Nicorandil improves diabetes and rat islet beta-cell damage induced by streptozotocin in vivo and in vitro.

OBJECTIVE: N-(2-hydroxyethyl)-nicotinamide nitrate (nicorandil) is a unique anti-anginal agent, reported to act as both an ATP-sensitive K(+) channel opener (PCO) and a nitric oxide donor. It also has an anti-oxidant action. We examined the effects of nicorandil on streptozotocin (STZ)-induced islet beta-cell damage both in vivo and in vitro. DESIGN AND METHODS: STZ-induced diabetic Brown Norway rats (STZ-DM) were fed with nicorandil-containing chow from day 2 (STZ-DM-N48), 3 (STZ-DM-N72), and 4 (STZ-DM-N96) to day 30. Body weight, blood glucose, and plasma insulin were measured every week. For the in vitro assay, neonatal rat islet-rich cultures were performed and cells were treated with nicorandil from 1 h before to 2 h after exposure to STZ for 30 min. Insulin secretion from islet cells was assayed after an additional 24 h of culture. We also observed the effect of nicorandil on the generation of reactive oxygen species (ROS) from rat inslinoma cells (RINm5F). RESULTS: Body weight loss and blood glucose levels of STZ-DM-N48 rats were significantly lower than those of STZ-DM rats. Immunohistochemical staining of insulin showed preservation of insulin-secreting islet beta-cells in STZ-DM-N48 rats. Nicorandil also dose-dependently recovered the insulin release from neonatal rat islet cells treated with STZ in in vitro experiments. Nicorandil did not act as a PCO on neonatal rat islet beta-cells or RINm5F cells, and did not show an inhibitory effect on poly(ADP-ribose) polymerase-1. However, the drug inhibited the production of ROS stimulated by high glucose (22.0 mmol/l) in RINm5F cells. CONCLUSIONS: These results suggested that nicorandil improves diabetes and rat islet beta-cell damage induced by STZ in vivo and in vitro. It protects islet beta-cells, at least partly, via a radical scavenging effect.

[A case of adrenal mixed tumor of pheochromocytoma and adrenocortical adenoma presenting diabetes mellitus and hypertension].

A 61-year-old woman with hyper-catecholaminemia and hyper-glucocorticoidemia due to a mixed tumor of the right adrenal gland is described. The patient, who had been medicated for hypertension since 1977, complained of thirst and general malaise in 1986. Body weight loss was remarkable. There was neither absolute truncal obesity nor moon face. In September 1986, her blood pressure was 180/110 mmHg and blood glucose level was 400mg/dl. Noradrenaline levels in plasma and in urine were remarkably elevated (1659 pg/ml and 120 micrograms/day, respectively), and adrenaline levels were also high (397 pg/ml in plasma, 34 micrograms/day in urine). Plasma cortisol and urinary 17-OHCS were elevated (39.2 micrograms/dl and 11.9 mg/day, respectively). Plasma ACTH was in the normal range (42.6 pg/ml). Oral administration of neither 1mg nor 8 mg of dexamethasone suppressed plasma cortisol or ACTH levels. Both 131I-metaiodobenzylguanidine and 131I-adosterol accumulated in the right adrenal gland. In 1987 the adrenal tumor (3.0 x 3.5 cm, 30 g) was resected. After the operation, her blood pressure and blood glucose level returned to normal, so that the medication became unnecessary. Histologically it was revealed that the tumor was a mixed adenoma consisting of adreno-medullary and cortical cells (corticomedullary adenoma). The literature on 21 cases of pheochromocytoma associated with Cushing's syndrome was briefly reviewed. Mathison (1969) reported the first case of a mixed tumor of adreno-medullary and cortical cells. So far as we know the present case is the second.

Abnormal lipoprotein and apolipoprotein pattern in lipoprotein glomerulopathy.

Recently, two cases of renal disease were observed in which there was an abnormal accumulation of lipids, "lipoprotein thrombi," in the glomerular capillary lumen. This disease has been designated as lipoprotein glomerulopathy. Four other cases have been diagnosed independently by renal histology in other clinical laboratories. All six patients showed proteinuria (1.6 to 10 g/d), normal lecithin-cholesterol acyltransferase (LCAT) activity, type III hyperlipoproteinemia-like lipoprotein profiles, and significantly (P less than 0.01) higher levels of plasma apolipoprotein (apo) E (greater than 10 mg/dL) compared with the control patients with hyperlipidemic nephrotic syndrome without lipoprotein thrombi and type IIb hyperlipoproteinemia without renal disease. Lipoprotein glomerulopathy is not familial type III hyperlipoproteinemia (dysbetalipoproteinemia), because apolipoprotein E3 is present. Apo E isoforms were all rare: five cases of E2/3 and one case of E4/4. These results suggest that excessive apo E is associated with apo E isoform and lipoprotein metabolic derangement in such a renal disease. Further studies are needed on the relationship between the apo E hyperlipoproteinemia and the formation of lipoprotein thrombi.

Effect of taurine administration on serum lipid and biliary lipid composition in man.

The effect of oral administration of taurine (3.2 g/day, 2 weeks) on the metabolism of lipids and bile acids was studied with healthy humans. Four male subjects were fed taurine. Another five male subjects were administered 1 g of cholesterol daily for two weeks and, at intervals of two weeks, cholesterol and taurine simultaneously. Serum lipoprotein and duodenal bile were analyzed. Oral administration of taurine resulted in the increase of taurine-conjugated bile acids. However, neither serum lipid nor biliary lipid composition was altered. Addition of taurine with cholesterol administration showed elevation of both the serum low density lipoprotein cholesterol level and the lithogenic index in bile. The ratio of glycine-to taurine-conjugated bile acids was changed from 4.1 to 0.63. The ratio of cholic acid/chenodeoxycholic acid was augmented from 0.57 to 0.81. The percentage of taurocholic acid, taurochenodexycholic acid and taurodeoxycholic acid were increased about 4-fold, 2.5-fold and 3-fold, respectively. Our results suggested that taurine administration alone did not influence the serum lipid level although taurine-conjugated bile acids were increased. The taurine intake would increase serum low density lipoprotein cholesterol and biliary cholesterol levels when excessive cholesterol is administered simultaneously.

Appearance of multidisperse low density lipoprotein and altered lipoprotein composition in non-insulin-dependent diabetes with type IIa hyperlipoproteinemia.

The purpose of the present study is to elucidate the characteristics of lipoprotein disorders in diabetes mellitus. By analytical ultracentrifugation, non-insulin-dependent diabetic patients (NIDDM) with type IIa hyperlipoproteinemia (HLP) showed significantly higher incidence of multidisperse low density lipoprotein (LDL) than non-diabetics with type IIa HLP. Furthermore, LDL multidispersity in diabetic subjects seemed to be directly related to neither triglyceride (TG) levels in very low density lipoprotein (VLDL) nor the degree of glycemic control. Diabetics with multidisperse LDL had a lipoprotein profile that was different from the subjects with paucidisperse LDL as follows: (1) enrichment in the cholesterol content of VLDL, (2) TG-rich LDL with small flotation coefficient, (3) low cholesterol levels in high density lipoprotein2 along with enrichment in TG, and (4) high plasma concentrations of apoprotein B. Although the underlying mechanism behind the prevalence of multidisperse LDL in NIDDM with type IIa HLP remains unknown, it seems important that lipoprotein disorders in diabetics with multidisperse LDL were potentially atherogenic.