Role of glycemic control and blood pressure in the development and progression of nephropathy in elderly Japanese NIDDM patients.

OBJECTIVE: To investigate the role of glycemic control and blood pressure in the development and progression of nephropathy and to suggest goals for glycemic control and blood pressure for the prevention of nephropathy in elderly Japanese NIDDM patients. RESEARCH DESIGN AND METHODS: A total of 123 age- and diabetes duration-matched elderly Japanese NIDDM patients (aged 60-75 years; 74 normoalbuminuric and 49 microalbuminuric) were retrospectively studied for 6 years. RESULTS: The group that developed microalbuminuria from normoalbuminuria (group NM: n = 24) showed a higher 6-year mean HbA1c than the group that remained normoalbuminuric (group NN: n = 50; 9.0 +/- 0.8 vs. 8.1 +/- 0.8%, P < 0.01) in spite of no significant difference in 6-year mean blood pressure (MBP). On the other hand, the group that progressed from microalbuminuria to overt proteinuria (group MP: n = 26) showed a higher 6-year MBP than the group that remained microalbuminuric (group MM: n = 23; 106 +/- 5 vs. 95 +/- 6 mmHg, P < 0.01) in spite of no significant difference in 6-year mean HbA1c. The cutoff level of HbA1c separating group NN from group NM was 8.5% (normal range < or = 6.5%), and that of MBP separating group MM from group MP was 100 mmHg. CONCLUSIONS: Glycemic control is a more potent factor than blood pressure level on the development of microalbuminuria. However, as far as the progression of microalbuminuria to overt proteinuria is concerned, hypertension is the most crucial factor in elderly NIDDM patients. Suggested goals for glycemic control and blood pressure level for the prevention of nephropathy in elderly Japanese patients are an HbA1c of < or = 8.5% (equivalent to 7.8% in the current measurement of stable HbA1c; normal range < or = 5.8%) and an MBP of < or = 100 mmHg.

Decreased activity of arachidonate 12-lipoxygenase in platelets of Japanese patients with non-insulin-dependent diabetes mellitus.

To study the metabolism of the platelet 12-lipoxygenase pathway in diabetes, we evaluated the correlation between the activity and amount of arachidonate 12-lipoxygenase in the platelets of patients with non-insulin-dependent-diabetes mellitus (NIDDM). There were four parts in this investigation: (1) examination of abnormalities in platelet 12-lipoxygenase in patients with NIDDM recruited from the Hospital of Juntendo University School of Medicine; (2) comparison of 12-lipoxygenase in the platelets of non-obese NIDDM patients without angiopathy versus normal subjects matched for age, sex, and body mass index (BMI); (3) evaluation of gender differences; and (4) assessment of the potential influence of glycemic control. The activity of 12-lipoxygenase was assayed by incubation of [1-14C]arachidonic acid with the platelet cytosol. The reaction mixture was extracted and separated by thin-layer chromatography, and the radioactive end products were detected. The activity of 12-lipoxygenase in the platelets of patients with NIDDM was significantly less than in normal subjects (P < .003), whereas the amount of 12-lipoxygenase protein did not differ between the two groups. Thus, the specific activity of 12-lipoxygenase in diabetic patients was significantly less than that of normal subjects (P < .001). The enzyme activity and the specific enzyme activity of 12-lipoxygenase in non-obese NIDDM patients without angiopathy were significantly lower than the values in normal subjects matched for gender, age, and BMI (P < .006 and P < .0007, respectively). No significant difference in the activity or amount of platelet 12-lipoxygenase was observed between males and females matched for age, BMI, and disease. In addition, no relationship was observed between 12-lipoxygenase activity and blood glucose levels measured at the time of specimen collection. However, slight negative correlations were noted between 12-lipoxygenase activity and 1,5-anhydroglucitol, hemoglobin A1c (HbA1c), and fructosamine (r = .369, -.354, and -.279, respectively). When recombinant 12-lipoxygenase was incubated with varying concentrations of glucose or fructose, enzyme inactivation was related to the length of incubation, and was unaffected by glucose or fructose. These observations suggest that the activity of 12-lipoxygenase in the platelets of patients with NIDDM is decreased by prolonged hyperglycemia. The mechanism involved requires further investigation.

Effects of shear stress on glycosaminoglycan synthesis in vascular endothelial cells.

Glycocalyx on the surface of endothelium has been suggested to be involved in vascular permeability and anticoagulation. In the present study, we demonstrated that fluid laminar shear stress enhanced a glycosaminoglycan (GAG) synthesis in porcine aortic endothelial cells, in vitro. Shear stress (15, 40 dyn/cm2) for 24 hours significantly increased GAG synthesis, assayed by [35S]sulfate incorporation, in "medium" fraction and "trypsinated" fraction which includes GAGs derived from the cell surface and from the solubilized matrix. Increased GAGs in the trypsinated and medium fractions consisted of mainly heparan sulfate and chondroitin/dermatan sulfate, respectively. Both heparan and chondroitin/dermatan sulfate increases are required to expose the cells to shear stress for more than 24 hours. Shear-stress-induced increase in GAG synthesis was concomitant with a decrease in DNA synthesis and an increase in protein synthesis. These data indicate that relatively high shear stress may suppress atherogenesis by changing endothelial GAG synthesis.

In vitro effects of trapidil on fatty acid and prostaglandin metabolism in platelets.

The effects of trapidil, a coronary vasodilator and platelet aggregation inhibitor, on fatty acid metabolism and prostaglandin (PG) formation in platelets were studied using platelet suspensions from six normal subjects. The addition of trapidil to fatty acids in platelet phospholipids decreased palmitoleic acid and arachidonic acid, and increased an unidentified substance, X2 (palmitoleic acid, P < 0.05; arachidonic acid, P < 0.05; X2, P < 0.05). Thrombin stimulation following the addition of trapidil resulted in an increase in stearic acid and a decrease in arachidonic acid, compared with the trapidil-free control samples (stearic acid, P < 0.05; arachidonic acid, P < 0.02). The addition of trapidil tended to increase immunoreactive PGE (iPGE) and iPGF dose-dependently. On the other hand, thrombin stimulation following the addition of trapidil decreased the formation of thromboxane B2 (TXB2) significantly compared with the levels of TXB2 in the trapidil-free samples (10 micrograms/mL trapidil, P < 0.005, 100 micrograms/mL trapidil, P < 0.001). These results show that trapidil increased arachidonic acid mobilization in the platelets.

Risk factors of avascular necrosis of the femoral head in patients with systemic lupus erythematosus under high-dose corticosteroid therapy.

A prospective study of systemic lupus erythematosus (SLE) patients under high doses of corticosteroid therapy (greater than 30 mg/day prednisolone) for a five-year period elucidated some risk factors of avascular necrosis of the femoral head (ANFH). A complete survey was performed on 62 patients, of whom nine patients developed ANFH during the period of study. The risk factors in the causation of ANFH were ascertained on the basis of characteristic clinical features of SLE, a typical pattern of laboratory data at the onset of ANFH, and the mode of glucocorticosteroid administration observed from a statistical point of view. The risk factors include stomatitis, drug-induced lupus, lupus erythematosus cell positive rheumatoid arthritis, interstitial pneumonitis, and thrombocytopenic purpura (characteristic clinical features); increased total cholesterol, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, alkaline phosphatase, red blood cell, hemoglobin, and albumin/globulin; advanced renal failure (pattern abnormality of laboratory data); and a rash introduction of high-dose corticosteroid therapy (greater than or equal to 30 mg/day prednisolone) without corticosteroid preloading (mode of administration).

Effect of prostaglandin E1 in collagen disease patients with inflammatory skin ulcer.

UNLABELLED: Clinical, physiological and biochemical studies of PGE1 were done in a series of collagen disease patients with skin ulcer, in a foot varix patient with skin ulcer as a non-inflammatory skin ulcer control, and in two diabetics without skin ulcer as no skin ulcer controls. Intravenous infusions of prostaglandin E1 (PGE1) were given continuously at the dose of 1 ng/kg/min for 72 hours. Blood samples were collected from the cubital vein, before, during, immediately after and at seven days after PGE1 therapy. Platelet aggregations were studied by light transmittance (PRP: modified by Born's method; whole blood: modified by Tohjima's method). Platelet iPGE (immunoreactive PGE-like material) levels were assayed by radio-immunoassay. Essential fatty acid compositions of plasma, platelet and red cells, were analysed by gas chromatography. Results were as follows: (1) in all cases, complete healing of skin ulcers was observed; (2) In most cases, skin temperature increased during PGE1 treatment; (3) Platelet aggregation was higher during PGE1 treatment than before and was higher in PRP than in whole blood during PGE1 treatment; (4) The platelet basal iPGE levels were significantly decreased by PGE1 (P less than 0.025); (5) The plasma and platelet linoleic acid levels were significantly higher than before PGE1 treatment (plasma: P less than 0.05, platelets: P less than 0.025); (6) Thrombocytosis of one case of MRA was healed by the second PGE1 treatment. CONCLUSION: The inflammatory skin ulcers in collagen diseases were healed completely by continuous intravenous infusion of PGE1. This effect might be brought about by the suppression of PG metabolism, especially in platelets.