Downloaded from British Journal of Nutrition (2007), 98, 702–710 doi: 10.1017/S0007114507742678 q The Authors 2007 https://www.cambridge.org/core Effects of miglitol, an a-glucosidase inhibitor, on glycaemic status and histopathological changes in islets in non-obese, non-insulin-dependent diabetic Goto-Kakizaki rats . IP address: Toshinao Goda1*, Kazuhito Suruga1, Akiko Komori1, Sachi Kuranuki1, Kazuki Mochizuki1, Yumi Makita2 and Toshihiko Kumazawa3 170.106.202.8 1Laboratory of Nutritional Physiology and COE Program in the 21st Century, University of Shizuoka School of Food and Nutritional Sciences, 52-1 Yada, Shizuoka 422-8526, Japan 2Mitsubishi Chemical Safety Institute Ltd., Ibaraki, Japan , on 3Sanwa Kagaku Kenkyusho Co., Ltd., Nagoya, Japan 26 Sep 2021 at 15:10:51 (Received 18 October 2006 – Revised 21 February 2007 – Accepted 9 March 2007) Miglitol, a 1-deoxynojirimycin derivative, is an a-glucosidase inhibitor. In the present study, the effects of acute (single-dose) and chronic (8-week) oral administration of miglitol in Goto-Kakizaki (GK) rats, an animal model of type 2 diabetes, were investigated. Dose-dependent , subject to the Cambridge Core terms of use, available at decreases in incremental blood glucose concentrations integrated over a period of 2 h (DAUC0–2h) for values of blood glucose after sucrose-load- ing in miglitol-treated GK rats were observed following an acute oral administration of miglitol (1, 3 or 10 mg/kg body weight). At 10 mg/kg, the DAUC0–2h of blood glucose was decreased by 45 % compared with the control group. Following the oral administration of miglitol in a dietary mixture (10 mg, 20 mg or 40 mg miglitol/100 g control diet) for 8 weeks, the ratio of HbA1c at 8 weeks compared with 0 weeks in GK rats treated with 40 mg miglitol/100 g control diet miglitol was significantly decreased compared with control GK rats without changes in body weight. In oral glucose tolerance testing, miglitol caused a slight decrease in the DAUC0–2h of plasma glucose concentration. In addition, miglitol treatment slightly inhibited the reduction in b-cell mass, and lessened the irregular contours and fibrosis of the islets in GK rats. These results indicate that miglitol ameliorates the hyperglycaemic state of GK rats and the impaired function of the pancreatic islets, as well as preventing the degener- ation of islets in GK rats. Miglitol: a-Glucosidase inhibitor: b-Cell mass: GK rats British Journal of Nutrition a-Glucosidase inhibitors, which are oral antidiabetic agents, Miglitol has recently been reported to reduce the plasma https://www.cambridge.org/core/terms delay carbohydrate absorption from the small intestine glucose concentration in a dose-dependent manner in normal by inhibiting intestinal a-glucosidase activity. These drugs rats13 and in several animal models of diabetes14– 16. (e.g. acarbose, voglibose, miglitol) improve postprandial hyper- The question of whether or not a reduction in hyperglycaemia glycaemia in diabetic patients1,2. Acarbose, a pseudotetrasac- is achieved by acute or chronic oral administration of miglitol charide, has been reported to be a competitive inhibitor of has not been investigated in Goto-Kakizaki (GK) rats, an sucrase, glucoamylase and isomaltase3–6. Voglibose, an N-sub- animal model of non-obese, non-insulin-dependent diabetes stituted valiolamine derivative, has been reported to have stron- characterised by low insulin secretion17,18. The effects of ger a-glucosidase inhibitory activity against maltase and acarbose and voglibose have, however, already been investi- sucrase7. gated19 – 23. It has been reported that b-cells in GK rats are Miglitol, a 1-deoxynojirimycin derivative, is another drug defective in their glucose-stimulated insulin secretion, whereas . https://doi.org/10.1017/S0007114507742678 selected for development as an antihyperglycaemic drug8. insulin synthesis is not affected24 – 26. This animal model exhi- Miglitol is a strong inhibitor of glucoamylase, sucrase and bits functional and structural features of diabetic complications isomaltase9, and has been used clinically in Europe and the and is therefore considered suitable for studying type 2 USA10,11. On the other hand, voglibose is not approved in diabetes27,28. It has also been reported that total b-cell mass Europe or the USA but has been widely used in the treatment was decreased in type 2 diabetic patients compared with control of patients with diabetes in Asia. Miglitol causes less subjects29 and that b-cell loss was enhanced by sucrose-feeding diarrhoea than acarbose and voglibose because it is almost via an increase in the rate of apoptosis in GK rats30. Further- completely absorbed in the upper region of the small intestine more, a reduction in b-cell volume was found to be inhibited in rats, whereas acarbose and voglibose are not absorbed8,12. by a reduction of hyperglycaemia in GK rats treated with Abbreviations: DAUC0–2h, incremental blood glucose concentration integrated over a period of 2 h; GK, Goto-Kakizaki. * Corresponding author: Dr Toshinao Goda, fax þ81 54 264 5565, email [email protected] Downloaded from Glycaemic control and islet in diabetes 703 https://www.cambridge.org/core voglibose19. However, the effects of oral administration of Table 1. Composition of the high sucrose and high fat miglitol for b-cell reduction as well as glycaemic control in control diet GK rats are still unknown. g/kg kcal/kg energy % In the present study, we examined the acute effects of a single dose of miglitol on blood glucose concentrations and Casein 178·7 714·8 19·9 insulin secretion after sucrose-loading, as well as the chronic DL-Methionine 2·6 10·2 0·3 effects of long-term miglitol treatment in a dietary mixture a-Cornstarch 21·3 85·2 2·4 Sucrose 425·5 1702·0 47·5 on glycaemic control and b-cell reduction in GK rats. Corn oil 66·0 594·0 16·6 Lard 53·2 478·8 13·4 . IP address: AIN76 Mineral mix 29·8 – Materials and methods AIN76 Vitamine mix 8·5 – Choline bitartrate 1·7 – Animals 2 % Agar 212·7 – 170.106.202.8 Total 1000 3585 100 Diabetic GK male rats were obtained from CLEA Japan Inc., Japan. Non-diabetic Wistar male rats were purchased from Japan SLC (Hamamatsu, Japan). The rats had free , on Each experiment consisted of one control Wistar rat group access to standard laboratory chow (MF; Oriental Yeast, 26 Sep 2021 at 15:10:51 and six GK rat groups as follows: (1) control Wistar rats fed Tokyo, Japan) and water, and were housed in a room con- the control diet; (2) control GK rats fed the control diet; (3) trolled for temperature (22 ^ 38C), humidity (55 ^ 15 %) miglitol-treated GK rats fed a diet containing 10 mg migli- and light (hours of time 07.00–19.00 hours). tol/100 g control diet; (4) miglitol-treated GK rats fed a diet containing 20 mg miglitol/100 g control diet; (5) miglitol- Effects of a single dose of miglitol in Goto-Kakizaki rats treated GK rats fed a diet containing 40 mg miglitol/100 g control diet; (6) voglibose-treated GK rats fed a diet contain- , subject to the Cambridge Core terms of use, available at GK rats were randomly assigned to a group based on body ing 0·1 mg voglibose/100 g control diet; (7) voglibose-treated weight and the results of oral glucose tolerance testing (2 g/ GK rats fed a diet containing 0·2 mg voglibose/100 g control kg body weight). Rats whose blood plasma glucose concen- diet. The rats were fed the control diet with either miglitol tration was less than 300 mg/dl were excluded. Eight rats or voglibose ad libitum for 8 weeks. Feed mixtures containing (10 weeks old) were used in each group and were fasted for miglitol or voglibose were prepared once a week. 18–20 h before the experiments. The experimental procedures The experimental procedures used in the present study were approved by the Ethical Committee for Animal Research conformed to the guidelines of the Animal Usage Committee of Mitsubishi Chemical Safety Institute Ltd. of the University of Shizuoka. Sucrose-loading test The rats were administered with a single oral dose of miglitol or Parameters voglibose (miglitol 1, 3, 10 mg/kg body weight; voglibose Blood glucose, body weight and food intake were measured British Journal of0·0125, Nutrition 0·0375, 0·125 mg/kg body weight) dissolved in saline. after 0, 2, 4, 6 or 8 weeks of feeding. Physical signs were Miglitol and voglibose provided by Bayer Yakuhin Ltd. observed on an occasional basis. https://www.cambridge.org/core/terms (Osaka, Japan) were used in the present study. GK rats adminis- HbA1c was assayed by HPLC (Waters, Tokyo, Japan) using tered with only saline served as controls. The drug solutions a TSKgel Boronate-5PW column system (Tosoh Corporation, were administered using a gastric tube in a volume of 5 ml/kg Tokyo, Japan). Blood samples were collected for determi- immediately before sucrose-loading (2 g/kg body weight, 5 ml/ nation of plasma glucose after the rats were fasted overnight. kg body weight). Plasma glucose was measured by the glucose oxidase method Blood for glucose and insulin measurements was obtained using a commercial kit (Wako Pure Chemical Industries, from a subclavian vein at 0·25, 0·5, 1, 2 or 4 h after sucrose- Osaka, Japan). loading. Blood glucose was measured by the enzyme electrode After treatment for 8 weeks, all animals underwent an oral glu- method using a blood glucose meter (Horiba, Kyoto, Japan). cose tolerance test. The rats were orally administered a . Plasma insulin was estimated using an insulin ELISA kit glucose solution (2 g/kg body weight, 10 ml/kg body weight) https://doi.org/10.1017/S0007114507742678 (Morinaga Institute of Biological Science, Kanagawa, after an overnight fast, and their plasma glucose and plasma insu- Japan).