The DPP-4 inhibitor MK0626 and exercise protect islet function in early pre-diabetic kkay mice

Li, Yupeng; Xiao, Jing; Tian, Hui; Pei, Yu; Lu, Yanhui; Han, Xiaofei; Liu, Yu; Zhong, Wu; Sun, Beicheng; Feng, Fang; Hua, Shucheng

doi:10.1016/j.peptides.2013.08.021

Cited by 17 publications

(34 citation statements)

References 30 publications

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“…The upregulation of pancreatic β-cell mass can be induced by β-cell regeneration (neogenesis and replication). Our data suggests that different transcription factors involved in β-cell function, such as NeuroD, Nkx6.1, Nkx2.2 and MafA 33–36 , are up-regulated by HBK001 treatment, which is consistent with other studies using GPR119 agonists 27, 31 and DPP4 inhibitors 37 .…”

Section: Discussionsupporting

confidence: 92%

“…Male ICR mice, female diabetic KKAy mice 37, 43, 44 and db/db (BKS.Cg-m+/+ Lepr db/J) mice were obtained and maintained as previously described 44 . All animal experiments were carried out according to the Standards for Laboratory Animals (GB14925-2001) and the Guideline on the Humane Treatment of Laboratory Animals (MOST 2006a), and all animal procedures were approved by Beijing Administration Office of Laboratory Animal (approval number: SCXK-Beijing-2009-0004).…”

Section: Methodsmentioning

confidence: 99%

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The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo

Huan

Jiang

et al. 2017

Sci Rep

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Glucagon like peptide-1 (GLP-1) plays a vital role in glucose homeostasis and sustaining β-cell function. Currently there are two major methods to enhance endogenous GLP-1 activity; inhibiting dipeptidyl peptidase-4 (DPP4) or activating G protein-coupled receptor 119 (GPR119). Here we describe and validate a novel dual-target compound, HBK001, which can both inhibit DPP4 and activate GPR119 ex and in vivo. We show that HBK001 can promote glucose-stimulated insulin secretion in mouse and human primary islets. A single administration of HBK001 in ICR mice can increase plasma incretins levels much more efficiently than linagliptin, a classic DPP4 inhibitor. Long-term treatment of HBK001 in KKAy mice can ameliorate hyperglycemia as well as improve glucose tolerance, while linagliptin fails to achieve such glucose-lowing effects despite inhibiting 95% of serum DPP4 activity. Moreover, HBK001 can increase first-phase insulin secretion in KKAy mice, suggesting a direct effect on islet β-cells via GPR119 activation. Furthermore, HBK001 can improve islet morphology, increase β-cell proliferation and up-regulate genes involved in improved β-cell function. Thus, we have identified, designed and synthesized a novel dual-target compound, HBK001, which represents a promising therapeutic candidate for type 2 diabetes, especially for patients who are insensitive to current DPP4 inhibitors.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo

Huan

Jiang

et al. 2017

Sci Rep

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“…To evaluate the effect of the E3 vaccine on glucose metabolism and pancreatic pathology, we used a spontaneous diabetic model: yellow KK mice that carry the obsess gene A y and develop obesity, hyperglycemia, and hyperinsulinemia. It has also been reported that the administration of DPP4 inhibitor in these mice effectively attenuates the hyperglycemia (26). The MTT was performed on day 28 after E3 vaccine immunization, and the immunized mice exhibited significant improvement in postprandial blood glucose levels (Fig.…”

Section: Improvement In Insulin Resistance Following Dpp4 Vaccinationmentioning

confidence: 73%

“…In our study, these defects were attenuated in the HFD-induced therapeutic model and young diabetic db/db mice after immunization with the E3 vaccine compared with the KLH control group, leading to increased insulin secretion. In addition, we used KK-A y mice, because the administration of DPP4 inhibitor effectively attenuated the hyperglycemia in KK-A y mice (26). The severity of KK-A y mice as a diabetic model is less than that of db/db mice, and insulin action can be improved by the inhibitor (26).…”

Section: Pang Et Al Pnas | Published Online March 17 2014 | E1261 Mmentioning

confidence: 99%

“…In addition, we used KK-A y mice, because the administration of DPP4 inhibitor effectively attenuated the hyperglycemia in KK-A y mice (26). The severity of KK-A y mice as a diabetic model is less than that of db/db mice, and insulin action can be improved by the inhibitor (26). In addition, we postulate that the E3 vaccine improved insulin secretion due to increased islet mass and β-cell proliferation.…”

Section: Pang Et Al Pnas | Published Online March 17 2014 | E1261 Mmentioning

confidence: 99%

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Therapeutic vaccine against DPP4 improves glucose metabolism in mice

Pang¹,

Nakagami

Osako

et al. 2014

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

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The increasing prevalence of type 2 diabetes mellitus is associated with a significant economic burden. We developed a dipeptidyl peptidase 4 (DPP4)-targeted immune therapy to increase glucagonlike peptide 1 hormone levels and improve insulin sensitivity for the prevention and treatment of type 2 diabetes mellitus. Immunization with the DPP4 vaccine in C57BL/6J mice successfully increased DPP4 titer, inhibited plasma DPP4 activity, and induced an increase in the plasma glucagon-like peptide 1 level. Moreover, this elevated titer was sustained for 3 mo. In mice fed a high-fat diet, DPP4 vaccination resulted in improved postprandial glucose excursions and insulin sensitivity and, in the diabetic KK-A y and db/db mice strains, DPP4 vaccination significantly reduced glucose excursions and increased both plasma insulin and pancreatic insulin content. Importantly, T cells were not activated following challenge with DPP4 itself, which suggests that this vaccine does not induce cell-mediated autoimmunity. Additionally, no significant immune-mediated damage was detected in cells and tissues where DPP4 is expressed. Thus, this DPP4 vaccine may provide a therapeutic alternative for patients with diabetes.

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Casein glycomacropeptide hydrolysates ameliorate hepatic insulin resistance of C57BL/6J mice challenged with high-fat diet

Song

Gao

et al. 2018

Journal of Functional Foods

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The DPP-4 inhibitor MK0626 and exercise protect islet function in early pre-diabetic kkay mice

Cited by 17 publications

References 30 publications

The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo

The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo

Therapeutic vaccine against DPP4 improves glucose metabolism in mice

Casein glycomacropeptide hydrolysates ameliorate hepatic insulin resistance of C57BL/6J mice challenged with high-fat diet

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