In order to analyze the oral glucose tolerance test in non-obesesubjects (normal: 96, borderline: 109, type 2 diabetes: 137), a data processing method was applied for evaluation. According to the fasting plasma glucose level, the patients with diabetes were subdivided into 3 groups (mild: FPG≤140 mg/dl, moderate: 140<FPG≤200 mg/dl, severe: FPG> 200 mg/dl). The following results were obtained.
1) In subjects with borderline, mild and moderate diabetes, the IRI/glucose values at fasting were not decreased, suggesting that decreased insulin sensitivity may play a role in fasting hyperglycemia in such subjects.
2) The insulin responses to glucose load were significantly impaired and delayed even in mild and moderate diabetic subjects. Regarding the increased glucose area from the fasting plasma glucose levels (Σ(ΔG)), normal and borderline subjects showed a greater glycemic response after 1 hour (⁶⁰Σ₀ (ΔG)>¹²⁰Σ₆₀ (ΔG)), while diabetics showed an inverse relation (⁶⁰Σ₀ (ΔG)<¹²⁰Σ₆₀ (ΔG)). These results suggested that both the secretion and effectiveness of insulin were abnormal in the diabetic state.
3) In severe diabetics, the IRI/glucose value at fasting decreased, and the insulin response was similarly low and delayed.
4) The following factors which separated glucose intolerance better and reflected insulin sensitivity are proposed.
(Gp/I, ¹²⁰Σ₆₀G/⁶⁰Σ₀I, ¹²⁰Σ₆₀ (ΔG)/⁶⁰Σ₀ (ΔI))
The IRI area during 120 min (¹²⁰Σ₀I) was higher in subjects with borderline glucose intolerance, but lowered in severe diabetes, and there were no differences in total insulin area (¹²⁰Σ₀I) between mild (moderate) diabetes and normals.
These results indicate that glucose intolerance in type 2 diabetes results not only from impaired insulin secretion but also from decreased insulin sensitivity. Determination of insulin as well as glucose during OGTT is useful for the quantification of such abnormalities.

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In order to investigate hormonal changes of the pancreas during the development of diabetes in the non-obese diabetic mouse (NOD mouse), the contents of insulin, glucagon and somatostatin in the pancreas were determined in NOD mice with various levels of fasting plasma glucose (FPG) and were compared with those of normal ICR-strain mice.Moreover, the plasma antibodies to Coxsackie virus type B-3 and reovirus 1, 2 & 3 types were measured.
In the pancreas of NOD mice with FPG less than 140 mg/dl, the insulin content in males was not significantly different from that of normal controls with a mean (±SE) value of 3.55±0.31U/g wet weight of pancreas whereas it was already significantly decreased to 0.85±0.52 U/g in females.The value was 0.002±0.001 U/g especially in mice with FPG more than 201 mg/dl. The glucagon content in the pancreas was 7.76±0.89μg/g in normal controls.It decreased slightly but significantly in the NOD mouse, although among the NOD mice of different FPG groups the values were not significantly different. Pancreas somatostatin showed a tendency to be higher in the NOD mice with FPG higher than 201 mg/dl, although the difference was not statistically significant.
Histologically, cell infiltration into the pancreatic islets was remarkable in mice with FPG higher than 201 mg/dl, but it was already found even in those with normal FPG. Plasma antibodies to Coxsackie virus type B-3 and reovirus 1, 2 & 3 types were not detected at any level of FPG in the NOD mice.

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We investigated procedures for the diagnosis and management of elderly diabetics by sending questionnaires to 268 councillors of the Japan Diabetic Society.We received 155 valid replies (57.8%).
Most answerers (87.5%) make their diagnosis of elderly diabetics according to the new criteria publiished by the Japan Diabetic Society in 1982 without modification.Regarding blood sugar control, 64.5% of the answerers seek a level which is higher by 10-30 mg/dl as regards fasting blood sugar in elderly compared to younger patients.The goals for fasting blood sugar level in elderly diabetics are 100-140 mg/dl, 110-150 mg/dl and 120-160 mg/dl on diet, oral hypoglycemic agents and insulin, respectively.Dietary restriction to elderly patients is mildly instructed by 68% of the answerers, and strictly instructed by 27% of them.When introducing insulin or oral hypoglycemic agents, 53% of the answerers do not distinguish elderly from younger patients, but 60% of them begin the drugs in small doses.Many of them pointed out that mild blood sugar control and small dose medication are for the prevention of hypoglycemia.The importance of education to elderly patients was again claimed by many answerers.

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Studies were conducted to determine whether there is a decrease in oxygen release capacity or not in diabetic patients with an increase of glycosylated hemoglobin (HbA_IC).
37 diabetics who had not undergone any treatment and who had high levels of HbArc were used as subjects for this study. 14 patients out of the 37 diabetics had mild background retinopathy and 23 patients had no retinopathy. None of them were acidotic or anemic. 31 nondiabetic healthy volunteers were used as normal control subjects. The P₅₀ of the oxyhemoglobin dissociation curve at in vivo pH among the 37 diabetics was significantly higher than in the normal control subjects (25.1±1.4 mmHg (M±SD) vs. 23.9±1.9 mmHg, p<0.01). The P₅₀ pH 7.4, venous pH and 2, 3-DPG were also significantly higher in the diabetics.There was a significantly positive correlation between the 2, 3-DPG and P₅₀ in vivo pH or P₅₀ pH 7.4 in the diabetic group (r=0.42, p<0.01; r=0.46, p<0.001, respectively). On the other hand, an inverse correlation existed between the hemoglobin concentration and 2, 3-DPG in both groups respectively (diabetics: r=-0.59, p<<0.001; controls: r=-0.53, p<0.005). In all subjects of both groups, HbA_IC had a slightly positive relation to venous pH, 2, 3 DPG and P₅₀ in vivo pH.
It is concluded that the P₅₀ in vivo pH can be maintained at above normal levels with increase of 2, 3-DPG, so that affinity hypoxia does not occur in untreated diabetics who have high levels of HbAIc and mild background retinopathy or no retinopathy.

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In order to determine the early signs of diabetic nephropathy, 33 diabetics including 29 without proteinuria and hypertension and 4 with nephropathy were examined for various kinds of urinary proteins by means of sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). No subjects had urinary tract infection.The electrophoretic patterns were classified as follows: normal (N) pattern only albumin stained predominantly;tubular (T) pattern=low molecular weight proteins stained predominantly;glomerular (G) pattern=high molecular weight proteins stained predominantly;mixed (M) pattern=both high and low molecular weight proteins stained. T pattern suggested tubular dysfunction.G pattern correlated closely with glomerular damage. M pattern indicated glomerulo-tubular damage.Abnormal electrophoretic patterns were found in 72.7% of all diabetics (39.3% with T pattern, 15.2% with G pattern, and 18.2% with M pattern), and in 69% of diabetics without proteinuria.Only N and T patterns could be obtained in diabetics within 1 year of the onset.M pattern could be found in those with diabetes of more than 1 year's duration and G pattern could be found in those with diabetes of more than 5 years' duration. All patterns existed in those with diabetes of more than 5 years' duration.The concomittant presence of diabetic retinopathy was 0 % in patients with N pattern, 23% in those with T pattern, 50% in those with M pattern, and 100% in those with G pattern.The concomittant presence of diabetic neuropathy was: N pattern 22%, T pattern 38.5%, M pattern 67%, and G pattern 100%.The mean glomerular filtration rate in the patients with T pattern was higher than in those with M pattern, which was higher than in those with G pattern.
These observations suggest that tubular dysfunction might be an early sign of diabetic nephropathy.

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The concentrations of plasma 6-keto-prostaglandin F_1α (6-keto-PGF_1α) and thromboxane B₂ (TXB₂), stable metabolites of prostacyclin and thromboxane A₂, respectively, were measured by radioimmunoassay at rest and after 3 min of touriquet ischemia in the upper limb of patients with diabetes mellitus and normal controls. Forty-five diabetic patients were grouped as follows: Group I (N=15) had no vascular complications; Group II (N=10) had only macroangiopathy; Group III (N=10) had only microangiopathy;group IV (N=10) had both macroangiopathy and microangiopathy.
The plasma 6-keto-PGF_1α concentrations at rest were not significantly different between the control subjects (245.6±14.3 pg/ml, mean±SE) and diabetic patients (235.6±13.2 pg/ml). After tourniquet ischemia, a significant increase in plasma 6-keto-PGF_1α concentration was found in the controls (324.8±24.5 pg/ml; p<0.01), but no significant change was observed in the diabetics with vascular complications (group III as well as groups II and IV with atherosclerotic lesions). In addition, no significant increase in plasma 6-keto-PGF_1α concentration after tourniquet ischemia was found in some patients of group I. The values of plasma TXB₂ were slightly higher in the diabetic patients (228.6±16.4 perrii) than in the control subjects (198.8±14.4 pg/ml), but the difference was not statistically significant, and no significant increase was observed in both groups.
These results suggest that impaired prostacyclin production in the vessel wall may play a role in the evolution of diabetic vascular complications.

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Glycosylated hemoglobins (HbA₁ or HbA_1c) have been widely used for assessing the long-term control of diabetes. Apart from this, nonenzymatic glycosylation of serum proteins has evoked special interest in relation to its role in the development of diabetic complications. In the present study, the glycosylation of serum low density lipoprotein (LDL) and of serum protein in diabetic patients was determined to substantiate its usefulness as an index for the short-term control of diabetes, since the half-lives of these proteins are much shorter than that of HbA₁.
Glycosylated LDL (GLP) and serum protein (GSP) were assayed by the thiobarbituric acid reaction, and their values were expressed as nanomoles of 5-hydroxymethylfurfural (HMF) per mg protein. The level of GLP in diabetics was significantly higher than that in nondiabetics (4.4±1.6 and 1.7±0.6, respectively; p<0.001), and correlated remarkably with the mean value of the fasting blood sugar (FBS) for one week (r=0.69). The level of GSP in diabetics was higher than that in nondiabetics (1.0±0.3 and 0.5±0.2, respectively; p<0.001), and correlated well with the mean FBS for two weeks (r=0.62). These results indicate that GLP and GSP might provide a valuable tool for assessing the shortterm control of diabetes. Moreover, it was demonstrated that the degree of glycosylation of LDL was greater than that of other serum proteins. A high value of GLP with probable changes in qality may play an important role in the development of diabetic angiopathy.

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The effect of sera from 3 patients with insulin receptor antibodies on the binding of insulin to isolated nuclei was studied. All sera (1: 4 dilution) inhibited insulin binding to the receptor on the plasma membrane to 46.8%, 56.7%, and 53.4% of the control, respectively. The amounts of receptor antibodies detected by immunoprecipitation of solubilized insulin receptor were not the same as those detected by binding inhibition. All three sera did not affect the binding of insulin to purified nuclei is olated from rat liver. These results indicate that the binding capacity of the nucleus for insulin is different from that of the insulin receptor of the plasma membrane.

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We examined the clinical and laboratory features of 10diabetics with hyporeninemic hypoaldosteronism (HRHA). These diabetics had no renal failure and the fasting blood glucose was 70 to160mg/dl. They showed the following clinical and Iaboratory characteristics.
Nine patients were of Type II diabetes mellitus and one was of Type I.The mean age was 54yr, with a range of 27-65yr. Eight patients were males and two were females. The known duration of diabetes mellitus was from5-20yr. On admission, the mean serum potassium was 5.4±0.3mEq/L. Hypertension in systolic blood pressure was present in nine patients and four of these nine patients had hereditary hypertension. All patients exhibited a 24-hr urinary protein excretion which was above normal, ranging from 500mg-5, 000mg/24hr. The mean creatinine clearance was 47±7m/min, with arange of 40-60ml/min. The mean serum creatinine was 1.6±0.2mg/dl, with a range of 1.2-1.8mg/dl.
Orthostatic hypotension was noted in six patients, and peripheral neuropathy in all patients. The six patients with orthostatic hypotension showed a significant (p<0.01) decrement in the plasma norepinephrine response to upright posture comparcd to the four patients without orthostatic hypotension, but showed no significant change in serum potassium, plasma renin or plasma aldosterone.
The optic fundus findings were Scott II or IIIa in four patiets and Scott IIIb, IV or Va in six patients.Two patients were treated through diet alone, two were treated with drugs and six were treated with insulin.
In conclusion, it can be said that HRHA in the diabetics was apparently closely related to hypertension, especially essential hypertension and nephropathy.

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It is well known that from the etiological view point, viral infection and autoimmunity are closely associated.However, reports of acute onset insulin dependent diabetes (IDDM) following Epstein-Barr virus (EBV) infection are very few.We experienced a case of IDDM caused by the suspected effects of EBV infection.
A 23-yr-old female was admitted due to diabetic ketosis.Ten days before her chief complaints of diabetes, she had experienced exanthema, myalgia and general malaise.On admission, her blood glucose level was 640 mg/dl, and her general condition was improved by continuous low dose insulin infusion (5U/hr).Subsequently, she has been treated with MC insulin.The biochemical data on her admission showed a slight increase in GOT and GPT levels, and antismooth muscle cell antibody and ICA were positive.During admission, her IgG antiboy to viral capsid antigen of EBV increased from a titer of1: 80 to one of1: 320, and her IgG antibody to early antigen of EBV increased from a titer of1: 10 to one of 1: 20 and became negative 2 months later.An increased percentage of double marker cells underwent a gradual decrease over a period of6 months.From these results, we judged that she was infected with EBV.Furthermore, the patient had never previously suffered from diabetes mellitus but was found to suffer from it soon after the EBV infection with hyperglycemia and low response of C-peptide reactivity. There was thus a clear possibility that the diabetes in this case had been induced by EBV.
On the other hand, during the clinical course, the microsome test and thyroid test were negative, and the patient's HLA typing was a phenotype of A9, Bw22, Cw1, Cw4, DR4 and MT 3. It was concluded that the diabetes in this case was induced by permanent damage to pancreatic B cells infected with EBV and by subsequent autoimmune mechanism.

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We investigated the effect of the specific sulfhydryl blockers, N-ethylmaleimide (NENI) and dithiobisnitrobenzoic acid (DTNB), on ¹²⁵I-insulin binding to adipocytes, adipocyte plasma membrane and IM-9 lymphocytes.
NEM markedly inhibited the insulin binding to intact cells to lower than50% of thc control whether NEM was added bcfbre or simultaneously with the ¹²⁵I-insulin to the cell suspension, but DTNB, showed no such effect. The inhibition was temperature, time and concentration dependent. Scatchard analysis of the binding indicated that NEM affected the affinity rather than the capacity.
However, both reagents did not affect the insulin binding to the adipocyte plasmamcmbrane.
We considerd that NEM did not act on the binding mechanism of the plasma membrane receptor but intracellularly, since NEM can freely cross the adipocyte plasma membranc but DTNB cannot.

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