The relationship between diabetic retinopathy and the GH responses after TRH injection was studied in 48 patients with diabetes mellitus. The patients were divided into three groups according to the severity of retinopathy and duration of the diabetic state. Group 1: 10 patients whose retinopathy had developed to the stage with numerous hemorrhages, exudates or proliferative retinopathy within 10 years. Group 2: 20 diabetics without retinopathy whose duration was over 11 years. Group 3: 18 patients who belonged to neither group 1 nor 2. Blood samples drawn periodically after the injection were subjected to radioimmunoassay of GH, PRL and TSH. The plasma GH levels at time 0, 15, 30, 60 and 120 min during the TRH test in group 1 were 2.6 ± 0.4 (mean ± SEM), 3.8±1.4, 4.4±1.8, 4.0±1.5 and 3.3±0.8ng/ml, respectively. On the other hand, in group 2, the levels were 1.5 ± 0.4, 2.2 ± 1.4, 1.7 ± 0.3, 1.2 ± 0.3 and 1.2 ± 0.4 ng/ml, respectively. There were statistically significant differences at 30 min (p<0.05), 60 min (p<0.02) and 120 min (p<0.02). The maximal GH increment during the test in group 1 was also significantly higher than that in group 2 (p<0.02). The GH responses were not related to the levels of glycosylated hemoglobin. The renal GH clearance rate during arginine infusion (0.5 g/kg, 30 min), determined in 5 subjects of group 1 and 7 of group 2, was not significantly different. The TSH and PRL responses in group 1 were not different from those in group 2.
These results suggest that the inappropriate rise of plasma GH levels after TRH injection must have reflected GH secretion from the pituitary gland but not impaired GH clearance, and might play some role in the development of diabetic retinopathy.

View full abstract

The effects of diet and insulin therapy on ventricular performance were compared in isolated, perfused heart of normal and experimental diabetic rats. A mild from of diabetes was induced by destructing the ventromedial hypothalamus (VMH) and was treated by restricting diet (VMHweight reduction). A severe form of diabetes was induced by injecting 50 mg/kg streptozotocin (DM) and was treated by injecting 4 u/rat insulin daily (DMI). Both the body and heart weight of VMH were significantly higher than those of either the control or VMH-weight reduction. The mean blood glucose level in DM was significantly higher than that in either the control or DMI.
The hearts were perfused with Krebs bicarbonate buffer containing 11 mM glucose for 10 min and electrically paced. Whole heart ischemia was then induced by using a one-way ball valve, followed by perfusion for 20 min in the VMH groups and 10 min in the DM groups, respectively. Aerobic reperfusion was continued for an additional 30 min in the VMH groups and 20 min in the DM groups, respectively, without pacing. Ventricular function as estimated from the product of the peak systolic pressure and heart rate was maintained equally well in all groups of hearts during the preischemic perfusion. However, it was decreased significantly in VMH and DM compared to their controls at the end of ischemia. During the aerobic reperfusion, ventricular function in both VMH and DM was significantly less than in either their controls or their treated groups. The coronary flow divided by dry heart weight was significantly lower in VMH than in either the control or VMH-weight reduction during the preischemic perfusion and aerobic reperfusion. However, there were no significant differences in coronary flow among the control, DM, and DMI. The levels of serum lipids were significantly increased in VMH and then decreased significantly in VMH-weight reduction compared with VMH.
In conclusion, it can be said that hearts from either VMH or DM maintained low levels of mechanical function in working heart preparations. However, they were more susceptible to global ischemia, but these effects of diabetes appeared to be reversible since hearts from the weight reduction group or insulin-treated group were significantly improved in their recovery of myocardial function. This improvement was reflected by both a shorter time required for the hearts to resume beating and by an increased heart rate and peak systolic pressure after resumption of beating. The beneficial effects may be related to improved coronary flow or to improved serum lipid levels following weight reduction in the mild form of diabetes. They may also be related to blood glucose correction by insulin in the severe form of diabetes.

View full abstract

The effect of insulin therapy on the exocrine pancreas was investigated by comparing the content of amylase in the pancreas and serum amylase levels in rats with streptozotocin-induced diabetes and which were treated with insulin. The insulin therapy (monocomponent NPH, 8 U/day, s.c.) was initiated from the second day or from 2 weeks after the streptozotocin (STZ, 65 mg/kg body weight) injection. The rats were killed at 1, 2, and 4 weeks after the STZ had been injected. The content of amylase in the pancreas of the diabetic rats was 12.1, 6.3, and 0.7% of normal controls and the serum amylase levels were 64.1, 79.3, and 73.8%, respectively.
When the diabetic state was fairly well controlled with insulin, as determined by the body weight, food and water ingestion, and blood sugar levels, the amylase content of the pancreas reverted to about half that of the normal controls, although the insulin content in the pancreas remained low. However, recovery of the serum amylase levels was not so evident at the time when the amylase content of the pancreas significantly increased in the presence of insuln.
These results support the clinical observation of a reversal of decreased exocrine pancreatic function (pancreozymin secretin test) without a significant recovery in decreased serum amylase levels, in patients with primary diabetes mellitus and in a fairly controlled diabetic state while on insulin.

View full abstract

In insulin-dependent diabetes mellitus (IDDM), there is a high incidence of islet cell surface antibodies (ICSA), but the significance of this phenomenon is not clear.
We examined ICSA in patients with autoimmune thyroid disease, comprising 20 patients with non-insulin dependent diabetes mellitus (NIDDM) with coexisting Graves disease, 12 with autoimmune thyroid disease with a high titer of thyroid microsomal antibodies (>102400) and 20 with autoimmune thyroid disease with a low titer of thyroid microsomal antibodies (<25600).ICSA were examined by the indirect immunofluorescence method. BALB/C mouse pancreases were used as the antigen.
ICSA were detected in one patient with NIDDM with coexisting Graves disease, in 4 with autoimmune thyroid disease (thyroid microsomal antibodies>102400), but in none of the patients with autoimune thyroid disease (thyroid microsomal antibodies<25600).
These results suggest that the appearance of ICSA is related to the abnormal immune mechanism of the patients. It has been reported that several types of autoantibody are produced in some organ specific autoimmune diseases. ICSA may be an antibody of such type.

View full abstract

An attempt was made to investigate the effect of age on the serum IRT levels in normals and diabetics. For this purpose, serum IRT concentrations were determined using a radioimmunoassay kit (CIS sorin) in 74 normal subjects and 233 diabetic patients.
The following results were obtained.
1) The mean serum IRT levels in 75 normal subjects were 30.9±13.5ng/ml (M±SD).The mean serum IRT levels increased significantly with increasing age. However, these changes were not found in diabetics, and moreover, the serum IRT levels were lower than normal in subjects of the same age.
2) No relationship was observed between the serum IRT levels of diabetics with or without retinopathy.
3) The serum IRT levels in diabetics who were alcohol users tended to be higher than those of non-users. The serum IRT levels in diabetics who were non-users of alcohol were always lower than in normal subjects of the same age. However, it was found that with increasing age of normal subjects, the serum IRT levels increased significantly.
4) Moreover, as glucose control worsened, the HbA₁ concentrations became higher and the serum IRT levels became lower (P<001).
5) Lower serum IRT levels before treatment, recovered to normal leves according to blood glucose control. HbA₁ concentrations fell at treatment in NIDDN, but in IDDM, the levels were always lower. These results suggest that the serum IRT concentration changes according to age, alcohol consumption and condition of diabetic control.

View full abstract

Fasting serum trypsin (IRT) and elastase I (IRE) levels were determined by radioimmunoassay in patients with diabetes (DM), and the diagnostic significance of these parameters was assessed. The oral BT-PABA load test (PFD) and oral PABA load test as a control of PFD were also carried out, and the ratio of the % recovery of PABA in the urine after BT-PABA and PABA load (PFD/PABA) was calculated for use as an index of pancreatic exocrine function.
In young healthy subjects at less than 20 year of age, both the IRT and IRE levels were low. They tended to increase with advancing age in normal health. IRT and IRE were increased in acute pancreatitis and decreased in chronic calcified pancreatitis. Both were also increased in DM with nephropathy, while only IRE was increased in DM with liver disorder.
The findings for these parameters in DM complicated with neither liver disorder nor nephropathy may be summarized as follows. The IRT levels were significantly lower than the age matched control level in not only patients with type I DM but also those with type II DM whose fasting plasma glucose levels exceeded 200mg/dl. There was a significant positive correlation between IRT and the PFD/PABA ratio. On the other hand, the IRE levels were significantly lower than the age matched control level in only those patients with ischemic change, as demonstrated by ECG, in the type II DM group. IRE was not significantly correlated with the PFD/PABA ratio.
These observations suggest that in DM without liver disorder or nephropathy, fasting serum IRT assay can be useful for ascertaining the pancreatic exocrine function, and the fasting serum IRE level may be correlated with the presence of complications of ischemic heart disease.

View full abstract

Recent work in our laboratory has shown that a single oral administration of triphenyltin compounds induces insulin-deficient diabetes in rabbits by inhibiting insulin secretion from morphologically intact B cells. The purpose of the present study was to compare the diabetic states induced by triphenyltin hydroxide (TPT) with those induced by alloxan. The results obtained were as follows.
1) Rabbits injected iv with alloxan (150 mg/kg) showed a rapid increase in blood glucose levels at 3 hours with a marked subsequent decrease. This hypoglycemic state was followed by a continued hyperglycemic state. On the other hand, TPT-treated rabbits did not show such a triphasic blood glucose pattern. The blood glucose levels increased steadily after TPT administration, reached a peak level on the 3rd day and then decreased. The different effects of TPT and alloxan on the blood glucose levels appeared to reflect the morphologic changes of islets provoked by these chemicals.
2) In alloxan-treated rabbits, hyperglucagonemia was accompanied with elevation of the fasting blood glucose, free fatty acid (FFA), β-hydroxybutyrate and triglyceride levels, while in TPT-treated rabbits, elevations of these levels were not accompanied by changes in fasting glucagon concentration.
These results suggest that the mobilization of FFA and onset of ketosis in TPT-treated rabbits occur independently of changes in glucagon concentration and that they are primarily induced by insulin deficiency.

View full abstract

This study was designed to assess which of the currently available methods for measuring R-R interval variation is the most suitable as a test of cardiac parasympathetic function. The relationship between the R-R interval variation and diabetic complications was also examined.
The following measurements of R-R interval variation were made in 36 maturity onset diabetics and 36 controls:(1) standard deviation (SD) and coefficient of variation (CV) of 100 successive R-R intervals during supine rest, supine deep breathing, and quiet standing in each person;(2) mean difference between the shortest and longest R-R intervals during deep breathing at six breaths per minute;(m (max-min)); and (3) ratio of the longest (C) to shortest (B) R-R interval after standing (C/B ratio).
The results showed that heart rate can affect SD, and that an unfixed respiratory rate can affect SD and CV during supine rest or quiet standing. The R-R interval variation was smaller while standing than while lying. The C/B ratio was less effective than the other measurements. It was concluded the most practical method is measuring CV or m (max-min) during deep breathing with the subject lying. There was no relationship between the R-R interval variation and sodium intake.
Diabetics who had retinopathy (>Scott III), continuous proteinuria (>150mg/day), or decreased Achilles tendon reflexes showed smaller R-R interval variations than controls. In diabetes, the R-R interval variation was correlated with blood pressure changes after standing, indicating coexistence of sympathetic and parasympathetic nervous dysfunction.

View full abstract

In previous reports, we demonstrated that the appearance of intestinal-type alkaline phosphatase (ALP) isoenzyme in the serum is related to the aggravation of diabetes mellitus, in addition to the genetic factors and fat intake.In the present study, the relationship between the appearance of intestinal-type ALP isoenzyme in the serum and the metabolic state of diabetes mellitus was investigated in the fasting state of patients having the same genetic factors.The total serum ALP activities and isoenzyme patterns were determined in 46 normal subjects, 170 cases of diabetes mellitus without ketosis, 15 patients with diabetic ketosis and 4 with diabetic coma, all of whom were of ABO blood group B or O and ABH secretors.Serum samples were obtained from these subjects early in the morning after a 12-hour fast.The prevalence of intestinal-type ALP isoenzyme was 28.3, 55.0, 86.7, and 100% in the normal subjects, diabetics without ketosis, diabetic ketosis and diabetic coma, respectively.These results suggest that the prevalence of intestinal-type ALP isoenzyme increases in parallel with aggravation of the metabolic state in diabetes mellitus.In fact, most of the patients with intestinal-type ALP isoenzyme were under poor control of diabetes mellitus or untreated when they were admitted.Moreover, the insulinogenic index was lower, while the fasting plasma glucose level was higher in patients having intestinal-type ALP isoenzyme than in those without intestinaltype ALP isoenzyme.Following a 2-week treatment for diabetes mellitus, the fasting plasma glucose levels of patients with diabetes mellitus having intestinal-type ALP isoenzyme were lowered to similar levels to those without intestinal-type ALP isoenzyme.Concomitant with the decline in plasma glucose levels, the total serum ALP activities were decreased and the intestinal-type ALP isoenzyme disappeared from the sera in 59 out of 104 patients having intestinal-type ALP.Thus, the prevalence of intestinal-type ALP isoenzyme in diabetes mellitus after treatment (23.8%) was similar to that in normal subjects (28.3%).
The present study demonstrates that aggravation of diabetes mellitus induces intestinal-type ALP isoenzyme in the serum, whereas normalization of the metabolic state in diabetes mellitus eliminates the intestinal-type ALP isoenzyme from the serum.

View full abstract