Clinical aspects of pregnant diabetics have recently changed in comparison with those of 10 years ago. We analyzed the clinical aspects of 89 pregnant diabetics, 109 deliveries and 110 children born from February 1964 to March 1982.
The incidence of deliveries by diabetics was 1.23%, and it has increased recently. The mean age of onset of the diabetes diabetes was 23.2 yr. The mean duration of diabetes was 5.9 yr. The number of pregnant diabetics who had diabetes before the age of 15 and whose duration was over 10 yr has increased.
Of 89 pregnant diabetics, 26 had Type I diabetes, and 63 had Type II. Since 1975 the incidence of Type I pregnant diabetics has increased. Eighty-one pregnant diabetics were treated with insulin. Fifty-three pregnant diabetics had retinopathy and half of them showed deterioration during pregnancy. Among pregnancy complications the commonest one was asymptomatic bacteriuria. The mean gestational age of delivery was 39.3 weeks. Half of the babies were delivered by Caesarean section. The perinatal mortality was 5.6%. No intrauterine deaths have been in our patients recently; however deaths due to major congenital malformation have increased. After 37 weeks of gestation the mean weight of neonates at birth was 3438 g. The percentage of infants who were heavy for their gestational age was 33.6%, Eighteen children had congenital malformations. The commonest complication among the newborns was hypoglycemia.

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We have experienced many diabetic patients in whom R-R interval variations appeared to be reversible, improving with control of the metabolic state. Case 1.59-year-old woman. She had shown a brittle-type variation in her blood glucose levels, which was stabilized by continuous subcutaneous insulin infusion. Her HbA₁ decreased from 19.6% to 12.0%. At the same time, her RR interval variation improved from 37 to 72 msec. Case 2.52-year-old man. He was newly found to have diabetes mellitus, when his fasting blood glucose (FBG) was 478 mg/dl and his HbA₁ was 16.0%. After diet therapy, these parameters were markedly improved (FBG 107 mg/dl, and HbA₁ 12.5%) and his R-R interval variation was increased from 244 to 339 msec.
To assess whether metabolic state affects R-R interval variations, 51 diabetic outpatients (22 males, 29 females, age 57±10) were studied. The FBG, HbA₁ and R-R interval variations were measured twice at an interval of one month. There was no relationship between the changes in FBG and R-R interval variation. Two groups were selected from among the patients in this study: one showed more than a 10% decreasing rate of HbA₁ (group A) and the other, more than a 10% increasing rate of HbA₁ (group B) during the one-month observation period. The change in R-R interval variation of group A was 6±14% and that of group B was -20±23%(p<0.02). From these results, it is suggested that the R-R interval variation is affected by the metabolic state during 1-2 months.

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The interaction of glucagon and rat renal tubular cells isolated by collagenase digestion and nylon mesh filtration was studied. The results obtained were as follows.
(1) ¹²⁵I-Glucagon binding study
Tubule-rich fraction (TRF) and ¹²⁵I-glucagon were incubated with or without a large excess of native glucagon (10μg/ml) in the presence of 500μM bacitracin at 4°C The specific ¹²⁵I-glucagon binding rate reached a plateau at 30-60 min and showed an almost linear correlation with the TRF protein concentration (up to 2.3 mg). A displacement study carried out by the addition of various concentrations of native glucagon to the above assay system resulted in a dose-dependent inhibition of binding, and the native glucagon concentration to obtain 50% binding inhibition was about 27 ng/ml. Scatchard plots of the above data yielded a curvilinear form, which suggested the presence of two kinds of receptor sites of different affinity or negative cooperativity. The high affinity site had a binding capacity of about 0.375 ng/1 mg TRF protein and an affinity constant of about 0.17×10⁹ M^-1.
(2) Cyclic AMP response to native glucagon
The cyclic AMP production of TRF incubated at 25°C increased in the presence of glucagon (6.25 μ/ml), and was correlated linearly with the incubation time (up to 10 min) and TRF protein concentration (up to 2 mg). The cyclic AMP response to various concentrations of glucagon was dose-dependent, and the concentration of glucagon to obtain half-maximum stimulation was about 12.5 ng/ml.
All the above results suggest that renal tubular cells have glucagon receptors and a glucagonsensitive adenyl cyclase system.

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Sixty-five patients without apparent retinopathy and 38 normal controls were examined by ocular fluorophotometry.
As regards the mean fluorescein concentration in the diabetics at one and two hours after intravenous dye injection, only the lenticular autofluorescence was statistically significantly higher compared to the normal controls. The variance in diabetics was larger in the retina, the vitreous, and the anterior chamber than in normals. The ratio of subjects showing a fluorescein concentration in the posterior vitreous of more than M±2 s. d. (the mean value and standard deviation of the normals) appeared to be significantly higher in the diabetics.
There were no significant differences among the diabetic subgroups classified according to the duration of the disease, blood glucose control, blood pressure, or plasma lipid concentration.

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To study the dynamic property of glucagon secretion in response to glucose concentration and the ability of glucagon to raise hepatic glucose production, an artificial endocrine pancreas was developed by preparing glucagon and glucose infusion algorithms as the counterregulatory system. The priniciple of glucose or glucagon infusion algorithm is set to be as the proportional plus derivative modes of action to blood glucose concentration with the time delay constant, as follows;
GIR (t) =Cp [BGp-BG (t-τ)] +Cd [-ΔBG (t-τ)]
GnIR (t) =Gp [BGp-BG (t-τ)] +Gd [-ΔBG (t-τ)] +Gc
where GIT (t) and GnIR (t) are glucose infusion rate (mg·kg^-1·min^-1) and glucagon infusion rate (ng·kg^-1·min^-1), respectively. BGp is the projected value of blood glucose concentration (mg/100ml), BG (t) and ΔBG (t) are blood glucose concentration at time t (mg·100ml^-1·min^-1), and the rate of change in blood glucose concentration at time t (mg·100ml^-1·min^-1) respectively. Cp and Cd are coefficients for glucose infusion, and Gp and Gd are those for glucagon infusion. Gc is the constant for basal glucagon supplementation.τ(min) is the time delay constant for glucose and glucagon infusion.
In depancreatized dogs, hypoglycemia was induced by iv bolus insulin injection, then the counterregulatory system was operated according to each of these algorithms by changing the parameters variously.
The following results were obtaind:
1) In the glucagon infusion algorithm, with the optimal parameters based on proportional plus derivative modes of action with a 10-min time delay (Gp/Gd/Gc/τ=0.2/0.4/0.4/10), both the blood glucose response curves and plasma glucagon profiles simulated perfectly those seen in normal dogs. On the other hand, glucagon infusion based on the proportional action only failed to mimic the blood glucose response and plasma glucagon profile of nromal dogs.
2) When glucose was infused on basis of the proportional action with a 20-min time delay (Cp/Cd/τ=0.2/0/20), the insulin-induced hypoglycemia in depancreatized dogs could be restored to nor moglycemia in the same manner as seen in normal dogs.
3) Since the amount of glucagon and the amount of glucose infused for 2 hours to obtain identical blood glucose response curves was 250 ng/kg and 237 mg/kg, respectively, it was revealed that 1 ng·kg^-1·min^-1 of glucagon infused might evoke 1 mg·kg^-1min^-1 of hepatic glucose production.
These results indicate that the dynamic property of glucagon secretion is proportional plus derivative mode of action to blood glucose concentration, and the mode of action of glucagon on hepatic glucose production is the proportional action with first-order delay.

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This prospecitve study was undertaken to examine whether glycemic normalization could have beneficial effects on the course of diabetic microvascular complications in 11 diabetic subjects comprising six insulin-dependent and five noninsulin-dependent diabetics.A significant Amelioration of glycemic regulation was achieved by following intensive glycemic control for a period of three months. Closed-loop contorol using an artificial endocrine pancreas, subcutaneous open-loop control using a pre-programmable insulin infusion pump and subsequent multiple insulin injections combined with short-acting and intermediate-acting insulins were utilized.
Remarkable improvements in diabetic microangiopathic findings were observed after the intensive glycemic control.These were accompanied by a significant reduction of urinary excretion of total protein and beta-2-microglobulin as well as dy marked amelioration of the nerve conduction velocity of the median nerve.The results of retinal fluorescein angiography showed that three cases out of nine who had had increased vascular permeability showed improvement, three indicated no change, and it was not possible to assess the other three cases because of previous lasercoagulation, while no changes were observed in any ophthalmoscopic findings.
These findings indicated that glycemic near-normalization could be of benefit for diabetic microangiopathies even after a relatively short-term treatment of three months.

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The oral glucose tolerance test (OGTT) has been introduced as a routine test for the diagnosis of diabetes mellitus.During OGTT, usually blood glucose levels have been measured at five or six points.However, there are few reports concerning the continuous measurement of blood glucose levels.
We studied continuous monitoring of blood glucose for 3 hours during a 75 g OGTT in 19 healthy subjects by means of the Biostator® which withdraws theblood continuously for measurement of blood glucose levels every minute.
The measurement of blood glucose by the Biostator® was found tofurnish satisfactory results compared with that by an Autoanalyzer, the glucose oxydase method (r=0.975, Y 0.949X+2.678).
In all cases, the blood glucose curves drawn by the Biostator® showed a biphasic pattern during OGTT.The first peak of the biphasic pattern was found at 45.8±4.1min (mean±SE) after glucose loading, and the mean blood glucose level was 142.3±3.3 mg/100ml. The mean blood glucose level at the second peak, which was found at 132.8±6.1min, was 109.9±3.7mg/100ml.
The biphasic pattern, however, could not be anticipated when we used the conventional intermittent measurement of blood glucose.
When serum IRI was measured every 15 min, the same biphasic patterns as seem in the blood glucose curves were seen.During OGTT, the significant elevationofglucagon, cortisol, growth hormone and catecholamine which enhanced the elevation of blood glucose levels was not observed.
We have shown that not only blood glucose curves drawn by the Biostator® but also IRI curves from samples taken every 15 min have two peaks during 75gOGTT in normal persons. However the origin of these peaks has not been sufficiently investigated.

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The aim of the present study is to investigate the plasma glucagon responses in a 63-year-old woman in whom pancreatic carcinoma was diagnosed and who received a total duodenopancreatectomy with partial gastrectomy. Various stimulants to glucagon were given and feedback control with an artificial endocrine pancreas (Biostator®) was performed. In this study we measured IRG (30K and OAL-123) and GLI (OAL-196).
Neither IRG nor total GLI showed any response in the arginine load test, insulin hypoglycemic test or intravenous glucose tolerance test. However, both IRG and total GLI responded to glucose given orally.One of the reasons for this phenomenon may be that glucose given orally directly stimulated IRG and GLI secretion cells in the remaining part of the gastrointestinal tract. also gut factors may be involved in the response of IRG and total GLI.
In this case, we found that extrapancreatic glucagon was present in a totally duodenopancreatectomized and partially gastrectomized patient, and that it responded to oral glucose load but not to arginine and rapid changes in the plasma glucose level.
Under the feedback control with the artificial endocrine pancreas the insulin requirements were 56 U/day and the infused glucose doses were almost none. After the feedback control the patient has been treated with three daily insulin injections (ultralenteinsulin before breakfast and actrapid insulin before each meal) and the blood glucose levels have been kept under relatively good control as assessed by home blood glucose monitoring.

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