Toshihiko Inukai

Serum concentrations of advanced glycation endproducts are associated with the development of atherosclerosis as well as diabetic microangiopathy in patients with type 2 diabetes

Abstract We measured serum concentrations of advanced glycation endproducts (AGEs) in patients with type 2 diabetes, to elucidate the mechanisms underlying the elevated serum concentrations of AGEs and to clarify the relationship between serum AGE concentrations and the development of microangiography and macroangiopathy. Serum AGEs were significantly higher in diabetic patients than in age-matched control subjects (p < 0.0001). In diabetic patients, serum AGEs were positively correlated with HbA1c (r = 0.47, p < 0.0001), urinary albumin excretion (UAE) (r = 0.42, p < 0.0001), diabetes duration (r = 0.31, p = 0.0030), and fasting plasma glucose (r = 0.34, p = 0.0010). Multiple regression analysis disclosed that only the HbA1c and UAE levels independently correlated with serum AGE levels. Serum AGEs in diabetic patients with progressive retinopathy and overt nephropathy were significantly higher than in those with less severe retinopathy and nephropathy. Serum AGEs were significantly higher in the diabetic patients with coronary heart disease (CHD) than in those without CHD. These results suggest that the HbA1c and UAE levels are independent risk factors for increased serum AGE concentrations in type 2 diabetic patients, and that higher serum AGE concentrations are associated with increased severity of diabetic retinopathy and nephropathy. Serum AGE concentrations may be a useful marker not only for the severity of diabetic microangiopathy but also for the development of CHD in patients with type 2 diabetes mellitus.

Relationship between soluble thrombomodulin in plasma and coagulation or fibrinolysis in type 2 diabetes

Serum concentration of soluble thrombomodulin (TM) is thought to be a marker for endothelial damage. Although several studies have reported that serum TM concentrations are increased in patients with diabetes mellitus, there is little information on the physiological function of soluble TM in human plasma. To evaluate the relationship of soluble TM in plasma between coagulation and/or fibrinolysis system in patients with diabetes, we measured plasma soluble TM, protein C activity (a natural anticoagulant induced by thrombin-TM complex), prothrombin F1+2 (a direct marker of thrombin generation), and plasmin-alpha 2-antiplasmin complex (PAP) and D dimer (measures of fibrinolytic activity) in 55 patients with type 2 diabetes mellitus. The plasma concentrations of soluble TM (P<0.01), protein C activity (P<0.01), prothrombin F1+2 (P<0.05), PAP (P<0.001) and D dimer (P<0.001) were significantly higher in the diabetic patients than the 48 age-matched control subjects. The plasma concentrations of TM and PAP were obviously increased in patients with diabetic nephropathy. In the diabetic patients, the plasma concentrations of soluble TM were inversely correlated with the protein C activity (r=-0.43, P<0.005), and were positively correlated with the plasma concentrations of prothrombin F1+2 (r=0.63, P<0.0001) and the plasma PAP concentrations (r=0.30, P<0.05). The present study demonstrated that both coagulation and fibrinolysis are enhanced concomitantly in patients with type 2 diabetes mellitus, and that an increase in plasma concentration of soluble TM is associated not only with hypercoagulability but also with enhanced fibrinolysis in diabetic patients.

Preperitoneal fat deposition estimated by ultrasonography in patients with non-insulin-dependent diabetes mellitus

UNLABELLED Preperitoneal fat is an indicator of visceral fat deposition, which is closely related to atherosclerosis and coronary heart disease in obese patients. We assessed the relationship of preperitoneal fat deposition and various clinical characteristics in 90 patients with non-insulin-dependent diabetes mellitus (NIDDM). Preperitoneal and subcutaneous fat deposition were measured by ultrasonography. In both the male and female diabetics, preperitoneal fat levels were significantly higher than in age-matched healthy subjects. We also determined blood pressures, fasting plasma glucose, glycosylated hemoglobin A1c, serum lipids, fasting immunoreactive insulin (FIRI), daily urinary C-peptide (CPR), serum leptin, urinary albumin excretion and body mass index (BMI). Of these parameters, BMI, FIRI, leptin and daily urinary CPR were positively correlated with preperitoneal fat deposition. Patients with diet therapy alone showed significantly higher preperitoneal fat levels than those receiving insulin therapy. In female, patients with increased preperitoneal fat showed higher prevalence of hypertension than those with decreased fat. Macroalbuminuric patients had a lower preperitoneal fat than microalbuminuric and normoalbuminuric patients. Patients with proliferative retinopathy exhibited lower preperitoneal fat than did those without retinopathy. Preperitoneal fat levels were positively correlated with motor or sensory nerve conduction velocity. CONCLUSION The present findings suggest that in NIDDM patients, increased preperitoneal fat deposition is closely associated with obesity, hypertension and hyperinsulinemia, and negatively modulates diabetic microangiopathy including nephropathy, retinopathy and neuropathy.

Mechanisms of Elevation of Serum and Urinary Concentrations of Soluble Thrombomodulin in Diabetic Patients: Possible Application as a Marker for Vascular Endothelial Injury

Serum and urinary levels of soluble thrombomodulin (TM) were measured in 71 patients with non-insulin-dependent diabetes mellitus (NIDDM) and 132 age-matched control subjects to elucidate the mechanisms involved in increased TM levels. We compared the TM level with urinary albumin excretion (UAE), creatinine (Cr) clearance, and indices of renal tubular damage such as urinary beta2-microglobulin. Serum TM was significantly higher in diabetic patients versus control subjects (P < .001) regardless of whether the patients had diabetic nephropathy. Urinary TM levels were also higher in diabetic patients than in control subjects (P < .001). Serum TM in diabetic patients was correlated positively with serum Cr and UAE and inversely with the Cr clearance rate (P < .001, respectively). The urinary level of TM in diabetic patients was significantly correlated with 24-hour glucose excretion and the serum level of 1,5-anhydroglucitol (1,5-AG) (P < .001). However, no correlations were found between urinary TM levels and renal function in diabetic patients. There was also no correlation between serum and urinary levels of TM in the patients. These results suggest that although the serum TM level is influenced by an impairment of the renal clearance of TM, this parameter may be a useful marker for vascular endothelial injury in diabetic patients. On the other hand, since the elevated urinary level of TM in the patients paralleled their urinary excretion of glucose, urinary TM levels do not correlate with vascular endothelial injury in diabetic patients.

Alterations in serum levels of 1α,25(OH)2 D3 and osteocalcin in patients with early diabetic nephropathy

UNLABELLED Serum levels of markers for bone remodeling and diabetic metabolic markers were measured in subjects with non-insulin-dependent diabetes mellitus (NIDDM) to investigate the relationship between early diabetic nephropathy and calcium/bone metabolism. 1 alpha,25(OH)2 D3 (Vit D), osteocalcin (OC), intact parathyroid hormone (PTH) and urine albumin excretion (UAE) were measured in all subjects. Serum levels of Vit D and OC were significantly decreased in diabetic subjects compared to age-matched, non-diabetic controls. In diabetic patients, a significant positive correlation was observed between intact PTH and OC. No significant correlation was found between levels of Vit D and OC. In early diabetic nephropathy without increased serum creatinine, Vit D decreased and OC increased with increasing UAE. Levels of hemoglobin Alc (HbAlc) and fructosamine (FRA) were not correlated with levels of Vit D or OC. Levels of Vit D were decreased and levels of OC were increased in diabetic subjects with proliferative retinopathy or with micro- or macro-albuminuria. CONCLUSIONS Results of the present study indicate that changes in bone remodeling markers such as Vit D and OC levels are present in the early stages of diabetic nephropathy, and that circulating intact PTH is important in restoring the reduced OC levels in diabetic patients, probably as a reflection of bone remodeling.

Plasma interleukin‐6 is associated with coagulation in poorly controlled patients with Type 2 diabetes

Aims  We investigated the relationship between interleukin (IL)‐6 and coagulation, i.e. whether changes in the plasma IL‐6 are associated with those in coagulation markers (D dimer and fibrinogen) after glycaemic control with sulphonylurea or insulin in poorly controlled patients with Type 2 diabetes.

Clinical significance of measurements of urinary and serum thrombomodulins in patients with non-insulin-dependent diabetes mellitus

UNLABELLED The aim of our study was to elucidate whether serum thrombomodulin (S-TM) and urinary thrombomodulin (U-TM) levels would reflect the pathogenesis of diabetic complications. Studies were conducted in 188 patients with non-insulin-dependent diabetes mellitus (NIDDM) and 132 age-matched healthy subjects. TM was measured by a newly developed enzyme immunoassay. Both S-TM and U-TM levels in NIDDM were much higher than those in healthy controls. S-TM values in NIDDM correlated significantly with age (P < 0.05), HbA1c (P < 0.05), serum 1.5 anhydroglucetol (AG) (P < 0.05) and urinary albumin concentration (UAC) (P < 0.01), respectively. On the other hand, fasting plasma glucose (FPG) (P < 0.001), HbA1c (P < 0 .01), serum fructosamine (P < 0.05) and serum 1.5 AG (P < 0.05) were closely correlated with U-TM values in NIDDM. Patients with clinical nephropathy showed obviously higher S-TM levels (P < 0.05) than patients with latent nephropathy. Furthermore, S-TM values in patients with diabetic proliferative retinopathy increased significantly compared with those in patients without diabetic retinopathy (P < 0.05). When all diabetic patients with normoalbuminuria were studied, no significant changes of S-TM were observed between the no diabetic retinopathy group and the proliferative diabetic retinopathy group. CONCLUSIONS The present data suggest that an increase in U-TM reflects the grade of glucose metabolism, whereas an increase in S-TM appears to reveal the advance of diabetic microangiopathy, including nephropathy.

Relationship between sympathetic skin response and power spectral analysis of heart rate variation in patients with type 2 diabetes

We measured sympathetic skin response (SSR), a measure of sympathetic sudomotor function, and compared SSR with other quantitative neurological tests including power spectral analysis (PSA) of heart rate variations in 60 type 2 diabetic subjects. SSR was detected in all 20 age-matched healthy subjects but was absent in 17 patients with type 2 diabetes (28%) (P<.01). Even after exclusion of diabetic patients with absent SSR, the SSR amplitude in diabetic patients was significantly lower than in healthy subjects (P<.05). Both the low frequency power of R-R intervals, which reflects both cardiac sympathetic and parasympathetic function, and the postural fall in systolic blood pressure were significantly lower in the diabetic patients with absent SSR than in those with present SSR (P<.05 and.001, respectively). However, we found no significant difference in the high frequency power of R-R intervals, which reflects accurately cardiac parasympathetic function, between the diabetic patients with absent SSR and those with present SSR. In the diabetic patients with present SSR, SSR amplitude was also positively correlated with the postural fall in systolic blood pressure, low-frequency (LF) power, and high-frequency (HF) power. These results suggest that SSR is a useful and sensitive method for evaluating diabetic autonomic neuropathy, and that sympathetic sudomotor neuropathy may be preceded by cardiac parasympathetic neuropathy in patients with type 2 diabetes.

Primary Antiphospholipid Syndrome Associated with Acute Adrenal Failure

We describe a 48-year-old woman with primary antiphospholipid syndrome who developed acute adrenal failure after an operation for a uterine myoma. After surgery, she developed a preshock state with hypotension, hypoglycemia, and hyponatremia. A diagnosis of primary antiphospholipid syndrome was made based not only on her past history of skin ulceration and recurrent spontaneous abortions but also on the presence of anticardiolipin antibodies. An abdominal computed tomography showed a bilateral enlargement of the adrenal glands but no high-density region in either gland. The patient recovered from the shock-like syndromes after the administration of glucocorticoids. Because it is possible that patients with antiphospholipid syndrome have acute or chronic adrenal failure caused by repeated hemorrhage or thrombosis, it may be important to monitor adrenal function in patients when the presence of this antibody is detected.

Clinical Usefulness of Doxazosin in Patients with Type 2 Diabetes Complicated by Hypertension: Effects on Glucose and Lipid Metabolism

This uncontrolled study investigated the effects of using the α1-blocker doxazosin (2 mg or 4 mg daily for 3 months) to treat 21 hypertensive patients with type 2 diabetes, including eight obese individuals (body mass index [BMI] > 25.0 kg/m2). A significant reduction in systolic and diastolic blood pressure, beginning after 1 month of treatment, was seen. There was no significant change in BMI. Although there was no obvious improvement in glucose metabolism, doxazosin treatment noticeably reduced insulin resistance and significantly lowered triglyceride and free fatty acid levels. No significant changes were found in total cholesterol, high-or low-density lipoprotein-cholesterol, atherosclerotic index, or small or large subfractions of low-density lipoprotein-cholesterol. None of the patients showed any adverse effects. The beneficial effects of doxazosin on blood pressure and lipid and glucose metabolism shown in this study suggest that this drug is clinically useful as an anti-hypertensive agent for patients with diabetes.