Hiromichi Taniwaki

Matrix Gla protein is associated with coronary artery calcification as assessed by electron-beam computed tomography

Matrix Gla protein (MGP) is an extracellular matrix protein with wide tissue distribution. It has been demonstrated that the expression of MGP is detected not only in the normal blood vessels but also calcified atherosclerotic plaques, and that MGP deficient mice develop extensive arterial calcification. MGP is thought to be a regulator of vascular calcification. A recent clinical study demonstrates the association between polymorphisms of the MGP gene and increased risk of myocardial infarction. However, there are no reports of the relationship between serum MGP levels and coronary artery calcification (CAC). We evaluated the severity of CAC using electron-beam computed tomography (EBCT), and measured serum MGP levels by enzyme-linked immunosorbent assay in 115 subjects with suspected coronary artery disease. CAC scores were correlated with traditional risk factors, such as age, gender, hyper-tension, diabetes, hyperlipidemia and smoking. The serum MGP levels were lower in patients with CAC than in those without CAC (p<0.001). As the severity of CAC increased, there was a significant decrease in serum MGP levels. Serum MGP levels (U/L) were 116.7 +/- 20.3, 104.9 +/- 19.2, 95.2 +/- 15.2 and 82.2 +/- 19.7, (medians 115.5, 105.0, 94.8, and 81.9) for the subjects with normal (CAC score=0), mild (CAC score=1 to 99), moderate (CAC score=100 to 400), and severe (CAC score >400) coronary calcification, respectively. We found that serum MGP levels are inversely correlated with the severity of CAC. These data suggest a possible role for MGP in the development of vascular calcification.

Femoral artery wall thickness and stiffness in evaluation of peripheral vascular disease in type 2 diabetes mellitus.

Stiffening and thickening of arterial wall are two important components of atherosclerosis. The purpose of this study was to evaluate the effects of femoral artery wall stiffness on clinical manifestation of peripheral vascular disease (PVD) in type 2 diabetes mellitus. The subjects were 315 patients with type 2 diabetes. Presence of intermittent claudication and/or leg pain at rest and reduced ankle-brachial blood pressure index (ABI<0.9) were used as a subjective and an objective index of PVD, respectively. Femoral artery intima-media thickness (FA-IMT) and stiffness parameter beta (FA-stiffness beta) were measured by ultrasound methods. Symptomatic patients (N=58) showed greater values for both FA-IMT and FA-stiffness beta than those without symptom (N=257). Similarly, patients with reduced ABI (N=56) had greater FA-IMT and FA-stiffness beta than those without (N=259). However, correlation between FA-IMT and FA-stiffness beta was not impressive, especially in the symptomatic patients. To evaluate the effect of FA-stiffness beta on PVD symptoms, the subjects were divided into three subgroups according to FA-IMT, and then FA-stiffness beta was compared between those with and without PVD symptoms in each subgroup. The symptomatic patients had greater FA-stiffness beta values than the asymptomatic subjects in all the three subgroups. Multiple logistic regression analysis indicated that the presence of PVD symptoms was associated more closely with increased FA-stiffness beta than with increased FA-IMT, whereas reduced ABI was associated more closely with FA-IMT than with FA-stiffness beta. These data suggest that stiffening of arterial wall has a significant impact on PVD manifestations, particularly on the leg symptoms, in patients with type 2 diabetes.

Impaired Endothelium-Dependent Vascular Responses of Retinal and Intrarenal Arteries in Patients With Type 2 Diabetes

Endothelial dysfunction has been implicated in the pathogenesis of diabetic microangiopathies such as retinopathy and nephropathy as well as macrovascular diseases. The aim of the current study was to determine whether endothelial function in the retinal and renal arteries is impaired in type 2 diabetes mellitus. We examined the effects of an intravenous infusion of L-arginine and a sublingual administration of nitroglycerin on the brachial, retinal, and interlobar arterial hemodynamics in 20 type 2 diabetic patients (10 with normoalbuminuria and 10 with microalbuminuria) and 10 aged-matched control subjects. Despite no difference in the nitroglycerin-induced vascular response of the brachial or retinal artery among the 3 groups, the L-arginine-induced vascular response of each artery was significantly lower in both the normoalbuminuric and microalbuminuric patients than in the control subjects and the microalbuminuric patients showed the lowest value among the 3 groups (P<0.01, each artery, respectively). The L-arginine-induced vascular response of each artery was significantly correlated with HbA1c levels (brachial artery, r=0.617, P=0.0003; retinal artery, r=0.599, P=0.0005; interlobar artery, r=0.636, P=0.0002). In addition, stepwise multiple regression analysis of all subjects showed that HbA1c level was an independent determinant for the L-arginine-induced vascular response of each artery. The results showed that the endothelium-dependent vascular responses of the retinal and intrarenal arteries as well as the brachial artery were impaired in diabetic patients before the clinical manifestation of diabetic nephropathy, and suggest that endothelial dysfunction in these arteries is associated with hyperglycemia in these patients.

Different risk factors for vascular calcification in end-stage renal disease between diabetics and nondiabetics: the respective importance of glycemic and phosphate control.

Vascular calcification is highly prevalent in dialysis patients, and significantly increases cardiovascular mortality. The presence and progression of vascular calcification is significantly associated with chronic inflammation and malnutrition. Disorders of mineral metabolism, particularly hyperphosphatemia, have been emphasized as risk factors for vascular calcification. Although vascular calcification has been reported to be highly prevalent in diabetic patients with end-stage renal disease (ESRD), the risk factors for vascular calcification in these patients have not been fully explored. Through a review of the literature and our recent studies examining vascular calcification in ESRD patients, hyperphosphatemia is significantly associated with vascular calcification in nondiabetic ESRD patients, while it may not be a significant risk factor for vascular calcification in diabetic ESRD patients. In diabetic patients, vascular calcification occurs long before the initiation of dialysis therapy, and the factors associated with vascular calcification in non-uremic diabetics appear to be hyperglycemia and related metabolic disorders, such as increased glycation and oxidative stress. In diabetic ESRD patients, hyperglycemia is also suggested to be a significant factor associated with the progression of vascular calcification. Thus, the importance of glycemic and phosphate control is suggested to be emphasized in diabetic and nondiabetic ESRD patients, respectively, for prevention of the progression of vascular calcification.

Diabetes mellitus Worsens Intrarenal Hemodynamic Abnormalities in Nondialyzed Patients with Chronic Renal Failure

Duplex Doppler sonography has been reported to be useful in examining the intrarenal hemodynamic abnormalities in various renal diseases. We investigated the impact of diabetes on intrarenal hemodynamics in patients with chronic renal failure (CRF). The resistive index and pulsatility index of the renal interlobar arteries were measured using duplex Doppler sonography in 90 CRF patients (serum creatinine >130 and <800 mmol/l, mean age 59 ± 11 years). Forty-eight patients had type 2 diabetes and 42 did not. Twenty-nine age-matched, healthy subjects served as controls. Both resistive index and pulsatility index were greater in CRF patients than in the controls (p < 0.0001). No significant differences existed in age, sex, body mass index, total serum cholesterol, serum creatinine, estimated creatinine clearance, or mean blood pressure between the diabetic CRF and nondiabetic CRF groups. Resistive index and pulsatility index were significantly increased in the diabetic CRF patients compared to the nondiabetic CRF patients (p < 0.0001). Multiple regression analysis of all CRF patients revealed that resistive index was independently affected by the presence of type 2 diabetes (F = 44.535), as well as decreased creatinine clearance (F = 18.157) and age (F = 15.160) (R2 = 0.559, p < 0.0001). These results clearly demonstrated that intrarenal arterial resistance is significantly increased in CRF patients with type 2 diabetes compared to similar patients without diabetes. The impact of diabetes mellitus and advanced age on intrarenal hemodynamics may be due to intrarenal arteriosclerosis and interstitital lesions. Measurements of RI values in addition to conventional ultrasound imaging may add further information on such renal lesions.

Gastric Myoelectrical Activity in Patients With Diabetes: Role of glucose control and autonomic nerve function

OBJECTIVE Gastric myoelectrical activity was studied in diabetic patients using electrogastrography (EGG) to elucidate the relationship between glucose control, diabetic autonomic neuropathy (AN), and gastrointestinal motility. RESEARCH DESIGN AND METHODS Cutaneous EGG was recorded during 1 h of fasting and 1 h after the ingestion of a standard meal in 57 diabetic patients and 10 healthy subjects. EGG was measured in 12 diabetic patients after glycemic control for 4 weeks. Diabetic patients were also studied with respect to the presence of gastrointestinal symptoms and AN. RESULTS The percentage of dominant electrical frequency (DF) in normal range (the percentage ratio between the power at 2.4–3.6 cycles/min [cpm] and at 1–10 cpm) was significantly lower in patients with AN than in either the control subjects or the patients without AN (P < 0.01). The dominant frequency instability coefficient (DFIC) was significantly higher in patients with and without AN than in the control subjects (P < 0.01). The postprandial-to-fasting power ratio (PR) was the lowest in patients with AN (P < 0.01). Multiple regression analysis revealed that HbA1c levels were independently associated with the DFIC (R2 = 0.099, P = 0.0170) and that AN and HbA1c levels were independently associated with the PR (R2 = 0.378, P < 0.0001) in diabetic patients. The percentage of normal DF increased and the DFIC decreased significantly after glycemic control in 12 diabetic patients (P = 0.0409; P = 0.0096, respectively). CONCLUSIONS There appears to be an association between improvement in gastric myoelectrical activity and autonomic nerve function. Abnormalities of gastric myoelectrical activity may be partly ameliorated via the improvement of autonomic nerve function, which accompanies glycemic control.

Relationship between Urinary Albumin Excretion and Glomerular Filtration Rate in Normotensive, Nonproteinuric Patients with Type 2 Diabetes mellitus

Background/Aim: In patients with type 2 diabetes mellitus, the relationship between glomerular filtration rate (GFR) and urinary albumin excretion remains an unresolved issue. In order to investigate the early renal function abnormalities, GFR and urinary albumin excretion were assessed, and their relationship was examined in normotensive patients with type 2 diabetes mellitus. Methods: In a cross-sectional study of 85 nonhypertensive Japanese patients with type 2 diabetes mellitus not showing overt proteinuria, the GFR was measured using 99mTc-diethylenetriamine pentaacetate renography. Fifty-one diabetic patients lacked microalbuminuria (albumin excretion <30 mg/day), while 34 patients showed microalbuminuria (between 30 and 300 mg/day). Fifteen healthy subjects served as controls. Results: The three groups were well matched with regard to gender, age, and body mass index. The GFR in microalbuminuric patients (134 ± 23 ml/min/1.48 m2) was significantly higher than in patients without microalbuminuria (108 ± 21 ml/min/1.48 m2) and in controls (109 ± 18 ml/min/1.48 m2; p < 0.0001). In type 2 diabetic patients, the GFR positively correlated with the logarithmically transformed urinary albumin excretion. Multiple regression analysis showed that the urinary albumin excretion was significantly and independently affected by GFR (β = 0.548), duration of diabetes (β = 0.297), and systolic blood pressure (β = 0.232; R2 = 0.409; p < 0.0001). Conclusion: It is suggested that one of the mechanisms underlying increased urinary albumin excretion in early nephropathy in normotensive type 2 diabetes is glomerular hyperfiltration.

Relationship Between Gastric Emptying and an α-Glucosidase Inhibitor Effect on Postprandial Hyperglycemia in NIDDM Patients

OBJECTIVE The purpose of the study was to examine the relationship between gastric emptying and the efficacy of an α-glucosidase inhibitor in NIDDM patients. RESEARCH DESIGN AND METHODS Sixteen NIDDM patients (4 patients treated with diet therapy alone and 12 receiving a sulfonylurea) were given 0.6 mg of voglibose daily for 4 weeks. The efficacy of voglibose was assessed by measurement of HbA1c, fasting plasma glucose, and 45- and 120-min postprandial plasma glucose (PPG) and serum insulin concentrations before and after the 4 weeks of voglibose therapy. Gastric emptying was evaluated using the proportional cumulative area under the absorption curve (% AUC) of plasma acetaminophen concentration at 60 min after ingestion of a liquid test meal containing 20 mg/kg of acetaminophen. These measurements were also taken before and after the therapy. RESULTS The change in the 45-min PPG levels from the fasting state correlated significantly with the % AUC of the plasma acetaminophen concentrations (r = 0.625, P = 0.0096) before the voglibose administrations. The mean 45-min and 2-h PPG levels were reduced significantly after 4 weeks of voglibose (P < 0.05 and P < 0.01, respectively). Two-hour postprandial serum insulin concentrations were also significantly reduced at the end of the treatment period (P < 0.05). The changes in the PPG levels between pre- and posttreatment periods correlated significantly with the % AUC of the plasma acetaminophen concentrations before the treatment period (r = 0.499, P = 0.0490; r = 0.713, P = 0.0019, respectively). There was no significant difference in the plasma acetaminophen concentrations between pre- and posttreatment periods. CONCLUSIONS The rate of gastric emptying affects the efficacy of voglibose therapy in NIDDM patients. Voglibose did not however alter the rate of gastric emptying.