Nagayuki Tani

Acute loading with proteins from different sources in healthy volunteers and diabetic patients

To evaluate the effects of protein loading on glomerular filtration rate (GFR), urinary excretion rate of albumin (AER), and plasma concentration of amino acids, 10 healthy volunteers and six diabetics were studied before and after eating tuna fish, egg white, cheese, or tofu. Furthermore, to study the possible role of glucagon, growth hormone (GH), atrial natriuretic peptide (ANP), or kallikrein in the responses of GFR, these substances were measured before and after protein loading. GFR increased significantly (p less than .001) after ingestion of tuna fish. No significant differences were seen between the GFR before and that after ingestion of the other foods. AER was unchanged following protein loading. Plasma concentrations of alanine, glycine, and arginine increased to a greater degree after ingestion of tuna fish than after digestion of the other foods. This result suggests that the response of GFR after protein loading may differ from one protein to another, and that these responses may not be directly mediated by glucagon, GH, ANP, or kallikrein.

Polymorphism of the angiotensin I-Converting enzyme gene in diabetic nephropathy in Type II diabetic patients with proliferative retinopathy

Recently, deletion (D)/insertion (I) polymorphism in the Angiotensin I-converting enzyme (ACE) gene has been suggested to be related to the development of diabetic nephropathy in type I diabetes mellitus. This hypothesis, however, remains controversial. Differences in clinical states between patients, especially in glycemic control or duration of diabetes, could be responsible for these contradictory results. In this study we examined the relationship between D/I polymorphism of the ACE gene and diabetic nephropathy in type II diabetic patients who had already developed proliferative retinopathy (n = 45), and were thought to have been in a hyperglycemic state for long enough to develop microangiopathy. The patients were divided into two subgroups: 24 with nephropathy (albumin excretion rate: AER > or = 20 micrograms/min) and 21 without (AER < 20 micrograms/min). There was no difference in the duration of diabetes, HbA1c levels or average blood pressure over the previous year between these subgroups and other clinical characteristics were comparable. Patients without nephropathy exhibited allele I more often than those with nephropathy (p = .025). AER was lowest in genotype II and highest in genotype DD patients but the difference was not statistically significant (p = .07). From these findings, it was concluded that genotype II for the ACE gene could be a marker for reduced risk of diabetic nephropathy.

Effects of acetyl salicylic acid and cilostazol administration on serum thrombomodulin concentration in diabetic patients

Serum thrombomodulin (sTM) is an endothelial cell marker which would reflect the endothelial damage. In order to examine whether some antiplatelet agents decrease the endothelial damage in diabetic patients, sTM concentrations were measured by enzyme-linked immunosorbent assay before and after oral administration of a daily 100 mg of cilostazol for 4 weeks in 9 diabetics or a daily 81 mg of acetyl salicylic acids (ASA) for 4 weeks in 8 diabetics. Basal concentrations of sTM were elevated in most of these patients as compared with healthy subjects. The sTM concentrations were decreased after administration of cilostazol from 28.1 +/- 7.1 ng/ml to 23.6 +/- 5.4 ng/ml (p < 0.01), and after ASA from 30.7 +/- 10.9 ng/ml to 27.9 +/- 11.6 ng/ml (p < 0.05). These results suggest that such drugs can decrease the endothelial damage, resulting in the reduced risk of diabetic vascular complications.

Effect of a somatostatin analogue (SMS 201–995) on renal function and urinary protein excretion in diabetic rats

We evaluated the effect of a somatostatin analogue (SMS 201-995) on diabetic nephropathy using urinary albumin excretion as a marker in a streptozocin-induced diabetic unilateral nephrectomized rat model. Nondiabetic rats were injected with either 0.9% sodium chloride (NaCl) (n = 10) or SMS (n = 10). Diabetic rats were also injected with either 0.9% NaCl (n = 10) or SMS (n = 10). The control saline and SMS groups showed significant increases in urinary albumin excretion (UAE) and albumin clearance. The diabetic saline-treated rats showed no significant changes in UAE or albumin clearance. The diabetic SMS-treated rats showed significant decreases in UAE (151 +/- 76 mg/day/kg to 98 +/- 46, P less than .005) and albumin clearance (5.85 +/- 3.34 mL/day/kg to 3.63 +/- 1.73, P less than .01). There was no significant difference in kidney weight between the two control groups, but a significant difference was found between the two diabetic groups (3.35 +/- 0.39 g vs. 2.68 +/- 0.26 g, P less than .001). The results suggest that in early diabetes with renal hyperfiltration and hypertrophy, the administration of SMS may prevent progression to late diabetic nephropathy.

Glomerular charge selectivity in non-insulin-dependent diabetes mellitus

To elucidate the stage of the charge selectivity defect in diabetic nephropathy, urinary excretions of IgG1 and IgG4 were measured in patients with non-insulin-dependent diabetes mellitus (NIDDM) and healthy controls. The molecular weights of IgG1 and IgG4 were the same but their isoelectric points were different. Therefore, by measuring both urinary IgG1 and IgG4 excretions, the stage of charge selectivity impairment in the nephropathy of NIDDM may be elucidated. Results were expressed as urinary excretion rate (IgG1 ER, IgG4 ER) and compared between diabetic patients with different urinary excretion rates of albumin (AER). IgG4 ER increased to the stage in which AER was more than 10 micrograms/min, whereas IgG1 ER did not increase to the stage of AER between 10 and 100 micrograms/min. This finding suggests that the charge selectivity defect in the kidney of the NIDDM patient is present at the stage when AER is more than 10 micrograms/min.

Changes in the glomerular pore size selectivity in patients with type II diabetes mellitus.

We measured the urinary excretion rate and clearance of three plasma proteins, albumin, transferrin, and IgG4, each of which has a similar isoelectric point, but a different molecular weight. This study consisted of 86 patients with type II diabetes mellitus and 15 healthy subjects. In the patients, the degree of the urinary excretion rate and clearance of both transferrin (TER and Ctrans) and IgG4 IgG4 ER and ClgG4) closely correlated with that of the urinary excretion rate of albumin (AER). Although significant increases in the medians of TER and Ctrans were found even in the patients with AER of less than 5 micrograms/min, significant increases in the medians of IgG4 ER and ClgG4 were observed only in the patients with AER of more than 10 micrograms/min, in comparison with age-matched healthy subjects. Considering the biochemical properties of these proteins, our results indicate that an alteration in the glomerular size selectivity may appear even in patients with normoalbuminuria, and in patients with AER of more than 10 micrograms/min, more extensive damage in glomerular size selectivity may occur.

Effect of vanadate on renal function in rats with streptozotocin-induced diabetes

The effects of vanadate on glycemic control (HbA1c) and renal function was assessed in streptozotocin-induced diabetic rats (STZ-D) with heminephrectomy. Vanadate-treated rats had a significantly lower HbA1c level compared with STZ-D rats without vanadate at 8 weeks after initiation of this study. In the STZ-D rats with vanadate, there were significant decreases in the urinary albumin and IgG excretion rates. The present findings suggest that glycemic control by oral administration of vanadate, which does not cause insulin release, improves diabetic renal function.

Asymptomatic ischemic heart disease and diabetic nephropathy: Relationship between prevalence of asymptomatic ischemic heart disease and urinary albumin excretion rate

To examine whether prevalences of asymptomatic ischemic heart diseases in type II diabetic patients are correlated with the degree of diabetic nephropathy, 201TI scintigraphies with dipyridamole loading were performed in 28 type II diabetic patients without any chest discomforts. Positive findings of ischemic changes were found in 5 (28%) of 18 patients with normoalbuminuria (urinary albumin excretion rate, AER less than 20 micrograms/min) and 5 (50%) of 10 patients with micro- or macroalbuminuria (AER greater than 20 micrograms/min). Coronary angiography (CAG) was performed in 6 of 10 patients with positive findings of 201TI scintigraphy. No stenotic findings were found in any patients, but wall motion was decreased in some patients and pulmonary artery pressure was increased in one patient. As stenosis of arteries with diameter of more than 0.3 mm can be detected by CAG, it seems likely that microangiopathy may play some role in the pathogenesis of asymptomatic ischemic heart disease detected with 201TI scintigraphy.

Hypercalciuria and hematuria in non-insulin-dependent diabetes mellitus.

This study was undertaken to examine whether patients with non-insulin-dependent diabetes (NIDDM) are hypercalciuric and whether there is a pathophysiologic relationship between urinary calcium excretion (UCE) and the degree of diabetic nephropathy. Although UCE did not parallel the increase of urinary albumin excretion rate (AER) and the presence of hematuria was not corrected with the degree of UCE, we confirmed that 36% of diabetic patients have hypercalciuria and that the prevalence of hypercalciuria is more frequent in diabetic patients with normo- or microalbuminuria than in the controls. In 6 months, the AER of two hypercalciuric patients increased. However, the blood pressure and HbA1c of these two patients increased during the same 6 months. Therefore, it remains unclear whether hypercalciuria induced an increase in the AER of these patients.