Gluconeogenesis and ammonia production in the isolated perfused rat kidney: the effect of starvation, acidosis and diabetic ketosis.
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Biomedical subjects
Publications and source records attributed to N Sakamoto.
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Livers of eight patients with chronic liver diseases were investigated by energy dispersive x-ray analysis. First, three kinds of preparations (osmium-Epon sections, glutaraldehyde-frozen sections, and unfixed-frozen sections) were compared for element detectability at a subcellular level. The glutaraldehyde-frozen sections were satisfactory as far as copper, sulfur, and phosphorus were concerned. Five patients (one patient with Wilson's disease, one chronic cholestasis, one chronic hepatitis, and two asymptomatic primary biliary cirrhosis) yielded x-ray images of copper and sulfur consistent with hepatocellular lysosomes. Second, the glutaraldehyde-frozen sections were utilized for a study of copper deposits in the patients' livers. There was a significant correlation between copper and sulfur contents in the lysosomes of all patients studied but no correlation in the remainder of the cytoplasm. Zinc was not detected in the lysosomes. Whatever the content of copper in the lysosomes, the ratio of delta copper to phosphorus (weight/weight) to delta sulfur to phosphorus was 0.60. These data indicate that most lysosomal copper binds to a thiol protein, probably metallothionein, in the liver.
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Octanoate and N6,O2'-dibutyryl adenosine 3',5'-monophosphate (dibutyryl cyclic AMP) cause a marked inhibition of net glucose utilization and lactate and pyruvate accumulation by hepatocytes isolated from meal-fed rats. Acetate is much less effective as an inhibitor of glycolysis. Fatty acid synthesis, as measured by tritiated water incorporation, is inhibited by dibutyryl cyclic AMP, whereas it is stimulated by 10 mM acetate and 1 mM octanoate. Stimulation of fatty acid synthesis by 1 mM octanoate, however, is lost paradoxically at higher concentrations of octanoate. Rates of fatty acid synthesis estimated by [1-14C]octanoate incorporation were consistently higher than rates calculated on the basis of tritiated water incorporation, raising the question as to which is the better index of the rate of de novo fatty acid synthesis. The effects of octanoate were studied because it was reasoned that this fatty acid should not inhibit acetyl-CoA carboxylase but should inhibit glycolysis and supply acetyl-CoA for lipogenesis. This was found to be the case, proving that glycolytic activity is not necessary for rapid rates of de novo fatty acid synthesis by liver.
The purpose of this trial was to minimize local inflammation caused by intravesical instillation of antitumor agents, especially Adriamycin, in the treatment of bladder tumor. Tranexamic acid was chosen as the solvent vehicle for Adriamycin and IV bolus injection of an antiallergic drug, Stronger neo-minophagen C, was given at the time of each instillation. Of 81 cases scheduled for Adriamycin instillation therapy, nine cases (11.1%) dropped out due to severe bladder inflammation, while 17 other cases (21%) experienced local side-effects which were tolerated. Of 62 evaluable cases in whom more than eight instillations were performed, complete regression was observed in six cases (9.7%) and partial regression in 20 cases (32.3%).
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Using fractionation, subcellular pathogenesis of the fatty liver was investigated. Floating lipids were isolated from a small amount of the liver obtained by needle biopsy. The volume of the floating lipids was correlated to the grading of fat infiltration of the intact tissue. Of lipid-rich particles bound by membranous structures, the volume of lipolysosomes in the patients with liver damage associated with diabetes mellitus was greater than that of alcoholics. Hypercholesterolemia was another feature characteristic of the liver disease exhibiting lipolysosome proliferation. These observations suggest a lysosomal involvement in fatty degeneration of the liver in diabetics through an overload of cholesterol.
Clinical studies were carried out on 526 out-patients with diabetes mellitus on whom the progress of the disease could be followed up for more than 5 years (average 10.3 years). The results obtained were as follows: (1) Ischemic ECC abnormality was noted at a higher frequency in the obese group than in the non-obese group. Even when comparisons were made of the same condition based on the duration of the disease, age, cholesterol level and blood pressure, a similar tendency was observed. (2) Ischemic ECG abnormality was encountered more frequently in the obese group undergoing treatment with insulin or oral hypoglycemic agents, whereas in the non-obese group no difference existed from those undergoing diet treatment. (3) Ischemic ECG abnormality developed in 40.2% of the oral agents group, 40.0% of the insulin group and 9.1% of the diet group in the obese diabetics, while no difference was observed between therapeutic agents in the non-obese diabetics. It might be concluded that a specific state of being obese, or obesity coupled with a state assisting endogenous and exogenous hyperinsulinemia may contribute to the development of atherosclerosis in diabetics.
The principal causes of death among 9,737 diabetics who died in 280 hospitals all over Japan during the period 1971-1980 have been analyzed retrospectively in this study. The main cause of death in Japanese diabetics was vascular complications. The mortality from vascular complications was 41.5%, 37.9% for males and 46.8% for females, increasing with the duration of diabetes and with age. The most interesting findings were of cardiovascular disease which was the cause of death in 12.3% of the subjects in our study as compared to 54.6% of the Joslin Clinic patients (1971). However, our incidence rate was almost twice that reported in Japan in 1967 by Goto (Japan). In contrast, cerebrovascular disease and nephropathy are much more common in Japanese than in American diabetics. Recently cancer has become more common in Japanese diabetics and 25.3% of the deaths have been assigned to it. In contrast, diabetic coma due to hyperglycemia accounted for only 4.1% of deaths. The average life span of Japanese diabetics is still over 10 years shorter than that of non-diabetics.
Gliclazide has been reported to decrease platelet function and to inhibit the progression of diabetic retinopathy in addition to having a hypoglycemic effect. To confirm these effects we performed a double-blind randomized study using glibenclamide as a reference drug. Thirty-eight hospitals from eight university groups in Japan performed the study on type II diabetic subjects. Evaluation of blood glucose control, platelet adhesiveness, platelet aggregation and blood lipids over 24 weeks were assessed by the central committee. Two hundred and eighty-nine patients were enrolled in the study. Twelve were excluded and 277 were statistically analysed. Homogeneity between the two diabetic groups was demonstrated for background factors. Forty mg of gliclazide was comparable to 2.5 mg of glibenclamide in the potency of hypoglycemic efficacy. Funduscopic aggravations were observed in a statistically smaller number of cases in the gliclazide group than in the glibenclamide group and in evaluation of serum lipids, the gliclazide group was also superior to the glibenclamide group. No significant difference between the two groups was found in platelet adhesiveness and aggregation. Gliclazide is a useful drug in the therapy of diabetes mellitus.
Experimental autoimmune hepatitis could be produced in SMA mice by monthly injections of syngeneic liver homogenate or liver-specific lipoprotein together with the polysaccharide of Klebsiella pneumoniae 03:K1 as a powerful adjuvant. Using a gel-diffusion technique, antibodies reacting with liver-specific lipoprotein and liver-specific membrane lipoprotein were detected in approximately 50% of sera from the immunized mice after an 8-mo period. After a full immunization schedule, 60%-80% of the livers of the sensitized mice developed infiltration of mono-nuclear cells consisting mainly of lymphocytes and plasma cells in portal areas, frequently associated with focal necrosis of hepatocytes. Moderate-to-severe piecemeal necrosis of hepatocytes appeared in 10 of 59 animals. However, a gradual decrease in the morphologic severity was observed 3-6 mo after cessation of injections. The transfer of splenic cells from animals with the damaged liver led to a hepatitis in recipients that was characterized by portal infiltration with mononuclear cells and by necrosis of liver parenchymal cells seen on day 14 after cell transfer. The suppressor cell activity determined by the ability of concanavalin A-activated cells to suppress blast transformation of splenic cells of normal SMA mice was significantly decreased (p less than 0.05) in mice immunized with a mixture of liver-specific lipoprotein and the polysaccaride of Klebsiella pneumoniae compared with mice immunized with the polysaccaride of Klebsiella pneumoniae alone or the polysaccaride of Klebsiella pneumoniae plus kidney lipoprotein.
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The authors experienced a case of histiocytosis X with a large intracranial mass resulting in a convulsive seizure. The patient showed left exophthalmos and a skin rash one year and two months after birth. Histiocytosis X was diagnosed from a skin biopsy, and predonine, endoxan and vincristine were administered. The rash disappeared, but the exophthalmos remained. At the age of two years and nine months, punched-out lesions appeared in the skull and 4,000 rads of radiation was applied. Thereafter, the exopthalmos persisted but there was no particular problem in the course. However, a convulsive seizure with fever suddenly appeared at nine years and ten months of age and the patient was hospitalized. At the time of admission, the general condition was good and there were no abnormalities in neurological tests. In neuroradiological examinations, a calcified and poorly vascularized mass 8 cm in maximum diameter was found to occupy the left middle cranial fossa. Chondrosarcoma was strongly suspected from these findings, but there was also symmetrical thickening of bone cortex in the peripheries of the long bones of the extremeties which appeared to be the recovery process from bone destruction caused by histiocytosis X. Therefore, the formation of an intracranial mass by histiocytosis X was diagnosed and surgery was performed. When left osteoplastic fronto-temporal craniotomy was performed, the mass was found to be raising the temporal lobe and it could be easily separated from the surrounding tissue. However, these was firm adherence to dura mater of the middle cranial fossa (especially that of the superior orbital fissure). Histologically, there were many cells with small nuclei, no polymorphism, abundant and clear cytoplasm which were darkly stained and slightly atypic. These findings matched those for histiocytosis X. Cases of histiocytosis X rarely show symptoms of the central nervous system or infiltration of the central nervous system. Only 31 such cases were seen in the literature investigated by the authors. Neurological symptoms include pyramidal symptoms such as hemiparesis and impairment of the cranial nerves, particularly paresis of the optic, trigeminal, facial and acoustic nerves. Convulsive seizures were seen in only five cases including the one reported here. It is also rare for intracranial masses to be formed in cases of histiocytosis X and only six cases, including the authors', have been found with masses of a maximum diameter of more than 5 cm.
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