Fumihiko Sato

Repetitive Fluctuations in Blood Glucose Enhance Monocyte Adhesion to the Endothelium of Rat Thoracic Aorta

Background—The aim of this study was to elucidate the effect of repetitive fluctuations in blood glucose concentrations on monocyte adhesion to the aortic endothelium. Methods and Results—Nonobese type 2 diabetes, Goto–Kakizaki (GK) rats were fed twice daily to induce repetitive postprandial glucose spikes. Then, we compared the number of monocytes adherent to the endothelium of thoracic aorta in these rats with that in rats fed ad libitum. To suppress the glucose spikes, rats were injected with an inhibitor of sodium–glucose transporter, phloridzin, just before each meal for 12 weeks. GK rats fed twice daily showed significantly lower HbA1c than GK rats fed ad libitum. However, the former group showed markedly higher number of monocytes adherent to the endothelium than the latter, together with increased arterial intimal thickening. Phloridzin significantly reduced the number of adherent monocytes in GK rats fed twice daily. Conclusion—Our data demonstrated that repetitive postprandial fluctuation in glucose concentration evokes monocyte adhesion to endothelial cells that was worse than that induced by stable hyperglycemia in vivo. Suppression of such fluctuations efficiently suppressed monocyte adhesion to the aortic endothelium.

Nateglinide Reduces Carotid Intima-Media Thickening in Type 2 Diabetic Patients Under Good Glycemic Control

Objective—Postprandial hyperglycemia observed in type 2 diabetes mellitus is a risk factor for atherosclerosis. The aim of this study was to investigate the effect of strict glycemic control by nateglinide on common carotid far wall intima-media thickness in type 2 diabetic patients who were already under good glycemic control. Methods and Results—We performed an open labeled randomized prospective trial on 78 drug-naive type 2 diabetic patients whose HbA1c was less than 6.5%. Thirty-eight patients were randomly assigned to receive nateglinide (270 mg/dL) and 40 to control group (no treatment). After 12 months, a significant reduction in HbA1c was observed in the nateglinide group, whereas a significant increase of HbA1c was observed in the untreated group. The carotid intima-media thickness at the end of 1-year follow-up was significantly reduced in the nateglinide group compared with the untreated group (−0.017±0.054 mm/year versus 0.024±0.066 mm/year, P=0.0064). Whereas nateglinide treatment also reduced triglyceride, highly-sensitive C-reactive protein, and E-selectin, multiple regression analysis identified HbA1c as the only significant independent determinant of the change in carotid intima-media thickness. Conclusion—In type 2 diabetic patients with good glycemic control, further strict glycemic control by nateglinide results in regression of carotid intima-media thickness.

Amelioration of glucose tolerance by hepatic inhibition of nuclear factor κB in db/db mice

Aims/hypothesisRecent studies have identified the involvement of inhibitor IκB kinase (IKK) in the pathogenesis of insulin resistance. To investigate the mechanism involved, we examined the role of nuclear factor κB (NF-κB), the distal target of IKK, in hepatic glucose metabolism.MethodsTo inhibit NF-κB activity, db/db mice were infected with adenovirus expressing the IκBα super-repressor.ResultsThe IκBα super-repressor adenovirus infection caused a moderate reduction of NF-κB activity in liver. The treatment was associated with improved glucose tolerance, reduction in the serum insulin level, and increased hepatic triacylglycerol and glycogen contents, but had no effect on insulin-stimulated phosphorylation of Akt. On the other hand, quantification of mRNA in the liver revealed marked reduction of expression of gluconeogenic genes, such as those encoding phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, concurrent with reduced expression of gene encoding peroxisome proliferator-activated receptor gamma coactivator-1α (PPARGC1A, also known as PGC-1α). Furthermore, the production of super-repressor IκBα suppressed the increase in blood glucose level after pyruvate injection.Conclusions/interpretationOur results indicate that moderate inhibition of NF-κB improved glucose tolerance through decreased gluconeogenesis associated with reduced PGC-1α gene expression in db/db mice, and suggest that inhibition of NF-κB activity in liver is a potentially suitable strategy for the normalisation of blood glucose concentration in type 2 diabetes.

Influencing factors on cardiac structure and function beyond glycemic control in patients with type 2 diabetes mellitus

BackgroundWe hypothesized that clinical factors other than glycemic control may influence abnormal cardiac function in patients with type 2 diabetes mellitus (T2DM). We aimed to investigate the independent factors for abnormal cardiac function among clinical factors in T2DM.MethodsWe studied 148 asymptomatic patients with T2DM without overt heart disease. Echocardiographic findings were compared between diabetic patients and 68 age-matched healthy subjects. Early (E) and late (A) diastolic mitral flow velocity and early diastolic mitral annular velocity (e’) were measured for assessing left ventricular (LV) diastolic function. We evaluated insulin resistance, non-esterified fatty acid, high-sensitive CRP, estimated glomerular filtration rate, waist/hip ratio, abdominal visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and other clinical characteristics in addition to glycemic control. VAT and SAT were quantified by computed tomography.ResultsIn T2DM, E/A and e’ were significantly lower, and E/e’, left atrial volume and LV mass were significantly greater than in control subjects. In multivariate liner regression analysis, VAT was an independent determinant of left atrial volume (β =0.203, p=0.011), E/A (β =−0.208, p=0.002), e’ (β =−0.354, p<0.001) and E/e’ (β=0.220, p=0.003). Age was also an independent determinant, whereas fasting plasma glucose and hemoglobin A1c levels were not. In addition to systolic blood pressure, waist-hip ratio (β=0.173, p=0.024) and VAT/SAT ratio (β=0.162, p=0.049) were independent determinants of LV mass.ConclusionExcessive visceral fat accompanied by adipocyte dysfunction may play a greater role than glycemic control in the development of diastolic dysfunction and LV hypertrophy in T2DM.

Effects of metformin on peripheral insulin sensitivity and intracellular lipid contents in muscle and liver of overweight Japanese subjects

Aim:  Recent studies suggest that insulin resistance is associated with increased intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) contents. While metformin improves insulin resistance mainly in liver, its effects on IHL and IMCL have not been clarified yet. The aim of this study was to investigate the effects of low‐dose metformin (750 mg/day) on peripheral insulin sensitivity, IHL and IMCL.

Determinants of intramyocellular lipid accumulation after dietary fat loading in non‐obese men

Aims/Introduction:  Accumulation of intramyocellular lipid (IMCL) is associated with insulin resistance. However, the factors affecting the change in IMCL remain to be elucidated. The aim of the present study was to determine the factors that influence the change in IMCL level after high‐fat loading.

Exercise-induced enhancement of insulin sensitivity is associated with accumulation of M2-polarized macrophages in mouse skeletal muscle.

Exercise enhances insulin sensitivity in skeletal muscle, but the underlying mechanism remains obscure. Recent data suggest that alternatively activated M2 macrophages enhance insulin sensitivity in insulin target organs such as adipose tissue and liver. Therefore, the aim of this study was to determine the role of anti-inflammatory M2 macrophages in exercise-induced enhancement of insulin sensitivity in skeletal muscle. C57BL6J mice underwent a single bout of treadmill running (20 m/min, 90 min). Twenty-four hours later, ex vivo insulin-stimulated 2-deoxy glucose uptake was found to be increased in plantaris muscle. This change was associated with increased number of CD163-expressing macrophages (i.e. M2-polarized macrophages) in skeletal muscle. Systemic depletion of macrophages by pretreatment of mice with clodronate-containing liposome abrogated both CD163-positive macrophage accumulation in skeletal muscle as well as the enhancement of insulin sensitivity after exercise, without affecting insulin-induced phosphorylation of Akt and AS160 or exercise-induced GLUT4 expression. These results suggest that accumulation of M2-polarized macrophages is involved in exercise-induced enhancement of insulin sensitivity in mouse skeletal muscle, independently of the phosphorylation of Akt and AS160 and expression of GLUT4.

Morningness–eveningness questionnaire score correlates with glycated hemoglobin in middle-aged male workers with type 2 diabetes mellitus

‘Morningness’ and ‘eveningness’ represent the sleep–wake patterns of the circadian rhythm might also affect glycemic control in patients with type 2 diabetes. The aim of this study was to examine the relationship between the morningness–eveningness trait and metabolic parameters.

Effects of sitagliptin on ectopic fat contents and glucose metabolism in type 2 diabetic patients with fatty liver: A pilot study

Recent data have shown that ectopic fat accumulation in the liver worsens hepatic glucose metabolism, suggesting that fatty liver in patients with type 2 diabetes is a therapeutic target. Glucagon‐like peptide (GLP)‐1 improves fatty liver, but the effect of dipeptidyl peptidase‐4 inhibitor on fatty liver is still unclear. The present pilot study determined the effects of 12‐week treatment with sitagliptin, a dipeptidyl peptidase‐4 inhibitor, on liver fat content in type 2 diabetes with fatty liver. We also evaluated intramyocellular lipid (IMCL) and glucose kinetics during oral glucose tolerance test (OGTT) before and after the treatment.

Efficacy and safety of nateglinide plus vildagliptin combination therapy compared with switching to vildagliptin in type 2 diabetes patients inadequately controlled with nateglinide

To investigate the efficacy and safety of vildagliptin, a potent dipeptidyl peptidase‐4 inhibitor, as add‐on to nateglinide, compared with switching to vildagliptin in Japanese type 2 diabetes patients poorly controlled with nateglinide.