Biosci. Biotechnol. Biochem., 77 (11), 2305–2308, 2013 Note Inhibition of Postprandial Hyperglycemia by Either an Insulin-Dependent or -Independent Drug Reduces the Expression of Genes Related to Inflammation in Peripheral Leukocytes of OLETF Rats
y Chihiro IMAI,1 Tomomi HARAZAKI,1 Seiya INOUE,1 Kazuki MOCHIZUKI,1;2 and Toshinao GODA1;
1Laboratory of Nutritional Physiology, Graduate School of Nutritional and Environmental Sciences, The University of Shizuoka, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan 2Research Branch 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 June 10, 2013; Accepted July 24, 2013; Online Publication, November 7, 2013 [doi:10.1271/bbb.130451]
Treatment with the dipeptidyl peptidase-4 inhibitor, already been reported that insulin resistance and hyper- anagliptin, or with the -glucosidase inhibitor, miglitol, glycemia in patients with IGT and type 2 diabetes were reduced the oral sucrose load-inducible expression of associated with elevated plasma levels of IL-1 , IL-6, interleukin (IL)-1 , IL-18, tumor necrosis factor- , IL-12, IL-18 and TNF- proteins.5–10) These inflamma- S100a8, S100a9, S100a11, IL-1R2, IL-1Rn and tumor tory cytokines activate macrophages/monocytes and necrosis factor receptor 2 genes in peripheral leukocytes induce the infiltration of macrophages into many tissues, of Otsuka Long-Evans Tokushima fatty (OLETF) rats resulting in the development and progression of arterio- at the stage of impaired glucose tolerance. Inhibiting sclerosis, insulin resistance, apoptosis of islet -cells, postprandial hyperglycemia reduced the expression of nephropathy and other complications.8) One of our genes related to inflammation in peripheral leukocytes previous studies has shown that intermittent treatment of OLETF rats. with miglitol, an inhibitor of -glucosidases that participate in carbohydrate digestion in the small Key words: postprandial hyperglycemia; inflammatory intestine,11) reduced the expression of such inflammatory cytokine; peripheral leukocytes; -glucosi- cytokine genes as IL-1 , IL-18 and TNF- in peripheral dase inhibitor; dipeptidyl peptidase-4 (DPP- leukocytes of low-dose streptozotocin (STZ)-treated rats 4) inhibitor with intermittent postprandial hyperglycemia.12) Such dipeptidyl peptidase-4 (DPP-4) inhibitors, which reduce Many recent studies have demonstrated that patients postprandial hyperglycemia by enhancing gut hormone with type 2 diabetes had a higher subsequent incidence incretins, as glucagon-like peptide-1 (GLP-1) and of such arteriosclerosis-related problems as cardiovas- glucose-dependent insulinotropic polypeptide (GIP) cular disease (CVD). In particular, the development of have recently been developed. These DPP-4 inhibitors CVD in subjects with impaired glucose tolerance (IGT) promote insulin secretion by enhancing the incretin as well as type 2 diabetic patients was related to the concentration in the blood through the inhibition of elevation of postprandial hyperglycemia. Epidemiolog- incretin breakdown. It is most likely that reducing ical studies like the DECODE and Funagata trials have postprandial hyperglycemia by DPP-4 inhibitors would reported that IGT, but not impaired fasting glucose, was reduce the risk of CVD by repressing inflammatory strongly and positively associated with the subsequent cytokine expression in peripheral leukocytes. We exam- incidence of CVD.1,2) In addition, the STOP-NIDDM ined in this study whether either the DPP-4 inhibitor, study on patients with IGT has demonstrated that anagliptin, or miglitol would reduce the expression of inhibiting postprandial hyperglycemia by the -glucosi- the inflammation-related genes in peripheral leukocytes dase inhibitor, acarbose, reduced the development of of Otsuka Long-Evans Tokushima fatty (OLETF) rats, type 2 diabetes and CVD.3,4) The inhibition of post- which exhibit obesity in addition to the late onset of prandial hyperglycemia in patients with IGT and type 2 chronic and slowly progressive hyperinsulinemia, hyper- diabetes is therefore important for suppressing associ- glycemia and hyperlipidemia caused by overeating,13) at ated complications, in particular CVD. Recent studies the stage of IGT. have shown that such inflammatory cytokines as Twenty-four male OLETF rats at 4 weeks of age were interleukin (IL)-1 , IL-6, IL-12, IL-18 and tumor obtained from the Otsuka GEN Research Institute necrosis factor (TNF)- secreted from activated leuko- (Tokushima, Japan). The rats were raised in individual cytes, including neutrophils, monocytes and macro- cages and maintained at a constant temperature phages, were linked to diabetic complications. It has (23 2 C) and humidity (55 5%) under a 12-h
y To whom correspondence should be addressed. Tel: +81-54-264-5533; Fax: +81-54-264-5565; E-mail: [email protected] Abbreviations: ANCOVA, analysis of covariance; ANOVA, analysis of variance; CVD, cardiovascular disease; DPP-4, dipeptidyl peptidase-4; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; HPRT, hypoxanthine-guanine phosphoribosyltransferase; IGT, impaired glucose tolerance; IL, interleukin; IL-1R, interleukin 1 receptor; IL-1Rn, interleukin 1 receptor antagonist; OLETF, Otsuka Long-Evans Tokushima fatty; RAGE, receptor for advanced glycation endproduct; TNF- , tumor necrosis factor- ; TNFR, tumor necrosis factor receptor; SEM, standard error of the mean; STZ, streptozotocin 2306 C. IMAI et al. Table 1. Sequences of Oligonucleotide Primers Used for Real-Time RT-PCR
Target mRNA Sequence 50-TGTGATGAAAGACGGCACAC-30 Interleukin 1 beta (IL-1 ) (#78) 50-CTTCTTCTTTGGGTATTGTTTGG-30 50-CAACGAATCCCAGACCAGAC-30 Interleukin 18 (IL-18) (#76) 50-ACATCCTTCCATCCTTCACAG-30 50-GTCTACTGAACTTCGGGGTGA-30 Tumor necrosis factor alpha (TNF- ) (#63) 50-ATGAGAGGGAGCCCATTTG-30 50-GCCACAAGGAGTAACAGAGCTT-30 S100 calcium binding protein A8 (S100a8) (#26) 50-TGACGACTTTATTCTGTAGACATATCC-30 50-AAGGACTTGCCAAATTTTCTGA-30 S100 calcium binding protein A9 (S100a9) (#85) 50-GGACAGTTGATTGTCCTGGTTT-30 50-CGACCGCATGATGAAGAAG-30 S100 calcium binding protein A11 (S100a11) (#44) 50-AAGCCACCAATAAGGTTGAGAA-30 50-GCAAGGTACACGAATGCAGA-30 Interleukin-1 receptor type 2 (IL-1R2) (#116) 50-CACACCAACTTCCAGAGTGC-30 50-TCTGGAGATGACACCAAGCTC-30 Interleukin-1 receptor antagonist (IL-1Rn) (#25) 50-GCGCTTGTCTTCTTCTTTGTTC-30 50-GAGGCCCAAGGGTCTCAG-30 Tumor necrosis factor receptor 2 (TNFR2) (#1) 50-GCTGCCATGGGAAGAATC-30 50-AGTCAACGGGGGACATAAAA-30 Hypoxanthine-guanine phosphoribosyltransferase (HPRT) (#22) 50-CTTCAACAATCAAGACGTTCTTTC-30