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1.
J Diabetes Investig ; 13(12): 2073-2080, 2022 Dec.
Article in English | MEDLINE | ID: mdl-35980305

ABSTRACT

AIMS/INTRODUCTION: To investigate the recognition status of stigma/advocacy in patients with type 2 diabetes in clinical practice settings. METHOD: A questionnaire survey on stigma/advocacy of patients with diabetes was carried out for members of the Kanagawa Physicians Association in July 2021. RESULTS: The respondents consisted of 33 (16.6%) physicians specializing in diabetes (the D group) and 166 (83.4%) non-specialists (the ND group). 100% of the D group and 48.8% of the ND group knew that patients may be prejudiced or discriminated against because of diabetes. In the question of whether they know the terms 'stigma' and 'advocacy', 'know' was 97.0% and 94.0% in the D group, compared with 45.8% and 36.7% in the ND group, respectively. 97.0% of the D group and 19.9% of the ND group know the advocacy activities of the Japanese Diabetes Society (JDS) and the Japan Association for Diabetes Education (JADEC). The specific contents of the stigma were often unknown or never experienced in the ND group. A free description of the strategy for reducing or eliminating stigma was analyzed by text mining. 'Giving consideration to the patients' feelings', 'Commitment to the problem', and 'Dialogue' were frequent, and there was no significant difference between the two groups. CONCLUSIONS: The clinician's understanding of stigma/advocacy associated with having diabetes was insufficient, and activities that alert clinicians to stigma/advocacy, especially those in the ND group, was a theme to be addressed. More awareness-raising activities for stigma/advocacy will lead to better treatment and a better quality of life for patients with diabetes.


Subject(s)
Diabetes Mellitus, Type 2 , Physicians , Humans , Quality of Life , Japan/epidemiology , Surveys and Questionnaires
2.
Physiol Rep ; 9(17): e15000, 2021 09.
Article in English | MEDLINE | ID: mdl-34491001

ABSTRACT

Autophagy is an evolutionarily conserved cellular catabolic process essential for cell homeostasis, and thus its failure is associated with several diseases. While autophagy has been reported to play a role in vascular smooth muscle cells (SMCs) in vascular disorders, its precise role in the pathogenesis of abdominal aortic aneurysm (AAA) has not yet been elucidated. In this study, we investigated the role of SMC autophagy in AAA formation. As a mouse model of AAA, we used control apolipoprotein E-deficient (apoeKO) mice and Atg7cKO (SMC-specific Atg7-deficient mice):apoeKO mice administered angiotensin II for 4 weeks. Intriguingly, Kaplan-Meier curves showed that the survival rates of Atg7cKO:apoeKO mice were significantly higher than those of apoeKO mice. The hematoma area in AAA of Atg7cKO:apoeKO mice was smaller than in apoeKO mice despite the lack of a significant difference in AAA incidence between the two groups. Furthermore, the amount of granulomatous tissues was significantly larger and the collagen-positive area within AAA was significantly larger in Atg7cKO:apoeKO mice than in apoeKO mice. In accordance with these findings, SMCs cultured from Atg7cKO mice showed increased expression of collagens, independent of angiotensin II action. Taken together, our data suggest that defective autophagy in SMCs elicits AAA healing that may underlie the better survival rate under dyslipidemia and angiotensin II infusion.


Subject(s)
Angiotensin II/toxicity , Aortic Aneurysm, Abdominal/pathology , Autophagy/physiology , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/pathology , Angiotensin II/administration & dosage , Animals , Aortic Aneurysm, Abdominal/chemically induced , Autophagy/drug effects , Cells, Cultured , Infusion Pumps, Implantable , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Muscle, Smooth, Vascular/drug effects , Myocytes, Smooth Muscle/drug effects
3.
J Clin Med Res ; 13(8): 425-433, 2021 Aug.
Article in English | MEDLINE | ID: mdl-34527098

ABSTRACT

BACKGROUND: Estimating the nutritional content of food is essential for self-management in people with type 2 diabetes mellitus, but it is a difficult skill to learn. The aim of this study was to investigate how diabetes management was impacted by the ability of patients to search for items they ate from a database of 26,300 different foods, and to visualize nutritional intake using the Japanese mobile application (app) "Calomeal." METHODS: This was a single-arm, single-center, pilot study. Eighteen outpatients with type 2 diabetes mellitus used the "Calomeal" app for 3 months. The primary endpoint was change in hemoglobin A1c (HbA1c). Secondary endpoints were changes in body weight (BW), lipid parameters, and quality of life scores. RESULTS: The baseline characteristics of the study subjects were as follows: age: 53.4 ± 7.8 years; male/female ratio: 11/7; HbA1c: 7.9 (7.58 - 8.23)%; and body mass index (BMI): 25.17 (21.63 - 28.59) kg/m2. Significant reductions in HbA1c and BMI were observed over 3 months (HbA1c: 7.9 (7.58 - 8.23)% to 7.6 (7.3 - 8.23)%, P = 0.0410; BMI: 25.17 (21.63 - 28.59) to 24.54 (21.57 - 27.81) kg/m2, P = 0.0057). Reductions in HbA1c and BMI both correlated with decreased carbohydrate intake estimated by the mobile app. CONCLUSIONS: Japanese patients who used their smartphones to visualize their nutritional intake using the "Calomeal" app demonstrated improved short-term glycemic control and BMI. Although the validity of the results should be tested in future randomized controlled trials, this approach may be a clinical option for improving self-management in Japanese patients with type 2 diabetes mellitus.

4.
Nutrients ; 13(2)2021 Feb 08.
Article in English | MEDLINE | ID: mdl-33567701

ABSTRACT

The aim of this study was to investigate the effects of 24-week synbiotic supplementation on chronic inflammation and the gut microbiota in obese patients with type 2 diabetes. We randomized 88 obese patients with type 2 diabetes to one of two groups for 24 weeks: control or synbiotic (Lacticaseibacillus paracasei strain Shirota (previously Lactobacillus casei strain Shirota) and Bifidobacterium breve strain Yakult, and galactooligosaccharides). The primary endpoint was the change in interleukin-6 from baseline to 24 weeks. Secondary endpoints were evaluation of the gut microbiota in feces and blood, fecal organic acids, high-sensitivity C-reactive protein, lipopolysaccharide-binding protein, and glycemic control. Synbiotic administration for 24 weeks did not significantly affect changes in interleukin-6 from baseline to 24 weeks (0.35 ± 1.99 vs. -0.24 ± 1.75 pg/mL, respectively). Relative to baseline, however, at 24 weeks after synbiotic administration there were positive changes in the counts of Bifidobacterium and total lactobacilli, the relative abundances of Bifidobacterium species such as Bifidobacterium adolescentis and Bifidobacterium pseudocatenulatum, and the concentrations of acetic and butyric acids in feces. No significant changes in inflammatory markers were found in the synbiotic group compared to the control group. However, synbiotic administration at least partially improved the gut environment in obese patients with type 2 diabetes.


Subject(s)
Diabetes Mellitus, Type 2/microbiology , Gastrointestinal Microbiome/physiology , Obesity/microbiology , Synbiotics/administration & dosage , Aged , Bifidobacterium breve , C-Reactive Protein/analysis , Chronic Disease , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Feces/microbiology , Female , Humans , Inflammation , Inflammation Mediators/blood , Lacticaseibacillus casei , Male , Middle Aged , Obesity/blood , Obesity/complications , Treatment Outcome
5.
J Endocr Soc ; 3(1): 42-51, 2019 Jan 01.
Article in English | MEDLINE | ID: mdl-30560227

ABSTRACT

CONTEXT: Accurate glucagon level measurements are necessary for investigation of mechanisms for postprandial hyperglycemia in type 2 diabetes. OBJECTIVE: To evaluate the accuracy of postprandial glucagon level measurements using a sandwich ELISA vs a recently established liquid chromatography-high resolution mass spectrometry (LC-HRMS) method in type 2 diabetes mellitus. DESIGN AND PARTICIPANTS: Twenty patients with type 2 diabetes treated with insulin underwent a meal test before and after administration of the dipeptidyl peptidase-4 inhibitor anagliptin for 4 weeks. Blood samples were taken serially after the meal, and glucagon levels were measured using both ELISA and LC-HRMS. We compared the change from baseline to 4 weeks (Δ0-4W) using the area under the curve for plasma glucagon during the meal test [area under the curve (AUC)0-3h] measured using ELISA and LC-HRMS. RESULTS: ELISA-based glucagon AUC0-3h was higher than LC-HRMS-based AUC0-3h at baseline and 4 weeks. However, differences in Δ0-4W-AUC0-3h measured using ELISA and LC-HRMS were not statistically significant. Additionally, Δ0-4W-AUC0-3h measured using ELISA and LC-HRMS were strongly correlated (r = 0.87, P < 0.001). CONCLUSIONS: Plasma glucagon levels during a meal test in patients with type 2 diabetes measured using ELISA were consistently higher than those measured using LC-HRMS. However, given that the changes in glucagon levels measured using ELISA before and after dipeptidyl peptidase-4 inhibitor therapy were similar to those based on LC-HRMS, this ELISA seems to be useful for evaluating the effect of the drug interventions on postprandial glucagon levels.

6.
Biochem Biophys Res Commun ; 505(4): 1141-1147, 2018 11 10.
Article in English | MEDLINE | ID: mdl-30318118

ABSTRACT

Autophagy is considered as an evolutionarily conserved cellular catabolic process. Defective autophagy has been implicated in various human diseases, including cardiovascular diseases. Recently, we and others demonstrated that defective autophagy in vascular smooth muscle cells (SMCs) promotes the progression of atherosclerosis. In this study, we investigated the role of autophagy in SMCs on plaque instability in vivo. We generated mice with a defect atg7in which is an essential gene for autophagy, in SMCs by crossing Atg7f/f mice with transgelin (Tagln) Cre+/0 mice (Atg7cKO). Then, Atg7cKO and apolipoprotein E (apoe)-deficient (apoeKO) mice were crossed to generate Atg7cKO:apoeKO mice. To generate a mouse model of plaque instability, we conducted to form a tandem stenosis in the carotid artery of Atg7cKO:apoeKO mice and their controls (apoeKO mice) at the age of 10 weeks. At 5 weeks after surgery, the percentage of cross-sectional stenosis area in the operated common carotid artery of Atg7cKO:apoeKO mice was significantly higher than that in apoeKO mice. In addition, thrombus, which was not observed in apoeKO mice, was frequently found in Atg7cKO:apoeKO mice. Furthermore, the number of Berlin blue staining-positive areas, which indicated intraplaque hemorrhage, was significantly higher in Atg7cKO:apoeKO mice than in control apoeKO mice. Taken together, our data suggest that defective autophagy in SMCs enhances plaque instability and the risk of plaque rupture.


Subject(s)
Autophagy , Myocytes, Smooth Muscle/metabolism , Plaque, Atherosclerotic/metabolism , Animals , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Disease Models, Animal , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocytes, Smooth Muscle/pathology , Plaque, Atherosclerotic/pathology , Spinal Stenosis/metabolism , Spinal Stenosis/pathology , Spinal Stenosis/surgery
7.
Autophagy ; 14(11): 1991-2006, 2018.
Article in English | MEDLINE | ID: mdl-30025494

ABSTRACT

Macroautophagy/autophagy is considered as an evolutionarily conserved cellular catabolic process. In this study, we aimed to elucidate the role of autophagy in vascular smooth muscle cells (SMCs) on atherosclerosis. SMCs cultured from mice with SMC-specific deletion of the essential autophagy gene atg7 (Atg7cKO) showed reduced serum-induced cell growth, increased cell death, and decreased cell proliferation rate. Furthermore, 7-ketocholestrerol enhanced apoptosis and the expression of CCL2 (chemokine [C-C motif] ligand 2) with the activation of TRP53, the mouse ortholog of human and rat TP53, in SMCs from Atg7cKO mice. In addition, Atg7cKO mice crossed with Apoe (apolipoprotein E)-deficient mice (apoeKO; Atg7cKO:apoeKO) showed reduced medial cellularity and increased TUNEL-positive cells in the descending aorta at 10 weeks of age. Intriguingly, Atg7cKO: apoeKO mice fed a Western diet containing 1.25% cholesterol for 14 weeks showed a reduced survival rate. Autopsy of the mice demonstrated the presence of aortic rupture. Analysis of the descending aorta in Atg7cKO:apoeKO mice showed increased plaque area, increased TUNEL-positive area, decreased SMC-positive area, accumulation of macrophages in the media, and adventitia and perivascular tissue, increased CCL2 expression in SMCs in the vascular wall, medial disruption, and aneurysm formation. In conclusion, our data suggest that defective autophagy in SMCs enhances atherosclerotic changes with outward arterial remodeling.


Subject(s)
Atherosclerosis/genetics , Autophagy-Related Protein 7/genetics , Autophagy/genetics , Muscle, Smooth, Vascular/physiology , Animals , Aorta/metabolism , Aorta/pathology , Apolipoproteins E/genetics , Atherosclerosis/metabolism , Atherosclerosis/pathology , Autophagy-Related Protein 7/deficiency , Cell Death/genetics , Cells, Cultured , Disease Models, Animal , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscle, Smooth, Vascular/pathology , Plaque, Atherosclerotic/genetics , Plaque, Atherosclerotic/metabolism , Plaque, Atherosclerotic/pathology , Vascular Remodeling/genetics
8.
Diabetes Obes Metab ; 20(11): 2675-2679, 2018 11.
Article in English | MEDLINE | ID: mdl-29893003

ABSTRACT

In the present randomized study, we assessed the efficacy of ipragliflozin compared with sitagliptin in 124 Japanese patients with type 2 diabetes. Sodium-glucose co-transporter-2 inhibitor-naïve and incretin-related agent-naïve patients were randomly assigned to receive additional 50 mg ipragliflozin or sitagliptin. The primary endpoint was the proportion of participants with >0.5% decrease in glycated haemoglobin (HbA1c) without body weight gain at 12 weeks. For secondary endpoints, we measured several biomarkers related to metabolic changes. After 12 weeks, 53.9% of participants in the ipragliflozin and 42.9% in the sitagliptin group reached the primary endpoint (P = 0.32). Decreases in homeostatic model assessment of insulin resistance, body fat percentage and skeletal muscle mass index, and increases in free fatty acids, ketone body concentration and HDL cholesterol levels were greater in the ipragliflozin group. Increases in homeostatic model assessment of ß-cell function and decreases in proinsulin-to-insulin ratio were greater in the sitagliptin group. No serious adverse events occurred in either group. In conclusion, ipragliflozin had beneficial effects on fat reduction, insulin resistance and lipid metabolism, while sitagliptin had beneficial effects on ß-cell function.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Glucosides/therapeutic use , Sitagliptin Phosphate/therapeutic use , Thiophenes/therapeutic use , Adult , Aged , Asian People , Blood Glucose/drug effects , Blood Glucose/metabolism , Body Weight/drug effects , Diabetes Mellitus, Type 2/blood , Female , Humans , Japan , Male , Middle Aged
9.
Biochem Biophys Res Commun ; 496(2): 328-334, 2018 02 05.
Article in English | MEDLINE | ID: mdl-29337057

ABSTRACT

Autophagy in ß cells has been demonstrated to play a pivotal role in cellular homeostasis and the progression of glucose intolerance. Although autophagic activity is affected by metabolic stress both in vivo and in vitro, it remains unclear as to what extent the autophagic status in each ß cell is different from its neighboring cells. To address this question, GFP-LC3 reporter mice, which can visualize the autophagic status of each ß cell as green-fluorescent puncta, were crossed with obese diabetic db/db mice. Imaging of green-fluorescent puncta in the islets of GFP-LC3 mice revealed that ß cells are a heterogeneous population, as the density of GFP-LC3 puncta in each cell was variable. Furthermore, the variability was greater in GFP-LC3; db/db mice than in non-diabetic GFP-LC3; db/+ mice. Furthermore, when GFP-LC3 mice were treated with a low dose of S961, which antagonizes insulin signaling without inducing overt hyperglycemia, the number of ß cells with a high density of GFP puncta was increased, suggesting that insulin resistance affects autophagic status independently of glucose profiles. These results suggest that pancreatic ß cells under metabolic stress are heterogeneous regarding their autophagic status, which provides insights into the cellular dynamics of each ß cell rather than the whole ß-cell population.


Subject(s)
Autophagy/drug effects , Glucose/metabolism , Insulin-Secreting Cells/metabolism , Microtubule-Associated Proteins/genetics , Peptides/drug effects , Receptor, Insulin/genetics , Animals , Autophagy/genetics , Cell Count , Cells, Cultured , Crosses, Genetic , Gene Expression Regulation , Genes, Reporter , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/pathology , Mice , Mice, Inbred C57BL , Mice, Obese , Mice, Transgenic , Microtubule-Associated Proteins/metabolism , Peptides/pharmacology , Receptor, Insulin/antagonists & inhibitors , Receptor, Insulin/metabolism , Signal Transduction , Single-Cell Analysis
10.
Expert Opin Pharmacother ; 18(18): 1921-1928, 2017 Dec.
Article in English | MEDLINE | ID: mdl-29141460

ABSTRACT

BACKGROUND: This study investigated the safety and efficacy of metformin up-titration in Japanese patients with type 2 diabetes mellitus treated with vildagliptin (100 mg/day) and low-dose metformin (500 or 750 mg/day). RESEARCH DESIGN AND METHODS: Fifty patients were randomly allocated to the control group (maintaining the initial low-dose of metformin) and the dose increase group (up-titrating of metformin to 1,500-2,250 mg/day) for 24 weeks. The primary outcome was change in HbA1c from baseline to 24 weeks. RESULTS: Among the 25 patients allocated to the dose increase group, four patients were not able to complete the study protocol because of gastrointestinal symptoms. HbA1c in the dose increase group was significantly but modestly lower than in the control group (change in HbA1c: 0.22 ± 0.57 vs. -0.15 ± 0.58%, group comparison, P < 0.05). The dose increase group did not gain weight during the study period, and no hypoglycemic events were reported in both groups. The rate of gastrointestinal symptoms in the dose increase group was profoundly higher than in the control group (32 vs. 0%, P < 0.01). CONCLUSIONS: In Japanese patients with type 2 diabetes treated with vildagliptin and low-dose metformin, metformin up-titration significantly but modestly improved glycemic control without hypoglycemia and weight gain.


Subject(s)
Adamantane/analogs & derivatives , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Metformin/therapeutic use , Nitriles/therapeutic use , Pyrrolidines/therapeutic use , Adamantane/adverse effects , Adamantane/therapeutic use , Aged , Blood Glucose/analysis , Body Weight , Drug Therapy, Combination , Female , Glycated Hemoglobin/analysis , Humans , Hypoglycemia/etiology , Japan , Male , Metformin/adverse effects , Middle Aged , Nitriles/adverse effects , Pyrrolidines/adverse effects , Treatment Outcome , Vildagliptin
11.
Sci Rep ; 7(1): 12115, 2017 09 21.
Article in English | MEDLINE | ID: mdl-28935921

ABSTRACT

Gut bacterial translocation to the blood may play an important role in the development of insulin resistance in type 2 diabetes. Here, we performed an interventional randomised control study to investigate whether probiotics could reduce bacterial translocation and cause changes in the gut microbiota. Seventy Japanese patients with type 2 diabetes were randomised to two groups: the probiotic group drank Lactobacillus casei strain Shirota-fermented milk, while the control group ingested no probiotics. The trial was conducted for 16 weeks. At baseline, 8 and 16 weeks, the gut microbiota composition in feces and blood, fecal organic acids, and other biochemical parameters were measured. At the end of the study, the fecal counts of the Clostridium coccoides group and Clostridium leptum subgroup in the probiotic group were significantly higher than in the control group. As expected, the fecal counts of total Lactobacillus were significantly higher in the probiotic group. Intriguingly, the total count of blood bacteria was significantly lower in the probiotic group. However, fecal organic acids were comparable between the two groups. Our results showed that probiotic administration reduced bacterial translocation and altered the gut microbiota in Japanese patients with type 2 diabetes mellitus.


Subject(s)
Diabetes Mellitus, Type 2/microbiology , Diabetes Mellitus, Type 2/therapy , Feces/microbiology , Gastrointestinal Microbiome , Lacticaseibacillus casei/physiology , Probiotics/therapeutic use , Aged , Animals , Clostridium/isolation & purification , Colony Count, Microbial , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/epidemiology , Female , Fermentation , Humans , Japan/epidemiology , Male , Microbiota , Middle Aged , Milk/microbiology
12.
Int J Endocrinol ; 2015: 406394, 2015.
Article in English | MEDLINE | ID: mdl-26366172

ABSTRACT

Epidemiological data suggest that postprandial hyperglycaemia and hypoglycaemia are potential risk factors for cardiovascular disease. However, the effects of repetitive postprandial glucose spikes, repetitive hypoglycaemia, and their combination on the progression of atherosclerosis remain largely unknown. The present study investigated the effects of rapid rises and falls in glucose, and their combination, on the progression of atherosclerosis in apolipoprotein (apo) E-deficient mice. In this study, apo E-deficient mice with forced oral administration of glucose twice daily for 15 weeks were used as a model of repetitive postprandial glucose spikes, and apo E-deficient mice given an intraperitoneal injection of insulin once a week for 15 weeks were used as a model of repetitive hypoglycaemia. In addition, we established a model of both repetitive postprandial glucose spikes and hypoglycaemia by combining the above interventions. Atherosclerosis was evaluated in all mice by oil red O staining. Administration of ipragliflozin, a selective inhibitor of sodium-glucose cotransporter 2, in the mouse model of repetitive glucose spikes inhibited the progression of atherosclerosis, whereas long-term repetitive glucose spikes, repetitive hypoglycaemia, and their combination had no significant impact on atherosclerosis. However, repetitive hypoglycaemia was associated with poor survival rate. The results showed that repetitive hypoglycaemia reduces the survival rate without associated progression of atherosclerosis in apo E-deficient mice.

13.
Int J Nephrol ; 2014: 164125, 2014.
Article in English | MEDLINE | ID: mdl-24829798

ABSTRACT

Aim. Chronic kidney disease (CKD) represents endothelial dysfunction. Monocyte adhesion is recognized as the initial step of arteriosclerosis. Indoxyl sulfate (IS) is considered to be a risk factor for arteriosclerosis in CKD. Oral adsorbent AST-120 retards deterioration of renal function, reducing accumulation of IS. In the present study, we determined the monocyte adhesion in the adenine-induced uremic rats in vivo and effects of AST-120 on the adhesion molecules. Methods. Twenty-four rats were divided into control, control+AST-120, adenine, and adenine+AST-120 groups. The number of monocytes adherent to the endothelium of thoracic aorta by imaging the entire endothelial surface and the mRNA expressions of adhesion and atherosclerosis-related molecules were examined on day 49. The mRNA expressions of ICAM-1 and VCAM-1 in human umbilical vein endothelial cells were also examined. Results. Adenine increased the number of adherent monocytes, and AST-120 suppressed the increase. The monocyte adhesion was related to serum creatinine and IS in sera. Overexpression of VCAM-1 and TGF- ß 1 mRNA in the arterial walls was observed in uremic rats. IS induced increase of the ICAM-1 and VCAM-1 mRNA expressions in vitro. Conclusion. It appears that uremic condition introduces the monocyte adhesion to arterial wall and AST-120 might inhibit increasing of the monocyte adherence with CKD progression.

14.
Endocrinology ; 155(6): 2244-53, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24684300

ABSTRACT

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.


Subject(s)
Carotid Arteries/drug effects , Carotid Artery Injuries/pathology , Epinephrine/blood , Hypoglycemia/metabolism , Insulin/pharmacology , Neointima/chemically induced , Tunica Intima/drug effects , Animals , Carotid Artery Injuries/physiopathology , Cell Cycle/drug effects , Cell Proliferation/drug effects , Hypoglycemia/blood , Hypoglycemia/chemically induced , Male , Muscle, Smooth, Vascular/cytology , Myocytes, Smooth Muscle/cytology , Myocytes, Smooth Muscle/drug effects , Rats
15.
Endocrinology ; 154(3): 1260-70, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23337530

ABSTRACT

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.


Subject(s)
Apolipoproteins E/deficiency , Atherosclerosis/prevention & control , Dipeptidyl Peptidase 4/physiology , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Muscle, Smooth, Vascular/drug effects , Animals , Apolipoproteins E/genetics , Atherosclerosis/pathology , Cell Line , Cell Proliferation/drug effects , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Monocytes/drug effects , Monocytes/metabolism , Monocytes/pathology , Muscle, Smooth, Vascular/pathology , Rats , Tumor Necrosis Factor-alpha/biosynthesis
16.
Biochem Biophys Res Commun ; 415(4): 545-50, 2011 Dec 02.
Article in English | MEDLINE | ID: mdl-22074825

ABSTRACT

The aim of this study was to investigate the role of insulin receptor substrate-2 (IRS-2) mediated signal in macrophages on the accumulation of macrophages in the vascular wall. Mice transplanted with IRS-2(-/-) bone marrow, a model of myeloid cell restricted defect of IRS-2, showed accumulation of monocyte chemoattractant protein-1-expressing macrophages in the vascular wall. Experiments using cultured peritoneal macrophages showed that IRS-2-mediated signal pathway stimulated by physiological concentrations of insulin, not by IL-4, contributed to the suppression of monocyte chemoattractant protein-1 expression induced by lipopolysaccharide. Our data indicated that IRS-2 deficiency in macrophages enhanced their accumulation in the vascular wall accompanied by increased expression of proinflammatory mediators in macrophages. These results suggest a role for insulin resistance in macrophages in early atherosclerogenesis.


Subject(s)
Blood Vessels/immunology , Insulin Receptor Substrate Proteins/deficiency , Macrophages/immunology , Animals , Bone Marrow Transplantation , Chemokine CCL2/metabolism , Insulin Receptor Substrate Proteins/genetics , Mice , Mice, Inbred C57BL
17.
Biochem Biophys Res Commun ; 405(1): 79-84, 2011 Feb 04.
Article in English | MEDLINE | ID: mdl-21215253

ABSTRACT

Glucagon-like peptide-1 is a hormone secreted by L cells of the small intestine and stimulates glucose-dependent insulin response. Glucagon-like peptide-1 receptor agonists such as exendin-4 are currently used in type 2 diabetes, and considered to have beneficial effects on the cardiovascular system. To further elucidate the effect of glucagon-like peptide-1 receptor agonists on cardiovascular diseases, we investigated the effects of exendin-4 on intimal thickening after endothelial injury. Under continuous infusion of exendin-4 at 24 nmol/kg/day, C57BL/6 mice were subjected to endothelial denudation injury of the femoral artery. Treatment of mice with exendin-4 reduced neointimal formation at 4weeks after arterial injury without altering body weight or various metabolic parameters. In addition, in vitro studies of isolated murine, rat and human aortic vascular smooth muscle cells showed the expression of GLP-1 receptor. The addition of 10nM exendin-4 to cultured smooth muscle cells significantly reduced their proliferation induced by platelet-derived growth factor. Our results suggested that exendin-4 reduced intimal thickening after vascular injury at least in part by the suppression of platelet-derived growth factor-induced smooth muscle cells proliferation.


Subject(s)
Neointima/prevention & control , Peptides/therapeutic use , Receptors, Glucagon/agonists , Tunica Intima/drug effects , Vascular System Injuries/drug therapy , Venoms/therapeutic use , Animals , Body Weight/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Exenatide , Glucagon-Like Peptide 1/metabolism , Glucagon-Like Peptide-1 Receptor , Glucose/metabolism , Humans , Mice , Mice, Inbred C57BL , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/pathology , Rats , Signal Transduction , Tunica Intima/pathology , Vascular System Injuries/pathology
18.
Biochem Biophys Res Commun ; 395(4): 477-83, 2010 May 14.
Article in English | MEDLINE | ID: mdl-20382109

ABSTRACT

Epidemiological studies suggest that insulin resistance is an independent risk factor for cardiovascular disease. However, there is little information on the role of insulin resistance in atherosclerogenesis independent of LDL cholesterol level. The aim of this study was to investigate the impact of systemic insulin resistance on monocyte adhesion to endothelial cells and atherosclerotic lesions independent of LDL cholesterol level. KKAy mice are obese mice with spontaneous diabetes and insulin resistance, and normal levels of LDL cholesterol. In parallel with systemic insulin resistance, decreased insulin signal, and the increased expression of monocyte chemoattractant protein-1 (MCP-1) were noted in macrophages isolated from KKAy mice. These mice showed enhanced monocyte adhesion to the endothelial cells of the thoracic artery. Furthermore, these mice showed expanded atherosclerotic lesions when fed high cholesterol diet. Our data indicate that insulin resistance promotes the atherosclerogenesis independent of LDL cholesterol level. Decreased insulin signaling in macrophages associated with systemic insulin resistance could be involved, at least in part, in this pathological process.


Subject(s)
Atherosclerosis/pathology , Endothelium, Vascular/physiology , Insulin Resistance , Monocytes/pathology , Animals , Atherosclerosis/metabolism , Cell Adhesion , Chemokine CCL2/metabolism , Cholesterol, LDL/blood , Cholesterol, LDL/metabolism , Diet , Endothelial Cells/physiology , Female , Macrophages/physiology , Mice , Mice, Inbred Strains , Monocytes/physiology
19.
Diabetes ; 59(4): 1030-7, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20068138

ABSTRACT

OBJECTIVE: Exogenous administration of glucagon-like peptide-1 (GLP-1) or GLP-1 receptor agonists such as an exendin-4 has direct beneficial effects on the cardiovascular system. However, their effects on atherosclerogenesis have not been elucidated. The aim of this study was to investigate the effects of GLP-1 on accumulation of monocytes/macrophages on the vascular wall, one of the earliest steps in atherosclerogenesis. RESEARCH DESIGN AND METHODS: After continuous infusion of low (300 pmol . kg(-1) . day(-1)) or high (24 nmol . kg(-1) . day(-1)) dose of exendin-4 in C57BL/6 or apolipoprotein E-deficient mice (apoE(-/-)), we evaluated monocyte adhesion to the endothelia of thoracic aorta and arteriosclerotic lesions around the aortic valve. The effects of exendin-4 were investigated in mouse macrophages and human monocytes. RESULTS: Treatment with exendin-4 significantly inhibited monocytic adhesion in the aortas of C57BL/6 mice without affecting metabolic parameters. In apoE(-/-) mice, the same treatment reduced monocyte adhesion to the endothelium and suppressed atherosclerogenesis. In vitro treatment of mouse macrophages with exendin-4 suppressed lipopolysaccharide-induced mRNA expression of tumor necrosis factor-alpha and monocyte chemoattractant protein-1, and suppressed nuclear translocation of p65, a component of nuclear factor-kappaB. This effect was reversed by either MDL-12330A, a cAMP inhibitor or PKI(14-22), a protein kinase A-specific inhibitor. In human monocytes, exendin-4 reduced the expression of CD11b. CONCLUSIONS: Our data suggested that GLP-1 receptor agonists reduced monocyte/macrophage accumulation in the arterial wall by inhibiting the inflammatory response in macrophages, and that this effect may contribute to the attenuation of atherosclerotic lesion by exendin-4.


Subject(s)
Atherosclerosis/pathology , Cell Adhesion/physiology , Endothelium, Vascular/physiology , Monocytes/physiology , Peptides/pharmacology , Peptides/therapeutic use , Venoms/pharmacology , Venoms/therapeutic use , Animals , Aorta/physiology , Atherosclerosis/drug therapy , Cell Adhesion/drug effects , Endothelium, Vascular/drug effects , Exenatide , Flow Cytometry , Glucagon-Like Peptide 1/pharmacology , Glucagon-Like Peptide 1/therapeutic use , Glucose Tolerance Test , Humans , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Islets of Langerhans/drug effects , Islets of Langerhans/physiology , Liver/drug effects , Liver/physiology , Lung/drug effects , Lung/physiology , Male , Mice , Mice, Inbred C57BL , Monocytes/drug effects , Reverse Transcriptase Polymerase Chain Reaction
20.
Biochem Biophys Res Commun ; 380(3): 620-6, 2009 Mar 13.
Article in English | MEDLINE | ID: mdl-19285011

ABSTRACT

Alpha-smooth muscle actin-positive endothelial cells have not been found in adult aortic endothelium except valve leaflets. Here, using en face immunostaining method, we identified alpha-smooth muscle actin-positive endothelial cells in the luminal surface of rat, mouse and human thoracic aortas. These cells express both endothelial markers and definite smooth muscle cell markers and were only occasionally observed in thoracic aorta of wild type mice and rats. Their density did not increase with aging. Given that alpha-smooth muscle actin-positive endothelial cells express low level of vascular endothelial-cadherin that is important for the maintenance of cell contact, these cells were frequently detected in the thoracic aorta of 5-week-old apolipoprotein-E deficient mice. In 20- to 24-week-old apolipoprotein-E deficient mice, marked accumulation of alpha-smooth muscle actin-positive endothelial cells was observed especially in the luminal surface of atheromatous plaques. Our findings indicate the existence of alpha-smooth muscle actin-positive endothelial cells in adult aortic endothelium and the possible association with progression of atherosclerosis.


Subject(s)
Actins/metabolism , Aorta, Thoracic/metabolism , Atherosclerosis/metabolism , Endothelium, Vascular/metabolism , Actins/analysis , Aging/metabolism , Animals , Apolipoproteins E/genetics , Humans , Mice , Mice, Mutant Strains , Rats
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