Yutaka Noto

Effects of Insulin on Vasoconstrictive Responses to Norepinephrine and Angiotensin II in Rabbit Femoral Artery and Vein

To determine whether insulin has a vasodilator action on the artery and vein, the effects of insulin at varying concentrations (120 μU/ml, 1.2 mU/ml, 12 mU/ml, and 120 mU/ml) on vasoconstriction by norepinephrine (NE) and angiotensin II (ANG II) were studied in the isolated rabbit femoral artery and vein. Helical strips were suspended in an organ bath filled with modified Krebs solution (pH 7.4), were gassed with 95% O2/5% CO2 at 36°C, and isotonic contractions were measured. Insulin significantly and dose dependently inhibited the vasoconstriction induced by NE (10−8 M for the artery and 10−7 M for the vein) at ≥1.2 mU/ml for both the artery and vein and the vasoconstriction induced by ANG II (3 × 10−10 M for the artery and 3 × 10−9 M for the vein) at ≥1.2 mU/ml for the artery and ≥12 mU/ml for the vein. The results indicate that insulin has an inhibitory effect on NE- and ANG II–induced contraction in both the artery and vein, and this appeared to be a contributory factor in the hypotensive effect observed in diabetic patients treated with insulin.

Inhibition by somatostatin of insulin release from isolated pancreatic islets

Since the finding of somatostatin, the hypothalamic inhibitor of pituitary growth hormone, many experimental data showing the inhibiting activity of somatostatin on the secretion of other hormones have been presented [ 11. As for the insulin secretion, somatostatin was reported to suppress a glucoseinduced rise of plasma insulin in humans [2] and to inhibit insulin secretion by perfused pancreases [2-41. However, concerning its direct effect on insulin release from the pancreatic islet of Langerhans there have so far been two controversial results; Although Efendic et al. [3] failed to demonstrate the inhibitory effect of somatostatin on insulin release from the isolated islet, Oliver and Wagle [5] have quite recently reported that the inhibition of insulin release from the islet was observed in experiments with incubation media containing somatostatin concentrations ranging from 0.2 to 100 pglml. Recently, we have isolated rat pancreatic islets under mild conditions of collagenase treatment, and studied the effect of somatostatin on glucose-induced insulin release by the islet. The purpose of present paper is to show that somatostatin, in such a low concentration as 10 &ml, did inhibit insulin release from the islet and that the somatostatin inhibition of insulin release was completely reversed by increasing Ca” concentration in the incubation medium.

Peripheral Circulatory Effects of Insulin in Diabetes

Peripheral circulatory effects of insulin were studied in the diabetic patients with and without autonomic neuropathy. Forearm blood flow, calf venous vol ume and calf venous distensibility were measured by strain gauge plethysmo graphy. In the diabetic patients with autonomic neuropathy, mean blood pres sure fell from 96±5 to 88±5 mmHg after an intravenous injection of 4 U of monocomponent insulin (p < 0.001). Forearm vascular resistance decreased from 53.99±8.29 to 45.88±7.76 mmHg•ml -1•100ml-1•min-1 after insulin (p < 0.01). Insulin increased calf venous volume from 1.20±0.19 to 2.23±0.44 ml/100ml (p < 0.05) and calf venous distensibility from 0.039±0.004 to 0.082±0.016 ml/mmHg (p < 0.05). In contrast, in the diabetic patients without autonomic neuropathy, there were no significant changes in the mean blood pressure, forearm vascular resistance, calf venous volume and calf venous dis tensibility. Symptoms of hypoglycaemia did not occur in any patient. These results suggest that insulin has a vasodilator action on both resistance and capacitance vessels, which may be one of the main factors in insulin-in duced hypotension.

Inhibition by kynurenine metabolites of proinsulin synthesis in isolated pancreatic islets.

SummaryThe effect of kynurenine metabolites on insulin biosynthesis was investigated in isolated pancreatic islets of the rat. Both quinaldic acid and 8-hydroxyquinaldic acid were found to produce significant inhibition of the proinsulin synthesis. However, the conversion process of proinsulin to insulin in the islet was not affected by these kynurenine metabolites. Furthermore, the inhibitory effect of these end-metabolites of kynurenine was characterized by preferential inhibition of proinsulin synthesis as distinct from non-insulin protein synthesis in the islet. In contrast to the significant inhibitory effect of quinaldic acid and 8-hydroxyquinaldic acid on proinsulin synthesis, xanthurenic acid and kynurenic acid were far less effective, and L-tryptophan, L-kynurenine, 3-hydroxyanthranilic acid and quinolinic acid showed little ability to inhibit proinsulin synthesis in islets.

MLL Gene Rearrangement in Acute Myelogenous Leukemia After Exposure to Tegafur/Uracil

We report a case of acute myelogenous leukemia (AML) withMLL (myeloid-lymphoid leukemia or mixed-lineage leukemia) gene rearrangement after exposure to tegafur/uracil. Cytogenetic and clinical findings in this patient: t(11;17) (q23;q25), AML-M4 morphology, development of AML within a short latent period after first exposure to tegafur/uracil, and good response to remission induction chemotherapy but short remission duration, have been considered typical features of therapy-related acute myelogenous leukemia (t-AML) after exposure to topoisomerase II—targeting agents. This case report suggests that t-AML may develop after exposure to tegafur/uracil and thatMLL gene rearrangement may not necessarily be specific to t-AML after exposure to topoisomerase II—targeting agents.

The First Case of Insulin-Dependent Diabetes mellitus with Prominent Spurious Hyperglucagonemia due to Interference of Immunoglobulin G in Glucagon Radioimmunoassay (OAL-123) System

A 51-year-old male was admitted to our hospital because of diabetic ketoacidosis. His symptoms were promptly improved with intensive insulin therapy, but his plasma glucagon immunoreactivity measured by the OAL-123 radioimmunoassay (RIA) system showed persistently high values (3,090-3,210 pg/ml). A computed tomographic scan, abdominal angiography and endoscopic examination of his gastrointestinal tract showed no evidence of glucagonoma. After removing the immunoglobulin fraction from the plasma, his immunoreactive plasma glucagon level returned to normal. Moreover, the immunoglobulin G fraction purified from the patients plasma inhibited the binding of [125I]glucagon to rabbit antiglucagon antiserum, OAL-123. Dot-blot analysis demonstrated that the immunoglobulin G of this patient cross-reacted against OAL-123. Therefore, it was considered that the prominent hyperglucagonemia in this patient was due to the presence of IgG, which interfered with the measurement of plasma-immunoreactive glucagon.