K Ishii

Factors related to stress in patients with non-insulin-dependent diabetes mellitus

Stress was assessed using State-Trait Anxiety Inventory scores in 40 non-insulin-dependent diabetes mellitus (NIDDM) patients, and the results were compared with those for 40 sex- and age-matched healthy controls. Fludiazepam was administered to the patients for 12 weeks and stress was reassessed. The Manifest Anxiety Scale score correlated with Trait (r = 0.548, P <0.0001) and State (r = 0.474, P < 0.0001) scores, validating the latter as measurements of stress. Both Trait (43.4 vs 35.8, P < 0.001) and State (41.6 vs 33.8, P < 0.001) scores were significantly higher in NIDDM patients than in healthy controls. Administration of an anxiolytic, fludiazepam (0.25 mg, three times daily, orally) for 12 weeks lowered Trait score (43.5 to 36.9, 0.0001), State score (41.6 to 35.8, P < 0.0002), glycosylated haemoglobin (8.4 to 7.3%, P < 0.0001), systolic blood pressure (151.2 to 143.4 mmHg, P < 0.0017) and diastolic blood pressure (84.2 to 77.7 mmHg, P < 0.0018). Multiple regression analysis revealed that the significant explanatory variables for the change in State score during anxiolytic administration were the changes in total cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein B: A1 and glycosylated haemoglobin (R 2 = 0.3224, P < 0.0022). The results indicate that stress is detected at a higher frequency in patients with NIDDM than in healthy controls, and that blood glucose and lipid metabolic factors are significant explanatory variables for this stress. This stress is correlated with glucose metabolism and blood pressure and, moreover, these factors could all be proved concomitantly by the administration of an anxiolytic.

Influence of prostaglandin E1 on heavy proteinuria in slightly azotaemic diabetics.

Treatment of non-insulin-dependent diabetes mellitus patients with nephropathy of the nephrotic type using 40 μg prostaglandin E1 given intravenously twice daily for 4 weeks reduced the urinary protein concentration. Prostaglandin E1 also increased the total serum protein and serum albumin concentrations, and reduced creatinine clearance and plasma renin activity following frusemide loading. Treatment with the prostaglandin did not, however, significantly affect the blood urea nitrogen and the serum creatinine concentration. It is concluded that prostaglandin E1 has overt effects on diabetic nephropathy.

Relationship between Cardiac Autonomic Neuropathy and Diabetic Microangiopathies and Macro Angiopathy in Patients with Non-Insulin-Dependent Diabetes Mellitus

The relationship between cardiac autonomic neuropathy and diabetic microangiopathies and macroangiopathy was investigated in 103 patients with non-insulin-dependent diabetes mellitus. Cardiac autonomic nerve function was assessed by determining the uptake of [123I]metaiodobenzyl-guanidine into the myocardium. Cardioparasympathetic nerve function was assessed by comparing electrocardiographically the expiratory and inspiratory respiratory rate (RR) interval ratios, during a period of deep breathing, and the coefficients of variation of the RR intervals. Nerve conduction velocity measurements were used to assess diabetic somatic neuropathy, and measurement of pulse-wave velocity provided an indication of the extent of aortic sclerosis. The only correlations between the parameters of cardiac autonomic neuropathy and parameters of diabetic microangiopathies and macroangiopathy were between the expiratory to inspiratory RR interval ratio and both the conduction velocity of the tibial nerve and pulse-wave velocity, and between the heart to lung ratio (cardiac autonomic nerve function) and nephropathy. These correlations may have occurred by chance; alternatively they may indicate a difference in the onset mechanisms of cardiac parasympathetic and sympathetic neuropathies in diabetics.

Improvement of Stress Reduces Glycosylated Haemoglobin Levels in Patients with Type 2 Diabetes

The effects of reducing stress on glucose metabolism in diabetics were evaluated in 20 patients with type 2 diabetes (10 of each sex) who were given an anxiolytic (fludiazepam) for 12 weeks. Patients were tested 4 weeks before the start of anxiolytic treatment (A), immediately before the first dose (B), and before the end of the study period (C) using the State-Trait Anxiety Index and glycosylated haemoglobin levels. There were no significant differences between the trait or state anxiety scores or the glycosylated haemoglobin levels at times A and B before treatment. However, for all three measurements, the values at time C, after treatment, showed significant improvements, compared with those at both times A and B (P < 0.05). The improvement in the trait anxiety score was weakly correlated with the decrease in the glycosylated haemoglobin level (r = 0.426, P < 0.01). No correlation was seen between state anxiety scores and glycosylated haemoglobin levels. The results suggest that suppressing anxiety in patients with type 2 diabetes reduces glycosylated haemoglobin levels.

Effect of Prostaglandin E1 on Renal Haemodynamics in a Patient with Diabetic Nephropathy

A 66-year old male with severe hyperglycaemia due to previously uncontrolled diabetes mellitus was also suffering from arteriosclerosis obliterans and diabetic nephropathy. The patient was treated with 16 IU/day insulin zinc suspension. In addition, an intravenous infusion of 80 μg/day prostaglandin E1 was given for 28 days in an attempt to improve the arteriosclerosis obliterans and diabetic nephropathy. Treatment resulted in a reduction in fasting blood glucose but no decline in urinary protein. Prostaglandin E1 treatment, however, produced an improvement in renal haemodynamics assessed by renography.

The Effect of an α-Glucosidase Inhibitor and Insulin on Glucose Metabolism and Lipid Profiles in Non-Insulin-Dependent Diabetes Mellitus

Studies were carried out to assess various ways of improving glycaemic control and lipid profiles of patients with non-insulin-dependent diabetes mellitus (NIDDM) in whom glucose metabolism was poor. Part or all of the dose of the sulphonylurea that had been used to treat patients in Group 1 (n = 8) was replaced by an α-glucosidase inhibitor. Symptoms related to hypoglycaemia disappeared and the postprandial blood glucose level was significantly increased (P < 0.043) but serum lipid levels were not significantly altered and the mean glycosylated haemoglobin level was unchanged. In Group 2 (n = 10) patients, a large part of the insulin dose was replaced by an α-glucosidase inhibitor. Hypoglycaemia-related symptoms disappeared but there were no significant changes in lipid profiles, postprandial blood glucose or glycosylated haemoglobin levels. The third group of patients (n = 9) had been treated with insulin alone and were given additional α-glucosidase inhibitor without changing their insulin dose. This did not significantly change their lipid profiles, postprandial blood glucose or glycosylated haemoglobin levels. In Group 4 (n = 9) the addition of an α-glucosidase inhibitor to the initial sulphonylurea did not produce any significant changes in mean postprandial blood glucose or glycosylated haemoglobin levels. The results for individual patients indicated that the glycosylated haemoglobin levels had improved after the change of treatment only in those patients whose connective peptide immunoreactivity was > 6.0 ng/ml.

Effect of an α-Glucosidase Inhibitor Combined with Sulphonylurea Treatment on Glucose Metabolism in Patients with Non-Insulin-Dependent Diabetes Mellitus

Ten patients with non-insulin-dependent diabetes mellitus who were being treated with a sulphonylureal compound but whose glucose metabolism needed further improvement were given a combination of their usual sulphonylurea treatment and an α-glucosidase inhibitor. Treatment with the α-glucosidase inhibitor (0.6 mg/day), in addition to glibenclamide (7.5 mg/day in two patients; 5.0 mg/day in four; 2.5 mg/day in one) or tolbutamide (500 mg/day in three patients) for 4 weeks, improved hyperglycaemia after meals from 237 – 247 mg/dl to 192 mg/dl, and reduced glycosylated haemoglobin levels from 8.5 – 8.6% to 7.9% without causing hypoglycaemia.

Influence of Prostaglandin E1 on Slight Proteinuria in Non-Azotaemic Diabetics

In an investigation into the effect of prostaglandin E1 on proteinuria in nephrotic diabetic nephropathy, five patients were treated with 40 μg prostaglandin E1 administered intravenously over 2 h twice daily for 4 weeks. The following parameters were compared before and after treatment: protein excretion in urine; total serum protein concentration; serum albumin concentration; creatinine clearance; blood urea nitrogen; and serum creatinine content. A further five patients with nephropathy resulting from non-insulin-dependent diabetes mellitus were selected as controls. Analysis of the results using Students t-test showed no significant change in any of the parameters before and after treatment.

Effect of Prostaglandin E1 on the Renin – Aldosterone System in Patients with Diabetic Nephropathy

The effect of prostaglandin E1 (PGE1) on the renin–aldosterone system was investigated in hospitalized patients with non-insulin-dependent diabetes mellitus presenting with continuous proteinuria but without nephrotic syndrome. Of the 20 patients studied, 10 had continuous positive proteinuria ≥ 200 mg/day and 10 had continuous positive proteinuria < 200 mg/day. Prostaglandin El (40 μg in 100 ml normal saline) was infused intravenously over 2 h twice daily for 4 weeks. Plasma renin activity (PRA) and the plasma aldosterone concentration (PAC) were determined by radioimmunoassay at 0 and 120 min after a frusemide injection given before the start of PGE1 treatment and during administration of PGE1 in week 4. The patients who had proteinuria < 200 mg/day showed significant decreases in the PRA0 and the ratio of PRA120:PRA0 and a decrease in the PAC120 during prostaglandin PGE1 administration. When the results for the two patient groups were combined, both the PAC120 and the PRA120 were found to be significantly lowered during administration of PGE1. The results indicate that PGE1 may be valuable in the treatment of diabetic nephropathy, since the compound inhibited the increased reactivity of the renin–aldosterone system in patients with non-insulin-dependent diabetes mellitus.

Does Protease Inhibitor Inhibit Complement Activation Caused by the Immune Complex Associated with Islet Cell Surface Antibody

Sera containing islet cell surface antibody were obtained from seven children with insulin-dependent diabetes mellitus soon after the onset of disease. After incubation of 51Cr-labelled rat islet cells with islet cell surface antibody, human AB-type serum with or without nafamostat mesylate was added before further incubation. Radioactivity in the supernatant was measured to determine complement-dependent antibody-mediated cytotoxicity. Cytotoxicity in untreated sera [mean (± SD) 19.4 ± 4.0%] was significantly (P < 0.001) inhibited by ethyleneglycoltetraacetic acid (EGTA) (7.1 ± 4.9%), ethylenediaminetetraacetic acid (EDTA) (2.5 ± 0.9%) and nafamostat mesylate (2.8 ± 1.8%). Cytotoxicity of nafamostat mesylate-treated serum was significantly (P < 0.05) lower than that of EGTA-treated serum but not significantly different from that of EDTA-treated serum. There was no difference in cytotoxicity between nafamostat mesylate-treated and untreated, inactivated human serum. The results indicate that the protease inhibitor nafamostat mesylate completely inhibited the complement activation of the immune complex associated with islet cell surface antibody by the classical and alternative pathways.