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Biomedical subjects

H Kajinuma

Publications and source records attributed to H Kajinuma.

At least 19 recordsLinked to original sources
PubMed1997

Changes in plasma glucose, insulin, glucagon, catecholamine, and glycogen contents in tissues during development of alloxan diabetes mellitus in rats.

Alloxan monohydrate (ALX) was given to rats (20 mg/100 g body weight) and plasma glucose (PG), immunoreactive insulin (IRI), immunoreactive glucagon (IRG), and catecholamine (CA) as well as the glycogen (G) content in the liver, muscle, and kidneys were measured. Although whether hypoglycemia was present immediately after injection was not clear, the PG level increased, with a modest peak after 2 h. The PG levels in rats receiving food 6 h after ALX injection increased substantially after 1 h and continued to increase after 24 h. Although the IRI level increased slightly 10 min after the injection, low amounts were present for up to 24 h due to continued fasting. There was a rise in the IRG level at 10 min after injection, and then it decreased again slowly to a low level during fasting. No change was observed in the CA level. Hepatic G further decreased at 30 min after ALX injection and started to increase from 2 h to a peak level after 18 h. Almost no changes were noted in muscle tissues. The G content in the renal cortex remained almost unchanged, although it tended to decrease slightly after 8 h. When rats were fed 6 h after ALX injection, the IRI level rose slightly. Hepatic G at 6 h after feeding was nearly equal to that during feeding itself, but it then decreased rapidly. Muscular G became equal to that during feeding. Renal G showed a clear tendency to increase 6 h after feeding and became about four times that during periods when rats were fed ad lib. In conclusion, not only PG, IRI, and IRG, but also tissue G levels were shown to change markedly in the early stage of ALX induced diabetes.

Alloxan↗
PubMed1992

The role of insulin-sensitive phosphodiesterase in insulin action.

The physiological role of the insulin-sensitive phosphodiesterase in mediating the antilipolytic actions of insulin was investigated in rat fat cells with two phosphodiesterase inhibitors, namely, 3-isobutyl-1-methylxanthine (IBMX) and griseolic acid. Insulin activates the phosphodiesterase when incubated with intact fat cells and blocks isoproterenol-induced cellular cAMP production and lipolysis, in a time- and dose-dependent manner. High concentrations of IBMX (1 mM), but not lower concentrations (0.1 mM), increased fat cell cAMP levels and lipolytic responses and overcame the antilipolytic effects of insulin; however, this treatment does not inhibit insulin-stimulated phosphodiesterase activity at earlier times (less than 30 min of incubation). These results may suggest that the level of cAMP under these conditions may be sufficient to stimulate lipolysis maximally, even though increases in cellular cAMP accumulation associated with the higher concentration of IBMX (1 mM) are partially suppressed by insulin. Cellular cAMP accumulation and the phosphodiesterase activation induced by IBMX are suppressed by the nonhydrolyzable adenosine analogue N6-phenylisopropyladenosine (PIA). These results suggest the involvement of adenosine receptors in mediating these responses. A novel phosphodiesterase inhibitor, griseolic acid, suppresses basal phosphodiesterase activity (approximately 50%), increases cellular cAMP content, and stimulates lipolysis in intact fat cells. It also partially suppresses insulin-stimulated phosphodiesterase activity (approximately 50%) and reduces the ability of insulin to decrease cellular cAMP concentration (approximately 40%) and lipolysis (approximately 65%). Because, unlike IBMX and other drugs, griseolic acid demonstrates only inhibition of phosphodiesterase activity, it may be a useful tool for studying the mechanism of insulin action in intact cells. The present work supports the concept that insulin's antilipolytic action is mediated by an activation of fat cell phosphodiesterase.

1-Methyl-3-isobutylxanthine↗
PubMed1991

A pilot clinical trial of a new oral hypoglycemic agent, CS-045, in patients with non-insulin dependent diabetes mellitus.

CS-045, (+/-)-5-[4-(6-hydroxy-2,5,7,8-tetramkethylchroman-2- ylmethoxy)benzyl]-2,4-thiazolidinedione, lowers plasma glucose in several animal models of non-insulin dependent diabetes mellitus (NIDDM) presumably by increasing insulin sensitivity. Little adverse effect was found in a phase 1 study on healthy male subjects. In order to test its efficacy in lowering plasma glucose in NIDDM in man, a pilot multi-center clinical trial of CS-045 was carried out in 146 patients with NIDDM whose glycemic control was inadequate (FPG greater than 140 mg/dl) on diet and/or other oral hypoglycemic agents. CS-045 was given orally in a daily dose of 200 mg or 400 mg for 12 weeks in addition to the previous treatment. The mean fasting plasma glucose (FPG) and fructosamine began to decrease within 2 weeks and the mean HbA1c within 8 weeks. After 12 weeks, the FPG fell from 192 +/- 41 to 155 +/- 45 mg/dl (P less than 0.01), fructosamine from 3.7 +/- 0.6 to 3.3 +/- 0.6 (P less than 0.01), and HbA1c from 8.9 +/- 1.5 to 8.1 +/- 1.5% (P less than 0.01). The drug was effective in 39% of patients in that FPG fell by more than 20% of the initial value. This rate of efficacy was the same when CS-045 was given alone or together with other oral hypoglycemic agents. The drug was more effective in a dosage of 400 mg than with 200 mg (the rate of efficacy 46% vs 25%) and more effective in obese patients than in lean patients (46% vs 25%).(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers↗
PubMed1990

Adrenalectomy-induced alterations in glucagon binding and lipolysis in isolated rat adipocytes.

Adipocytes from adrenalectomized rats nearly lost their lipolytic response to glucagon concomitant with a 90% decrease in the number of glucagon receptors per cell. Quantitative analysis of the relation between amount of cell-bound glucagon and hormone-stimulated lipolysis revealed that the ability of the remaining 10% of glucagon receptors to induce lipolysis was not impaired. Binding of the beta-adrenergic antagonist [3H]dihydroalprenolol and maximal lipolysis induced by (-)-isoproterenol, (Bu)2cAMP, 3-isobutyl-1-methylxanthine, and adenosine deaminase were reduced only 10 to 20% after adrenalectomy. Furthermore, glucagon-stimulated cAMP production was greatly decreased in adrenalectomized animals, but isoproterenol-stimulated cAMP production was not. Hydrocortisone replacement in adrenalectomized rats only partially prevented the loss of glucagon receptors and glucagon effects on both cAMP production and lipolysis. These findings suggest that lipolytic cascade distal to hormone receptors was not greatly impaired in adipocytes after adrenalectomy and that the unresponsiveness of these cells to glucagon was mostly due to a marked reduction in the number of glucagon receptors.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Glucagon inhibits insulin activation of glucose transport in rat adipocytes mainly through a postbinding process.

Incubation of rat adipocytes with 1 microM glucagon plus adenosine deaminase (5 micrograms/ml) inhibited maximally insulin-stimulated 3-O-methyl-D-glucose (MeGlc) transport by approximately 70%, concomitant with 30% and 55% decreases in insulin binding and cellular ATP, respectively. In contrast, under conditions where cellular ATP levels are well preserved (i.e. high albumin concentration in the medium), the inhibition of transport was reduced to about 30%, but that of insulin binding was not. Because depletion of the cellular ATP level by more than 60% by metabolic inhibitors induced 40% or more inhibition of insulin-stimulated MeGlc transport, the greater inhibition of the transport with the low albumin concentration appears to be caused in part by the secondary effect of ATP loss. The relationship between the amount of cell-bound insulin and hormone-stimulated transport activity showed that glucagon does not modulate insulin action at the step of insulin binding to its receptors. Furthermore, glucagon suppressed insulin-stimulated MeGlc transport, mainly through an attenuation of the hormone-induced increase in maximum velocity. The data show that glucagon modulates the process of signal transduction of insulin action. However, the possibility that glucagon directly modulates the process of translocation or the intrinsic activity of the glucose transporters cannot be eliminated.

3-O-Methylglucose↗
PubMed1989

High prevalence of proliferative retinopathy in diabetic patients with low pancreatic B-cell capacity.

A retrospective study on the role of pancreatic B-cell insulin secretory capacity in the development of proliferative diabetic retinopathy was performed in 160 diabetic patients with a duration of diabetes of more than 10 years (mean 19.5 +/- 7.9 years). Pancreatic B-cell insulin secretory capacity was assessed in terms of the quantity of C-peptide excreted into urine per day (24-h urinary C-peptide). When the patients were divided into three groups according to the quantity of 24-h urinary C-peptide (group I, C-peptide less than 30 micrograms, n = 49; group II, 30 micrograms less than or equal to C-peptide less than 80 micrograms, n = 76; and group III, C-peptide greater than or equal to 80 micrograms, n = 35), the prevalence of proliferative diabetic retinopathy was much higher in group I (26.5%) than in group II (5.3%) or group III (2.9%). The incidence of proliferative diabetic retinopathy during the follow-up period (mean 9.8 +/- 4.8 years) was also highest in group I (20.0%, 2.7%, and 2.9% in groups I, II, and III, respectively). Other factors which might affect the development of proliferative diabetic retinopathy, including duration of diabetes and past glycemic control, were comparable in these three groups. In contrast, a division of the patients according to glycemic control revealed a strong correlation between glycemic control and background diabetic retinopathy whereas no such correlation was apparent with proliferative diabetic retinopathy. These data are consistent with the view that low pancreatic B-cell insulin secretory capacity may be a risk factor for the development of proliferative diabetic retinopathy.

Biomarkers↗
PubMed1989

Decreased glucagon binding and glucagon-stimulated lipolysis in adipocytes from streptozotocin-diabetic rats.

Adipocytes from streptozotocin-diabetic rats showed a markedly reduced lipolytic response to glucagon concomitant with a 90% or greater decrease in the number of glucagon receptors per cell. In contrast, beta-adrenergic receptors assessed by [3H]dihydroalprenolol binding and lipolysis stimulated by isoproterenol, dibutyryl 3'5'-cyclic AMP and 3-isobutyl-1-methylxanthine were reduced by only 10-25% in diabetic rats compared with controls. Furthermore, quantitative analysis of the relationship between the amount of cell-bound glucagon and the hormone-stimulated lipolysis revealed that the function of the remaining 10% of glucagon receptors remained intact in cells from diabetic animals. These findings suggest that the lipolytic cascades, including beta-adrenergic receptors, in adipocytes are not greatly impaired by diabetes, and therefore, the unresponsiveness of these cells to glucagon is mostly due to a marked reduction in the number of glucagon receptors, probably as a result of a down-regulation by postprandial hyperglucagonemia.

Adipose Tissue↗
PubMed1989

Evaluation and clinical applications of measurement of urinary growth hormone in diabetic subjects.

Quantities of growth hormone (GH) excreted into the urine over 24 h were measured by the highly sensitive sandwich enzyme immunoassay in 63 non-insulin-dependent diabetes mellitus (NIDDM) subjects, 6 insulin-dependent diabetes mellitus (IDDM) subjects, and 17 age-matched nondiabetic control subjects. GH-provocative tests with intravenous infusion of arginine revealed that urinary GH levels are closely correlated with the integrated concentrations of serum GH (r = .931, n = 14, P less than .001). Furthermore, 24-h urinary GH in control and diabetic subjects was inversely related to body mass index (r = .359, n = 80, P less than .001). The mean 24-h urinary GH in NIDDM subjects was 11.1 +/- 1.9 ng/g creatinine (Cr), which was not significantly different from that in nondiabetic control subjects (9.2 +/- 2.7 ng/g Cr). By contrast, the individual values for IDDM subjects varied widely, and their mean values (42.5 +/- 20.8 ng/g Cr) were much greater than those in the control and NIDDM subjects (P less than .01). The degree of glycemic control does not seem to affect 24-h urinary GH in NIDDM. The mean 24-h urinary GH in 7 subjects with proliferative diabetic retinopathy was comparable to that in subjects without retinopathy or with background retinopathy. Thus, the measurement of 24-h urinary GH appears to provide reliable assessments of endogenous GH secretion under physiological conditions and will be a useful tool for obtaining further insight into the role of GH in diabetes.

Adult↗
PubMed1987

Initial phase II clinical studies on midaglizole (DG-5128). A new hypoglycemic agent.

Midaglizole (DG-5128), 2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-phenylethyl]pyridine dihydrochloride sesquihydrate, is a new type of oral antidiabetic agent that has an alpha 2-adrenoceptor-antagonizing effect. As previously reported, midaglizole reduces plasma glucose, mainly by stimulation of insulin secretion, and inhibits epinephrine-induced platelet aggregation in normal human subjects. In this study, the clinical safety and efficacy of short-term administration of midaglizole were evaluated in 47 patients with non-insulin-dependent diabetes mellitus (NIDDM). After an observation period on diet or sulfonylurea treatment (1 patient was on insulin), patients received 150-250 mg 3 times a day of midaglizole for 2-4 wk, (some patients continued treatment for greater than 4 wk). In 20 of the patients first treated with diet and then switched to midaglizole treatment, fasting plasma glucose (FPG) decreased significantly from 187 +/- 10 mg/dl (mean +/- SE) to 147 +/- 13 mg/dl (P less than .05) and 120 +/- 6 mg/dl (P less than .01) 2 and 4 wk, respectively, after administration of midaglizole. Glycosylated hemoglobin (HbA1) also decreased from 12.0 +/- 0.7 to 11.3 +/- 1.1 and 10.7 +/- 0.6% after 2 and 4 wk, respectively. In 23 of the patients whose treatment was changed from sulfonylureas to midaglizole, FPG, and HbA1 levels were maintained at the same values obtained before administration of midaglizole. In patients treated with midaglizole for greater than 12 wk, FPG and HbA1 were kept at the lowered levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1984

Risk factors for worsening to diabetes in subjects with impaired glucose tolerance.

In a 5-12 year follow-up study of 288 subjects with impaired glucose tolerance after a 100-g glucose load, 48 worsened to overt Type 2 (non-insulin-dependent) diabetes with the elevation of fasting blood glucose. The initial level of blood glucose was a major predictor of subsequent worsening to diabetes. In addition, subjects with a lower insulin response to glucose showed a higher incidence of worsening to the disease, irrespective of blood glucose levels. Multivariate analysis indicated that a diminished insulin response and a high maximal body weight index, as well as a high level of fasting and 2-h glucose values at the initial 100-g oral glucose tolerance test were significant independent risk factors for the development of diabetes in Japanese subjects.

Adult↗
PubMed1983

On the pathogenesis of type II diabetes with special reference to diminished insulin response and obesity: a 5-12 year follow-up study of subjects with borderline glucose tolerance.

In a 5-12 year follow-up study of 288 subjects with borderline glucose tolerance, 56 of them worsened to overt noninsulin dependent diabetes mellitus (NIDDM). Multivariate analysis indicated that a high level of fasting and 2-hour blood glucose values at the initial 100 g oral glucose tolerance test, a large maximal body weight index (Max. BWI) and a diminished insulin response to glucose load were significant independent risk factors for worsening to diabetes. Deterioration to diabetes was observed 4.5 times, 6.1 times and 2.1 times more frequently in subjects with fasting blood glucose greater than or equal to 100 mg/100 ml, 2-hour blood glucose greater than or equal to 180 mg/100 ml and Max. BWI greater than or equal to 130%, respectively, as compared with those having lower values of each variable. Diabetes developed almost exclusively from low insulin responders in 253 non- or mildly obese subjects, while in 35 severely obese subjects a certain number of 'normal or high' insulin responders did develop diabetes. In conclusion, the majority of cases of NIDDM develop on the basis of low insulin secretion, with an additional precipitating factor of obesity, and, in some with higher insulin responses diabetes develops when extreme obesity exists, though these cases form a minor group in Japan today.

Blood Glucose↗
PubMed1983

Analysis of risk factors in the development of diabetic retinopathy.

Assumed risk factors in the development of diabetic retinopathy were examined in 401 diabetic patients who had visited our clinic at regular intervals over 5 years. These subjects showed no funduscopic abnormalities at their first visit, whereas 114 out of 401 cases (28.4%) developed retinopathy within 5 years while 287 cases (71.6%) remained unaffected. 110 cases each were selected both from the affected and unaffected groups, matching in sex, age at onset and duration, and the frequencies of various risk factors were compared. In the affected and unaffected groups, the mean maximal body weight indexes were 125. 5 +/- 19.6% and 123.5 +/- 20.1%, respectively, but the number of subjects with excessive obesity (greater than or equal to 130%) was greater in the former than in the latter (p less than 0.05, chi 2-test). The number of patients with poor blood glucose control was greater in the former while that with good control was greater in the latter (p less than 0.05, chi 2-test). No differences were observed between the two groups for other parameters, including method of treatment. In conclusion, among the various risk factors examined, only obesity and poorer blood glucose control were significant contributors to the development of diabetic retinopathy.

Adult↗