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Biomedical subjects

A Hisatomi

Publications and source records attributed to A Hisatomi.

At least 37 records · Page 2Linked to original sources
PubMed1992

The effects of FK506 and cyclosporine on the exocrine function of the rat pancreas.

The effects of FK506 on exocrine function of the pancreas in Sprague-Dawley rats were examined and compared with those of cyclosporine. FK506 did not affect the levels of amylase and lipase in the pancreas of rats given the drug orally in a daily dose of 1 or 5 mg/kg for 2 weeks. Furthermore, the pancreas of the rats showed good exocrine secretion of enzymes such as amylase and lipase on stimulation with carbachol in vitro. Cyclosporine 50 mg/kg given in the same way as FK506 also was free of effect on enzyme levels in the rat pancreas, but the exocrine secretion of the enzyme from the pancreatic lobules on stimulation with carbachol was impaired. It is concluded that FK506 does not affect pancreatic exocrine function in rats.

Amylases↗
PubMed1992

Effect of pravastatin on serum lipids, apolipoproteins and lipoprotein (a) in patients with non-insulin dependent diabetes mellitus.

In 43 patients with non-insulin dependent diabetes mellitus (NIDDM) associated with hypercholesterolemia, the effect of pravastatin, a potent HMG CoA-reductase inhibitor, on serum lipids, apolipoproteins and lipoprotein (a) was examined. After 1 to 3 months administration of 10 mg per day of pravastatin, the serum levels of total cholesterol, triglycerides and low-density lipoprotein cholesterol (LDL-C) were significantly decreased, while the serum level of high density lipoprotein cholesterol (HDL-C) was significantly increased in patients with NIDDM. The levels of apolipoproteins B (apo B) and E were significantly decreased, while apolipoprotein AI (apo A-I) was not changed by the administration of pravastatin. The atherogenic indices (LDL-C/HDL-C and apo B/apo A-I) were significantly decreased by the administration of this drug. The serum lipoprotein (a), which was increased in the diabetic patients, was not affected by the pravastatin treatment. Plasma glucose and hemoglobin A1c levels were not affected by the treatment. We concluded that pravastatin is a potentially useful agent in the treatment of hypercholesterolemia in patients with NIDDM.

Apolipoproteins↗
PubMed1992

Relative hypersecretion of amylin to insulin from rat pancreas after neonatal STZ treatment.

With isolated perfused pancreases from normal and diabetic model rats, we studied alterations of the secretion of islet amyloid polypeptide, or amylin, which has been recently identified as a major component of amyloid deposits in the pancreatic islets of patients with non-insulin-dependent diabetes mellitus. Neonatal (n) Wistar-King albino rats given streptozocin (STZ) on the 2nd (n2STZ) or 5th (n5STZ) neonatal day exhibited moderate and marked elevations, respectively, of plasma glucose and HbA1 as adults compared with control rats given the vehicle. The release of amylin from the perfused pancreases in response to glucose and arginine paralleled that of insulin in all three groups. However, the molar ratio of secreted amylin to insulin in response to 16.7 mM glucose by n5STZ pancreases (6.55 +/- 0.71%) was significantly greater than that for either n2STZ (1.71 +/- 0.24%, P less than 0.05) or the control (0.60 +/- 0.03%, P less than 0.05) pancreases. The secreted amylin-insulin ratio of n2STZ pancreases also was significantly greater than that of the controls (P less than 0.05). The increased amylin-insulin molar ratios of both n2STZ and n5STZ pancreases also occurred during infusions of 33.3 mM glucose and 10 mM arginine. These findings suggest that amylin secretion may be preserved in diabetic rats with reduced beta-cell mass and that hyperglycemia may increase amylin production independently of that of insulin, which may be significant in the pathogenesis of non-insulin-dependent diabetes mellitus.

Amyloid↗
PubMed1992

Platelet-derived growth factor and growth-promoting activity in the serum samples and platelets of patients with non-insulin-dependent diabetes mellitus.

Although platelet-derived growth factor (PDGF) is thought to be a major mediator of atherosclerotic disease, the pathophysiology of diabetic vasculopathy, including atherosclerosis, is unclear. By means of an enzyme immunoassay that used a monoclonal antibody against human PDGF-B chain, PDGF-like immunoreactivity was determined in serum, platelet-poor plasma, and platelet lysate of 28 patients with non-insulin-dependent diabetes mellitus and 11 control subjects. Growth-promoting activity was also measured by tritiated thymidine incorporation into DNA of cultured human fibroblasts. The PDGF-like immunoreactivity in serum was correlated (r = 0.42; p less than 0.01) with that in platelet lysate prepared from a fixed volume of blood. Furthermore, a correlation (r = 0.70; p less than 0.001) was found between the PDGF-like immunoreactivity and the growth-promoting activity in platelet lysate but not in serum. There was no significant difference between patients with diabetes and control subjects with respect to the PDGF-like immunoreactivity in serum or in platelet lysate (38.2 +/- 2.2 vs 42.8 +/- 3.1 ng/ml or 49.1 +/- 2.4 vs 56.2 +/- 3.4 ng/mg protein; mean +/- SEM). In contrast, the serum growth-promoting activity was lower (p less than 0.05) in patients with diabetes than in control subjects (88.1% +/- 7.1% vs 117.4% +/- 6.9%) and there was a negative correlation (r = -0.39; p less than 0.05) between the serum growth-promoting activity and the fasting plasma glucose level. The growth-promoting activity in platelet lysate of patients with diabetes did not differ from that of the control subjects (59.9% +/- 11.6% vs 65.9% +/- 11.2%).(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Platelets↗
PubMed1991

A case of insulin allergy: the crystalline human insulin may mask its antigenicity.

We report an unusual case of insulin allergy. A 48-year-old man with non-insulin-dependent diabetes mellitus receiving biosynthetic isophane human insulin (Humulin N) developed itchy wheal-and-flare reactions at the sites of injection. When Humulin N was changed to a semi-synthetic crystalline human insulin zinc (Novolin U), the allergic reactions completely disappeared. Evaluation of his serum showed a high level of insulin-specific IgE. Skin testing with all commercially available insulins showed immediate local reactions to all agents tested except for Novolin U. In addition, decrystallized Novolin U prepared by lowering the pH with acetic acid also induced a positive reaction. These observations suggest that the crystallized structure of human insulin may mask its antigenicity for allergic reactions.

Diabetes Mellitus, Type 2↗
PubMed1991

Effects of glucagon-like peptide 1 (7-36) amide and glucagon on amylin release from perfused rat pancreas.

The effects of glucagon-like peptide 1 (7-36) amide [GLP-1 (7-36) amide] and glucagon on the release of islet amyloid polypeptide (IAPP), or amylin, from the isolated perfused rat pancreas were studied. In the presence of 5.6 mM glucose, GLP-1 (7-36) amide and glucagon stimulated the release of amylin from the perfused pancreas. The infusion of GLP-1 (7-36) amide at a concentration of 10(-9) M elicited a biphasic release of amylin similar to that of insulin. The cumulative output of amylin induced by 10(-9)M GLP-1 (7-36) amide was significantly higher than that by 10(-9)M glucagon (p less than 0.01). The amylin/insulin molar ratios induced by GLP-1 (7-36) amide and glucagon were about 1% and did not differ significantly. These findings suggest that GLP-1 (7-36) amide and glucagon stimulate the release of amylin from the pancreas and that the concomitant secretion of amylin and insulin might contribute to glucose homeostasis.

Amyloid↗
PubMed1991

Serum 1,5-anhydro-D-glucitol and glycemic control in patients with non-insulin-dependent diabetes mellitus.

Serum 1,5-anhydro-D-glucitol (AG) levels, which have been reported to decrease specifically in diabetics, were measured in 102 patients with non-insulin-dependent diabetes mellitus (NIDDM). The mean of serum AG levels was 7.9 +/- 0.7 micrograms/ml (mean +/- S.E.). It was found a significant negative correlation between serum AG level and HbA1c or fasting blood sugar level. The decrease in serum AG levels inversely correlated with the extent of glycemic control in the patients with NIDDM. Additionally, the changes of serum AG levels negatively correlated with the changes of HbA1c levels during long-term (2 years) treatment. Furthermore, serum AG levels were compared between the patients with and without diabetic complication such as retinopathy, proteinuria or neuropathy. It was found that each group of the patients with complication had significantly decreased serum AG level compared with the complication free group. On the other hand, however, no differences were found in serum AG levels corrected by HbA1c levels using the linear regression formula between the group of the patients with and without diabetic complication.

Adult↗
PubMed1991

Release of amylin from perfused rat pancreas in response to glucose, arginine, beta-hydroxybutyrate, and gliclazide.

Amylin is a 37-amino acid peptide isolated from the islet amyloid of patients with non-insulin-dependent diabetes mellitus. The isolated perfused normal rat pancreas was used to evaluate the effects of glucose and insulin secretagogues, such as arginine, beta-hydroxybutyrate, and gliclazide, on amylin secretion. Glucose and the other stimulants tested elicited a significant release of amylin from the rat pancreas in a biphasic pattern, similar to that of insulin. Dose-response studies of the glucose-induced release of amylin and insulin revealed that they possessed a similar dependency on glucose. However, the release of amylin induced by high concentrations of glucose was partially dissociated from that of insulin; that is, the amylin-insulin molar ratios induced by 22.2 and 33.3 mM glucose (1.11 +/- 0.05 and 1.05 +/- 0.04%, respectively) were significantly higher than those induced by 16.7 mM glucose (0.90 +/- 0.04%, P less than 0.01 vs. 22.2 mM glucose, P less than 0.05 vs. 33.3 mM glucose). Additionally, when the basal concentration of glucose in the perfusate was increased from 5.6 to 11.1 mM, the response of amylin was unchanged. These data suggest that amylin may be an islet hormone whose abundant response to high concentrations of glucose might contribute to the oversecretion of amylin in the hyperglycemia that accompanies diabetes mellitus.

3-Hydroxybutyric Acid↗
PubMed1990

Amylin release from perfused rat pancreas in response to glucose and arginine.

The effects of glucose and arginine on the release of amylin from the perfused rat pancreas were studied. Amylin, or islet amyloid polypeptide, is a 37-amino acid peptide isolated from pancreatic islet amyloid of patients with non-insulin-dependent diabetes mellitus (NIDDM). Glucose stimulated dose-dependently amylin release, showing a typical biphasic pattern. Additionally, 10 mM arginine in the presence of 5.5 mM glucose also stimulated amylin release. These findings suggest that amylin is a secretory protein and its release from the pancreas is regulated by glucose and other nutrients.

Animals↗
PubMed1990

Effect of galanin on arginine-stimulated pancreatic hormone release from isolated perifused rat islets.

The effect of galanin on pancreatic hormone release was studied using isolated perifused rat pancreatic islets. In the presence of 100 mg/dl glucose, 10(-8) mol/L galanin significantly inhibited the basal somatostatin release compared with the perifusion without galanin, whereas there was no significant change in the basal insulin and glucagon release. However, under stimulation of 20 mmol/L arginine, 10(-8) mol/L galanin significantly enhanced glucagon release and suppressed insulin and somatostatin release. These effects disappeared immediately after cessation of galanin infusion. Additionally, 10(-8) mol/L galanin significantly enhanced the first and second phase of glucagon release stimulated by arginine, whereas arginine-stimulated insulin and somatostatin releases were significantly inhibited in both phases. In the cysteamine-treated rat islets, neither enhancement of glucagon release nor suppression of insulin release by galanin was reproducible. These findings indicate two possible explanations. First, it is suggested that the effects of galanin on insulin and glucagon release may be direct and reversed by non-specific effect of cycteamine. Secondly, it seems likely that galanin-enhanced glucagon release may be indirect and in part due to the concomitant somatostatin suppression. Galanin may have an important regulatory function on endocrine pancreas.

Animals↗
PubMed1990

Decreased VIP content in peripheral nerve from streptozocin-induced diabetic rats.

After induction of diabetes with streptozocin (STZ-D) in rats, we measured vasoactive intestinal polypeptide (VIP) content in sciatic nerve and spinal cord obtained from nondiabetic, untreated STZ-D, and insulin-treated STZ-D rats. Eight weeks after the onset of diabetes, caudal nerve conduction velocity (NCV) in the untreated STZ-D rats (n = 13) was slower than in the controls (n = 11; mean +/- SE 30.9 +/- 0.6 vs. 41.4 +/- 1.8 m/s, P less than 0.001). The decrease in NCV was less marked in the insulin-treated STZ-D rats (n = 11; 36.3 +/- 0.9 m/s, P less than 0.05 vs. control). VIP content in sciatic nerve decreased in the untreated STZ-D rats (1.33 +/- 0.23 ng/g wet wt) compared with the other groups (control, 3.10 +/- 0.44, P less than 0.01; insulin-treated STZ-D, 2.44 +/- 0.55, P less than 0.05). However, in spinal cord, VIP content was not significantly different among the three groups. The VIP levels in sciatic nerve showed a positive correlation with NCV (r = 0.430, P less than 0.01). In addition, an inverse correlation between VIP levels and blood glucose levels was observed (r = -0.5624, P less than 0.001). NCV was also inversely correlated with blood glucose levels (r = -0.7662, P less than 0.001). Together with a previous morphological study, these findings suggest a possible causal relationship between reduced VIP content and diabetic neuropathy.

Animals↗
PubMed1989

Binding specificity and intramolecular signal transmission of uncleaved insulin proreceptor in transformed lymphocytes from a patient with extreme insulin resistance.

An alteration of an amino acid sequence in the processing site of the insulin proreceptor by a point mutation of the insulin receptor gene produced extreme insulin resistance. We characterized functional properties of the unprocessed insulin receptor in transformed lymphocytes from a patient. Insulin binding to intact cells and to a partially purified insulin receptor preparation was radically decreased to 20% and 18% of the control values, respectively. In competitive insulin binding to intact cells, [LeuA3]-, [LeuB24]-, [SerB24]-insulin, and mini-proinsulin ([ B(1-29)-Ala-Ala-Lys-A(1-21)]-insulin) had the same relative binding activity in both the patient's and the control cells, but proinsulin and IGF-I were markedly less able to displace 125I-insulin in the patient's cells. In contrast to the study in intact cells, proinsulin and IGF-I as well as other insulin analogues had the same relative binding activity to bind to the partially lectin-purified insulin receptor preparations from both the patient's and the control cells. As regards the signal transduction after receptor binding, insulin-stimulated autophosphorylation of the unprocessed insulin proreceptor occurred proportionally to the amount of decreased insulin binding. With 0.025% trypsin treatment, the abnormal binding characteristics and autophosphorylation were normalized through conversion to functionally normal receptors. In spite of the abnormal processing, self-association of receptors into oligomeric structures was observed in the proreceptor. These results suggest that the unprocessed insulin proreceptor in the plasma membranes has an altered conformation which affects its binding characteristics but not its intramolecular signal transmission.

Adult↗
PubMed1989

Unprocessed insulin proreceptor in cultured fibroblasts from a patient with extreme insulin resistance.

Insulin receptors and IGF-I receptors in cultured fibroblasts were investigated in a patient with extreme insulin resistance due to unprocessed insulin receptors. Insulin binding to cultured fibroblast monolayers and partially purified insulin receptors was extremely decreased to 27% and 18% of control value, respectively. Affinity cross-linking study revealed that molecular weight of the insulin receptor was 210 kDa and that it could not be dissociated to alpha- and beta-subunit with dithiothreitol treatment. Because IGF-I binding to the fibroblasts from the patient was normal and alpha-subunit of IGF-I receptor was 135 KDa, the defect was specific to the insulin receptor. Autophosphorylation of the 210 kDa unprocessed insulin proreceptor was stimulated by insulin in a dose-dependent manner. In the fibroblasts from the patient, insulin-stimulated alpha-aminoisobutyric acid uptake was fivefold shifted to the right in the dose-response curve (ED50 20 ng/mL for the patient v 3.5 ng/mL for the control subjects), but the maximally stimulated uptake was normal. With 0.025% trypsin treatment, insulin binding and alpha-aminoisobutyric acid uptake were normalized. These results suggested that (1) abnormal processing of insulin proreceptor also occurred in the cultured fibroblasts, (2) the postreceptor steps of insulin action were totally intact, and (3) IGF-I receptors were normally processed in this patient.

Adult↗
PubMed1989

Unprocessed insulin proreceptors due to point mutation at the cleavage site.

Two sisters presented with severe insulin resistance and markedly decreased insulin binding to erythrocytes, cultured fibroblasts and transformed lymphocytes. The dose-response curve of insulin-stimulated amino acid uptake in the fibroblasts was shifted to the right. The molecular weight of the insulin receptor on the transformed lymphocytes from the patients was 210,000 and could not be dissociated to alpha- and beta-subunits by dithiothreitol treatment. However, the proreceptor was cleaved by trypsin and this led to the production of alpha-subunit with normal insulin binding. We performed cDNA sequence analysis of the cleavage site of the insulin proreceptor from the patients. The polymerase chain reaction was used to obtain a large amount of cDNA coding for the region including the interconnecting site. A thermostable DNA polymerase, Taq polymerase, successfully produced enough cDNA for the region to be sequenced. The results showed an AGG (Arg) to AGT (Ser) point mutation, resulting in the change of the interconnecting sequence of the two subunits from -Arg-Lys-Arg-Arg- to -Arg-Lys-Arg-Ser-. These results suggest that the tertiary structure change of the cleavage site leads to production of unprocessed insulin proreceptors.

Adult↗
PubMed1989

Effect of islet-activating protein (IAP) on glucagon release from isolated perifused rat islets.

The present study was undertaken to evaluate the effect of islet-activating protein (IAP) on glucagon release using perifused isolated rat pancreatic islets. Glucagon release stimulated by 20 mM arginine was significantly enhanced in the IAP-treated rat pancreatic islets as compared with the IAP-untreated controls. Additionally, the effect of 1 ng/ml somatostatin on glucagon release was examined during ongoing stimulation by arginine. In the IAP-treated islets somatostatin inhibits glucagon secretion to the same extent as in the IAP-untreated islets. These results demonstrate that IAP potentiates arginine-induced glucagon release from perifused rat pancreatic islets, and IAP fails to antagonize the inhibitory effect of somatostatin in the pancreatic A cell.

Animals↗
PubMed1988

Insulin resistance by unprocessed insulin proreceptors point mutation at the cleavage site.

Failure to cleave the interconnecting site between alpha- and beta-subunit produced insulin proreceptors in the plasma membranes which had markedly low affinity to insulin, leading to extreme insulin resistance in a patient. We performed cDNA sequence analysis of the cleavage site of the insulin proreceptor from the patient. Polymerase chain reaction was used to obtain large amount of cDNA coding for the region including the interconnecting site. A thermostable DNA polymerase, Taq polymerase, successfully produced enough amount of cDNA of the region to be sequenced. The results showed AGG (Arg) to AGT (Ser) point mutation, resulting in the change of interconnecting sequence of the two subunits from -Arg-Lys-Arg-Arg- to -Arg-Lys-Arg-Ser-. These results suggest that the tertial structure change of the cleavage site leads to production of unprocessed insulin proreceptors.

Base Sequence↗
PubMed1988

Defective processing of insulin-receptor precursor in cultured lymphocytes from a patient with extreme insulin resistance.

We have studied a patient with extreme insulin resistance, acanthosis nigricans, and decreased erythrocyte insulin binding. EBV-transformed lymphocytes from this patient exhibited markedly reduced binding of 125I-insulin. Radioiodination of cell surface receptors followed by immunoprecipitation with anti-receptor antibodies revealed the presence of increased amounts of a 210-kD protein but no detectable alpha or beta subunits. Continuous labeling with 2-[3H]mannose revealed the synthesis of a 190-kD precursor and a 210-kD protein. The 210-kD protein was phosphorylated in an insulin-dependent manner at high insulin concentrations. These results suggest that in this patient the biosynthesis of 190-kD receptor precursor, its terminal glycosylation, and intracellular transport to the cell surface proceed normally, while proteolytic maturation to alpha and beta subunits does not occur. We postulate that this defect either results from mutation(s) within the insulin-receptor gene, which render the precursor resistant to cleavage, or from a defect in the receptor processing enzyme.

Acanthosis Nigricans↗