The effects of exogenous insulin on food intake were investigated in medial basal hypothalamic deafferented rats which were newly developed as experimental obese animals by Ohshima et al.
Female Wistar rats weighing 190-210 g were injected with streptozotocin (60 mg/kg) to deplete endogenous insulin. Medial basal hypothalamic deafferentation (8 rats) and sham-operation (12 rats) were performed with a Halasz's knife 8 days after the streptozotocin treatments. One week after the operation we injected 4 U of N PH insulin per rat subcutaneously daily for 8 days and 8U/rat for the following 8 days. Daily food intake and body weight were measured every day. Increased food intake and body weight were observed in the hypothalamic deafferented rats immediately after the operation despite the lack of insulin. However, both of them gradually decreased to the same level as in the sham-operated rats.
Food intake in the hypothalamic deafferented rats was significantly increased by administration of insulin in a dose-dependent manner in association with a significant increase in body weight. Incontrast, in the sham-operated rats food intake was decreased significantly by administration of insulin.
These results indicate that medial basal hypothalamic deafferentation modulates the effects of insulin on feeding behavior. It is suggested that not only hyperinsulinemia itself but also this enhancing effect of insulin on food intake contribute to the development of obesity in hypothalamic deafferented obese rats by acceleration of hyperphagia.

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The extent of protein-bound fluorescence generation upon nonenzymati fructosylation was compared with that upon nonenzymatic glucosylation. Bovine serum albumin was incubated with fructose or glucose in sodium phosphate buffer. Fluorescence at 435 nm was measured serially by excitation at 350 nm. Fluorescence intensity was increased time-dependently in both groups. The fluorescence intensity of fructosylated samples increased more rapidly than that of glucosylated samples. For the first 14 days of incubation, fructose was 5.4 times as effective as glucose at producing fluorophores. When aminoguanidine was added to these incubation mixtures, fructose-induced as well as glucose-induced fluorophore formation was significantly decreased, After glucose was removed at 28 days of incubation, incubation was continued for another 28 days with or without aminoguanidine. In the presence of aminoguanidine, fluorescence intensity decreased slowly. Whereas in the absence of aminoguanidine, fluorescence increased continuously.
These results indicated that 1) Fructose is more efficient in producing fluorescent material than glucose. 2) Aminoguanidine inhibits the formation of fluorescence derived from not only glucose but fructose. 3) Conversion from Amadori products to fluorophores can take place even in the glucose-free condition. Aminoguanidine also inhibited this process.

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To investigate the pathogenesis and treatment of diabetic neuropathy (DN), electrophysiological, biochemical and morphometric analyses were performed in streptozocin induced diabetic rats after administration of prostaglandin E₁, (PGE₁) analogues (TFC612 and OP1206·αCD), aldose reductase inhibitor (0NO2235), and methylcobalamin. PGE₁ analogues most improved the decrease in sciatic motor nerve conduction velocity (MCV) in short-term DN. ONO2235 and methylcobalamin partially improved the decreased sciatic MCV in diabetic rats. In both short-and long-term DN, PGE₁ analogues ameliorated the decrease in MCV, nerve blood flow (NBF) measured by laser doppler flowmeter, Na⁺, K⁺-ATPase activity, and atrophy of myelinated nerve fibers without normalizing abnormal sorbitol or myo-inositol content in the diabetic sciatic nerve. This agent also normalized dilated endoneurial microvessels in long-term DN. These therapeutic effects of PGE₁ analogues on DN may be mediated by improving decreased NBF, and Na⁺, K⁺-ATPase activity. These results suggest that oral PGE₁, analogues may be potent compounds for treatment of DN and that vascular impairment may be closely associated with the pathogenesis and progression of DN.

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To investigate the rheological factors in the development of diabetic microangiopathy, the sialic acid levels in the erythrocyte membrane and the sialidase activity in the corresponding serum were measured in 60 diabetic patients and 25 healthy subjects.
The sialic acid levels in the red cells were determined by the enzymatic method and sialidase activity was measured with a highly sensitive fluorogenic substrate (4-MU NANA).
A significant decrease in the sialic acid levels in the erythrocyte membrane was observed in the diabetic patients. Those of diabetic patients with microangiopathy (nephropathy or retinopathy) were significantly lower than those of patients without microangiopathy. Sialidase activity in the serum was significantly increased in diabetic patients, especially in diabetics with microangiopathy.
The sialic levels in the erythrocyte membrane and the sialidase activity in the serum of diabetic patients were only significantly different in the insulin-treated group. Significant negative correlations were noted between sialic acid in the erythrocyte membrane and fasting blood sugar (FBS) and HbAi in diabeticpatients with microangiopathy.
Since the negative charge of sialic acid in the erythrocyte membrane is important in inhibiting the aggregation of red cells, these findings suggest that a relationship between abnormalities in microrheology and the progress of diabetic microangiopathy. The measurement of these factors might be an important index in the treatment of diabetics.

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Alloxan diabetes was induced in 18 rabbits. Five days later, the thoracic aorta and the intima that had grown inside the surface of the artificial vessel, which was grafted at the site of the carotid artery more than 3 months before, were separated. The radioactivity of ¹⁴CO₂ and ¹⁴C-lactate were measured after incubation of the tissue with 1-¹⁴C-glucose and 6-¹⁴C-glucose.
The ratios of ¹⁴CO₂ produced from 1-¹⁴C-glucose and 6-¹⁴C-glucose in the intima were 7.8±4.1 in the control group and 78.9±58.7 in the diabetic group (p<0.025), and the ratio was positively correlated with the levels of blood glucose and plasma triglyceride; the ratios in the aorta were 2.33±0.89 and 3.67±1.37, respectively (p<0.025). The ratios of ¹⁴C-lactate produced from 1-¹⁴C-glucose and 6-¹⁴C-glucose in the intima were 0.74±0.23 in the control group and 1.03±0.38 in the diabetic group (n. s.); the ratios in the aorta were 0.83±0.18 and 0.60±0.12, respectively (p<0.005).
These results suggested that activity of the hexose monophosphate shunt is relatively enhanced in intima from diabetic rabbits, a finding which may be related to vascular complications in diabetes mellitus.

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The preventive effects of conventional therapies on declining renal function in diabetic nephropathy (non-insulin-dependent diabetes mellitus, NIDDM) were evaluated retrospectively. Seventy-nine NIDDMpatients with overt proteinuria were followed for more than three years. Clinical data before and after various therapies were compared. These therapies included a calcium antagonist (CaA), alpha-methydopa (αMD), angiotensin converting enzyme inhibitor (ACEI), anti-platelet agents (APL), essential amino acid (EAA) and oral absorbent (AST-120). The decrease in renal function was analyzed bycomparing the slopes of the regression rate of the reciprocals of serum creatinine (Al/Cr). The results were as follows. Al/Cr (before and after treatment)[(mg/dl×years)-¹]: CaA (-0.170, -0.120), αMD (-0.132, -0.077), ACEI (-0.170, -0.017), APL (-0.158, -0.147), EAA (-0.179, -0.091) and AST-120 (-0.241, -0.203). Administration of ACEI and EAA showed that Δ1/Cr improved after the initiation of treatment. However, only the EAA group showed significant differences. It was suggested that administration of EAA was beneficial with regards to protection against renal failure in NIDDM patients with diabetic nephropathy.

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To determine the influence of changes in blood glucose levels on the improvement of diabetic neuropathy, tibial nerve conduction velocity (NCV) was measured in 96 NIDDM patients on the 5th and 12th day after hospitalization. NCV was found to improve after a week with diet and exercise alone. On the whole, however, the improvement was not remarkable. The decrement of fasting plasma glucose (ΔFPG) was not related to the degree of NCV improvement (ΔNCV). This suggested that a certain level of blood glucose control was necessary before improvement in neuropathy occurred. Therefore, the patients were classified into 3 groups according to whether the fasting plasma glucose level (FPG) recorded on the 2nd and 12th day after hospitalization was more or less than 150 mg/dl. Significant improvement was seen in the group whose FPG was over 150 mg/dl on the 2nd day and less than 150 mg/dl on the 12th Day. In contrast, an unchanged or worsening tendency was seen in the group whose FPG remained over 150 mg/d/ on the 12th day after hospitalization. From the above results, it was concluded that when NCV is evaluated in diabetics, the metabolic status should also be considered, because NCV can rapidly improve even under the influence of diet and exercise alone. However, such functional improvement is dependant on the FPG being controlled to less than approximately 150 mg/dl.

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We have encountered a case of insulinoma without typical hypoglycemic symptoms. The patient was 40-year-old businessman with an unremarkable disease history. At the end of 1987, he was found to have a low fasting plasma glucose concentration of 47 mg/dl.
No abnormal results except low fasting plasma glucose concentrations were noted at the other hospital. He was referred to our hospital at the end of June, 1988 for the further evaluation.
After admission, he had low fasting plasma glucose concentrations and relatively high plasma IRI levels. There were no hypoglycemic symptoms even after 27 hours of fasting. Endocrine tests such as the 75 g OGTT, IVGTT, and arginine infusion test yielded no abnormal results. An insulinoma (diameter 1.6 cm) was detected in the body of the pancreas by MRI, angiography, and selective percutaneous transhepatic portal venous sampling. During hypoglycemic and euglycemic clamps using an artificial pancreas, there was no significant suppression of plasma C-peptide levels before surgery. Quite interestingly, there was no significant increase in catecholamine (CA) levels in response to hypoglycemic stimulation such as prolonged fasting or hypoglycemic clamping.
Plasma glucose concentration and CA responses to hypoglycemic stimulation retuned to normal after surgery. Poor CA response during hypoglycemia might be a major reason of disappearance of typical hypoglycemic symptoms.

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A 52-year-old man sufferring from diarrhea, vomiting and delirium was admitted to the hospital. He had had flu-like symptoms for 4 days prior to the onset of the disease. He had drunk 400 ml of sake daily for 30 years. Laboratory data on admission revealed a high blood glucose level (1, 261 mg/d/) and strongly positive urinary ketone bodies. Diabetic ketoacidosis (DKA) was diagnosed, and insulin and saline infusions were initiated immediately. In spite of the high blood glucose level, his HbA_IC, value was close to normal (6.4%). These findings suggested that his diabetes had developed quite recently. It was also noted that serum myoglobin and pancreatic enzymes (trypsin, lipase and elastase 1) were markedly elevated on admission. After successful treatment of the DKA with insulin and fluid supplement, both serum myoglobin and pancreatic enzyme levels decreased. They reached the normal level within 4 days and 4 weeks respectively. The myolysis and pancreatitis might have been caused by a severe metabolic abnormality including electrolyte disturbance and/or circulatory failure due to DKA although no apparent decrease in blood pressure and no serious alteration in vital signs could be observed. Cytomegalovirus infection, which was suggested by a mild elevation of the antibody titer, could have some relation to destruction of pancreatic islet cells and acinal cells, and that could have caused the IDDM of this patient.

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