Reduced Food Intake is the Major Contributor to the Protective Effect of Rimonabant on Islet in Established Obesity-Associated Type 2 Diabetes
Sang-Man Jin,1 Bae Jun Oh,2 Suel Lee,2 Jung Mook Choi,3 Soo Jin Yang,4 Sung Woo Park,5 Kwang-Won Kim,1 Jae Hyeon Kim,1 and Cheol-Young Park5 | |
1Division of Endocrinology and Metabolism, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. | |
2Samsung Biomedical Research Institute, Seoul, Korea. | |
3Diabetes Research Institute, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea. | |
4Department of Food and Nutrition, Chonnam National University, Gwangju, Korea. | |
5Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea. | |
Corresponding authors: Dr. Jae Hyeon Kim, Division of Endocrinology and Metabolism, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul 135-710, Korea. Tel: 82-2-3410-1580, Fax: 82-2-3410-3849, Email:jaehyeon@skku.edu Corresponding authors: Dr. Cheol-Young Park, Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, 29 Saemunan-ro, Jongno-gu, Seoul 110-746, Korea. Tel: 82-2-2001-2440, Fax: 82-2-2001-1588, Email: cyber.park@samsung.com
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Received July 25, 2012; Revised October 01, 2012; Accepted November 26, 2012. | |
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. | |
Abstract
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PurposeAlthough the presence of cannabinoid type 1 (CB1) receptor in islets has been reported, the major contributor to the protective effect of rimonabant on islet morphology is unknown. We determined whether the protective effect of rimonabant on pancreatic islet morphology is valid in established diabetes and also whether any effect was independent of decreased food intake.
Materials and MethodsAfter diabetes was confirmed, Otsuka Long-Evans Tokushima Fatty rats, aged 32 weeks, were treated with rimonabant (30 mg/kg/d, rimonabant group) for 6 weeks. Metabolic profiles and islet morphology of rats treated with rimonabant were compared with those of controls without treatment (control group), a pair-fed control group, and rats treated with rosiglitazone (4 mg/kg/d, rosiglitazone group).
ResultsCompared to the control group, rats treated with rimonabant exhibited reduced glycated albumin levels (p<0.001), islet fibrosis (p<0.01), and improved glucose tolerance (p<0.05), with no differences from the pair-fed control group. The retroperitoneal adipose tissue mass was lower in the rimonabant group than those of the pair-fed control and rosiglitazone groups (p<0.05). Rimonabant, pair-fed control, and rosiglitazone groups showed decreased insulin resistance and increased adiponectin, with no differences between the rimonabant and pair-fed control groups.
ConclusionRimonabant had a protective effect on islet morphology in vivo even in established diabetes. However, the protective effect was also reproduced by pair-feeding. Thus, the results of this study did not support the significance of islet CB1 receptors in islet protection with rimonabant in established obesity-associated type 2 diabetes.
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Keywords: Cannabinoid receptor CB1, rimonabant, islet, type 2 diabetes. |
INTRODUCTION
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Sequential hypertrophy and atrophy of pancreatic islets, accompanied with progressive disorganization and fibrosis, is characteristic of rodent obese type 2 diabetes mellitus models such as Otsuka Long-Evans Tokushima Fatty (OLETF) rats1 and Zucker Diabetes Fatty rats.2To date, only few drugs such as thiazolinediones1,3 and rimonabant, a cannabinoid type 1 (CB1) receptor antagonist with full inverse agonist activity and high binding affinity at CB1,2,4 have been proven to preserve islet architecture in these rodent models. Recently, safety issues have been raised regarding the clinical use of thiazolinediones5–8 and there is an increasing interest in alternative drugs with protective effects on islets.
Although rimonabant was withdrawn from the market for adverse psychological effects,9several strategies to avoid the unwanted effect are under investigation.10 Use of neutral antagonist or partial agonist of CB1 receptor, that does not block or impair constitutive CB1 activity, could maintain the metabolic benefit of rimonabant while avoiding adverse psychological effects.11,12 Another strategy is the use of peripheral CB1 receptor antagonists, which do not pass through the blood-brain barrier. Recently, it was reported that one of the peripheral CB1 receptor antagonists led to weight-independent improvements in glucose homeostasis, fatty liver, and plasma lipid profiles in a rodent pre-diabetic obesity model.13
While some of these strategies would be promising, there are some uncertain areas in the protective effect of rimonabant on islet. Firstly, previous studies have not adequately addressed whether rimonabant can protect pancreatic islets from the typical progressive disorganization and fibrosis seen in established diabetes. For example, one study focused on metabolic profiles in a pre-diabetic model without analyzing pancreatic histology,13 which other studies showed that rimonabant preserves islet architecture in rodent obese type 2 diabetes mellitus models, but the animals were not confirmed to be diabetic before the initiation of rimonabant.2,4 Secondly, previous studies did not include pair-feeding control groups in their analyses of islet morphology.2,4 Although the presence of CB1 receptors in islets14,15 and favorable direct effects of CB1 antagonism on insulin secretion in an ex vivo model16,17 have been reported, their importance in vivo has not been adequately addressed. If the protective effect of rimonabant on islet is not reproduced in pair-fed animals, it might suggest the role of islet CB1 receptor in protective effect of rimonabant on islet morphology.
The aim of this study was to reproduce the protective effect of rimonabant against morphological disintegration of islets in an animal model with established diabetes, furthermore, if the effect is reproducible, we planned to determine whether the protective effect of rimonabant is independent of reduced food intake. To this end, we analyzed the protective effect of the CB1 receptor antagonist rimonabant on islet morphology in OLETF rats which were confirmed to be diabetic before treatment. The results were compared to those in pair-fed controls to determine if a protective effect exists that is independent of reduced food intake. In addition, we also compared the results for rimonabant-treated rats to those of rats treated with rosiglitazone, an insulin-sensitizer with a known protective effect on the disintegration of islets in a rodent obese type 2 diabetes model.1,3
MATERIALS AND METHODS
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RESULTS
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DISCUSSION
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In this study, rimonabant treatment reduced food intake, glycated albumin levels, and insulin resistance, and transiently improved glucose tolerance in diabetic OLETF rats. Rimonabant also reduced islet fibrosis in vivo even after the establishment of diabetes, as shown in pre-diabetic obesity models of previous studies. However, this protective effect was not different from that in the pair-fed control group.
In both LETO and diabetic OLETF rats, rimonabant significantly reduced food intake. Although difference in body weight was not significant in diabetic OLETF rats because the control lost body weight due to severe hyperglycemia (Fig. 1G), reduced food intake by rimonabant and pair-feeding was sufficient to cause significant metabolic benefit such as prevention of post-treatment hyperglycemia, protection from islet fibrosis, and lower levels of insulin resistance in diabetic OLETF rats. Interestingly, treatment with rimonabant transiently improved glucose tolerance despite a lack of significant differences in relative beta-cell area. This could at least in part be explained by the improved insulin sensitivity in rimonabant group. Another possibility is that antagonism of the CB1 receptor might potentiate insulin secretion and attenuate glucagon secretion. Although a previous static incubation study showed conflicting results, a perifusion study showed that CB1 antagonism can stimulate insulin secretion.24 In isolated human islets, CB1 receptor antagonism blocked CB1-induced stimulation of glucagon and somatostatin secretion.25
In this study, rimonabant protected OLETF rats against morphological degradation and fibrosis of islets even when treatment was initiated after establishment of diabetes. Because there was no difference between rimonabant and pair-feeding groups, the mechanism of reduced islet fibrosis involves likely improved systemic insulin sensitivity, rather than direct action via islet CB1 receptor. Histologic changes in the pancreas of OLETF rats have been suggested to be the result of over-activity of beta-cells to compensate for insulin resistance.19 The reduced levels of HOMA-IR in rimonabant and pair-feeding groups in diabetic OLETF rats, which were comparable to that of rosiglitazone group, could explain the reduced islet fibrosis. However, there were several different features in adiponection levels and adipose tissue mass between rimonabant/pair-feeding groups and rosiglitazone group. While rosiglitazone group was characterized by increased adiponectin levels in both LETO and OLETF rats, rimonabant and pair-feeding groups showed lower levels of adiponectin than that of rosiglitazone group in both LETO and OLETF rats. In contrast, rimonabant group was characterized by reduced epididymal and mesenteric fat mass in LETO rats, and reduced retroperitoneal fat mass in diabetic OLETF rats. Interestingly, the retroperitoneal fat mass of rimonabant group in diabetic OLETF rats was significantly lower than that of pair-feeding group. These results are consistent with previous studies showing that rimonabant significantly enhances lipolysis in diet-induced obesity, directly leading to a reduction in adipose tissue mass.26,27 Collectively, the action of rimonabant on adipose tissue, which was different from that of rosiglitazone, renews the clinical interest in CB1 pathway as a potential target of new insulin-sensitizing agent in diabetic patients. In addition, although the presence of CB1 receptors in islets24,25and the favorable direct effects of CB1 antagonism on insulin secretion in an ex vivo model17have been reported, the lack of differences in islet fibrosis between the rimonabant and pair-fed control groups in this study did not support significance of their role in islet protection with rimonabant.
Several limitations of this study should be addressed. Firstly, the sample size would be insufficient to demonstrate subtle difference between groups, although the results of this study showed some positive findings in several outcomes. Secondly, diabetic OLETF rats in this study do not represent general population with type 2 diabetes. In OLETF rats, satiety deficit, which might come from the lack of cholecystokinin (CCK)-A receptors, leads to increases in meal size, overall hyperphagia, and obesity.28 Therefore, the metabolic benefit of rimonabant in this study is more relevant to the type 2 diabetes patients with severe obesity, in whom correction of hyperphagia by education is difficult. Thirdly, the metabolic benefit of rimo-nabant in diabetic OLETF groups should be interpreted in the context that glucotoxicity was present in the control group in OLETF rats.
In conclusion, rimonabant had a protective effect on pancreas islet morphology in vivo, even when the treatment was initiated after the establishment of diabetes. The main contributor of this protective effect was reduced food intake, which resulted in improved insulin sensitivity and less glucotoxicity. The present results did not indicate the significance of islet CB1 receptors in the prevention of morphological degradation of islets by rimonabant in obesity-associated type 2 diabetes.
Figures
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Notes
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ACKNOWLEDGEMENTS
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This work was supported by grants from the Samsung Biomedical Research Institute (Project SBRI C-B0-309-1), the Korean Diabetes Association (2007), and the Ministry of Health & Welfare, Republic of Korea (Project A110741). The funding agencies had no roles in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
References
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