The Effect of Long-term Treatment of Ramipril on Glucose Tolerance and Pancreatic Islets in Type 2 Diabetes Animal Model (OLETF Rats)

Ko, Seung Hyun; Yoon, Kun Ho; Kim, Myung Mi; Ahn, Yu Bae; Song, Ki Ho; Yoo, Soon Jib; Son, Hyun Shik; Cha, Bong Yun; Lee, Kwang Woo; Son, Ho Young; Kang, Sung Koo

Abstract

BACKGROUND: In a Heart Outcomes Prevention Evaluation HOPE study, ramipril, a long- acting angiotensin-converting enzyme (ACE) inhibitor, significantly reduced the death rates the number of myocardial infarctions, strokes, heart failure as well as the risk of complications related to diabetes and of diabetes itself. However, it is known that ACE inhibitors improve glucose tolerance or insulin sensitivity or reduce the incidence of diabetes.
METHODS
24 week-old OLETF (Otsuka Long Evans Tokushima Fatty) rats weighing 400~450 g were used in this study. 4 groups of rats were examined in parallel for 40 weeks. The OLETF rats were randomized for treatment with an aqueous solution of ramipril ( 5mg/Kg) daily [OL (RMP), n=10)] and with saline [OL(CON), n=10)]. The LETO rats were also randomized in the same was as the OLETF rats (LT (RMP), n=10, LT (CON), n=10). The blood glucose level, body weight, systolic and diastolic blood pressure was assessed every month. At 3 and 6 months, the 24hrs urinary protein concentration was measured, and as insulin tolerance test and oral glucose tolerance test were conducted in all experimental groups. After 6 months, the body weight was matched for 2 months in each corresponding group. Subsequently, a 15% sucrose loading was done for 2 months. After the glucose tolerance test, the pancreas was excised and immunohistochemical staining was conducted for insulin to quantify the beta cell mass by a point-counting method. In addition, the islet morphology was evaluated in the pancreas.
RESULTS
Ramipril treatment for a period of 6 months improved the 2hr blood glucose level, the area under the glucose curve in the oral glucose tolerance test, insulin sensitivity in addition to lowering significantly systolic and diastolic blood pressure and 24hrs urinary protein level significantly in OLETF rats. Of note, a lower weight gain was observed in both the ramipril-treated animals at 6 months. After weight matching, the AUCg and 2hr blood glucose level values were similar between the corresponding groups, but a 15% sucrose loading worsened the AUCg value. Histologically, the islets were less disorganized and the extent of fibrosis was lower in the ramipril- treated OLETF rats in the trichrome stain.
CONCLUSION
Long-term treatment of ramipril, a long acting angiotensin-converting enzyme inhibitor may be useful for suppressing weight gain and proteinuria in addition to having aprotective effect on the islet to harmful stimuli such as hyperglycemia.