In the long-term treatment of diabetic patients with sulfonylurea (SU) drugs, some patients require increasingly large doses of the drug, probably because of the failure of dietary treatment. In 97 diabetic patients who received the same SU drug for 5-7 years, we have followed changes in body weight as an indication of the efficiency of dietary treatment, and have investigated the relationship between the change in body weight, the dosage of the SU drug, and the degree of control of blood sugar levels.
The three SU drugs employed were Glycodiazine, Glyclopyramide, and Glibenclamide. To evaluate the long-term effect of these drugs, the patients were classified into three groups according to the effect of the drug in controlling blood sugar levels in the first and second halves of the treatment period. In group I, the effect was maintained in the second half of the treatment period; in group II, the effect decreased partially ; and in group III, the drug became ineffective in the second half of the treatment period. The numbers of patients in each group whose weight increased or decreased, and the average degree of obesity in each group, were compared between the first and second halves of the treatment period.
For the numbers of cases in each SU drug, group I was largest and group III smallest, showing that treatment with the same drug is possible for a long period. Also, for each drug, the numbers of patients who lost weight was greatest in group I, and the degree of obesity decreased in the second half of the treatment period in group I, while groups II and III showed no significant difference. These results suggest that the effect of SU drugs is maintained in patients whose body weight decreases toward normal with a correctly miantained diet.

View full abstract

In order to evaluate the influence of long-term sulfonylurea therapy on the development of vascular complications (ECG abnormality, retinopathy and albuminuria) a study was made on 236 diabetic patients during a period of treatment which extended from 3 years to 18 years.
165 patients were treated with sulfonylurea (SU-group), 23 patients with insulin (I-group) and 48 patients by diet alone.
None of the patients had ever received any diabetic therapy.
No significant difference was found in the frequency of ECG abnormality in the SU-group between the results before and after SU treatment.
The frequency of ECG abnormarity in the I-group was higher than in the SU-group at 5 years and at 10 years, but this difference was not statistically significant.The frequency of retinopathy was significantly higher in the I-group than in the SU-group at 5 years and at 10 years.
There was no significant difference among the three groups in the frequency of albuminuria.
The appearance and the development of vascular lesions were examined in 55 patients who had been treated with SU for 10 years and in 11 patients who had been treated with insulin for 10 years continuously.
The rate of appearance of ECG abnormality in the SU-group increased gradually during the 1 years follow up, however it increased rapidly in the I-group after 4 years, and it was found to be more significant in the I-group than in the SU-group at 7, 9 and 10 years.
The rate of abvance of retinopathy was high at 5 years in the SU-group and was stable thereafter.
On the other hand the rate of advance of retinopathy in the I-group was elevated step-wise after 5 years follow up, and at 9 and 10 years it was significantly higher in the insulin than in the SUgroup.
The incidence of albuminuria in both groups was elevated after 8 years.
These findings showed that the frequency and the development of vascular complications in the SU-group were lower than that in the I-group during long term treatment.

View full abstract

Changes of the blood lactate, pyruvate and plasma NEFA levels during the 40 g oral galactose tolerance test were investigated in 21 healthy subjects, 42 patients with liver diseases and 47 patients with diabetes mellitus.
The blood galactose concentration was measured by the enzymatic method using the galactose dehydrogenase reagent prepared by Boehringer-Mannheim Co. The blood lactate and pyruvate were also determined by enzymatic methods. The plasma NEFA was estimated colorimetrically by a modification of Duncombe's method. The results of the galactose tolerance test were classfied into three groups based on the previously described criteria, namely 0-1 grade is normal, 2-4 grade moderately abnormal, and 5-6 grade far abnormal.
In the normal group of the galactose tolerance test, the blood lactate levels increased markedly and reached the maximum point in 60 min. after the galactose loading and came down to the previous levels in 120 min. The blood pyruvate levels showed a transient increase as with lactate in both healthy and diabetes groups, but no significant changes in the liver diseases group.
The relationship between the blood lactate and pyruvate levels during the galactose tolerance test showed a significant positive correlation in healthy subjects (γ=+0.465, p<0.01) and in diabetes subjects (γ=+0.568, p<0.01) but no significant correlation in the liver diseases subjects.
In the moderately abnormal groups, the lactate and pyruvate levels after the galactose loading showed slight elevations in both liver diseases and diabetes subjects.
In the far abnormal groups, increases of the blood lactate and pyruvate levels after the galactose loading were hardly observed.
It was demonstrated that the results of the galactose tolerance test closely were related to the variation of the blood lactate and pyruvate levels after the galactose loading, therefore this test would be suitable for estimating the redox potential of the liver cytoplasma.
Furthermore, in the abnormal groups, contrary to the normal group, a significant negative correlation between Δlactate and ΔNEFA during the galactose tolerance test were found in liver diseases subjects (γ=-0.343, p<0.01) and in diabetes subjects (γ=-0.363, p<0.01). Consequently it was suggested that a compensative relationship between the liver and the fatty tissue might be discussed on the galactose metabolism.

View full abstract

The immunogenicity of Monocomponent Insulin (MC-insulin) was studied in 7 non-insulin treated patients, 11 conventional insulin-treated patients and patients with an insulin allergy against con ventional insulin.
The immunogenicity was estimated with serum insulin antibody titer and serum total insulin level during MC-insulin treatment and with serum IgE insulin antibody level and allergic phenomena in the patients with insulin allergy.
In non-insulin treated patients, the treatment with MC-insulin provoked no significant elevation of antibody titer or total insulin level except in one case where the antibody and total insulin level rapidly elevated and showed no tendency to decrease even after one year's treatment with MCinsulin.
The patients previously treated with conventional insulin (C-insulin) were separated into two groups one group was treated with MC-insulin and the other group was treated with C-insulin for one year. The antibody titer and insulin level decreased significantly in the patients treated with MC-insulin except in one case, but no change or a slight increase was observed in patients treated with C-insulin.
The one case with insulin allergy treated with MC-insulin showed a decrease of antibody titer and IgE antibody level and allergic symptoms subsided gradually. But the other cases with insulin allergy showed no decrease of antibody titer and IgE antibody level even after one year of treatment with MC-insulin and allergic symptoms still persisted.
From the above results, it is concluded that Monocomponent insulin has a low antigenicity as compared to conventional insulins but still has a weak antigenicity in some sensitive patients.

View full abstract

We have re-examined Sluiter et al's report in which they proposed a mathematical approximation of two independent parameters, the beta-cell response and the peripheral insulin activity after 100g OGTT. It was confirmed that there exists a straight-line relationship between G and I/G for each individual during the early period after the glucose loading. Furthermore, we were able to deduce a very similar equation to theirs for the corrected insulin response as CIR = I₃₀-100/G₃₀ (G₃₀-70) from the mean slope of the straight-line obtained from data of non-obese healthy subjects. There exists a definite correlation between CIR and insulinogenic index. Also, peripheral insuln activity (A) correlated well with insulin sensitivity indicies which were calculated from the speed of the blood glucose fall following a single intravenous injection of insulin.
By these means, we have observed the following:
1) The more obese person had a higher CIR and a smaller A.
2) There were no specific differences in either of the parameters according to age and sex.
3) CIR and A showed a concomitant decrease, as glucose tolerance diminished. In patients with diabetes mellitus, however, only CIR decreased further when FBS exceeded 120 mg/100 ml.
4) Patients with chronic liver diseases revealed a significantly higher CIR and smaller A, when compared with control subjects who showed the same degree of glucose tolerance.
5) 10 hrs after an oral administration of 2 mg dexamethasone, a significant decrease in A was observed, while 8 of 10 persons showed increases in CIR.

View full abstract

Coagulation-fibrinolytic activities were assayed in 45 diabetics. Platelet Factor 4 increased in 77.8 antithrombin III decreased in 61.5%, fibrinogen increased in 100% and antiplasmin decreased in 65.9% of all cases.
A relative coagulative tendency without comparable in fibrinolysis seemed to exist in diabeticsirrespective of age, duration, treatment and serum lipid level.
These changes seem to be 7 “the preceding state of chronic low grade disseminated intravascular coagulation”(Ultin, O. N.: 1975) and can possibly contribute to the pathogenesis of the diabetic vascular complications, especially of microangiopathy.

View full abstract

Studies on the absorption of glucagon preparation have until now been few, and so we studied the relationship between the absorption and the biological effects of glucagon preparation (NOVO) by determining IRG, BS, and IRI at appropriate intervals after.a subcutaneous injection of the agent of four different doses (O.5, 1.0, 5.0, and 10.0μg/kg) in normal fasting dogs.
Various pharmacokinetic parameters calculated according to Wagner-Nelson's one compartment model from plasma IRG concentration curves were as follows:
From the above data, it was clear that the absorption of glucagon preparation and its metabolic rate were very rapid. On the other hand, the hyperglycemic effect, one of the biological effects of glucagon, occurred promptly. It is within reason for a rapid absorption of glucagon to take place but the intensity of the hyperglycemic effect was not in proportion to the plasma IRG levels. Besides, it was demonstrated that the minimum dose of glucagon causing a hyperglycemic effect was 0.5 μg/kg.
The insulinogenic activity of glucagon was also observed promptly, and its peak time was at fifteen minutes after the injection. This effect depended on dosage but it was temporary, and disappeared at forty-five minutes after the injection with all the dosages employed in the present study.
Since plasma IRG levels were dose-dependent at this time, the results were inconsistent with the effect at peak time. It was assumed that some internal protection systems might act in accordance with first insulin secretion, causing a fall of blood glucose in pancreatic regions.

View full abstract

The nature of insulin receptors in ascites hepatoma AH-66 were studied. The hepatoma plasma membranes were found to contain at least two types of insulin receptors with affinity constants of 9.0 × 109M^-1 and 2.8 × 109M^-1. Their affinity constants were almost equal to those in plasma membranes from normal rat liver. The capacity of the high affinity binding sites in AH-66 cells was larger by 50% as compared with that of normal liver. No differences were detected between AH-66 cells and normal livers in the inhibiting effect of concanavalin A on ¹²⁵I-insulin binbing. Furthermore, neither glucagon, ACTH, TSH, nor HGH inhibited ¹²⁵I-insulin binding to plasma membranes from AH-66 cells. Addition of 2mM N-ethylmaleimide to the assay system increased the affinity constant, binding capacity, and specific ¹²⁵I-insulin binding.
These results indicate that the plasma membrane of ascites hepatoma AH-66 has high and low affinity insulin receptors which are specific for insulin as that of the normal liver cell.

View full abstract

The hyperglycemic effect of glucagon has been established, but its effect on hypoglycemia in animals has been scarcely reported. We examined the effect of glucagon on insulin-induced hypoglycemia with various injection times in dogs. We aimed at obtaining information on the clinical application of glucagon in the hypoglycemic state.
Blood sugar levels were measured serially after subcutaneous injection of insulin (Actrapid, 0.4U/kg) with and without subsequent glucagon administration (10μg/kg, subcutaneously) at 15, 30 or 90 min. after the insulin injection.
In cases where glucagon was administered at 15 min. or at 30 min. after the insulin injection, blood sugar levels increased significantly, even though temporarily, as compared to those in the control dogs which received the single insulin injection.
On the other hand, when glucagon was injected at 90 min. after the injection of insulin, blood sugar levels were significantly higher than in the control at 15-60 min. after glucagon injection.
Moreover, blood sugar peak levels at 30 and 45 min. after glucagon injection were very high, and increased 10 per cent more than normal levels. It was assumed that glycogen synthetase was activated by the pre-injected insulin, leading to increased glycogen synthesis which might thus account for the sustained hyperglycemia induced by glucagon in this series.
It was concluded that glucagon must be administered carefully taking the injection time into consideration on insulin-induced hypoglycemia in clinical use because of its effect in response to the glycogen contents in liver.

View full abstract

A case of diabetes with moderate insulin resistance, marked hypergammaglobulinemia and macroamy. lasemia is reported here. A 45-years old male, who was a heavy alcoholic beverage drinker, was admitted with chief complaints of dyspnea and pain of lower extremities. Three years before admission, clinical symptoms of diabetes had appeared and he had been treated with oral hypoglycemic agents without much success. Physical examinations revealed crepitant rales in the lower lung fields, splenomegaly, clubbed fingers, vascular spider, palmar erythema, hyporeflexia and hypesthesia of the lower extremities. There was a moderate insulin resistance; a daily dose of 92 units (Conventional Lente, Ultralente, and Rapitard insulins) failed to control his blood sugar. By the use of Monocomponent Semilente insulin, however, diabetic control became better ; fasting blood sugar and urine sugar were decreased, and insulin dosage was also reduced. Serum total protein was 9.2 g/dl and marked polyclonal elevation of gamma globulins was detected with a marked increase in IgG. Serum amylase was always high, but urine amylase activity was subnormal. By gel filtration at pH 8.0 and 3.4, the serum amylase was found to be a macroamylase which dissociated at acid pH. Most of the amylase activity was associated with IgA, as revealed by affinity chromatography using anti-IgA coupled Sepharose. As much as 5.4 m-units insulin was extracted from 1 ml serum with acid ethanol, but extractable insulins decreased after Monocomponent Semilente insulin treatment. The insulin antibody was found to be IgG by use of the immunoprecipitation technic. Increases in serum gamma globulins, which were primarily caused by liver cirrhosis and diffuse interstitial pneumonia, might have been related to insulin resistance due to the presence of IgG-type insulin antibody, and with macroamylasemia due to a binding of the amylase to IgA.

View full abstract

A twenty-eight year old woman suffering from chylomicronemia with acute pancreatitis during pregnancy was presented, she had had diabetes mellitus 4 years ago. She was admitted complaining of fever, and severe epigastralgia. The fetus died on the sixth day after admission. The serum triglyceride was 7592mg/dl, total cholesterol 1706mg/ml, FFA 5.58mEq/l, and amylase was within normal limits in the serum and in the urine. The serum was grossly creamy, and lipemia retinalis was discovered. A high concentration of prebeta lipoprotein was also present. The patterns thus closely resembled those of genetically determined type V hyper-lipemia as described by Fredrickson et al. This patient had no family history of similar illnesses. Chylomicronemia had already appeared before the episode of acute pancreatitis. These findings indicated that the hyperlipemia might have been a cause of the pancreatitis. Probe laparotomy revealed the number of granuloma pseudoxanthomatodes around the pancreas which showed the healed pancreatitis. It should be noted that the lipids of the fetus were within normal limit.
The primary cause of this chylomicronemia was considered to be insulin deficiency in the diabetic state and pregnancy, chiefly being due to the reduction of lipoprotein lipase activity.

View full abstract

According to Kuribayashi's review in 1976, only 51 cases of renal papillary necrosis have been reported in Japan. The incidence of diabetes in those cases was very high. Only 3 cases were diagnosed by detection of the necrotic papillae in the urine.
The authors present here a patient with diabetic triopathy who developed renal papillary necrosis which was suspected by the excretion of necrotic tissue in the urine.
Case report: A 49 year old man, having a diabetic family history, was pointed out diabetes mellitus at 38 year old. Since this time he has been treated temporary with the insulin. At 47 year old in 1974, he was first admitted to our clinic with the chief complaints of thirst and polydipsia. At this time diabetic triopathy was obvious. Insulin therapy was initiated again and the patient had a good control. During the subsequent course of ambulatory therapy, he developed the urinary tract infection, and readmitted November in 1976.
A culture of the urine yielded an abundant growth of pseudomonas (4.3×10⁴). Because of the progression of azotemia hemodialysis therapy was intiated. During this therapy, the patient excreated the tissue fragment 8×5 mm in size in the urine. On the 49th day of the admission, he died of uremia. At autopsy, renal papillary necrosis (medullary form) was confirmed in both kidneys. In addition nodular changes of the glomeruli, hyalinosis of the arterio-arterial wall in the kidneys were found. In the pancreas there were a decrease in the number of Langerhans islet and partial hyalinosis of Langerhans islet.

View full abstract

Plasma C-peptide immunoreactivity (CPR) levels during insulin-induced hypoglycemia were measured in a patient with insulinoma and in normal subjects, in order to investigate the change in the suppressibility of endogenous insulin secretion by hypoglycemia in insulinoma.
A 42-year-old man, who had suffered from hypoglycemic symptoms for about 10 years was found to have an islet tumor. His fasting blood sugar levels were 34 to 84 mg/dl, and plasma immunoreactive insulin (IRI) levels were 17 to 37μU/ml before operation. Although after being fasted for 20 hours his blood sugar level fell to 12 mg/dl, plasma IRI and CPR remained to be 23μU/ml and 4.45 pg/ml, respectively. Insulin tolerance test (ITT) is intravenous administration of Mc actrapid insulin® at a shot at the rate of 0.1 U/kg, was performed in the patient before operation and on the 29th day after the surgical resection of a benign adenoma weighing 2.0g; the responses of plasma CPR and blood sugar to the injection were compared with those in 19 normal subjects. In the patient, following the insulin injection, blood sugar level fell to the nadir at 30 minute (26 mg/dl) before the surgery and at 45 minute (50 mg/dl) after the surgery. These blood sugar responses were not so markedly different from the normal. However, the lowest plasma CPR level following the insulin injectin was 71.9% of the initial value before the surgery, which was significantly higher than the corresponding normal value (39.9±11.9%). After the surgery the response of plasma CPR to the insulin injection was restored to the normal, and the lowest CPR after the insulin injection was 32.5% of the initial value. These findings suggest the lack or the diminution of suppressibility of endogenous insulin secretion in insulinoma, and the measurement of CPR in ITT may be of use for the clinical diagnosis of insulinoma.

View full abstract

There have not been many reports on myoglobinuria in Japan. This is a report on a case of diabetes mellitus with myoglobinuria supposedly induced by hypopotassemia. Case report: A 60 yearold woman was found to be diabetic in 1973. Since then she had been controlled with doses of 2.5 mg glibenclamide, but the control had become ineffective about the end of June, 1976 and at the beginning of July she was admitted to hospital with a rapid lowering of the strength of the lower limbs and of muscular strength in general. At the time of admittance, she was fully concious but she could not move her legs herself and strong signs of dehydration were observed. Blood sugar was 710mg/dl, ketone bodies in the urine were negative, osmotic pressure in the blood was 375 mOsm/l. Also, in addition to dehydration, electrolytes were abnormal: Serum sodium was 184 mEq/l, potassium 1.9 mEq/l, and the electrocardiogram indicated low potassium. Serum CPK was 3260 wu/ml, and her urine was dark brown. In hospital, she was given treatment to regulate the electrolyte. When these returned to a normal state, she recovered her muscular strength and she could walk by herself on the 8th day in hospital. The results of various laboratory examinations denied primary aldosteronism. It was thought that myoglobinuria caused by poor acclimatization to the rapid weather changes at the start of the Rainy Season (a very unsettled season in Japan hot and humid with very heavy rain) resulted in poor control of the diabetes and caused dehydration and hypopotassemia.
It may be suggested that a diabetic might suffer from myoglobinuria when he or she become dehydrated and also high show electrolyte derangement. More attention should therefore be paid to these aspects during future research.

View full abstract

Verapamil, a calcium antagonist, is known to inhibit glucose-induced and sulfonylurea-induced insulin release in vitro. However, there have been no reports on in vivo effects. The effect of verapamil on the peripheral IRI, blood sugar (BS) and calcium levels was investigated in thirteen normal subjects.
Verapamil, 5 mg, given to four subjects intravenously, caused a slight, but not significant, decrease in IRI, IRI/BS at thirty minutes. A fifty grams oral GTT was performed on nine subjects. Two days later, fifty grams of glucose was administered orally with verapamil 40 mg P. O. and 5 mg I. V. to the same subjects, who had been orally pretreated with 200 mg verapamil in the previous two days. Verapamil inhibited the IRI rise significantly at thirty minutes, but had no effect on BS and calcium levels at any time. The BS and IRI peaks were found at sixty minutes with the verapamil load while both peaks were found at thirty minutes during usual GTT.
These findings were consistent with in vitro studies even with the possible lower concentration of verapamil in vivo.

View full abstract

Recently, immunoreactive glucagon, gastrin, somatostatin and VIP have been found both in pancreatic and in gastrointestinal tissues. The pancreas develops from entodermal cells that arise from the foregut. This suggests that insulin might also be found in gastrointestinal tissues.
Normal dogs were caused to fast overnight and were subjected to laparotomy under nembutal anesthesia, and the stomachs were removed. Mucosal scrapes were obtained from upper part of the stomachs. The extraction procedure was essentially that described by Kenny. Bio-gel P-30 columns, equilibrated with 3 M acetic acid were used to separate the mucosal extract. Chromatography showed two major peaks of immunoreactive materials. One of those eluted corresponded to ¹²⁵I-insulin. The amounts of immunoreactive insulin (2.7-9.1 ng/g wet tissue) were quite high. The other appeared in the void volume. On using polyacrylamide disc gel electrophoresis, the pool containing the insulin fraction showed immunoreactivity with electrophoretic similar mobility to that of bovine insulin.

View full abstract