Dipeptidyl peptidase-4 inhibitor anagliptin ameliorates diabetes in mice with haploinsufficiency of glucokinase on a high-fat diet

Nakaya, Keizo; Kubota, Naoto; Takamoto, Iseki; Kubota, Tetsuya; Katsuyama, Hisayuki; Satō, Hiroyuki; Tokuyama, Kumpei; Hashimoto, Shinji; Goto, Minoru; Jomori, Takahito; Ueki, Kohjiro; Kadowaki, Takashi

doi:10.1016/j.metabol.2013.01.010

Cited by 17 publications

(17 citation statements)

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“…The dose of anagliptin was determined from previous reports. [22][23][24] In order to determine whether the dose of anagliptin (300 mg/kg/day) was adequate to inhibit DPP4 activity, DPP4 activity was measured as described in the next section, and we found DPP4 activity in this study was inhibited in nearly equal level compared with those of previous experiments (80-90% inhibition of DPP4 activity). 22,25,26) Echocardiography was performed in order to evaluate the cardiac function of the mice at day 52 (four weeks after MI induction).…”

Section: Animals and Ethical Statementsmentioning

confidence: 65%

DPP4 Inhibition Ameliorates Cardiac Function by Blocking the Cleavage of HMGB1 in Diabetic Mice After Myocardial Infarction

et al. 2017

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SummaryHigh mobility group box 1 (HMGB1), a ubiquitous DNA-binding protein, promotes angiogenesis and tissue repair, resulting in restored cardiac function after myocardial infarction (MI). Although dipeptidyl peptidase 4 (DPP4) degrades certain peptides, it remains unclear as to whether HMGB1 is a substrate of DPP4 and whether DPP4 inhibition prevents the cleavage of HMGB1.In transgenic mice with cardiac-specific overexpression of HMGB1 (TG) and wild-type mice (WT), a diabetic state was induced by streptozotocin, and MI was created by ligation of the left anterior descending coronary artery. To inhibit DPP4 activity, a DPP4 inhibitor anagliptin was used. The plasma levels of HMGB1, infarct size, echocardiographic data, angiogenesis, and vascular endothelial growth factor (VEGF) expression in the peri-infarct area were compared among non-diabetic MI WT/TG, diabetic MI WT/TG, and anagliptin-treated diabetic MI WT/TG mice.DPP4 activity was increased in the diabetic state and blocked by anagliptin administration. The HMGB1 plasma levels were reduced in the diabetic TG compared with the non-diabetic TG mice, but DPP4 inhibition with anagliptin increased HMGB1 plasma levels in the diabetic TG mice. The infarct area was significantly larger in the diabetic TG than in the non-diabetic TG mice, and it was reduced by DPP4 inhibition. Cardiac function, angiogenesis, and VEGF expression were impaired in the diabetic TG mice, but they were ameliorated by the DPP4 inhibition to levels similar to those found in the non-diabetic TG mice.The DPP4 inhibitor ameliorated cardiac function by inhibiting the inactivation of HMGB1 in diabetic mice after MI.(Int Heart J 2017; 58: 778-786) Key words: Angiogenesis, Ischemic heart disease, Diabetes mellitus A cute myocardial infarction (MI) is an emergent disease caused by occlusion of the coronary artery. The morbidity and mortality of MI remain high despite the advancement of emergency medical services and the development of optimal therapies, including pharmacological treatment and percutaneous coronary intervention, and surgical technique. 1) Infarct size is known as an important prognostic predictor; thus, many studies of ischemic heart disease have been performed to determine how to limit the extent of infarction, focusing on the mechanisms of collateral development, ischemic reperfusion injury and ischemic preconditioning, among others. 2-4)High mobility group box 1 (HMGB1) is a ubiquitous non-histone DNA-binding protein that mediates gene transcription.5-7) HMGB1 secreted from necrotic cells into the extracellular space triggers tissue repair as a cytokine. [8][9][10][11] Moreover, several studies have proven that HMGB1 is involved in limiting the size of the infarct area and preserving cardiac function by promoting angiogenesis. 12,13) In addition, we have previously demonstrated that HMGB1 promotes angiogenesis and tissue repair by enhancing mobilization and differentiation of endothelial progenitor cells from bone marrow, resulting in preserving cardiac function after MI.14) Th...

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Section: Animals and Ethical Statementsmentioning

confidence: 65%

DPP4 Inhibition Ameliorates Cardiac Function by Blocking the Cleavage of HMGB1 in Diabetic Mice After Myocardial Infarction

et al. 2017

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“…In this study, we did not observe digestive symptoms in the OLETF rats fed a diet containing 600 ppm miglitol. Regarding anagliptin, feeding diets containing 500 and 3,000 ppm anagliptin to mice for 10 or 16 wk reduced IGT development in a dose-dependent manner (27,36). Therefore, it is considered that the doses of miglitol and anagliptin in the diet used in this study are within adequate ranges for OLETF rats.…”

Section: Discussionmentioning

confidence: 98%

“…Thus, anagliptin treatment may improve insulin resistance in OLETF rats. Indeed, previous studies showed that another DPP-4 inhibitor, teneligliptin, improved insulin resistance in type 2 diabetic patients (26) and that anagliptin ameliorated insulin resistance in the mouse liver (27). The issue of whether treatment with miglitol or anagliptin ameliorates insulin resistance in OLETF rats should be further assessed using insulin tolerance tests.…”

Section: Discussionmentioning

confidence: 99%

Treatment with DPP-4I Anagliptin or α-GI Miglitol Reduces IGT Development and the Expression of CVD Risk Factors in OLETF Rats

Imai

Harazaki

Inoue

et al. 2015

J Nutr Sci Vitaminol

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Recent cohort studies such as Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) in Europe and FUNAGATA in Japan have demonstrated that postprandial hyperglycemia is a strong independent risk factor for the development of cardiovascular diseases (CVD) in subjects with impaired glucose tolerance (IGT), reflecting pre-diabetic subjects, or type 2 diabetes (1, 2). Furthermore, the Study To Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) trial reported that suppression of postprandial hyperglycemia in subjects with IGT, the pre-diabetic stage, by treatment with the a-glucosidase inhibitor (a-GI) acarbose, which suppresses postprandial hyperglycemia by inhibiting the carbohydrate digestion in the small intestine, reduces the incidence of CVD as well as the development of type 2 diabetes (3). These lines of evidence indicate that inhibition of postprandial hyperglycemia from the pre-diabetic stage could inhibit CVD development.Many previous studies have shown that CVDs are related to activation of leukocytes such as neutrophils, monocytes, and macrophages, and associated disorders of vascular endothelial function. Postprandial hyperglycemia activates the leukocytes through the production of reactive oxygen species (ROS) by activated neutrophils and enhanced glucose metabolism in mitochondria (4). The activated leukocytes secrete inflammatory cytokines such as interleukin (IL)-1b and tumor necrosis factor (TNF)-a (5, 6). These inflammatory cytokines Summary It has been reported that postprandial hyperglycemia from the pre-diabetic stage, especially from the impaired glucose tolerance (IGT) stage, is positively associated with subsequent incidences of cardiovascular diseases (CVD) and type 2 diabetes. In this study, we aimed to investigate whether treatment with a dipeptidyl peptidase-4 inhibitor (DPP-4I) or an a-glucosidase inhibitor (a-GI), either of which suppresses postprandial hyperglycemia, reduces the expression of CVD risk factors in an IGT animal model. A DPP-4I, anagliptin (1,200 ppm), or an a-GI, miglitol (600 ppm), in the diet was administered for 47 wk to Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model for spontaneously-developed type 2 diabetes, at the IGT stage. We examined whether each treatment reduced the expression of CVD risk factors such as inflammatory cytokines/cytokine-like factors in peripheral leukocytes and adhesion molecules in the aortic tissues and circulation. Treatment with either drug reduced IGT development and repressed expression of the interleukin-1b, tumor necrosis factor-a, S100a9, and S100a11 genes in peripheral leukocytes in the fasting state at weeks 25 and 39. The mRNA levels of E-selectin in aortic tissues and protein levels of the soluble forms of E-selectin and ICAM-1 in arterial blood were significantly lower in the anagliptin and miglitol groups than in the control group. Our results suggest that long-term treatment with anagliptin or miglitol in OLETF rats at the IGT stage suppresses the expression of inflammatory ...

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“…Furuta et al observed the pharmacokinetic properties of anagliptin in rats and dogs and observed that anagliptin was rapidly absorbed and distributed to tissues with high levels of DPP-4 expression [3]. Preclinical studies have shown that improved glucose tolerance results from both low-and high-dose anagliptin in highfat diet fed mice with haploinsufficiency for glucokinase [4]. Furthermore, anagliptin has been reported to exert anti-atherosclerotic effects via its direct inhibition of smooth muscle cell proliferation and the inflammatory reaction of monocytes in a mouse model [5].…”

Section: Safety Assessmentsmentioning

confidence: 99%

“…, Kyung Wan Min 2) , Sung Woo Park 3) , Choon Hee Chung 4) , Kyong Soo Park 5) , Sung Hee Choi 6) , Ki-Ho Song 7) , Doo-Man Kim 8) , Moon-Kyu Lee 9) , Yeon-Ah Sung 10) , Sei Hyun Baik 11) , In Joo Kim 12) , Bong-Soo Cha 13) , Jeong Hyun Park 14) , Yu Bae Ahn 15) , In-Kyu Lee 16) , Soon Jib Yoo 17) , Jaetaek Kim 18) , Ie Byung Park 19) , Tae Sun Park 20) and Kun-Ho Yoon 1) years whose conditions were inadequately controlled with diet or exercise were included. Only those with a fasting blood glucose of <14.99 mmol/L and an HbA1c level ≥6.5% and ≤10.0% at screening were enrolled in this study.…”

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confidence: 99%

A randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of anagliptin in drug-naïve patients with type 2 diabetes

et al. 2015

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Abstract. The aim of this study was to evaluate the efficacy and safety of anagliptin in drug-naïve patients with type 2 diabetes in a double-blind randomized placebo-controlled study. A total of 109 patients were randomized to 100 mg (n=37) or 200 mg (n=33) anagliptin twice daily or placebo (n=39). The primary objective was to alter HbA1c levels from baseline at a 24-week endpoint. The overall baseline mean age and body mass index were 56.20 ± 9.77 years and 25.01 ± 2.97 kg/m 2 , respectively, and the HbA1c level was of 7.14 ± 0.69 %. Anagliptin at 100 mg and 200 mg produced significant reductions in HbA1c (-0.50 ± 0.45 % and -0.51 ± 0.55%, respectively), and the placebo treatment resulted in an increase in HbA1c by 0.23 ± 0.62 %. Both doses of anagliptin produced significant decreases in fasting plasma glucose (-0.53 ± 1.25 mmol/L and -0.72 ± 1.25 mmol/L, respectively) and the proinsulin/insulin ratio (-0.04 ± 0.15 and -0.07 ± 0.18, respectively) compared with placebo. No meaningful body weight changes from baseline were observed in three groups. Plasma dipeptidyl peptidase (DPP)-4 activity was significantly inhibited after 24 weeks of anagliptin treatment, and >75% and >90% inhibitions were observed during the meal tolerance tests with 100 mg and 200 mg anagliptin, respectively. The incidences of adverse or serious adverse events were similar among the three study groups. Twice-daily anagliptin therapy effectively inhibited DPP-4 activity and improved glycemic control and was well-tolerated in patients with type 2 diabetes.

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Dipeptidyl peptidase-4 inhibitor anagliptin ameliorates diabetes in mice with haploinsufficiency of glucokinase on a high-fat diet

Cited by 17 publications

References 34 publications

DPP4 Inhibition Ameliorates Cardiac Function by Blocking the Cleavage of HMGB1 in Diabetic Mice After Myocardial Infarction

DPP4 Inhibition Ameliorates Cardiac Function by Blocking the Cleavage of HMGB1 in Diabetic Mice After Myocardial Infarction

Treatment with DPP-4I Anagliptin or α-GI Miglitol Reduces IGT Development and the Expression of CVD Risk Factors in OLETF Rats

A randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of anagliptin in drug-naïve patients with type 2 diabetes

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Dipeptidyl peptidase-4 inhibitor anagliptin ameliorates diabetes in mice with haploinsufficiency of glucokinase on a high-fat diet

Cited by 17 publications

References 34 publications

DPP4 Inhibition Ameliorates Cardiac Function by Blocking the Cleavage of HMGB1 in Diabetic Mice After Myocardial Infarction

DPP4 Inhibition Ameliorates Cardiac Function by Blocking the Cleavage of HMGB1 in Diabetic Mice After Myocardial Infarction

Treatment with DPP-4I Anagliptin or &alpha;-GI Miglitol Reduces IGT Development and the Expression of CVD Risk Factors in OLETF Rats

A randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of anagliptin in drug-na&iuml;ve patients with type 2 diabetes

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Treatment with DPP-4I Anagliptin or α-GI Miglitol Reduces IGT Development and the Expression of CVD Risk Factors in OLETF Rats

A randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of anagliptin in drug-naïve patients with type 2 diabetes