The kinetic behavior of biosynthetic human C-peptide (BHCP) was studied in 13 non-diabetic controls and 9 non-insulin dependent diabetic (NIDDM) patients. Each subject received intravenous bolus injections of 75 microgram of BHCP. After iv bolus injections, metabolic and kinetic parameters of BHCP (t1/2, distribution space, metabolic clearance rate and rate constants) were determined. The t1/2, DS and MCR were 37.5±1.2 min, 71.8±3.1 ml/kg and 4.52±0.23 ml/kg/min in normals, and 39.8±4.5 min, 92.7±6.8 ml/kg and 5.80±0.54 ml/kg/min in NIDDM patients, respectively. This data indicates that there was no significant difference between non-diabetic subjects and NIDDM patients. Rate constants in the two compartment model (pool 1: intravascular BHCP pool 2: extravascular BHCP) were also analysed and shown as follows; mean values in normals: K₂₁=0.09962/min, K₁₂=0.06880 and K₀₁=0.05608, and in NIDDM patients: K₂₁=0.10254/min, K₁₂=0.07981 and K₀₁=0.05107. These values again show no difference between non-diabetics and NIDDM patients and are useful as parameters for two compartment model, when prehepatic insulin secretions are calculated in normals and NIDDM patients.

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The clinical features of microalbuminuric patients with non-insulin dependent diabetes mellitus (NIDDM); albumin excretion rate (AER:μg/min), blood pressure, HbAI and other clinical parameter were observed for three years in 62 patients, to investigate the factor which relates to the appearance and progression of microalbuminuria in these patients. At the begining of the observation, 15 of 62 diabetics (24.2%) had an AER of over 20μg/min and were defined as being microalbuminuric. Twelve of the 47 initially “normoalbuminurics” (25.5%) developed microalbuminuria in three years. The systolic blood pressure appeared to start rising significantly in the year when microalbuminuria was detected. Four of the 15 initially microalbuminurics (26.7%) who progressed to overt diabetic nephropathy (AER>200μg/min) had elevated systolic blood pressures throughout the study period compared to the rest of patients. These results suggest that (1) patients with “normoalbuminuria” are likely to become microalbuminuric with considerable frequency in three years, and (2) the microalbuminuria is strongly associated with a rise of systolic blood pressure even in the patients with non-insulin dependent diabetes.

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To clarify the significance of portal insulin delivery in glucose control, the effects of insulin infused via the peripheral (Pe) or portal (Po) route on glucose flux and glycemic response during i. v. glucose load (10 mg/kg/min for 60 min) were examined using artificial endocrine pancreas (AP) in five depancreatized dogs. The hepatic production rate (Ra) and metabolic clearance rate (MCR) of glucose were calculated by the tracer method. The extraction rate of glucose by unilateral hind limb (EX) determined by A-V difference technique was used as an index for peripheral glucose disposal. Data shown are means±SD of the last 30 min of glucose challenge.
Ra was suppressed more than 80% from prevalues in all experiments. The Po delivery route resulted in less Ex (10.3±2.0vs 15.7±3.4%) but the same glycemic response (171 ±22 vs 175 ± 19) and MCR (4.8±0.6 vs 4.3± 0.7ml/kg/min) in spite of lower peripheral IRI levels (13.2±5.8 vs 23.8±6.1 μU/ml) compared with the Pe route. Po insulin infusion (170%) augmented by AP achieved physiological peripheral IRI levels (20.8 μU/ml), but this increase in Po insulin dosage had no significant effects on either glycemia (166±20 mg/dl) or MCR (5.0±0.4ml/kg/min). These data suggest that the Po insulin delivery route results in a smaller gain in hepatic glucose handling and enhances splanchnic glucose uptake. Thus the Po access for insulin administration appears to be more suitable and safer for long-term clinical use in terms of stable glycemic control.

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Profiles of total and free insulins in diabetic patients' plasma with insulin antibodies were studied before and after subcutaneous insulin injections. We have developed an easy acid-ethanol extraction method for the determination of bound insulin. A strong correlation existed between the total insulin level determined by the acid-PEG method (Nakagawa et al. 1973) and our acid-ethanol method; however, the latter gave much less coprecipitation and better recovery (99.2%). Small decreases in total and free insulin levels were found during sample storage prior to assay.
Total and free insulins were measured in 22 diabetics with insulin antibodies before and 2 hours after subcutaneous insulin injections. The increment in free insulin revealed no significant correlation with antibody level. The increment in bound insulin, however, was greater in patients with high antibody levels, suggesting a lower metabolic rate of bound insulin.

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Estimation of abnormalities in vibratory Sensation, thermal sensation and autonomic nerve function is believed to be useful for the evaluation of diabetic neuropathy. The quantitative routine assessment of thermal sensation, however, has been difficult compared with that of vibratory sensation and autonomic nerve function.
We have developed a new unit, the Thermostimulator, suitable for routine use and applied it to the assessment of abnormalities of thermal sensation in NIDDM patients, by determining the thermal discrimination threshold (TDT) in the lower extremities in 26 normal age-matched controls and 82 diabetics under the age of 60 years. The vibratory perception threshold (VPT) in the lower extremities, and disturbances of somatic and autonomic nerve functions as assessed by clinical findings were also evaluated.
The results were as follows. 1) The frequency of abnormal TDT was 43% in diabetics, comparable to that of VPT (50%). 2) Diabetics with apparent peripheral neuropathy had higher TDT values than those without peripheral neuropathy. 3) The average TDT values in diabetics with autonomic symptoms were significantly higher than those in diabetics without such symptoms. 4) All 14 NIDDM patients with autonomic symptoms had abnormal TDT values.
These results clearly indicated that the quantitative assessment of abnormalities of thermal sensation in diabetics with the newly developed Thermostimulator could be useful for the comprehensive evaluation of neuropathy in NIDDM patients.

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Serum type IV collagen levels were measured in 328 healthy subjects and 186 diabetics using a newly developed sandwich enzyme immunoassay of whom the values are believed to reflect fibrogenetic activity. Levels in diabetics without diabetic complications were significantly (p<0.01) higher than in healthy subjects. The levels increased in proportion to the duration and degree of diabetic nephropathy, retinopathy and neuropathy. Levels in diabetics with abnormal elevations of blood urea nitrogen, serum creatinine and β₂-microglobulin were significantly (p<0.01) higher than in diabetics with normal values for these indices. In contrast, levels were not significantly different in groups which did or did not exhibit abnormal increments in urinary β₂-microglobulin and β-N-acetyl-D-glucosaminidase. It appears that the serum level of type IV collagen is a useful biochemical marker for monitoring diabetic complications which mainly involve abnormal metabolism of the basement membrane, and that it is closely correlated with renal glomerular filtration rate.

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We report a case of IDDM associated with diabetic ketoacidosis and acute renal failure. A 28-year-old man was found in a semicoma 3 days after drinking a moderate amount of alcohol. His past history was non-contributory.
Marked hyperglycemia (1, 200 mg/dl), metabolic acidosis (pH 6.99), ketonuria, and elevation of serum pancreatic enzymes including amylase, trypsin and lipase were observed on admission. Insulin, fluid and FOY treatment were started immediately. In the early part of treatment, rhabdomyolysis with hypermyoglobinemia (221 ng/ml) and increased serum CPK (16, 100 IU/l) were observed. Hemodialysis was required to treat acute renal failure due to myoglobinemia.
He completely recovered from his acute renal failure and acute pancreatitis, but has needed insulin therapy continuously ever since. Although ICA (anti-islet cell antibody) was negative, we diagnosed IDDM on the basis of his HbAic (8.5%) and CPR (0.3 ng/ml) on admission. The relationship between acute pancreatitis and diabetic ketoacidosis was reviewed. In this case, a chain reaction is believed to have been triggered by alcohol ingestion at the onset of IDDM.

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A 31-year-old woman was first diagnosed as having diabetes mellitus in her second pregnancy. She had a variety of autoantibodies, such as anti-islet cell surface, anti-pituitary, anti-microsomal, and anti-thyroglobulin antibodies. She was given insulin during pregnancy. After delivery, she was treated with diet alone, however glycemic control became worse. She was admitted to our hospital 4 months after the delivery. On admission she had a diffuse goiter, and showed very low insulin response to oral glucose administration, with HLA DR4 antigen and islet cell surface antibody, indicating that she had IDDM. The levels of TSH and T4 were normal. She was treated with insulin with a good glycemic control. However she became hypothyroid a month after admission. Three months later thyroid function returned to normal without medication. She was, therefore, diagnosed as transient postpartum hypothyroidism. We speculated that the autoimmune abnormality mainly contributed to the pathogenesis of the diabetes mellitus in the present case.

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High levels of lipoprotein [a](Lp [a]) are strongly associated with atherosclerosis, leading to premature myocardial infarction and stroke. We recently observed hyper Lp [a] aemia in a patient with diabetic nephropathy. A 72-year-old male was admitted to our hospital because of chest oppression, leg edema, and visual disturbance. The patient was nephrotic due to diabetic nephropathy, with plasma concentrations of cholesterol, triglyceride, and HDL cholesterol of 282, 133, and 48 mg/dl, respectively. An extra beta band was observed in the LDL fraction isolated by preparative ultracentrifugation. Disc electrophoresis disclosed a mid-band which reacted with anti-Lp [a] antibody. Plasma concentrations of Lp [a] were remarkably elevated in this patient compared with those of controls (134 vs 18.6± 0.9 mg/dl). Apo VLDL from the patient revealed phenotype E 4/2.
Two of his siblings and two of his children had normal Lp [a] levels (24, 21.8, 23, 9.8 mg/dl, respectively). A stress electrocardiogram showed eveidence of ischemic heart disease. Selective coronary angiogram revealed 25% stenosis in segments 1, 3, 7. An increased rate of Lp [a] synthesis and/or decreased catabolism may contribute to the elevated levels of Lp [a] found in patients with nephrotic syndrome due to diabetic nephropathy. We conclude that hyper-Lp [a]-aemia in addition to nephrotic syndrome may play an important role in the development of premature atherosclerosis in diabetic patients. Long-term prospective study is needed to elucidate the significance of hyper Lp [a] aemia in this kind of patient.

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The Maillard reaction has attracted attention because of its possible involvement in diabetic complications. Recently, prevention of diabetic complications by inhibiting the Maillard reaction has been widely studied. We investigated in-vitro inhibition of the Maillard reaction by (E)-[(2, 6-dichlorobenzylidene) amino] guandine acetate (guanabenz acetate), an α₂-adrenergic agonist and antihypertensive agent. Guanabenz acetate is an aminoguanidine structurally.
Guanabenz acetate inhibited the glucose-induced polymerization of lysozyme and acted on 3-deoxyglucosone, an active intermediate of the Maillard reaction, to inhibit the increase in fluorescence intensity of the Maillard products stimulated by 3-deoxyglucosone. These results suggested that the effective inhibition of the Maillard reaction by guanbenz acetate may be useful clinically in preventing diabetic complications in diabetics with hypertension in light of the fact that guanabenz acetate has already been used as an antihypertensive agent without major side effects or impairment of long-term diabetic control.

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