Improved Glucose Tolerance in Zucker Fatty Rats by Oral Administration of the Dipeptidyl Peptidase IV Inhibitor Isoleucine Thiazolidide

Pederson, Raymond A.; White, Heather A; Schlenzig, Dagmar; Pauly, Robert P.; McIntosh, Christopher H.S.; Demuth, Hans‐Ulrich

doi:10.2337/diab.47.8.1253

Cited by 218 publications

(136 citation statements)

References 7 publications

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“…The final 1-(2-(S)-cyanopyrrolidin-1-yl)-3-(4-iodophenyl)-1-oxopropan-2-aminium trifluoroacetate was obtained as a white solid. The structure was confirmed by 1 H-NMR, 13 volumes of protein at a concentration of 20 mg͞ml with the reservoir solution (20-22% PEG 2000͞0.1 M ammonium sulfate͞ 0.1 M Tris⅐HCl, pH 8.0) by using the sitting drop vapor diffusion method. We covered the crystallization drop with perfluoropolyether (PFPE) oil and harvested the crystals by using a loop with humidity control (22).…”

Section: Methodsmentioning

confidence: 99%

“…DP IV as a Target for Drug Design. DP IV-activity strongly correlates with many diseases, such as diabetes, obesity, and tumor progression (13,14,(16)(17)(18) making it a top target of pharmaceutical research. Our inhibitor structure identified important recognition elements at DP IV's active site and represents an excellent starting point for rational design of active site-directed inhibitors.…”

Section: Comparison Of ␤-Propellermentioning

confidence: 99%

“…DP IV specifically processes regulatory peptides, leading to their biological activation or inactivation (9). This mechanism relates to its role in diseases like diabetes mellitus (10)(11)(12)(13)(14), obesity (15), tumor growth (16)(17)(18), and HIV infection (19).…”

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confidence: 99%

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The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism

Engel

Hoffmann

Wagner

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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296

251

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The membrane-bound glycoprotein dipeptidyl peptidase IV (DP IV, CD26) is a unique multifunctional protein, acting as receptor, binding and proteolytic molecule. We have determined the sequence and 1.8 Å crystal structure of native DP IV prepared from porcine kidney. The crystal structure reveals a 2-2-2 symmetric tetrameric assembly which depends on the natively glycosylated ␤-propeller blade IV. The crystal structure indicates that tetramerization of DP IV is a key mechanism to regulate its interaction with other components. Each subunit comprises two structural domains, the N-terminal eight-bladed ␤-propeller with open Velcro topology and the C-terminal ␣͞␤-hydrolase domain. Analogy with the structurally related POP and tricorn protease suggests that substrates access the buried active site through the ␤-propeller tunnel while products leave the active site through a separate side exit. A dipeptide mimicking inhibitor complexed to the active site discloses key determinants for substrate recognition, including a Glu-Glu motif that distinguishes DP IV as an aminopeptidase and an oxyanion trap that binds and activates the P 2-carbonyl oxygen necessary for efficient postproline cleavage. We discuss active and nonactive site-directed inhibition strategies of this pharmaceutical target protein.serine protease ͉ oxyanion hole ͉ substrate channeling ͉ drug design ͉ diabetes mellitus

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Section: Methodsmentioning

confidence: 99%

Section: Comparison Of ␤-Propellermentioning

confidence: 99%

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The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism

Engel

Hoffmann

Wagner

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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296

251

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“…DPP-4 inhibition has thereby been demonstrated to be anti-diabetic both in animal models of diabetes (4)(5)(6)(7) and in patients with type 2 diabetes (8)(9)(10). The antidiabetic action of DPP-4 inhibition is explained by increased insulin secretion in association with inhibited glucagon secretion with a possible long-term action to increase β-cell mass (1)(2)(3).…”

Section: Introductionmentioning

confidence: 99%

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with β-cell-specific overexpression of human islet amyloid polypeptide

Åhrén

Winzell

Wierup

et al. 2007

Regulatory Peptides

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Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently explored as a novel therapy of type 2 diabetes. The strategy has been shown to improve glycemia in most, but not all, rodent forms of glucose intolerance. In this study, we explored the effects of DPP-4 inhibition in mice with β-cell overexpression of human islet amyloid polypeptide (IAPP). We therefore administered the orally active and highly selective DPP-4 inhibitor, vildagliptin (3µmol/mouse daily) to female mice with β-cell overexpression of human IAPP. Controls were given plain water, and a series of untreated wildtype mice was also included. After five weeks, an intravenous glucose tolerance test showed improved glucose disposal and a markedly enhanced insulin response in mice treated with vildagliptin. After eight weeks, a gastric tolerance test showed that vildagliptin improved glucose tolerance and markedly (approximately ten-fold) augmented the insulin response in association with augmented (approximately five-fold) levels of intact glucagon-like peptide-1 (GLP-1). Furthermore, after nine weeks, islets were isolated.Islets from vildagliptin-treated mice showed augmented glucose-stimulated insulin response and a normalization of the islet insulin content, which was reduced by approximately 50% in transgenic controls versus wildtype animals. Double immunostaining of pancreatic islets for insulin and glucagon revealed that transgenic islets displayed severely disturbed intra-islet topography with frequently observed centrally located α-cells. Treatment with vildagliptin restored the islet topography. We therefore conclude that DPP-4 inhibition improves islet function and islet topography in mice with specific ß cell transgenic overexpression of human IAPP.

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“…In the case of allergic diseases it can be expected that the local concentration of chemokines such as CCL11/eotaxin and the expression of its corresponding receptor, the CCR3 determine to a large extent their biological effects, for example the recruitment of eosinophils. N-terminal truncation of chemokines by peptidases such as dipeptidyl peptidase IV (DPPIV), 4 regulating their biological activity, adds another level of complexity to their local action at inflammatory sites, including but not limited to allergy-like reactions of the skin.…”

mentioning

confidence: 99%

Inhibition of CD26/Dipeptidyl Peptidase IV Enhances CCL11/Eotaxin-Mediated Recruitment of Eosinophils In Vivo

Forssmann

Stoetzer

Stephan

et al. 2008

The Journal of Immunology

104

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Chemokines mediate the recruitment of leukocytes to the sites of inflammation. N-terminal truncation of chemokines by the protease dipeptidyl peptidase IV (DPPIV) potentially restricts their activity during inflammatory processes such as allergic reactions, but direct evidence in vivo is very rare. After demonstrating that N-terminal truncation of the chemokine CCL11/eotaxin by DPPIV results in a loss of CCR3-mediated intracellular calcium mobilization and CCR3 internalization in human eosinophils, we focused on the in vivo role of CCL11 and provide direct evidence for specific kinetic and rate-determining effects by DPPIV-like enzymatic activity on CCL11-mediated responses of eosinophils. Namely, it is demonstrated that i.v. administration of CCL11 in wild-type F344 rats leads to mobilization of eosinophils into the blood, peaking at 30 min. This mobilization is significantly increased in DPPIV-deficient F344 rats. Intradermal administration of CCL11 is followed by a dose-dependent recruitment of eosinophils into the skin and is significantly more effective in DPPIV-deficient F344 mutants as well as after pharmacological inhibition of DPPIV. Interestingly, CCL11 application leads to an up-regulation of DPPIV, which is not associated with negative feedback inhibition via DPPIV-cleaved CCL11(3–74). These findings demonstrate regulatory effects of DPPIV for the recruitment of eosinophils. Furthermore, they illustrate that inhibitors of DPPIV have the potential to interfere with chemokine-mediated effects in vivo including but not limited to allergy.

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Improved Glucose Tolerance in Zucker Fatty Rats by Oral Administration of the Dipeptidyl Peptidase IV Inhibitor Isoleucine Thiazolidide

Cited by 218 publications

References 7 publications

The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism

The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with β-cell-specific overexpression of human islet amyloid polypeptide

Inhibition of CD26/Dipeptidyl Peptidase IV Enhances CCL11/Eotaxin-Mediated Recruitment of Eosinophils In Vivo

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