting CRP-Driven Diabetic Nephropathy

      2021, Molecular Therapy
      Citation Excerpt :

      DPP4 cleaves a wide range of substrates, including growth factors, chemokines, and peptides, in addition to its major role in glucose metabolism.21 DPP4 was highly expressed in kidney under disease conditions found in experimental rodent models, including high-fat-diet-induced diabetes and acute ischemia-reperfusion injury.22,23 It is noted that DPP4i can delay the degradation of incretins in order to rebalance the glycemic control of the patients by prolonging insulin secretion.24,25

    • Reno-protective effect of linagliptin against gentamycin nephrotoxicity in rats

      2019, Pharmacological Reports
      Citation Excerpt :

      Indeed, recent studies suggested a role of enhanced DPP-4 activity in mediating both diabetic and non-diabetic kidney diseases [19–21]. Similarly, several studies reported on DPP-4 upregulation in glomerular and tubular cells, under pathologic conditions, such as T2D [6,22] and in high-fat fed and streptozotocin-treated rats [23]. Moreover, urinary DPP-4 activity was found to be significantly higher in diabetic patients with albuminuria compared with non-albuminuric diabetics or healthy individuals [24,25].

    View all citing articles on Scopus
    View full text