Biomedical subjects
Publications and source records attributed to Y Harano.
Lipid peroxide content in hepatocytes isolated from ketotic diabetic rats was higher than normal, and the release of peroxide into the media was also elevated for the initial 18 h. Insulin suppressed both peroxide release and synthesis by cultured hepatocytes isolated from normal and from diabetic rats.
Serum levels of acetoacetate, 3-hydroxybutyrate and the 3-hydroxybutyrate/acetoacetate ratio were determined in Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients by a new sensitive method. Efforts were made to differentiate Type 1 and Type 2 diabetes by serum levels of ketone bodies and to determine whether their measurement is a useful way of monitoring diabetic control. In Type 2 diabetes, serum levels of total ketone bodies did not exceed 2.0 mmol/l even if the patients were untreated or poorly controlled. In Type 1 diabetic subjects, treated with once or twice daily injections of insulin, morning serum levels of acetoacetate, 3-hydroxybutyrate and total ketone bodies were significantly elevated by four-, ten- and sevenfold, respectively. In Type 2 diabetic subjects treated with diet or sulphonylureas, serum levels of 3-hydroxybutyrate were highest before breakfast, next highest before dinner and decreased after each meal. The changes were roughly inversely proportional to serum insulin levels. In addition, insulin treatment normalized fasting serum levels of ketone bodies better than diet or sulphonylurea treatment. Acetoacetate was also significantly increased in both types of diabetes to a lesser extent, but no apparent diurnal rhythm was observed. Determination of serum levels of ketone bodies is useful for the diagnosis of Type 1 diabetes (those with total ketone bodies greater than 2 mmol/l) and for detecting insufficient insulin therapy.
In order to assess insulin sensitivity for glucose utilization in the other type of diabetes, insulin sensitivity tests were performed in subjects with pancreatitis, liver disease, steroid treatment and hyperthyroidism. Insulin sensitivity for glucose utilization decreased in subjects with liver disease, steroid treatment and hyperthyroidism irrespective of the presence or absence of glucose intolerance. Hyperinsulinism was associated in most of the subjects with liver disease and steroid treatment, but even in normo-insulinemic subjects, insulin insensitivity was observed. Obesity was associated with only 2 cases in both pancreatitis and liver diseases and therefore was excluded as a major cause for insulin insensitivity in subjects studied. In subjects with pancreatitis, insulin sensitivity was not significantly decreased. It is to be noted that 4 out of 5 subjects with diabetic OGTT (oral glucose tolerance test) exhibited normal insulin sensitivity. The results indicate that in pancreatitis, tissue insulin sensitivity for glucose metabolism is not altered and therefore can be used as a marker to differentiate the other type of diabetes due to pancreatitis from type 1 or 2 diabetes. Although hyperinsulinemia may be attributable to insulin insensitivity in subjects studied at least in part, steroid and thyroid hormone are thought to act directly antagonistically with insulin for glucose metabolism.
A chronic diabetic state was produced in Macaca fuscatus , and these diabetic monkeys were kept without insulin treatment for up to 25 mo. The metabolic derangements were characterized by hyperglycemia, insulinopenia, hyperglucagonemia, ketonemia, and hyperlipidemia. Significant thickening of the capillary basement membrane of the gastrocnemius muscle was observed in the chronically diabetic monkeys, and became obvious in the course of diabetic state; 732 +/- 35 A in controls, 750 +/- 58 A in diabetic monkeys with duration of 4 mo, and 1165 +/- 112 A in those with duration of more than 11 mo. In addition to duration of the diabetic state, severity of hyperglycemia is also thought to play an important role in the capillary basement membrane thickening judging from the fact that diabetic monkeys with constant hyperglycemia showed a greater membrane thickening. Ultrastructural alterations, such as significant thickening of glomerular basement membrane and increase of mesangial matrix, were observed in kidney as well. These results indicate that diabetic microangiopathy has been produced by metabolic derangements characterized by chronic hyperglycemia, insulinopenia, and hyperlipidemia.
A highly sensitive and simplified method for the differential determination of serum ketone bodies has been developed. Serum was deproteinized with perchloric acid, and acetoacetate contained in the supernate was reacted with newly synthesized p-nitrobenzene diazonium fluoroborate at 37 degrees C for 10 min. The formed hydrazo compound was converted by alkali to the more stable azo compound which has a peak absorbance at 645 nm. For the determination of 3-hydroxybutyrate, this was enzymatically converted to acetoacetate using 3-hydroxybutyrate dehydrogenase, LDH, NAD and pyruvate. Using 0.2 ml serum, acetoacetate and 3-hydroxybutyrate could be quantitated in 30 min. The described method is five times more sensitive than the enzymatic photometric method and can detect individual ketone bodies at concentrations as low as 20 mumol/l. Differential determination of serum levels of ketone bodies is clinically useful for the diagnosis of type 1 diabetes and in monitoring diabetic control.
The effects of alpha- and beta-adrenergic stimulation on ketogenesis were examined in freshly isolated rat hepatocytes in order to determine which alpha- or beta-adrenergic stimulation is involved in the enhancement of ketogenesis. In the presence of 0.3 mmol/L (U-14C)-palmitate, epinephrine, norepinephrine, and phenylephrine at 500 ng/mL increased ketogenesis by 25% (16.0 +/- 0.17 v 12.8 +/- 0.13 nmol/mg protein per hour), 20% (15.3 +/- 0.28) and 20% (15.4 +/- 0.36), respectively. However, isoproterenol even at 1 microgram/mL did not stimulate ketogenesis. Phentolamine (5 micrograms/mL) almost completely abolished the effect of epinephrine on ketogenesis (13.7 +/- 0.30 v 16.0 +/- 0.17) but propranolol did not inhibit the stimulation by epinephrine (15.6 +/- 0.38 v 16.0 +/- 0.17). Trifluoperazine (10 mumol/L), presumably an inhibitor of calcium-dependent protein kinase, abolished the effect of epinephrine (13.6 +/- 0.22 v 16.0 +/- 0.17). These results indicate that catecholamines increase ketogenesis predominantly through the alpha-adrenergic system independent of cyclic AMP, and calcium-dependent protein kinase is thought to be involved in the activation of ketogenesis. On the other hand, glucagon stimulated ketogenesis with an increase of cyclic AMP, which was not inhibited by alpha- and beta-adrenergic antagonists. Alpha-adrenergic stimulation increased hepatic glycogenolysis much more at much lower concentrations when compared with ketogenesis. Stimulation of ketogenesis by catecholamines seemed to be less sensitive and responsive compared with hepatic glycogenolysis.
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Light and electron microscopic studies on exocrine pancreas of diabetic dogs with duration of diabetes up to a year induced by streptozotocin were performed. In the pancreatic acinar cells of the long-term diabetic dogs, atrophy, hyperplastic nodules, and interacinar and interlobular fibrosis were exclusively observed by light microscopy and autophagic vacuoles, lipid droplets, fragmentation of rough endoplasmic reticulum, and decrease or varying size of zymogen granules were much more frequently found by electron microscopy compared with the control. The results might indicate the possibility that insulinopenia causes the injurious effect on exocrine pancreas to produce interacinar fibrosis.
Insulin sensitivity has been determined in primary nonobese diabetics and subjects with borderline glucose intolerance by a newly devised technique using glucose, insulin, and somatostatin infusion. Insulin sensitivity for glucose utilization was decreased in both adult- and juvenile-onset diabetics. Eight out of 88 diabetics had normal insulin sensitivty and were free from microvascular complications. In lean subjects with borderline glucose intolerance, insulin sensitivity was decreased, although an overlap with normal was noted. All obese subjects with borderline glucose intolerance had reduced insulin sensitivity. An inverse relationship was observed between insulin sensitivity and fasting plasma glucose (FPG), and a significant correlation was observed between FPG and steady state plasma glucose levels (SSPG; r = 0.57; P less than 0.001). Improvement of diabetic control in eight diabetics with sulfonylureas decreased SSPG in all (P less than 0.05), although normalization of SSPG was observed in only one. These results indicate that decreased sensitivity of insulin for peripheral glucose utilization may play an important role in the pathogenesis of diabetes. Elevated FPG levels reflect the presence of decreased insulin sensitivity in diabetes mellitus. Although decreased sensitivity is difficult to normalize, it can be enhanced by improving the diabetic control. An effort to maintain or enhance tissue insulin sensitivity in diabetes mellitus may be more important than attempts to stimulate the deteriorating pancreatic beta-cells to secrete more insulin.
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A modified erythrocyte insulin receptor assay was developed. The major advantage of our method is the smaller amount of blood necessary for the assay and consequent simple handling in the binding assay. Three ml of blood is enough for this assay, making it possible to assess insulin receptors in a group of pediatric patients. There was a close relationship between mononuclear cells and erythrocyte insulin binding assays (r = 0.900, p < 0.05). With this method insulin binding studies were done on normal subjects and adult onset non-obese diabetics. Decreased insulin binding was seen in the diabetic group, and this was due to a decreased number of insulin receptors. This erythrocyte insulin receptor assay can be useful tool for the study of the mechanism of insulin resistance.
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