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

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Treatment with DPP-4I Anagliptin Or A-GI Miglitol Reduces IGT Development and the Expression of CVD Risk Factors in OLETF Rats J Nutr Sci Vitaminol, 61, 313–321, 2015 Treatment with DPP-4I Anagliptin or a-GI Miglitol Reduces IGT Development and the Expression of CVD Risk Factors in OLETF Rats Chihiro IMAI1, Tomomi HARAZAKI1, Seiya INOUE1, Kazuki MOCHIZUKI1,2 and Toshinao GODA1,* 1 Laboratory of Nutritional Physiology, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, Shizuoka 422–8526, Japan 2 Laboratory of Food and Nutritional Sciences, Department of Local Produce and Food Sciences, Faculty of Life and Environmental Sciences, University of Yamanashi, Yamanashi 400–8510, Japan (Received November 26, 2014) 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 hyperglyce- mia, reduces the expression of CVD risk factors in an IGT animal model. A DPP-4I, ana- gliptin (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 expres- sion 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 expres- sion of inflammatory cytokines in peripheral leukocytes and adhesion molecules in aortic tissues. Key Words postprandial hyperglycemia, impaired glucose tolerance, cardiovascular dis- ease, inflammatory cytokines, adhesion molecules Recent cohort studies such as Diabetes Epidemiol- or type 2 diabetes (1, 2). Furthermore, the Study To Pre- ogy: Collaborative Analysis of Diagnostic Criteria in vent Non-Insulin-Dependent Diabetes Mellitus (STOP- Europe (DECODE) in Europe and FUNAGATA in Japan NIDDM) trial reported that suppression of postprandial have demonstrated that postprandial hyperglycemia is hyperglycemia in subjects with IGT, the pre-diabetic a strong independent risk factor for the development of stage, by treatment with the a-glucosidase inhibitor cardiovascular diseases (CVD) in subjects with impaired (a-GI) acarbose, which suppresses postprandial hyper- glucose tolerance (IGT), reflecting pre-diabetic subjects, glycemia by inhibiting the carbohydrate digestion in the small intestine, reduces the incidence of CVD as well as * To whom correspondence should be addressed. the development of type 2 diabetes (3). These lines of E-mail: [email protected] evidence indicate that inhibition of postprandial hyper- Abbreviations: a-GI, a-glucosidase inhibitor; ALT, alanine glycemia from the pre-diabetic stage could inhibit CVD aminotransferase; ANOVA, analysis of variance; AST, aspar- development. tate aminotransferase; CVD, cardiovascular diseases; DPP-4, Many previous studies have shown that CVDs are dipeptidyl peptidase-4; DPP-4I, dipeptidyl peptidase-4 inhibi- related to activation of leukocytes such as neutrophils, tor; GLP, glucagon-like peptide; g-GTP, g-glutamyl transpep- monocytes, and macrophages, and associated disorders tidase; HDL, high-density lipoprotein; HUVECs, human um- bilical vein endothelial cells; ICAM, intercellular adhesion of vascular endothelial function. Postprandial hypergly- molecule; IFN, interferon; IGT, impaired glucose tolerance; IL, cemia activates the leukocytes through the production interleukin; LDL, low-density lipoprotein; NEFA, non-esterified of reactive oxygen species (ROS) by activated neutro- fatty acid; OGTT, oral glucose tolerance test; OLETF rat, Otsuka phils and enhanced glucose metabolism in mitochon- Long-Evans Tokushima Fatty rat; ROS, reactive oxygen species; dria (4). The activated leukocytes secrete inflammatory TG, triacylglycerol; TNF, tumor necrosis factor; STZ, strepto- cytokines such as interleukin (IL)-1b and tumor necro- zotocin; VCAM, vascular cell adhesion molecule. sis factor (TNF)-a (5, 6). These inflammatory cytokines 313 314 IMAI C et al. trigger the production of E-selectin, intercellular adhe- ment with the DPP-4I anagliptin or a-GI miglitol, sion molecule (ICAM)-1, and vascular cell adhesion either of which suppresses postprandial hyperglyce- molecule (VCAM)-1, which are adhesion molecules mia, reduces the expression of inflammatory cytokines from the vascular endothelium (7). These adhesion in peripheral leukocytes, adhesion molecules in aortic molecules enhance the attachment of leukocytes, par- tissues, and circulating soluble adhesion molecules in ticularly neutrophils, to the vascular endothelium, and OLETF rats at the pre-diabetic (IGT) stage. the leukocytes then secrete ROS and a protease, neu- MATERIALS AND METHODS trophil elastase, resulting in the induction of vascular endothelium function disorders (8). It has been reported Animals. Twenty-four male OLETF rats, 4 wk of in several cross-sectional studies that circulating IL-1b age, were obtained from the Otsuka GEN Research Insti- and TNF-a concentrations are positively associated with tute (Tokushima, Japan). The rats were bred in indi- moderate obesity, IGT, and/or type 2 diabetes mellitus in vidual cages and maintained at a constant temperature Japan and Western countries (9–11). In addition, pre- (2362˚C) and humidity (5565%) under a 12-h/12-h vious longitudinal and cross-sectional studies including light/dark cycle (lights on: 07:00–19:00). After being Japanese populations have demonstrated that serum fed a standard laboratory diet (MF; Oriental Yeast Co., concentrations of soluble (s) E-selectin in particular, as Ltd., Tokyo, Japan) for 10 d, all rats consumed a 40% well as sICAM-1 and sVCAM-1, are positively associated sucrose solution ad libitum from a water bottle during with arteriosclerosis-related clinical parameters and the the period from 6–10 wk of age. At 4 wk after the start subsequent incidence of CVD in type 2 diabetic patients of sucrose solution administration, the rats were given (12–15). These results indicate that circulating levels regular water and fed a high carbohydrate experimental of inflammatory cytokines such as IL-1b and TNF-a, rodent diet (control diet) until 13 wk of age. The diet was and soluble adhesion molecules such as sE-selectin, based on the recommendations of the American Insti- sICAM-1, and sVCAM-1 could be indicators for subse- tute of Nutrition (AIN) (21) and contained 20% (w/w) quent development of CVD as well as type 2 diabetes. casein, 27.8% cornstarch, 27.8% sucrose, 9.5% corn oil, Our previous study demonstrated that treatment with 5% lard, 3.5% AIN93 vitamin mix, 1% AIN93G mineral miglitol, an a-GI that effectively represses postprandial mix, 5% cellulose, 0.3% L-cystine, and 0.25% choline hyperglycemia earlier than other a-GIs such as acarbose bitartrate. The rats were then assigned to one of three and voglibose, from the pre-diabetic stage reduced the groups (n58) without significant differences in their expression of inflammatory cytokine genes (IL-1b, TNF- 14-h-fasted plasma glucose concentrations [mean6 a, IL-6, and interferon (IFN)-g) in peripheral leukocytes standard error of the mean (SE): 142.761.8 mg/ of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a dL], hemoglobin A1c (4.860.1%), or body weight model of natural type 2 diabetes development (16). Fur- (453.161.2 g). From 13 wk of age, the control group thermore, our recent study revealed that increases in rats were fed a control diet, the miglitol group rats were the IL-1b, TNF-a, and S100a8/9/11 mRNA levels in the fed a diet containing 600 ppm (0.6 g/1,000 g diet) peripheral leukocytes of OLETF rats at the IGT stage by a miglitol, and the anagliptin group rats were fed a diet single oral sucrose loading were suppressed by adminis- containing 1,200 ppm (1.2 g/1,000 g diet) anagliptin. tration of a dipeptidyl peptidase (DPP)-4 inhibitor (DPP- Both drugs were provided by Sanwa Kagaku Kenkyusho 4I), anagliptin, or an a-GI, miglitol (17). S100 proteins Co. Ltd. (Aichi, Japan), and replaced in cellulose. All rats are known to be diagnostic inflammatory markers for were allowed free access to their respective diet and tap cancer, Kawasaki disease, Alzheimer disease, and diabe- water for 47 wk. At 11, 25, and 39 wk after the start of tes, and some of them (S100a8/9/12) are also thought the experimental diets, following a 14-h fast, blood sam- to be cytokine-like factors (18). DPP-4I treatment sup- ples were collected from the tail vein using a capillary presses postprandial hyperglycemia by promoting insu- tube (Terumo Co. Ltd., Tokyo, Japan). All rats were sub- lin secretion through enhanced levels of the biologically jected to an oral glucose tolerance test (OGTT) at 45 wk active peptides incretins in the blood by inhibition of after the start of the experimental diets. Plasma samples their breakdown, with a smaller risk of the incidence of for glucose analyses and blood RNA extractions were hypoglycemia in type 2 diabetic patients (19, 20). Thus, collected from the tail vein. The rats were euthanized it appears that treatment of pre-diabetic animals with by decapitation in a non-fasting state at 47 wk after the either insulin-independent drugs (a-GIs) or insulin- start of the experimental diets (60 wk of age), and arte- dependent drugs (DPP-4Is) can reduce the expression of rial blood and aortic tissues were collected.
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