Dipeptyl peptidase-4 (DPP-4) inhibitors modulate the progression of atherosclerosis. To gain insights into their mechanism of action, 9-wk-old male apolipoprotein E (apoE)-deficient mice were fed a DPP-4 inhibitor, anagliptin-containing diet. The effects of anagliptin were investigated in, a monocyte cell line, human THP-1 cells, and rat smooth muscle cells (SMCs). Treatment with anagliptin for 16 wk significantly reduced accumulation of monocytes and macrophages in the vascular wall, SMC content in plaque areas, and oil red O-stained area around the aortic valve without affecting glucose tolerance or body weight. Serum DPP-4 concentrations were significantly higher in apoE-deficient mice than control mice, and the levels increased with aging, suggesting the involvement of DPP-4 in the progression of atherosclerosis. Indeed, soluble DPP-4 augmented cultured SMC proliferation, and anagliptin suppressed the proliferation by inhibiting ERK phosphorylation. In THP-1 cells, anagliptin reduced lipopolysaccharide-induced TNF-α production with inhibiting ERK phosphorylation and nuclear translocation of nuclear factor-κB. Quantitative analysis also showed that anagliptin reduced the area of atherosclerotic lesion in apoE-deficient mice. These results indicated that the anti-atherosclerotic effect of anagliptin is mediated, at least in part, through its direct inhibition of SMC proliferation and inflammatory reaction of monocytes.
Hypoglycemia associated with diabetes management is a potential risk for cardiovascular diseases. However, the effect of hypoglycemic episodes including a surge of sympathetic activity on the progression of neointima formation after vascular injury remains largely unknown. In this study, insulin was injected intraperitoneally into nonobese diabetic Goto-Kakizaki (GK) rats, once every 3 days for 4 weeks after balloon injury of carotid artery to induce hypoglycemia. Then, we evaluated balloon injury-induced neointima formation. Insulin treatment enhanced neointima formation and increased the number of proliferating cell nuclear antigen (PCNA)-positive cells in the carotid artery. Injection of glucose with insulin prevented hypoglycemia and abrogated intimal thickening. Also, bunazosin, an α1 adrenergic receptor antagonist, prevented intimal thickening and accumulation of PCNA-positive cells induced by insulin treatment despite the presence of concomitant hypoglycemia and high adrenaline levels. Incubation of cultured smooth muscle cells with adrenaline resulted in a significant increase in their proliferation and G0/G1 to S phase progression, which was associated with activation of extracellular signal-regulated kinase, enhanced expression of cell cycle regulatory molecules such as cyclin D1, and cyclin E, and phosphorylation of retinoblastoma protein. These adrenaline-induced effects were abrogated by bunazosin. Our data indicated that increased adrenaline induced by repetitive hypoglycemia promotes intimal thickening and smooth muscle cell proliferation after endothelial denudation in GK rats.
Aims/Introduction: The present study was designed to determine the effects of pioglitazone on glycemic control and atherosclerosis in patients with poorly controlled type 2 diabetes on insulin therapy.Materials and Methods: The study was a prospective, randomized controlled trial involving 48 patients with inadequately controlled type 2 diabetes treated with insulin. We assigned patients to oral pioglitazone titrated from 15–30 mg (n = 22) or no pioglitazone (n = 26), to be taken in addition to their glucose‐lowering drugs and other medications. Daily insulin doses and numbers were recorded during the study period.Results: The adjusted mean glycosylated hemoglobin (HbA1c) values decreased significantly by 1.13 ± 1.50% and 0.55 ± 0.76% in the pioglitazone and control groups, respectively. Significant decrease of HbA1c level was observed in the pioglitazone group compared with the control group (P < 0.05). The insulin dose lowered by 0.04 ± 0.10 units/kg/day in the pioglitazone group and increased by 0.03 ± 0.10 units/kg/day in the control group (P < 0.05). The number of insulin injections decreased by 0.1 ± 0.6 times/day in the pioglitazone group and increased by 0.2 ± 0.4 times/day in the control group (P < 0.05). The carotid intima‐media thickness estimated by B‐mode echography was carried out in both groups and decreased significantly at the end‐point only in the pioglitazone group, relative to the baseline.Conclusions: These findings show that pioglitazone is useful in improving glycemic control and preventing the progression of atherosclerosis in poorly‐controlled type 2 diabetics on insulin therapy. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00064.x, 2010)
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