Hiroaki Kakizawa

The ratio of leptin to adiponectin can be used as an index of insulin resistance

The level of leptin increases with obesity, whereas that of adiponectin decreases with obesity. It is reported that the ratio of leptin to adiponectin (L/A) is associated with insulin resistance. It is difficult to evaluate insulin resistance in diabetic patients who have a dysfunction of insulin secretion. The aim of this study was to examine whether the L/A ratio is a useful marker for insulin resistance in diabetic patients. We examined L/A in the serum of a total of 139 Japanese patients with type 2 diabetes mellitus (66 women and 73 men) and 7 healthy individuals recruited in our hospital. Changes in the levels of leptin and adiponectin were observed using the oral glucose tolerance test and a hyper- and euglycemic clamp test. Twenty-one patients with type 2 diabetes mellitus were observed for more than 6 months after treatment with pioglitazone, and 31 patients with type 2 diabetes mellitus were observed for more than 6 months after the treatment with metformin. The mean value of L/A in 139 Japanese patients with type 2 diabetes mellitus was 1.22 +/- 1.41 (1.68 +/- 1.76 in women, 0.81 +/- 0.80 in men; P = .0002). In the clamp tests, L/A correlated with glucose infusion rate (GIR) (r(2) = 0.26, P = .0034). The correlation of L/A and GIR indicated a stronger correlation than either leptin (r(2) = 0.144, P = .03) or adiponectin alone (r(2) = 0.023, P = .41), or the homeostasis model assessment of insulin resistance (r(2) = 0.103, P = .08). The average hemoglobin A(1c) (HbA(1c)) improved from 10.2% +/- 1.2% to 9.2% +/- 1.6% (P = .0037) in 6 months after treatment with pioglitazone. Our results indicate pioglitazone to be effective for HbA(1c) improvement in subjects with high L/A and low L/A. The average HbA(1c) improved from 9.2% +/- 0.9% to 8.0% +/- 1.2% (P = .0002) in 6 months after treatment with metformin. Our results indicate metformin to be effective for HbA(1c) improvement in subjects with a low L/A. In conclusion, we demonstrate that L/A is different between male and female subjects. The correlation of L/A and GIR by the euglycemic hyperinsulinemic clamp test suggests that L/A is a useful indicator for the choice of drug to treat diabetes mellitus.

Changes in Superoxide Dismutase Activities and Concentrations and Myeloperoxidase Activities in Leukocytes from Patients with Diabetes Mellitus

To investigate whether the two free-radical scavengers, Cu, Zn- and Mn-superoxide dismutase (SOD), are changed in leukocytes of diabetic patients, and the alteration of these enzymes correlates with the diabetic state, we measured the activity and concentration of these enzymes in leukocytes from diabetic patients. Both Cu, Zn-SOD and Mn-SOD activities in neutrophils and lymphocytes were significantly lower in patients with non-insulin-dependent diabetes mellitus than in healthy controls. The concentrations of these enzymes in leukocytes from diabetic patients, however, did not differ from those in controls. Cu, Zn-SOD and Mn-SOD activities in neutrophils inversely correlated with HbA(1c) concentrations. Myeloperoxidase activity in leukocytes was significantly reduced in NIDDM patients. These findings suggest that changes in these enzymes may affect the susceptibility to infection and immunocompetence of patients with diabetes.

Reduction of activity, but no decrease in concentration, of erythrocyte Cu, Zn-superoxide dismutase by hyperglycaemia in diabetic patients

Cu,Zn‐superoxide dismutase (SOD) activity in erythrocytes is affected by various diseases, including diabetes mellitus (DM). We investigated changes in the Cu,Zn‐SOD activity compared to changes in the Cu,Zn‐SOD concentration in erythrocytes obtained from patients with Type 2 (non‐insulin‐dependent) diabetes mellitus. Cu,Zn‐SOD activity in erythrocytes was significantly lower in Type 2 DM patients than in healthy non‐diabetic subjects. The activity correlated negatively with HbA1c, but not with other indicators of metabolic control, such as fasting blood glucose or plasma cholesterol or triglyceride. However, there was no statistically significant difference in erythrocyte concentration of Cu,Zn‐SOD between diabetic and control samples. Concentration did not correlate with enzymatic activity or HbA1c. These findings indicate that the inactivation of Cu,Zn‐SOD activity in erythrocytes of Type 2 DM patients by hyperglycaemia may be slow, because there is a negative correlation between the enzyme activities and HbA1c levels, but not fasting blood glucose levels. This is consistent with glycosylation of the active site of Cu,Zn‐SOD, without any effect of hyperglycaemia on the concentration of Cu,Zn‐SOD.

Effects of thyroid hormone on the sorbitol pathway in streptozotocin-induced diabetic rats

Sorbitol accumulation plays an important role in diabetic complications involving the kidney, nerves, retina, lens and cardiac muscle. To investigate the influence of thyroid hormone on the sorbitol pathway, we studied the effects of thyroid hormone on polyol metabolism in normal and diabetic rats. Rats were divided into three groups: controls, streptozotocin (STZ)-induced diabetic euthyroid rats (DM) and STZ-induced diabetic hyperthyroid (thyroxine-injected) rats (DM+HT). The sorbitol (Sor) concentrations in the kidney, liver and sciatic nerve (2.53+/-0.74, 0.97+/-0.16 and 24.0+/-5.1 nmol/mg protein, respectively) of the DM rats were significantly higher than those (1.48+/-0.31, 0.58+/-0.13 and 3. 1+/-0.6 nmol/mg protein) of the control rats. The Sor concentrations in the kidney and sciatic nerve of the DM+HT rats (1.26+/-0.29 and 9. 40+/-1.2 nmol/mg protein) were significantly lower than those in the DM rats. These values were reduced in the liver, unchanged in the kidney, and increased in the sciatic nerve from the hyperthyroid rats without diabetes. Thyroid hormone reduced the aldose reductase (AR) activities in the kidney, liver and sciatic nerve of the DM rats, and similarly reduced AR in the kidney and liver, but not in the sciatic nerve, of the non-diabetic rats. The sorbitol dehydrogenase (SDH) activities were decreased by thyroid hormone in the kidney and liver but not the sciatic nerve of DM rats. In the non-diabetic rats, this enzyme activity was decreased in liver, but not in kidney or sciatic nerve. A positive correlation between the Sor concentration and AR activity was observed in the kidney and liver but not in the sciatic nerve from control, DM and DM+HT rats. A negative correlation was observed between the Sor concentration and SDH activities in the same organs. These data suggest that thyroid hormone affects the sorbitol pathway, but the detailed mechanism whereby this hormone reduces the sorbitol content (especially in diabetic rats) remains to be clarified.

The therapeutic effect of lipo PGE1 on diabetic neuropathy-changes in endothelin and various angiopathic factors.

A high blood concentration of endothelin (ET)-1 may participate in the onset and progress of diabetic microangiopathy, resulting in neuropathy. We examined the therapeutic effects of prostaglandin E1 (PGE1), which possesses both a peripheral vasodilating action and inhibition of platelet aggregation, on diabetic microangiopathy. Increases in both skin temperature and peripheral never conduction velocity in diabetic patients were recorded four weeks after Lipo PGE1 administration. A quantitative decrease in urinary albumin concentration was also observed, suggesting its efficacy of action was on diabetic nephropathy. Lipo PGE1 administration reduced the elevated circulating plasma ET-1 levels in the diabetic patients. As an increase in ET-1 concentrations is thought to correlate with the onset and progress of diabetic microangiopathy, the reduction of plasma ET-1 concentration by Lipo PGE1 administration may be one reason for the improvement in diabetic neuropathy and nephropathy.

Alteration of Endothelin-1 Concentration in STZ-Induced Diabetic Rat Nephropathy

Background: Recently, an endothelin (ET-1) with a potent vasoconstrictive activity and stimulative activity of vascular muscular cell growth was discovered and blood ET-1 levels were higher in diabetic patients than in healthy subjects, suggesting that high ET-1 levels assist development and progression of diabetic microangiography. Methods: We examined renal function, and serum and tissue ET-1 levels in streptozotocin (STZ)-induced diabetic rats treated with a prostaglandin (PG) I2 derivative to investigate the effect of PGI2 in diabetic vascular disturbance. Results: Renal weight, urinary albumin, urinary N-acetyl-β,D-glucosaminidase (NAG) and serum ET-1 levels increased in STZ-induced diabetic rats, and a tendency to increase in renal tissue ET-1 levels was observed. Furthermore, electron-microscopic findings in the kidneys showed mesangial cell proliferation and mesangial matrix expansion which might be caused by diabetic nephropathy. The PGI2 derivative reduced urinary albumin and NAG levels in STZ-induced rats. It was considered, therefore, that the PGI2 derivative is effective in diabetic nephropathy. As the PGI2 derivative also reduced renal tissue ET-1 levels, improvement of diabetic nephropathy partially was considered to result from the reduction of renal tissue ET-1 levels. Conclusion: In STZ-induced rats, increased serum ET-1 levels and a tendency to increase in renal tissue ET-1 levels were associated with increases in urinary albumin and NAG levels, and these levels were decreased by a PGI2 derivative. These findings suggested that increased ET-1 concentrations assist development and progression of diabetic nephropathy, especially diabetic microangiopathy, and the PGI2 derivative may be effective for inhibition of diabetic microangiopathy mediated by reduction of ET-1 concentrations.

Surface expression and release of soluble forms of CD8 and CD23 in CD40- and IL-4-activated mononuclear cells from patients with Graves' disease (GD).

We investigated the effect of T cell‐dependent B cell activation on the surface expression and release of the soluble forms of CD8 and CD23 by peripheral blood mononuclear cells (PBMC) obtained from patients with GD, versus patients with Hashimotos thyroiditis, and normal controls. Incubating the PBMC with anti‐CD40 MoAbs and IL‐4 increased the soluble CD23 levels in cells from all three groups. An increase in the number of CD23+ cells was observed in the PBMC from the patients with GD, but not in PBMC from Hashimotos thyroiditis or controls. Less soluble CD8 was released from anti‐CD40 antibody and IL‐4‐stimulated PBMC obtained from patients with GD relative to those from the controls. In addition, the number of CD8+ cells was significantly reduced in stimulated PBMC from the GD patients relative to those from controls. Incubation of PBMC with anti‐CD40 antibody plus IL‐4 did not affect the proportions of CD4+, CD20+, Fas+CD4+, and Fas+CD8+ cells. The addition of T3 to cultured PBMC from controls did not reproduce the changes in CD23+ and CD8+ cells noted in the samples from GD patients. Thus, T cell‐dependent B cell activation, mediated by a CD40 pathway, may reduce the number of CD8+ cells, causing exacerbation of GD.

Changes in Erythrocyte Sorbitol Concentrations Measured Using an Improved Assay System in Patients With Diabetic Complications and Treated With Aldose Reductase Inhibitor

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