We examined the preventive effect of pravastatin, an HMG-CoA reductase inhibitor, on diabetic nephropathy using streptozotocin (STZ)-diabetic rats. Male Wistar rats, weighing 200-250 g, were made diabetic with STZ 40 mg/kg and were divided into 3 groups. Group DM included diabetic rats (N =6) without treatment. Group P-DM included diabetic rats (N=6) treated with 250 mg/l pravastatin which was administered in the drinking water. Group NC were normal controls (N= 8). The leves of serum lipids, plasma glucose, urinary NAG and albumin were measured for up to 3 months. After killing the kidney weight, sorbitol content and the thickness of the glomerular basement membrane were measured. Pravastatin had no influence on the serum cholesterol and triglyceride levels of diabetic rats. Urinary NAG (DM; 0.8±0.1 vs P-DM; 0.4±0.2 U/day, p<0.01) and urinary albumin (DM; 5.1±1.3 vs P-DM; 2.5±0.9 mg/day, p<0.01) however, were significantly reduced and the thickening of the basement membrane was suppressed by pravastatin treatment (DM 205±18.0 vs P-DM; 150±6.0 nm, p<0.01). The sorbitol content of the kidney was elevated significantly in diabetic rats, but was not influenced by the treatment (DM; 314±33 vs P-DM 305±33 nmol/g, NS). These data suggest that pravastatin has a preventive effect on the progression of diabetic nephropathy without improvement of the level of serum lipids and sorbitol content of the kidney.

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To clarify whether insulin or heparin prevents the development of nephropathy in streptozotocininduced diabetic rats (STZ rats), the change in urinary albumin excretion rate was observed for 8 weeks, and the number of anionic sites (AS) on lamina rara externa of glomerular basement membrane (GBM) was evaluated at the end of the experiment in the follwing groups of rats: normal control, STZ, insulin-treated STZ, and heparin-administrated STZ. UAE of the STZ rats was markedly increased from 2 to 8 weeks; however, elevation of UAE was suppressed (p<0.01) both in the insulin-treated STZ rats and heparin-administrated STZ rats. Moreover, elevation of UAE in insulin-treated STZ rats with good glycemic control was suppressed more strongly than that in heparin-administrated STZ rats without control of hyperglycemia. The number of AS of GBM was remarkably decreased in the STZ rats (p< 0.02). This decrease in the number of AS was prevented in both insulin-treated and heparin-administrated STZ rats.
From these results, it can be concluded that both insulin and heparin act to prevent the development of nephropathy in STZ diabetic rats, though the mechanisms involved seem to differ.

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We previously reported a patient who had severe insulin resistance due to unprocessed insulin proreceptors resulting from point mutation at the cleavage site. To confirm the presence of the mutation in the patient's genomic DNA, direct sequence analysis was performed on double-strand DNA. The result showed that the mutation was a homozygote. Transfection of normal or mutated cDNA followed by Northern blot, affinity cross-linking and surface labeling confirmed the expression of both insulin receptors. Scatchard analysis of insulin binding, competitive binding study with proinsulin and miniproinsulin, and the sensitivity to trypsin to produce normal-sized receptors were similar to those of the patient's cells. However, decreased autophosphorylation and slightly increased insulin binding of the mutant proreceptors compared with those of the patient's cells were observed in the transfected cells. The discrepancy may be due to the difference in the cell type or involvement of exon 11 in the transfection vector. These results suggest that the mutation was the cause of unprocessed insulin proreceptors in the patient with insulin resistance.

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To study the causes of death among diabetics, surveys were conducted three times on patients treated at nationwide member hospitals and clinics of MIN-I-REN during the 15 years beginning in 1970. Responses from these institutions were collected from around the country. Data compilation was incomplete for the first survey, so analyses were based mostly on the data obtained from the second and third surveys. Results can be summarized as follows.
1) The age of onset of diabetes and age at death due to diabetes increased. These trends were particularly notable among female patients. 2) With respect to causes of death, the number of patient deaths due to heart disease increased markedly, but those related to cerebrovascular diseases and renal disease decreased. The number of hepatic carcinoma and liver cirrhosis deaths also increased. 3) Geographically, the percentage of cardiac patients in the Kansai area was greatly increased, while Hokkaido and Tohoku regions exhibited smaller decreases in cerebrovascular disease than other regions. 4) Heart disease was prevalent among older female patients. The incidence of hepatic cell carcinoma was high among males aged between 51-60 years, and liver cirrhosis was paticularly high in 40-to 50-year-old males, suggesting a relationship with alcohol intake. 5) Hypertension greatly affected vascular disease. We conclude that the above factors are strongly influenced by the increasing life-spans of diabetic patients.

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The aim of this study is to elucidate whether renal hypertrophy is relevant to the progression of incipient nephropathy in non-insulin dependent diabetes mellitus (NIDDM). The follow up study was performed in 14 patients with NIDDM and incipient nephropathy (11 normotensive, 3 hypertensive; age 52.1±6.1 (mean±SD) yr, diabetes duration 13.1±4.2 yr) over a 45±8 month period. To minimize the effect of hemodynamic abnormalities on the urinary albumin excretion rate (AER, μ9/ min) antihypertensive therapy (using ACE inhibitor) was introduced in 10 patients. Renal size was evaluated according to Simon's method (mean kidney length/height of second lumbar spine and its disc: renal ratio, RR). Mean values of AER, HbA1, systolic blood pressure (SBP) and Ccr in the first and last 12 months were 48.5, 157.1 μg/min ; 9.1, 8.4%; 127, 122 mmHg; and 94.7, 84.4 ml/min, respectively. RR correlated significantly with AER in the last 12 months (r=0.675, p<0.02). RR and SBP were statistically higher in 5 patients (group B) who showed the worsening AER than those in the other 9 patients (group A) who exhibited no worsening AER (3.74±0.12 vs 3.30±0.11, p<0.001; 127±5 vs 119±7 mmHg, p<0.05). But no significant differences were found between groups A and B in HbA1 and Ccr in the last 12 months.

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We investigated the relationship between growth hormone and the incidence of diabetic retinopathy in NIDDM. Plasma GH levels were determined after moderate exercise in 48 NIDDM patients with no retinopathy or mild background retinopathy. Patients were divided into two groups ; group I, 27 patients whose GH levels after exercise were less than 5 ng/ml; group II, 21 patients whose GH levels after exercise were more than 5 ng/ml. There were no significant differences in body mass index, duration, fasting plasma glucose, HbA1 and blood pressure between the two groups. We examined all patients for incidence and progression of retinopathy every year for 5 years. After 5 years, only one patient had developed retinopathy in group I, but eight in group II (p<0.01) had. These results suggest that growth hormone levels after exercise may contribute to differences individual variability in the development of retinopathy.

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A 72 year old male was urgently hospitalised with unconsciousness. On admission, no signs of organic disorder were detected by physical examination or by brain CT. But hypoglycemia was revealed, and intravenous administration of glucose was followed by a complete recovery of consciousness. However, hypoglycemic attacks occurred repeatedly despite frequent intravenous glucose administration. Because of the difficulty in maintaining normoglysemia, alcoholic odor in the breath, and marked dilatation of the stomach found by abdominal CT, alcoholic hypoglysemia due to exessive ethanol production by intragastric fermation was suggested. A considarable amount of gastric content with an alcoholic odor was aspirated, and pyloric stenosis secondary to a gastric ulcer was diagnosised endoscopically. The ethanol concentration in the serum was 0.2 mg/dl, and declined to undetectable levels after gastric aspiration. The hypoglysemic attacks also disappeard. A great number of yeasts were found microscopically in a specimen of gastric contens. They were identified as Candida albicans and Torulopsis glablata culture confirmed ethanol production from glucose with the yeasts isolated from the gastric juice. The above results indicate that the hypoglysemia seen in this patient was induced by an excess of ethanol produced by fermenting yeasts in a stomach dilatated by pyloric stenosis.

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Hypoglycemia is a major side effect of insulin treatment in diabetic patients. However, warning symptoms generally prevent neuroglycopenia severe enough to cause coma or death. We report here a hypoglycemia-induced cardiorespiratory arrest in a patient with severe diabetic autonomic neuropathy. After successful resuscitation, he required artificial respiration for 6 hours and was confused for the 2 following days. He had severe autonomic neuropathy which manifested as orthostatic hypotension (80 mmHg decrease in systolic blood pressure upon standing), and no blood pressure and heart rate responses to the valsalva maneuver, deep breathing, cold stimuli and atropine infusion, i. e. his heart was almost totally denervated. We tested his counterregulatory hormonal responses to hypoglycemia using an insulin-glucose clamp technique. He suddenly lost consciousness at a 45mg/dl blood glucose level without any prior warning symptoms and adrenaline and glucagon did not increase in response to the hypoglycemia. These data strongly suggest that his cardiorespiratory arrest and severe hypoglycemia were closely related to his endocrine and neurogenic impairment. Cardiorespiratory arrests have been reported in the patients with severe diabetic autonomic neuropathy, usually in the status of respiratory restriction. This is one of two cases of hypoglycemia-induced cardiorespiratory arrest in severe diabetic autonomic neuropathy reported in Japan. However, such patients may increase in number with longer durations of insulin treatment.This case reminds us that hypoglycemia could easily be fatal in diabetic patients with severe autonomic neuropathy.

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1, 5-Anhydroglucitol (AG) is decreased in the serum of poorly controlled diabetic patients. Although the metabolism of AG is largely unknown, the low serum AG concentration of the patients has been attributed to the increased urinary excretion of AG in association with glycosuria. In order to clarify the effects of impaired renal function on the metabolism of AG, we measured both serum and urinary AG concentrations in 28 non-diabetic patients with renal disease (RD group) who had no glycosuria in association with various degrees of decreased glomerular filtration rate (GFR).
Serum AG concentrations were decreased in the RD group even in the absence of glycosuria. The degree of decrease in serum AG level was correlated with the reduction in GFR. No correlation was observed in diabetic patients with glycosuria. Urinary excretion of AG appeared to be increased in the RD group based on their low serum AG level.
These results suggest that the low serum concentrations of AG in patients with chronic renal failure may be caused, at least partly, by an increase in the urinary excretion of AG.

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We have reported that the vasotropic agent, prostaglandin E₁ analogue OP1206·α-CD (OP) ameliorates the decrease in sciatic motor nerve conduction velocity (MCV) and Na⁺/K⁺-ATPase activity of rats with streptozocin-induced diabetes without normalizing abnormal nerve sorbitol or myo-inositol content. This observation suggests that nerve Na⁺/K⁺-ATP-ase activity may be regulated by unknown metabolites other than myo-inositol. In order to examine this possibility, the effect of OP on Na⁺/K⁺-ATPase activity was examined in vitro.
Twenty-seven 8-week-old Sprague-Dawley rats were used in the experiment. Diabetes mellitus was induced by intravenous injection of streptozocin 45 mg/kg. Six weeks after the injection, the diabetic rats had significantly higher levels of plasma glucose, lower body weights and slower sciatic motor nerve conduction velocities than the control rats (all p<0.001). Sciatic nerves isolated six weeks after treatment were incubated with various concentrations of OP: the decreased Na⁺/K⁺-ATPase activity was ameliorated in a dose-dependent manner, and the improvement was significant at concentrations higher than 0.5ng/ml in the diabetic rats. Nerve cAMP concentrations were also increased in a dose-dependent manner in the diabetic rats.
These rasults suggest that OP has a direct effect on diabetic nerve tissue via a mechanism which might be associated with an increase in nerve cAMP levels rather than a vasotropic action.

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