Takeshi Kuzuya

Increase in insulin response after treatment of overt maturity-onset diabetes is independent of the mode of treatment.

SummaryThe changes in insulin response to a 100 g glucose tolerance test after treatment by diet, sulphonylurea and insulin were compared in non-ketotic diabetic patients who had fasting blood glucose concentrations higher than 160 mg/100 ml. Patients were selected so that their pre-treatment and post-treatment blood glucose levels were comparable between different treatment groups. Their insulin responses were poor initially but increased significantly when the diabetic state was improved by each treatment. The degree of improvement of insulin response was similar between different treatment groups, when their fasting blood glucose decreased below 140 mg/100 ml and the glucose tolerance curves were improved to a similar extent. Preand post-treatment ∑ IRI values (sum of insulin values during glucose tolerance test, mean±SD) were 102±50 and 200±37 μU/ml in diet-treated group (n = 28), 90±40 and 195±53 μU/ml in sulphonylurea-treated-group (n=48), and 83±28 and 193±38 μU/ml in insulin-treated group (n = 13), respectively. The data suggest that the poor insulin response in overt diabetes results not only from an inherent insensitivity of B-cells to glucose but also from the metabolic derangement of diabetes. Poor insulin response and overtly diabetic metabolism seems to form a vicious cycle.

Positive Correlation of Serum Lecithin: Cholesterol Acyltransferase Activity with Relative Body Weight

Abstract. The activity of serum lecithin:cholesterol acyltransferase (LCAT) was measured in 33 subjects who had no apparent diseases except obesity in some cases. Their liver function tests were all within normal limits. The correlations of serum LCAT activity with sex, age, glucose tolerance, relative body weight, basal immunoreactive insulin, and fasting serum cholesterol and triglyceride were studied. – The results indicate that an increase in serum LCAT activity is significantly correlated with increases in relative body weight, serum total cholesterol, serum unesterified cholesterol, serum basal immunoreactive insulin, and serum triglyceride. – At present the physiological significance of serum cholesterol es‐terification is not fully established. However, the present findings suggest an increased turnover of serum esterified cholesterol in obese subjects.

Insulin secretory response of diabetics during the period of improvement of glucose tolerance to normal range

SummarySerum insulin responses to 100 g oral glucose, intravenous tolbutamide, and oral glucose plus intravenous glucagon and tolbutamide, were studied in patients who were definitely diabetic but subsequently improved to have normal glucose tolerance following treatment. “Definite diabetes” was diagnosed when the patient had had fasting blood sugar higher than 150 mg/ 100 ml or had clear diabetic retinopathy plus glucose intolerance. This improved group, whether nonobese or obese, had significantly decreased insulin responses during glucose tolerance test and glucose-glucagon-tolbutamide test, but the insulin response to intravenous tolbutamide was not significantly different from the control. In contrast, in the secondary diabetes group, whose glucose intolerance might be attributable to other diseases than diabetes, insulin response to glucose was enhanced, and was normalized when glucose tolerance became normal. The insulin response to glucose of the prediabetes group (i.e. with both parents diabetic) with normal glucose tolerance was intermediate between those of the healthy and diabetes groups. It seems that the low insulin response to glucose is a less easily corrigible feature than glucose intolerance and probably constitutes one of the most fundamental abnormalities in primary diabetes.

Immunological reactivity of insulin to sepharose coupled with insulin-antibody---its use for the extraction of insulin from serum.

Abstract Anti-insulin serum globulin fraction coupled to agarose (Sepharose 2B) bound labeled and nonlabeled insulin at pH 8.2–8.4 by a specific antigen-antibody reaction. Insulin bound to this matrix was dissociated with 1 M acetic acid. Anti-insulin globulin-coupled agarose could be used repeatedly after regeneration of its insulin-binding capacity by washing with Tris-HCl-albumin buffer (pH 8.2–8.4). The column of this matrix appeared of practical value to extract insulin from serum.

Reproducibility of the Oral Glucose Tolerance Test and the Rice-Meal Test in Mild Diabetics

Reproducibility of 100 gm. oral glucose tolerance test and of Sakaguchis rice-meal test were studied in sixty untreated mild diabetic patients with fasting blood sugar below 140 mg. per 100 ml. (Hagedorn-Jensen method). The tests were performed twice within a one-week interval. There were considerable variations of blood sugar levels in the same individuals between the duplicate tests. Variations were of similar magnitude after glucose or rice-meal and were smaller for the fasting blood sugar. There was no positive relationship between blood sugar levels after loading and their variability. Such a relationship was, however, clearly demonstrated for the fasting blood sugar levels of 360 newly referred diabetics. Average blood sugar levels and standard deviations for each group remained very stable despite individual variability. Implications of the data on evaluation of the results of these oral tests are discussed.

Plasma insulin response to intravenously administered xylitol in dogs

Intravenous injection of xylitol (0.4 Gm./Kg.) resulted in a sharp and marked rise in plasma insulin, the peak value of which was about 212 times as high as that produced by the same amount (0.4 Gm./Kg.) of glucose in the same dogs. After injection of xylitol, plasma glucose increased slightly for a while then decreased below the fasting level.

FREQUENCY, DEGREE, AND PROGRESSION WITH TIME OF PROTEINURIA IN DIABETIC PATIENTS

Abstract The frequency of proteinuria in 333 Summaryn patients attending a diabetes clinic regularly for at least four years was analysed. Frequency of + + or more proteinuria at the initial visit increased from 4·0% in a subgroup with known duration of diabetes of less than one year, to 16·4% when known duration exceeded ten years. Among the groups which, on the basis of repeated fasting blood-sugar measurement, were judged as achieving good control during follow-up, the frequency of progression of proteinuria was low and was unrelated to the pretreatment fasting blood-sugar.

Demonstration of anti-“a-component” antibody — A possible means to differentiate patients with auto-antibodies to endogenous insulin from insulin-treated patients

SummaryThe presence of anti-“a-component” antibody was examined in sera of 4 groups of patients with or without anti-insulin antibody, using 125 I-a-component and the polyethylene glycol precipitation method. 125I-a-component crossreacted with insulin antibody. This cross-reactivity was abolished after preincubation of these sera with monocomponent insulin. The specific anti-“a-component” antibody could be estimated in this procedure. After preincubation with monocomponent insulin, significant binding of 125I-a-component was demonstrated in sera of most patients treated with ordinary commercial insulin, but not in sera of 2 hypoglycemic patients suspected of an insulin autoimmune syndrome. Some cases treated with commercial insulin for less than one year and all cases treated with monocomponent insulin for 7–10 months did not have significant anti-“a-component” antibody. The test for the presence of anti-“a-component” antibody is not definitive but if positive it differentiates “auto-antibodies” from the antibodies produced by injections of commercial insulin.

Comparison of the Early Time Courses of the Release of Insulin That Follow Injections of Tetragastrin, Tolbutamide, Xylitol, and Glucose into the Pancreatic Artery of Dogs

The early time courses of insulin release were studied by injecting insulinotropic substances directly into a dogs pancreatic artery. Blood samples from the pancreatic vein were collected every five seconds continuously over 90 seconds and were assayed for their insulin concentrations. Injections were repeated two to five times, with intervals of 30 minutes. Insulin release was stimulated within one minute after injection of each of tetragastrin, tolbutamide, xylitol, and glucose, but the time courses of the release of insulin were different with different stimulants: Tetragastrin and tolbutamide increased insulin release faster than did glucose; xylitol produced a slower insulin release than did glucose. The slower insulin-releasing effects of glucose and xylitol than the other agents would be compatible with the theory that their metabolism is required to cause release of insulin, but it is also possible that the glucoreceptor mechanism may require a longer lag time than the other receptor mechanisms for the perception and transfer of the signal to release insulin.

Studies on the mechanism of xylitol-induced insulin secretion in dogs

SummaryThe effect of infusion of small doses of xylitol into the pancreatic artery upon insulin release was studied in anaesthetized dogs, in order to decide whether the strong insulin-releasing effect of xylitol in dogs is mediated by a direct action of xylitol upon the islets or indirectly by some of its metabolites. Xylitol or glucose was infused at 0.5–1.0 mg/kg · min either into the femoral vein or into the superior pancreaticoduodenal artery, and the changes in plasma insulin were measured in the superior pancreaticoduodenal vein. Infusion into the pancreatic artery always resulted in a sharp increase in insulin release, whereas intravenous infusion caused no or little increase. Infusion of xylitol into the superior pancreaticoduodenal artery produced a prompt increase in plasma insulin in the superior pancreaticoduodenal vein but not in the splenic vein. These data suggest that xylitol has a direct stimulatory effect upon islet cells. — During intravenous infusion of epinephrine (1.0 μg/kg. min), plasma insulin did not increase despite intravenous administration of glucose or xylitol (0.4 g/kg). There was a rebound rise of plasma insulin after cessation of epinephrine infusion. Plasma insulin responses to intravenous injection of glucose or xylitol (0.4 g/kg) were inhibited also by the intravenous infusion of diazoxide (0.2 mg/kg · min), but this was somewhat variable among individual dogs. The suppression by epinephrine or diazoxide of both glucose and xylitol-induced hyperinsulinaemia may suggest that there is some common mechanism between the insulin-releasing effects of glucose and xylitol.RésuméLeffet sur la sécrétion dinsuline de linfusion de petites doses de xylitol dans lartère pancréatique a été étudié chez des chiens anesthésiés, afin de savoir si leffet fortement insulino-sécréteur du xylitol chez les chiens est dû à une action directe du xylitol sur les îlots ou à une action indirecte par lintermédiaire de certains de ses métabolites. Le xylitol ou le glucose était infusé la dose de 0.5–1.0 mg/kg. min, soit dans la veine fémorale, soit dans lartère pancréatico-duodénale supérieure, et les variations de linsuline plasmatique étaient mesurées dans la veine pancréatico-duodénale supérieure. Linfusion dans lartère pancréatique provoquait toujours une rapide augmentation de la sécrétion dinsuline, tandis que linfusion intraveineuse ne causait pas ou peu daugmentation. Linfusion de xylitol dans lartère pancréaticoduodénale supérieure provoquait une augmentation prompte de linsuline plasmatique dans la veine pancréatico-duodénale supérieure, mais pas dans la veine splénique. Ces données suggèrent que le xylitol a un effet stimulateur direct sur les cellules des îlots. — Pendant linfusion intraveineuse dadrénaline (1.0 μg/kg. min), linsuline plasmatique naugmentait pas malgré ladministration intraveineuse de glucose ou de xylitol (0.4 g/kg). Après larrêt de linfusion dadrénaline, linsuline plasmatique présentait un phénomène de rebound. Les réponses de linsuline plasmatique linjection intraveineuse de glucose ou de xylitol (0.4 g/kg) étaient également inhibées par linfusion intraveineuse de diazoxide (0.2 mg/ kg. min), mais ceci était un peu variable selon les chiens. La suppression par ladrénaline ou le diazoxide de lhyperinsulinémie provoquée par le glucose et le xylitol peut suggérer quil existe un mécanisme commun entre les effets insulino-sécréteurs du glucose et du xylitol.ZusammenfassungAn anaesthesierten Hunden wurde die Wirkung der Infusion kleiner Xylit-Mengen in die Pankreasarterie auf die Insulinfreisetzung untersucht, um zu klären, ob das Xylit direkt oder über einen seiner Metabolite auf die Insulinausschüttung wirkt. Xylit oder Glucose wurde in Mengen von 0.5–1.0 mg/kg/min entweder in die Femoralvene oder in die A.pankreaticoduodenalis sup. infundiert und die Änderung des PlasmaInsulins in der V.pankreatico-duodenalis sup. gemessen. Zufuhr über die Pankreasarterie löste immer eine abrupte Steigerung der Insulinfreisetzung aus, während intravenöse Gaben zu keinem oder nur einem geringen Anstieg führten. Die Xylit-Infusion in die A.pankreaticoduodenalis sup.bewirkte zwar eine prompte Steigerung der Plasma-Insulinspiegel in der V.pankreatico duodenalis sup., nicht aber in der Milzvene. — Diese Befunde sprechen dafür, daß Xylit die Inselzellen direkt stimuliert. Während einer i.v.Infusion von 1.0 μg/kg/min Adrenalin stieg das Plasma-Insulin trotz intravenöser Zufuhr von 0.4 g/kg Glucose oder Xylit nicht an. Nach Beendigung der Adrenalin-Infusion wurde ein verstärkter Wiederanstieg des Plasma-Insulins beobachtet. Auch durch i.v.Gaben von 0.2 mg/kg/min Diazoxid ließ sich die Wirkung der Infusion von 0.4 g/kg Glucose oder Xylit unterdrükken, wobei sich jedoch Unterschiede zwischen den einzelnen Tieren ergaben. Die Aufhebung des Xylit- u. Glucose-Effektes auf die Insulinsekretion durch Adrenalin und Diazoxid könnte darauf hinweisen, daß die Steigerung der Insulinfreisetzung durch Glucose und Xylit auf einem gemeinsamen Mechanismus beruht.