The contribution of diabetic duration, both total and postpubertal, to the development of microangiopathy in Japanese IDDM subjects was investigated. Sixty-three subject g were examined ophthalmoscopically, with 15 having developed background or proliferative retinopathy. Twelve out of 60 patients had microalbuminuria, defined as a urinary albumin concentration greater than 30mg/l. Life-table analyses by total and postpubertal IDDM duration were used to evaluate differences in the prevalence of background retinopathy and microalbuminuria in subjects diagnosed before and during puberty as defined by the age at IDDM onset marker of 11 years for girls and 12 years for boys. The prevalences of retinopathy and microalbuminuria by total duration were significantly greater in subjects diagnosed during puberty than in those diagnosed before pubety (p=0.014, p=0.039, respectively). However, similar analysis by postpubertal duration showed no differences in retinopathy and microabluminuria prevalences between the two groups.
The results suggest that the effect of prepubertal duration on the risk of microangiopathy may be minimal in Japanese IDDM subjects.

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We determined the frequency of antibodies to glutamic acid decarboxylase (GAD-Ab) using a new radioimmunoassay (RIA) developed by Hoechst Japan Ltd, and examined the relatioship between GAD-Ab and islet cell antibodies (ICA). The subjects of our study were 35 patients with IDDM who were less than 25 years of age at onset (male 13, female=22;age at onset.16.46±4.9 years; duration of diabetes, 5.54±4.6years). GAD-Ab was measured by RIA using GAD purified from porcine brain as an antigen. We expressed the titer of GAD-Ab in units based on the percentage of radioactivity of the reference serum, and determined a positivity limit of 8 U.ICA was assessed with a conventional indirect immunofluorescence method. GAD-Ab was positive in 17 of 35 patients (48.6%). The frequency of GAD-Ab was 60.0%(108.8±106.0 U;mean±SD of titers) in those patients with a duration of less than 1year, 50.0%(20.2±16.5 U) with 1 to 3 years, 62.5%(58.7±111.5 U) with 3 to 5 years, 40.0%(47.3±119.1 U) with 5 to 10years, and 37.5%(26.1±33.4 U) in those with a duration exceeding 10years. The mean of titers decreased with increasing duration of diabetes. There was a relationship between ICA and GAD-Ab (p<0.05). The prevalence of ICA increased as GAD-Ab titers rose.We conclude that GAD-Ab is related to ICA, and is comparable to ICA as an IDDM-associated marker.

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We measured the concentration of transferrin (TF), albumin (Alb), A microglobulin (AM), and creatinine (Cr) in first-voided morning urine samples from 61type-2diabetic patients and19normal subjects. We also determined urinary Alb and TF excretion rates before and after treatment in 6 diabetic patients.
In the 34 adequate glycemic control patients (HbA₁c<8.0%), a significant correlation was found between the urinary TF/Cr and β₂M/Cr ratios (r=0.46, p<0.02), but no significant correlation was detected between the urinary Alb/Cr and AM/Cr ratios. The urinary TF/Alb ratio was higher in the 17 adequate glycemic control patients with microalbuminuria than in the17adequate control patients with normoalbuminuria (p<0.01). An elevated urinary TF/Alb ratio was correlated with an elevated urinary Alb/Cr ratio (r=0.61, p<0.02). Among the 28 patients with normoalbuminuria, the urinary TF/Cr and TF/Alb ratios were higher in the 17 adequate glycemic control patients than in the II poor glycemic control patients. In 6 patients, the posttreatment urinary TF/Cr and TF/Alb ratios were significantly lower than the pretreatment ratios (p<0.02).

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We have reported the usefulsess of transcutaneous oxygen tension (TCPO₂) as a marker of the diabetic foot in NIDDM.TCPO₂ was already reduced in several subjects without clinical manifestations of peripheral vascular disease (PVD). In the present study, we investigated the relationship between TCPO₂, clinical symptoms and numerous variables to analyze risk factors contributing to the reduction of TCPO₂. The subjects were 181 NIDDM patients (group D), including 56 patients with PVD and 34 non-diabetic controls (group C).
1) The TCPO₂ in group D, especially in subjects with PVD, was significantly lower than in the controls, and 50 mmHg could serve as a reasonable cut-off point for TCPO₂.
2) TCPO₂ in subjects with intermittent claudication or pain at rest was significantly lower than in subjects without symptoms in their legs.
3) Multiple regression analysis demonstrated that aging, arterial obstruction, microangiopathy, and autonomic neuropathy were the independent risk factors of reduction in TCPO₂.

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A 50-year-old man was admitted with spontaneous hypoglycemia and retroperitoneal mesothelioma. As his fasting plasma IRI level was low, he was diagnosed as having non-islet-cell tumor hypoglycemia (NICTH)
He had a high blood concentration of insulin-like growth factor II (IGF-II), with an increase in the percentage of the large molecular weight form, as well as altered blood IGF II-IGF binding protein formation. His plasma IGF-I was also low.Before tumorectomy, three types of insulin-secretion test were conducted. On the i. v. glucose loading test, the early phase of the insulin response was almost intact, but the later phase showed gradual suppression. On the oral glucose test, secretion was grossly suppressed. On the i. v. glucagon test, the response was completely suppressed. After tumorectomy, all of the above humoral factors and the results of the three tests returned to normal.
These data suggest that heterogenous IGF-II is produced and that IGF binding proteins are altered in patients with NICTH. It was also noteworthy that, in the same patient, intrinsic insulin and its secretion were suppressed with variable responses to three different stimulations. These observations led us speculate that some unknown substance related to appropriate insulin suppression is involved, in an undefined way, in the pathogenesis of NICTH and the role of IGF-II.

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A 66-year-old man was admitted to our hospital because of intermittent claudication, pretibial edema and blurred vision in his right eye. He was diagnosed as having diabetes mellitus accompanied by hypertension, arteriosclerosis obliterans and multiple brain infarctions.On admission, he had preproliferative retinopathy in his right optic fundus, whereas his left eye was unaffected. Brain CT revealed old multiple infarctions in the right basal ganglia and left occipito-temporal region.Cerebral angiography revealed occlusion of the left internal carotid artery, together with stenosis of the right internal carotid and right ophthalmic arteries.The left ophthalmic artery was filled by the left external carotid artery.In this case, retinopathy did not exist on the completely occluded side, but rather on the less severely sclerotic side of the internal carotid artery, probably due to unusual collateral circulation in the intracranial arteries and also in the external-internal vasculature.Since asymmetric retinopathy in diabetic patients probably reflects the existence of an extraocular local hemodynamic disturbance leading to stroke, carotid and intracranial arteries in such patients should be carefully examined.

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We report a case of diabetes mellitus accompanied by pheochromocytoma. A 68-year-old woman was admitted to our hospital because of uncontrolled diabetes mellitus in April 1991.During this hospitalization, she was newly diagnosed as having pheochromocytoma.Her diabetes had been treated with oral hypoglycemic agents, and then with insulin, during this hospitalization. Immediately after tumorectomy she experienced complete remission of the diabetic state with a dramatic increment in insulin secretion. However, her blood glucose rose again with a slight weight gain four months after tumorectomy. The clinical course suggests that diabtes mellitus was aggravated by pheochromocytoma, in addition to genetic factors, in this patient. The prognosis of diabetes after tumorectomy has not yet been analysed.This patient's clinical course indicates the necessity of following glucose tolerance even after tumorectomy.Although diabetic retinopathy rarely accompanies pheochromocytoma, in this case preproliferative retinopathy was observed before the tumorectomy and diminished postoperatively.

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We examined the insulin receptor gene in a 20-year-old woman with type A insulin resistance who presented with acanthosis nigricans and polycystic ovary.An oral glucose tolerance test showed a diabetic pattern and hyperinsulinemia.Resistance to exogenous insulin was evident. Insulin binding to fibroblasts and Epstein-Barr virus-transformed lymphocytes (EBTL) was within the normal range, but autophosphorylation and tyrosine kinase activity were reduced in partially purified insulin receptors from EBTL.We determined the nucleotide sequence for all 22 exons of the insulin receptor gene directly by the polymerase chain reaction.We demonstrated that the patient was heterozygous for a mutation substituting valine for glycine at codon 1008 in the tyrosine kinase domain.This mutation was the same as type A Hokkaido (Odawara et al.Science, 245, 66, 1989), but we could not find any relationship between the two families. The father was heterozygous for the same mutation and had an impaired glucose tolerance with mild hyperinsulinemia.The mother and two brothers had normal glucose tolerance.We conclude that the mutation in the tyrosine kinase domain caused dominant insulin resistance.

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Patients with diabetes prick their skin for blood glucose monitoring.They subsequently insert a needle for injecting insulin. Because two needle sticks are necessary to complete these maneuvers, a major stress is potentially present for patients anticipating two painful procedures in succession.
To slove this problem, we suggest a new system, in which a small amount of blood can be vacuumed from the needle insertion site of insulin injection and used for blood glucose measurement. In this paper, we would like to explain our clinical results in humans.
Eleven healthy men and 23 diabetic patients were studied by comparing blood glucose data obtained by the conventional method and the new method.
As a result, the blood glucose level obtaned by the conventional method was 165±73mg/dl (mean±SD), and that by the new method was 164±73mg/dl. The correlation was strong (0.99;p<0.001). During the procedure used for the new method, no subjects complained of any pain on vacuuming.
This indicates that the two maneuvers can be safely accomplished from the same stick.Thus, patients will be able to share in the benefits of the new system, which makes blood glucose measurement maneuvers completely free of additional pain.

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