The dynamics of the plasma insulin and glucose curves during intravenous glucose tolerance tests were mathematically analyzed by a linear differential equation model assuming two compartments for insulin distribution in the body. A steepest descent method with a least squared error criterion could estimate six unknown parameters in 126 out of 134 cases consisting of 43 diabetic and 91 non-diabetic patients. In 8 percent of the cases, it was impossible to approximate the clinical curve with the model equations.
The estimated parameter values were compared with the parameters which had been obtained by Ackerman's model using the identical data sets. The physiological impertinence, the positive sign of the parameter, which was found in the study based on Ackerman's model, completely disappeared in this analysis. Replacing Ackerman's model with this two-insulin-compartment model, also contributed to a reduction in the variation of values in each parameter.
The parameters which represent the dynamic properties of the glucose regulation appropriately correlated with the steady state levels of plasma glucose and insulin. Such parameters as the rate constant of insulin release mediated by plasma glucose concentration (r=0.481, p<0.01), the rate constant of insulin-independent glucose uptake (r=0.573, p<0.01) and the remote insulin effect (r=0.408, P<0.01) correlatedwiththefastingPlasmaglucosclevel, andthesteadystateofinsulin, that is, the fasting plasma insulin correlated with the rate constant of disappearance of insulin from the plasma (r=0.425, p<0.01), the remote insulin effect (r=0.314, p<0.01) and the insulin release (r=0.244, p<0.01).
The model with two insulin compartments could be accepted as a rational and appropriate model for clinical study to estimate the clinical state of diabetes mellitus and to evaluate glucose intolerance in various diseases.

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The relationships between change in body weight before the beginning of treatment, degree of metabolic disorder, and effect of dietary treatment were investigated in newly diagnosed noninsulin dependent diabetics. The following results were obtained. (1) Based on the extent of weight loss during a period of 3 months before the beginning of treatment, 90 diabetics were grouped as follows. Group I (N=33, 36.7%) showed no significant loss of weight;Group II (N=40, 44.4%) showed a loss of weight of less than 3 kg per month; and Group III (N=17, 18.9%) showed a loss of weight of more than 3 kg per month. (2) The mean fasting blood sugar (FBS) levels at the beginning of treatment in these three groups were 168.1±41.6 mg/dl (Group I), 230.8 ±60.8mg/dl (Group II) and300.4+49.9mg/dl (Group III).The hemoglobin AIC (HbAIc) levels were 5.2±1.3%(Group I), 7.5±1.9%(Group II) and 9.1±2.1%(Group III). The ΣIRI/ΣBS values during 509 O-GTT were 0.19±0.17 (Group I), 0.09±0.07 (Group II).and 0.02±0.01 (Group III).Among the three groups, the differences in mean values of FBS, HbAIc and ΣIRI/ΣBS were statistically significant, respectively. (3) Dietary treatment was effective for all cases in Group I, irrespective of the values of FBS, HbAic and E, ΣIRI/ΣBS at the beginning of treatment, but was not effective in some cases of Group II (30.0%) and Group III (64.7%) whose FBS levels were similar to those in cases of Group I.In Group II, the mean FBS (278.8±61.9 mg/dl) and HbAic (9.3±0.9%) in noneffective cases were higher than in effective cases (210.3±48.2 mg/dl and 6.5±1.6%). In Group III, the HbArc in noneffective cases (9.5±1.5%) was significantly higher than in effective cases (7.8±0.4%).Futhermore, in Groups II and III, dietary treatment was less effective in non-obese diabetics at the beginning of treatment.
These findings suggest that changes in body weight before the beginning of treatmenC, may serve as a good indicator of the therapeutic outcome of dietary treatment in patients with NIDDM.

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It is widely accepted that quantitation of autonomic neuropathy in diabetic patients can be achieved by measuring heart rate changes under various conditions. Although many tests based on cardiovascular reflexes have been advocated to assess diabetic autonomic neuropathy, strict comparisons of these tests in the same group of patients have not previously been reported.
In the present study, five parameters of autonomic function, i.e., heart rate responses to standing (30: 15 ratio) and during deep breathing (E/I ratio), and beat-to-beat variations during rest (coefficient of variation=CV, mean R-R and max/min ratio) were measured in 26 diabetic patients and 22 healthy subjects in order to evaluate the sensitivity and reproducibility of each test parameter.
All parameters except for the mean R-R were significantly correlated with each other and strongly influenced by age in both the diabetics and healthy controls, and by the duration of diabetes in the diabetics. There was no visible diurnal change in any parameter. The CV was 2.54±1. 49% in 16 diabetic patients without orthostatic hypotension, and significantly lower than that of 11 age-matched healthy subjects (4.6±2.07%). However, none of the other parameters was significantly different among the two groups. On the other hand, all parameters were markedly impaired in those diabetics with orthostatic hypotension.
It is concluded that the CV may represent the most sensitive parameter for assessing autonomic dysfunction in diabetic patients, although its reproducibility may be the least. One prerequisite could thus be to use more than one parameter in testing the autonomic function of diabetic patients.

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The clinical features and causes of hyperchloremic acidosis in diabetics were examined in three patients. All of them had a history of diabetes mellitus of more than 10 years and were complicated with advanced retinopathy, neuropathy including autonomic nerve involvement, severe to moderate nephropathy and hypertension. Both case 1 (59-year-old male) and case 2 (44-year-old male) showed hyperkalemia, aciduria (pH5.0) and hyporeninemic hypoaldosteronemia. These clinical features corresponed to the renal tubular acidosis type IV described by Sebastian et al. Potassium load by hemolysis (case 2) and rapid depletion of plasma volume by spironolactone and furosemide (cases 1 and 2) were considered to be triggers of the acidosis. It is thought that hyperkalemia provoked a severe decrease in ammonium production by the distal tubules of these patients which were already impaired, and that hypovolemia and spironolactone promoted their hyporeninemic hypoaldosteronism. Case 3 (46-year-old male) showed the hypokalemic type of hyperchloremic acidosis triggered by acetazolamide which was administered for his glaucoma. Although acetazolamide was the direct cause of this acidosis, it is suspected that some renal abnormality such as in the two above patients was another contributory factor. Their acidosis was normalized by the oral administration of NaHCO3 and removal of the probable triggers.
These findings suggest that in advanced diabetics, rapid depletion of plasma volume by spironolactone and/or administration of acetazolamide may present a hazard which leads to severe metabolic acidosis.

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The skin blood flow (periflux blood flow: PBF) in the finger tip was measured with a periflux laser doppler flowmeter (PLDF). PLDF is a new instrument for the direct, continuous and noninvasive measurement of blood flow in skin capillaries. A 2 mW He-Ne laser was used as the light source.
In the present study, the pattern of PBF was evaluated as a measure of diabetic auto nomic neuropathy.
The response upon standing was studied in 78 normal subjects and 52 diabetic patients and its pattern was classified into four types. The response time (RT) and orthostatic dysreaction ratio (ODR) were chosen as indices of the PBF response.
The results obtained were as follows.
1) Ninety-five percent of normal subjects showed a normal response pattern. On the other hand, about half of the diabetic patients showed abnormal response patterns. That is, 27%, 23% and 6 % of the diabetic patients were of the “delayed recovery type”, “incomplete recovery type”, and “other type”, respectively.
2) The RT in normal subjects was 15.3±5.7 sec (mean±S.D.). The correlation coefficient between RT and the motor conduction velocity was-0.504 (p<0.025) and that between RT and the sensory conduction velocity was-0.444 (p<0.05).
3) Significant negative correlations were found between ODR and ΔP (blood pressure fall)(r=-0.817, 0.817, p<0.001) and ΔP (change in pulse rate) on standing (r=-0.802, p<0.005).
4) The diabetic patients were divided into two groups according to the presence or absence of diabetic autonomic neuropathy, i.e. “Symptomatic” and “asymptomatic” groups. There were significant differences in RT and ODR values between the two groups (RT: p<0.005, ODR: p<0.05).
These results suggest that measurement of PBF is clinically useful for evaluating diabetic complications.

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Since the skeletal muscle is a major site of insulin action and glucose utilization, we investigated the insulin binding and insulin stimulated 2-deoxyglucose (2 DOG) uptake in isolated rat soleus muscles. Soleus muscles were incubated for 4.5 hr at 15°C in 2.0 ml Hepes-Tris buffer (10mg/ml, BSA, pH 8.0), 2mM pyruvate, 125I-insulin at 0.2ng/m/, and unlabeled insulin (0-500ng/m/). The specific binding to the soleus muscles was 4.62±0.22%(mean±SEM) per 100mg wet wt of muscle at 0.2ng/ml insulin. Non-specific binding (measured in the presence of unlabeled insulin at 200μg/ml) amounted to less than 30% of the total binding. The insulin concentration required for half-maximal inhibition of insulin binding was 6ng/m/. The insulin degradation determined by the TCA solubility method was 16.3±2.1% at a trace concentration of insulin.
Soleus muscles were preincubated for 30 min at 25°C in 5.0ml KRP-Hepes buffer (20mg/ml BSA, pH7.4) containing 2mM pyruvate, and the muscles were then incubated with insulin for 120min. Following insulin preincubation, we determined the specific 2 DOG uptake by subtracting the L-glucose uptake (simple diffusion and extracellular space) from the total 2 DOG uptake for 30min at 25°C. The insulin (100ng/ml) stimulated 2 DOG uptake was 2.5 times greater than the basal uptake and this stimulation was due to an increase in the Vmax of glucose transport and phosphorylation but not to a change of Km. The insulin concentration required for half-maximal insulin stimulation was 5ng/ml.
This system appears to represent a useful model for investigating the receptor binding and the mechanism of insulin action in skeletal muscles.

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A 27-year-old female was admitted to our hospital in November1979 because of frequent episodes of mental confusion and/or episodes of coma. In December 1974, she had an attack of paresthesia of the hands and legs followed by unconsciousness. She experienced similar episodes once a month and was given diphenylhydantoin and carbamazepine for 5 years, after a diagnosis of symptomatic epilepsy.
On admission, the blood sugar was found to be 32 mg/dl. Mental function and cranial nerves were normal. There was weakness and wasting in the distal leg muscles. All tendon reflexes in the lower limbs were absent. There was tingling and numbness in her hands and feet. Needle EMG studies provided evidence of denervation of small muscles ofthe hand and of distal muscles in the legs. The right median nerve motor conduction velocity and right sural nerve conduction velocity were reduced slightly, while the left peroneal motor and right median and ulnar sensory action potentials were not evoked. The histologic findings in the peroneus brevis muscle were consistent with the neurogenic changes. A sural nerve biopsy disclosed a slight reduction in large myelinated fibers and the presence of Schwann cell clusters.
These findings are consistent with axonal degeneration. Following removal of the insulinoma, the patient showed remarkable improvement in paresthesia of the hands and legs, and slight improvement in motor conduction velocity. This situation suggested that hypoglycemia in the insulinoma resulted in the peripheral nerve damage. We now report for the first time in Japan, the occurrence of peripheral neuropathy in association with insulinoma studied histologically and electrophysiologically.

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A 55-yr-old insulin-dependent diabetic man with 8 episodes of acute respiratory arrest is described. Physical examination on admission revealed severe diabetic complications including proliferative retinopathy and anasarca due to nephropathy. In addition to the presence of sensory polyneuropathy, there were several clinical signs of autonomic neuropathy (orthostatic hypotension without increase of heart rate, intractable vomiting and severe constipation).
The first and second acute respiratory arrests occurred before the induction of hemodialysis. There were 6 similar episodes after the induction of hemodialysis. These attacks occurred without any signs and symptoms of hypoglycemia or dysrhythmia. Cardiac arrest was not accompanied with acute respiratory arrest except in the first episode. Mechanical ventilation resuscitated this patient rapidly.
Moreover, as regards the etiology of these episodes, the autonomic neuropathy might be influenced by chronic renal failure due to diabetic nephropathy.
There are three previous reports of cardiorespiratory arrest due to diabetic autonomic neuropathy in Japan. The present case is thus the fourth report of such a patient.

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