Biol. Pharm. Bull. 31(11) 2103-2107 (2008)

Royal jelly (RJ) produced by honey bees is known to contain three major nutrients including amino acids, vitamins and minerals. 1) Additionally, RJ has various biological activities such as a hypotensive effect, insulin-like action and antitumor activity. 2-4) Therefore, it is possible that RJ may have some effects on insulin resistance, which is considered to be a cause of various lifestyle-related diseases. Many clinical studies have shown a possible relationship between hypertension and insulin resistance, since patients with type 2 (noninsulin dependent) diabetes mellitus frequently have insulin resistance associated with hypertension. 5-7) Chronic administration of fructose to rats has been reported to cause insulin resistance, which is characterized by increased serum insulin and euglycemia. 8) Especially, a hyperinsulinemic state associated with hypertension was more prominently induced by fructose drinking than by fructose feeding. 9) Previously, we reported that rats with chronic hyperinsulinemia, which was induced by giving a 15% fructose solution in drinking water for 10 weeks (fructose-drinking rats, FDR), showed deficient neuronal regulation of vascular tone, and this leads to hypertension. 12) Thus, in the present study, we investigated the effects of RJ on the insulin resistance in FDR. We also examined whether RJ prevents hypertension and altered vascular responsiveness induced by insulin resistance using isolated mesenteric vascular beds of rats. MATERIALS AND METHODS Animals Six week-old male Wistar rats were used in this study. They were given 15% fructose solution as drinking water ad libitum for 8 weeks. The control group was given tap water instead of 15% fructose solution. Three rats were housed in each cage (W 220ϫL 320ϫH 135 mm; Natsume Seisakusho, Tokyo, Japan), and given normal rat chow (Oriental Yeast, Tokyo, Japan). They were housed in the Animal Research Center of Okayama University at a controlled ambient temperature of 22Ϯ2°C with 50Ϯ10% relative humidity and with a 12-h light/12-h dark cycle (lights on at 8:00 a.m.). This study was carried out in accordance with the Guidelines for Animal Experiments at Okayama University Advanced Science Research Center, Japanese Government Animal Protection and Management Law (No. 105) and the Japanese Government Notification on Feeding and Safekeeping of Animals (No. 6). Every effort was made to minimize the number of animals used and their suffering. Long-Term Administration of RJ RJ, which was enzymatically treated and supplied by Yamada Apiculture Center, Inc. (Okayama, Japan) (Lot No. 020605), was used in this study. RJ was diluted by adding distilled water and orally administered at doses of 100 mg/kg/d and 300 mg/kg/d for 8 weeks from 6 to 14 weeks of age. Each animal was lightly anesthetized with ether and orally administrated RJ solution at a volume of 2 ml/kg once a day (09:00 to 10:00). The control group was orally administrated the same volume of tap water once a day. Measurements of Body Weight and Food and Liquid Intake Body weight was measured once a week, and food and liquid intakes were measured every 2 d from 6 to 14 Royal jelly (RJ) is known to contain excellent nutrition and a variety of biological activities. The present study was designed to investigate the effects of RJ on insulin resistance (hyperinsulinemia) in fructose-drinking rats (FDR; insulin resistance animal model). Male Wistar rats (6 weeks old) received 15% fructose solution in drinking water for 8 weeks. FDR showed significant increases in plasma levels of insulin and triglyceride, Homeostasis Model Assessment ratio (HOMA-R, an index of insulin resistance), and systolic blood pressure, but not blood glucose levels, when compared with control rats. RJ (100, 300 mg/kg, p.o.) treatment for 8 weeks significantly decreased the plasma levels of insulin and triglyceride, HOMA-R, without affecting blood glucose or total cholesterol levels and tended to lower systolic blood pressure. In isolated and perfused mesenteric vascular beds of FDR, RJ treatment resulted in a significant reduction in sympathetic nerve-mediated vasoconstrictor response to periarterial nerve stimulation (PNS) and tended to increase the calcitonin gene-related peptide (CGRP) nervemediated vasodilator response to PNS, compared with those in untreated FDR. However, RJ treatment did not significantly affect norepinephrine-induced vasoconstriction or CGRP-induced vasodilation. These results suggest that RJ could be an effective functional food to prevent insulin resistance associated with the development of hypertension