We have characterized the relationship between the subunit structure of insulin receptors and their function. Pretreatment of rat liver and brain membranes with dithiothreitol caused an increase in subsequent ¹²⁵I-insulin binding to these membranes. Binding was enhanced most when liver and brain membranes were treated with 3 mM and 30 mM dithiothreitol, respectively. In autoradiograms of ¹²⁵I-insulin cross-linked to pretreated membranes, the intensity of affinity-labeled bands of the αβ-and α-subunits of insulin receptors was increased, especially when maximum binding was attained.
Affinity-labeled 120 kDa and 110 kDa bands of the a-subunit in partially reduced liver and brain membranes moved to 130 kDa and 120 kDa respectively when reduced further. Double electrophoresis of the partially reduced bands in the presence of reductants clearly demonstrates that the a-subunit contains intrasubunit disulfide bonds.
Results, therefore, show that the partially reduced form of insulin receptors has higher affinity than the native form, and the a-subunit of insulin receptors contains intrasubunit disulfide bonds whose partial reduction may be responsible for an increase in insulin binding.

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This study was carried out to explore the relationship between the incidence of diabetic microand macroangiopathy and residual B cell function. One hundred and eighty-eight diabetic patients were selected at random and divided into three groups according to their ruinary C-peptide excretion rate, and each group was further divided into two subgroups according to duration of the disease. There was no significant difference in incidence of retinopathy, nephropathy and neuropathy in relation to urinary CPR excretion among patients with a duration of diabetes of less than 10 years. Among patients with a longer duration (≥10 yrs), the low CPR group (<30μg/day) demonstrated a significantly higher incidence of retinopathy, nephropathy and neuropathy than the other two groups. Patients with diabetes of a longer duration (≥10 yrs) were substantially more susceptible to development of the triopathy than those with a shorter duration, when the urinary CPR excretion rate was less than 30μg/day. In contrast to microangiopathy, there was no significant correlation between the occurence of macroangiopathy and the urinary CPR excretion rate.
These results suggest that not only the duration of diabetes but the residual B cell function could be determinant factors for development of diabetic microangiopathy.

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Recently the number of pregnant diabetics with a long history of diabetes and complicated with diabetic retinopathy has increased. Especially in the case of proliferative retinopathy, it has become more difficult to decide whether to continue a pregnancy.
We managed 166 pregnancies from February 1964 to December 1984. During pregnancy retinopathy was present in 89 patients (53.6%). Of these, 11 had proliferative retinopathy, and 78 had background retinopathy.
Photocoagulation was performed in six patients, most of whom came to our outpatient clinic after conception and had been receiving no prepregnancy management. Progression of the retinopathy was prevented by photocoagulation and improved diabetic control. The retinopathy further improved in five patients after delivery.
Four patients had undergone photocoagulation for proliferative retinopathy two to three years before becoming pregnant. As their retinopathy improved, they were permitted to get pregnant. Their retinopathy did not worsen during pregnancy.
In patients with proliferative retinopathy during pregnancy, photocoagulation combined with strict diabetic control should be attempted before therapeutic abortion is performed. The importance of prepregnancy management and planned pregnancy is emphasized in relation to retinopathy.

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To clarify the mechanism of glucose intolerance in hepatic cirrhosis, tissue sensitivity to insulin was studied by using the euglycemic clamp technique in six cirrhotic patients and seven controls. The rate of glucose utilization (M), the rate of metabolic clearance of glucose (MCR_G) and the insulin sensitivity index (M/I×100) were used as indices of tissue sensitivity to insulin.
The M, MCRG and M/I×100 in the cirrhotic patients were all significantly lower than those in the controls: M=5.77±0.72 vs. 10.57±1.24 mg/kg/min (p<0.01); MCRG=6.56±0.84 vs. 13.05 1.42 ml/kg/min (p<0.005); and M/I×100=1.76±0.43 vs. 3.95±0.47 (p<0.01). There were highly significant inverse correlations between the rate of glucose utilization and bothΣBG after a 75-g oral glucose tolerance test (r=-0.85, p<0.05) and fasting serum insulin (r=-0.91, p<0.05). The metabolic clearance rate for insulin showed no significant difference between the cirrhotics and the controls (12.5±2.2 vs. 15.5±1.7 ml/kg/min, NS).
By using the euglycemic clamp technique, we demonstrated the presence of decreased tissue sensitivity to insulin in hepatic cirrhosis. Our results suggest that this decreased sensitivity may play a significant role in the pathogenesis of glucose intolerance. The insulin resistance seems to be related to the hyperinsulinemia often seen in hepatic cirrhosis.

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Intensified conventional insulin therapy using human ultralente insulin (U-HM) and human actrapid insulin (Novo pen system'I) was tried in 10 diabetic patients poorly controlled with conventional therapy.
1) Both fasting plasma glucose (211±27 vs. 125±12 mg/dl, p<0.01) and hemoglobin A1 (12.5±0.4 vs. 10.6±0.4%, p<0.01) levels decreased after about 2 months of intensified conventional insulin therapy.
2) With this regimen the circadian profile of free insulin concentraion became more physiological with an increase in free insulin level after each meal. Improvement of circadian variation of plasma glucose was also found.
3) There was a good correlation between the dose of U-HM and free insulin concentration at 3 a.m. (r=0.793, p<0.05) and between the dose of U-HM and basal infusion rate (0-8 a.m.) determined by an artificial pancreas (r=0.782, p<0.05).
These results indicate that intensified conventional insulin therapy using the pen system and U-HM may provide the proper amount of insulin both postprandial (by the pen system) and in the basal state (by U-HM) and be a useful method for the treatment of patients poorly controlled by conventional insulin therapy.

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Two cases of abrupt onset type 1 diabetes associated with elevation of elastase 1 and diabetic ketoacidosis are reported. Patient 1 is a 22 year-old woman who gave a normal response to an oral glucose tolerance test 13 weeks before admission. In September 1983, in the 40th week of pregnancy, she delivered a dead fetus. Since she lost consciousness soon after delivery, she was transferred to our hospital. Patient 2 is a 20 year-old man who was admitted to our hospital because of nausea and vomiting of 2 days duration following a common cold. Both cases were diagnosed as diabetic ketoacidosis, and the patients were treated with insulin and saline. Although their glycemic levels were very high, HbA₁ values were normal on admission. Furthermore they showed no intrinsic insulin secretion. They were considered to have developed type 1 diabetes recently. The levels of their elastase 1 were very high (i.e. 2500 and 1800 ng/dl), but amylase and lipase levels were normal. After insulin treatment, their amylase levels showed a slight transient elevation, while elastase 1 decreased gradually.
We compared the levels of elastase 1 in three other ketotic or ketoacidotic diabetic patients with those in case 1 and 2. We propose inflammation of the exocrine pancreatic cells around the islets associated with the insulitis as a possible mechanism of the elevation of elastase 1 in these diabetic ketoacidotic patients.

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