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

Abstract

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 ...

Combining bioinformatics, network pharmacology and artificial intelligence to predict the mechanism of celastrol in the treatment of type 2 diabetes

“…BMP7 gene therapy counteracts insulin resistance and obesity ( 46 ). S100A11 expression is reduced during the treatment of impaired glucose tolerance, further reducing the prevalence of T2D ( 47 ). Of these, HBB is a hub gene and is described in the GeneCards database as a protein-coding gene for HBB.…”

Undernutrition in Pregnant Rats Induces Glucose Intolerance with Enhanced Expression of Inflammation-Related Genes in Peripheral Leukocytes of the Offspring

“…IL-1b mRNA expression in peripheral leukocytes was reported to be higher in patients with T2DM than in healthy subjects (22). In addition, studies in rodent models have demonstrated that pronounced or moderate postprandial hyperglycemia was associated with the enhanced expression of inflammation-related genes including those encoding TNF-a, IL-1b, S100A8, and S100A9 (17,23,24). The S100A8/A9 heterodimer is also known as a ligand of the receptor for advanced glycation end products (RAGE) and is associated with atherogenesis (25).…”

Effects of the Mean Amplitude of Glycemic Excursions and Vascular Endothelial Dysfunction on Cardiovascular Events in Nondiabetic Patients With Coronary Artery Disease

“…Both DM and non‐DM patients who exhibit postprandial hyperglycemia have been reported to have exacerbated insulin resistance and decreased glucagon‐like peptide‐1 levels . These adverse effects on glucose handling and endothelial function can potentially be ameliorated by glycemic variability–reducing drugs, such as dipeptidyl peptidase 4 inhibitors, when taken by nondiabetic patients with high MAGE …”