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Kikuchi K, Murata M, Kageyama Y, Shinohara M, Sasase T, Noda K, Ishida S. Spontaneously Diabetic Torii Fatty Rat Shows Early Stage of Diabetic Retinopathy Characterized by Capillary Changes and Inflammation. J Diabetes Res 2025; 2025:3800292. [PMID: 40297222 PMCID: PMC12037240 DOI: 10.1155/jdr/3800292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 03/19/2025] [Indexed: 04/30/2025] Open
Abstract
Purpose: The Spontaneously Diabetic Torii (SDT) fatty rat is an animal model of obese Type 2 diabetes. We previously reported that the SDT fatty rats develop diabetic cataracts. This study aimed to elucidate early diabetic changes in the retina of the SDT fatty rats. Materials and Methods: The retinal thickness, capillary diameter, and pericyte/endothelial cell (P/E) ratio were assessed in the male SDT fatty rats and Sprague-Dawley (SD) rats at 24 weeks of age. Immunostaining was performed to assess the intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels in the retinal capillaries. DNA microarray analysis was performed to detect inflammation-associated molecules in the retina of the SDT fatty rats. Real-time PCR and Magnetic Luminex Assay were performed to validate the results. Results: The retinal thickness in the SDT fatty rats was significantly greater than that in SD rats. The capillary diameter in the retina of the SDT fatty rats was significantly higher than that of SD rats. The P/E ratio in the SDT fatty rats was significantly lower than that in SD rats. ICAM-1 and VCAM-1 were observed in the retinal vessels of the SDT fatty rats. The levels of mRNA and protein of Mcp1, Il1b, Icam1, and Tnf were upregulated in the retinal tissues of the 24-week-old SDT fatty rats. Conclusions: Our study demonstrated that the SDT fatty rats exhibited early diabetic retinal changes, suggesting that the SDT fatty rats may be useful in research on the pathogenesis of early human diabetic retinopathy.
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Affiliation(s)
- Kasumi Kikuchi
- Laboratory of Ocular Cell Biology & Visual Science, Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Miyuki Murata
- Laboratory of Ocular Cell Biology & Visual Science, Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
| | | | | | - Tomohiko Sasase
- Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Takatsuki, Osaka, Japan
| | - Kousuke Noda
- Laboratory of Ocular Cell Biology & Visual Science, Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
- Sapporo Sousei East Clinic, Sapporo, Hokkaido, Japan
| | - Susumu Ishida
- Laboratory of Ocular Cell Biology & Visual Science, Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
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Zhang X, Chen Y, Qian J, Si Y, Wang C, Wang J, He Q, Ma J. Animal models in the study of diabetic erectile dysfunction: mechanisms and applications. Front Endocrinol (Lausanne) 2025; 16:1512360. [PMID: 40196453 PMCID: PMC11973095 DOI: 10.3389/fendo.2025.1512360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 02/26/2025] [Indexed: 04/09/2025] Open
Abstract
Background Diabetic erectile dysfunction (DMED) is a common complication of diabetes. While research on DMED relies primarily on animal models, replicating the intricate etiology and multi-system interactions of human DMED in a single model remains a challenge. Aim This article provides a comprehensive overview of animal models used in DMED research and emphasizes the crucial role they play in understanding the pathogenesis and treatment of DMED. Methods A comprehensive medical literature was searched in PubMed and Medline, focusing on original studies and systematic reviews of original studies involving animal models of diabetic erectile dysfunction. Clinical studies, editorials, letters, reviews, and non-English articles were excluded. Results This article compiles various animal models currently used in the study of diabetes and diabetic erectile dysfunction (DMED), with a particular emphasis on the application of rodent models such as rats and mice. These animals demonstrate significant advantages in terms of economy, practicality, and reproducibility in DMED research and share similarities with humans in tissue morphology and functional characteristics. Conclusion This manuscript offers researchers multiple insights into selecting animal models for DMED, particularly considering their practicality, cost-effectiveness, and reproducibility. The integrated information serves as a valuable reference for researchers in choosing suitable models.
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Affiliation(s)
- Xin Zhang
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yihao Chen
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jiahua Qian
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yuhe Si
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Chenxi Wang
- The First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jingwei Wang
- Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Qiang He
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
- Zhejiang Key Laboratory of Research and Translation for Kidney Deficiency-Stasis-Turbidity Disease, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jianxiong Ma
- Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, Zhejiang, China
- Zhejiang Key Laboratory of Research and Translation for Kidney Deficiency-Stasis-Turbidity Disease, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
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Nath D, Barbhuiya PA, Sen S, Pathak MP. A Review on In-vivo and In-vitro Models of Obesity and Obesity-Associated Co-Morbidities. Endocr Metab Immune Disord Drug Targets 2025; 25:458-478. [PMID: 39136512 DOI: 10.2174/0118715303312932240801073903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 06/20/2024] [Accepted: 06/26/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND Obesity is becoming a global pandemic with pandemic proportions. According to the WHO estimates, there were over 1.9 billion overweight individuals and over 650 million obese adults in the globe in 2016. In recent years, scientists have encountered difficulties in choosing acceptable animal models, leading to a multitude of contradicting aspects and incorrect outcomes. This review comprehensively evaluates different screening models of obesity and obesity-associated comorbidities to reveal the advantages and disadvantages/limitations of each model while also mentioning the time duration each model requires to induce obesity. METHODS For this review, the authors have gone through a vast number of article sources from different scientific databases, such as Google Scholar, Web of Science, Medline, and PubMed. RESULTS In-vivo models used to represent a variety of obesity-inducing processes, such as diet-induced, drug-induced, surgical, chemical, stress-induced, and genetic models, are discussed. Animal cell models are examined with an emphasis on their use in understanding the molecular causes of obesity, for which we discussed in depth the important cell lines, including 3T3-L1, OP9, 3T3-F442A, and C3H10T1/2. Screening models of obesity-associated co-morbidities like diabetes, asthma, cardiovascular disorders, cancer, and polycystic ovarian syndrome (PCOS) were discussed, which provided light on the complex interactions between obesity and numerous health problems. CONCLUSION Mimicking obesity in an animal model reflects multifactorial aspects is a matter of challenge. Future studies could address the ethical issues surrounding the use of animals in obesity research as well as investigate newly developed models, such as non-mammalian models. In conclusion, improving our knowledge and management of obesity and related health problems will require ongoing assessment and improvement of study models.
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Affiliation(s)
- Digbijoy Nath
- Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
- Centre for Research on Ethnomedicine, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
| | - Pervej Alom Barbhuiya
- Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
- Centre for Research on Ethnomedicine, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
| | - Saikat Sen
- Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
- Centre for Research on Ethnomedicine, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
| | - Manash Pratim Pathak
- Faculty of Pharmaceutical Science, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
- Centre for Research on Ethnomedicine, Assam Down Town University, Sankar Madhab Path, Gandhi Nagar, Panikhaiti, Guwahati, Assam, 781026, India
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Kawana T, Imoto H, Tanaka N, Tsuchiya T, Yamamura A, Saijo F, Maekawa M, Tamahara T, Shimizu R, Nakagawa K, Ohnuma S, Kamei T, Unno M. The Significance of Bile in the Biliopancreatic Limb on Metabolic Improvement After Duodenal-Jejunal Bypass. Obes Surg 2024; 34:1665-1673. [PMID: 38512643 PMCID: PMC11031486 DOI: 10.1007/s11695-024-07176-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 03/13/2024] [Accepted: 03/14/2024] [Indexed: 03/23/2024]
Abstract
INTRODUCTION Duodenal-jejunal bypass (DJB) is an experimental procedure in metabolic surgery that does not have a restrictive component. Changes in bile acid (BA) dynamics and intestinal microbiota are possibly related to metabolic improvement after DJB. Our previous studies involving obese diabetic rats showed the crucial role of the biliopancreatic limb (BPL) in metabolic improvement after DJB caused by BA reabsorption. We established a new DJB procedure to prevent bile from flowing into the BPL and aimed to elucidate the importance of bile in the BPL after DJB. METHODS Otsuka Long-Evans Tokushima Fatty rats with diabetes were divided into three groups: two DJB groups and a sham group (n = 11). Duodenal-jejunal anastomosis was performed proximal to the papilla of Vater in the DJB group (n = 11). However, the DJB-D group (n = 11) underwent a new procedure with duodenal-jejunal anastomosis distal to the papilla of Vater for preventing bile flow into the BPL. RESULTS Glucose metabolism improved and weight gain was suppressed in the DJB group, but not in the DJB-D and sham groups. Serum BA level and conjugated BA concentration were elevated in the DJB group. The gut microbiota was altered only in the DJB group; the abundance of Firmicutes and Bacteroidetes decreased and that of Actinobacteria increased. However, the DJB-D group exhibited no apparent change in the gut microbiota, similar to the sham group. CONCLUSION BAs are essential in the BPL for metabolic improvement after DJB; they can improve the gut microbiota in these processes.
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Affiliation(s)
- Tomomi Kawana
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Hirofumi Imoto
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan.
| | - Naoki Tanaka
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Takahiro Tsuchiya
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Akihiro Yamamura
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Fumito Saijo
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Masamitsu Maekawa
- Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan
| | - Toru Tamahara
- Tohoku University, Tohoku Medical Megabank Organization, Sendai, Japan
| | - Ritsuko Shimizu
- Tohoku University, Tohoku Medical Megabank Organization, Sendai, Japan
| | - Kei Nakagawa
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Shinobu Ohnuma
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-Machi, Aoba-Ku, Sendai, 980-8574, Japan
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Athmuri DN, Shiekh PA. Experimental diabetic animal models to study diabetes and diabetic complications. MethodsX 2023; 11:102474. [PMID: 38023309 PMCID: PMC10661736 DOI: 10.1016/j.mex.2023.102474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 11/03/2023] [Indexed: 12/01/2023] Open
Abstract
Diabetes is an endocrine illness involving numerous physiological systems. To understand the intricated pathophysiology and disease progression in diabetes, small animals are still the most relevant model systems, despite the availability and progression in numerous invitro and insilico research methods in recent years. In general, experimental diabetes is instigated mainly due to the effectiveness of animal models in illuminating disease etiology. Most diabetes trials are conducted on rodents, while some research is conducted on larger animals. This review will discuss the methodology and mechanisms in detail for preparing diabetic animal models, considering the following important points. The exact pathophysiology of the disease may or may not be replicated in animal models, the correct induction doses must be given and the combination of different approaches for the models is recommended to get desired results.•Animal models are essential to understand diabetes etiology and pathophysiology.•Diabetic models can be developed in both rodents and non-rodents.•Chemically induced and genetic models of diabetes are widely used to study diabetes and diabetic complications.
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Affiliation(s)
- Durga Nandini Athmuri
- SMART Lab, Centre for Biomedical Engineering, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India
| | - Parvaiz Ahmad Shiekh
- SMART Lab, Centre for Biomedical Engineering, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India
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Emini L, Salbach‐Hirsch J, Krug J, Jähn‐Rickert K, Busse B, Rauner M, Hofbauer LC. Utility and Limitations of TALLYHO/JngJ as a Model for Type 2 Diabetes-Induced Bone Disease. JBMR Plus 2023; 7:e10843. [PMID: 38130754 PMCID: PMC10731141 DOI: 10.1002/jbm4.10843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 10/06/2023] [Accepted: 10/25/2023] [Indexed: 12/23/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) increases risk of fractures due to bone microstructural and material deficits, though the mechanisms remain unclear. Preclinical models mimicking diabetic bone disease are required to further understand its pathogenesis. The TALLYHO/JngJ (TH) mouse is a polygenic model recapitulating adolescent-onset T2DM in humans. Due to incomplete penetrance of the phenotype ~25% of male TH mice never develop hyperglycemia, providing a strain-matched nondiabetic control. We performed a comprehensive characterization of the metabolic and skeletal phenotype of diabetic TH mice and compared them to either their nondiabetic TH controls or the recommended SWR/J controls to evaluate their suitability to study diabetic bone disease in humans. Compared to both controls, male TH mice with T2DM exhibited higher blood glucose levels, weight along with impaired glucose tolerance and insulin sensitivity. TH mice with/without T2DM displayed higher cortical bone parameters and lower trabecular bone parameters in the femurs and vertebrae compared to SWR/J. The mechanical properties remained unchanged for all three groups except for a low-energy failure in TH mice with T2DM only compared to SWR/J. Histomorphometry analyses only revealed higher number of osteoclasts and osteocytes for SWR/J compared to both groups of TH. Bone turnover markers procollagen type 1 N-terminal propeptide (P1NP) and tartrate-resistant acid phosphatase (TRAP) were low for both groups of TH mice compared to SWR/J. Silver nitrate staining of the femurs revealed low number of osteocyte lacunar and dendrites in TH mice with T2DM. Three-dimensional assessment showed reduced lacunar parameters in trabecular and cortical bone. Notably, osteocyte morphology changed in TH mice with T2DM compared to SWR/J. In summary, our study highlights the utility of the TH mouse to study T2DM, but not necessarily T2DM-induced bone disease, as there were no differences in bone strength and bone cell parameters between diabetic and non-diabetic TH mice. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Lejla Emini
- Department of Medicine III and Center for Healthy AgingTechnische Universität Dresden Medical CenterDresdenGermany
| | - Juliane Salbach‐Hirsch
- Department of Medicine III and Center for Healthy AgingTechnische Universität Dresden Medical CenterDresdenGermany
| | - Johannes Krug
- Department of Osteology and BiomechanicsUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Katharina Jähn‐Rickert
- Department of Osteology and BiomechanicsUniversity Medical Center Hamburg‐EppendorfHamburgGermany
- Mildred Scheel Cancer Career Center HamburgUniversity Cancer Center Hamburg, University Medical Center Hamburg‐EppendorfHamburgGermany
| | - Björn Busse
- Department of Osteology and BiomechanicsUniversity Medical Center Hamburg‐EppendorfHamburgGermany
- Mildred Scheel Cancer Career Center HamburgUniversity Cancer Center Hamburg, University Medical Center Hamburg‐EppendorfHamburgGermany
- Interdisciplinary Competence Center for Interface Research (ICCIR)University Medical Center Hamburg‐Eppendorf (UKE)HamburgGermany
| | - Martina Rauner
- Department of Medicine III and Center for Healthy AgingTechnische Universität Dresden Medical CenterDresdenGermany
| | - Lorenz C. Hofbauer
- Department of Medicine III and Center for Healthy AgingTechnische Universität Dresden Medical CenterDresdenGermany
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Yagihashi S. Contribution of animal models to diabetes research: Its history, significance, and translation to humans. J Diabetes Investig 2023; 14:1015-1037. [PMID: 37401013 PMCID: PMC10445217 DOI: 10.1111/jdi.14034] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/10/2023] [Accepted: 05/16/2023] [Indexed: 07/05/2023] Open
Abstract
Diabetes mellitus is still expanding globally and is epidemic in developing countries. The combat of this plague has caused enormous economic and social burdens related to a lowered quality of life in people with diabetes. Despite recent significant improvements of life expectancy in patients with diabetes, there is still a need for efforts to elucidate the complexities and mechanisms of the disease processes to overcome this difficult disorder. To this end, the use of appropriate animal models in diabetes studies is invaluable for translation to humans and for the development of effective treatment. In this review, a variety of animal models of diabetes with spontaneous onset in particular will be introduced and discussed for their implication in diabetes research.
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Affiliation(s)
- Soroku Yagihashi
- Department of Exploratory Medicine for Nature, Life and HumansToho University School of MedicineChibaJapan
- Department of PathologyHirosaki University Graduate School of MedicineHirosakiJapan
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Hong OK, Kim ES, Son JW, Kim SR, Yoo SJ, Kwon HS, Lee SS. Alcohol-induced increase in BMP levels promotes fatty liver disease in male prediabetic stage Otsuka Long-Evans Tokushima Fatty rats. J Cell Biochem 2023; 124:459-472. [PMID: 36791312 DOI: 10.1002/jcb.30385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 01/15/2023] [Accepted: 01/30/2023] [Indexed: 02/17/2023]
Abstract
Alcohol consumption exacerbates liver abnormalities in animal models, but whether it increases the severity of liver disease in early diabetic or prediabetic rats is unclear. To investigate the molecular mechanisms underlying alcohol-induced liver steatosis or hepatitis, we used a prediabetic animal model. Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Fatty (LETO) rats were pair-fed with an ethanol-containing liquid diet for 6 weeks. Compared with controls, OLETF and LETO rats displayed more pronounced liver steatosis and higher plasma levels of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SPGT), indicating liver injury. Ethanol-fed LETO (Pd-L-E) rats showed mild liver steatosis and no inflammation compared with ethanol-fed OLETF (Pd-O-E) rats. Although precursor and active SREBP-1 levels in the liver of ethanol-fed OLETF rats significantly increased compared with control diet-fed OLETF rats (Pd-O-C), those of Pd-L-E rats did not. Bone morphogenetic protein (BMP) and TGF-β1 balance in Pd-O-E rats was significantly altered because BMP signaling was upregulated by inducing BMP2, BMP4, BMP7, BMP9, Smad1, and Smad4, whereas TGF-β1, Smad3, and Erk were downregulated. Activation of TGF-β/Smad signaling inhibited BMP2 and BMP9 expression and increased epithelial-mesenchymal transition (EMT) marker levels (Hepcidin, Snail, and Twist) in the liver of LETO rats. Livers of ethanol-fed OLETF rats showed increased levels of vimentin, FSP-1, α-SMA, MMP1, MMP13, and collagen III compared with rats of other groups, whereas EMT marker levels did not change. Thus, BMP exerted anti- and/or pro-fibrotic effects in ethanol-fed rats. Therefore, BMP and TGF-β, two key members of the TGF-β superfamily, play important but diverse roles in liver steatosis in young LETO and OLETF rats.
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Affiliation(s)
- Oak-Kee Hong
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Eun Sook Kim
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jang-Won Son
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung-Rae Kim
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Soon Jib Yoo
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyuk-Sang Kwon
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seong-Su Lee
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Rashmi P, Urmila A, Likhit A, Subhash B, Shailendra G. Rodent models for diabetes. 3 Biotech 2023; 13:80. [PMID: 36778766 PMCID: PMC9908807 DOI: 10.1007/s13205-023-03488-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 01/19/2023] [Indexed: 02/11/2023] Open
Abstract
Diabetes mellitus (DM) is associated with many health complications and is potentially a morbid condition. As prevalence increases at an alarming rate around the world, research into new antidiabetic compounds with different mechanisms is the top priority. Therefore, the preclinical experimental induction of DM is imperative for advancing knowledge, understanding pathogenesis, and developing new drugs. Efforts have been made to examine recent literature on the various induction methods of Type I and Type II DM. The review summarizes the different in vivo models of DM induced by chemical, surgical, and genetic (immunological) manipulations and the use of pathogens such as viruses. For good preclinical assessment, the animal model must exhibit face, predictive, and construct validity. Among all reported models, chemically induced DM with streptozotocin was found to be the most preferred model. However, the purpose of the research and the outcomes to be achieved should be taken into account. This review was aimed at bringing together models, benefits, limitations, species, and strains. It will help the researcher to understand the pathophysiology of DM and to choose appropriate animal models.
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Affiliation(s)
- Patil Rashmi
- Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Paud Road, Erandwane, Pune, 411038 India
| | - Aswar Urmila
- Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Paud Road, Erandwane, Pune, 411038 India
| | - Akotkar Likhit
- Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Paud Road, Erandwane, Pune, 411038 India
| | - Bodhankar Subhash
- Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Paud Road, Erandwane, Pune, 411038 India
| | - Gurav Shailendra
- Department of Pharmacognosy, Goa College of Pharmacy, Goa University, Panaji, Goa India
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Dalco LJ, Dave KR. Diabetic Rodent Models for Chronic Stroke Studies. Methods Mol Biol 2023; 2616:429-439. [PMID: 36715951 DOI: 10.1007/978-1-0716-2926-0_30] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Chronic diabetes may cause secondary complications like stroke and also increase post-stroke brain damage. In stroke research, the Stroke Therapy Academic Industry Roundtable (STAIR) identified criteria to increase translational value of preclinical studies, which highlighted the importance of using animal models of comorbidities. Numerous animal models have been used to study the aggravation of ischemic brain damage in diabetics. In this chapter, we discuss rat and mouse models of streptozotocin (STZ)-induced diabetes, with an efficient method provided. We also provide an overview of spontaneously diabetic rodent models. We present different pathophysiological features of diabetes in each rodent model along with the advantages and disadvantages of each model. Utilizing these models may aid the advancement of novel treatments and therapies to lower ischemic brain damage in patients of diabetes.
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Affiliation(s)
- Lea Julie Dalco
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, Department of Neurology and Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Kunjan R Dave
- Peritz Scheinberg Cerebral Vascular Disease Research Laboratories, Department of Neurology and Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL, USA.
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Cornejo MA, Jardines E, Nishiyama A, Nakano D, Ortiz RM. Simultaneous SGLT2 inhibition and caloric restriction improves insulin resistance and kidney function in OLETF rats. Mol Cell Endocrinol 2023; 560:111811. [PMID: 36397615 DOI: 10.1016/j.mce.2022.111811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 10/21/2022] [Accepted: 10/22/2022] [Indexed: 11/08/2022]
Abstract
SGLT2 inhibitors (SGLT2i) are emerging as a novel therapy for type 2 diabetes due to their effective hypoglycemic and potential cardio- and nephroprotective effects, while caloric restriction (CR) is a common behavioral modification to improve adiposity and insulin resistance. Therefore, both interventions simultaneously may potentially further improve metabolic syndrome by enhancing carbohydrate metabolism. To test this hypothesis, cohorts of 10-week old, male Long Evans Tokushima Otsuka (LETO) and Otsuka Long Evans Tokushima Fatty (OLETF) rats were treated with SGLT2i (10 mg luseoglifozin/kg/day x 4 wks) (OLETF only) and/or 30% CR (2 wks at 12 weeks of age). CR maintained body mass in both strains while SGLT2i alone did not have any effect on body mass. Simultaneous treatments decreased SBP in OLETF vs SGLT2i alone, decreased insulin resistance index (IRI), and increased creatinine clearance vs OLETF ad lib. Conversely, CR decreased albuminuria independent of SGLT2i. In conclusion, SGLT2i treatment by itself did not elicit significant improvements in insulin resistance, kidney function or blood pressure. However, when combined with CR, these changes where more profound than with CR alone without inducing chronic hypoglycemia.
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Affiliation(s)
- Manuel A Cornejo
- Department of Molecular & Cell Biology, School of Natural Sciences, University of California, Merced, CA, USA.
| | - Eira Jardines
- Department of Molecular & Cell Biology, School of Natural Sciences, University of California, Merced, CA, USA
| | - Akira Nishiyama
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Daisuke Nakano
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Rudy M Ortiz
- Department of Molecular & Cell Biology, School of Natural Sciences, University of California, Merced, CA, USA
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12
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Gvazava IG, Karimova MV, Vasiliev AV, Vorotelyak EA. Type 2 Diabetes Mellitus: Pathogenic Features and Experimental Models in Rodents. Acta Naturae 2022; 14:57-68. [PMID: 36348712 PMCID: PMC9611859 DOI: 10.32607/actanaturae.11751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 07/19/2022] [Indexed: 11/20/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is the most common endocrine disorder (90%) in the world; it has numerous clinical, immunological, and genetic differences from type 1 diabetes mellitus. The pathogenesis of T2DM is complex and not fully clear. To date, animal models remain the main tool by which to study the pathophysiology and therapy of T2DM. Rodents are considered the best choice among animal models, because they are characterized by a small size, short induction period, easy diabetes induction, and economic efficiency. This review summarizes data on experimental models of T2DM that are currently used, evaluates their advantages and disadvantages vis-a-vis research, and describes in detail the factors that should be taken into account when using these models. Selection of a suitable model for tackling a particular issue is not always trivial; it affects study results and their interpretation.
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Affiliation(s)
- I. G. Gvazava
- Institute of Developmental Biology, Russian Academy of Sciences, Moscow, 119334 Russia
| | - M. V. Karimova
- Institute of Developmental Biology, Russian Academy of Sciences, Moscow, 119334 Russia
| | - A. V. Vasiliev
- Institute of Developmental Biology, Russian Academy of Sciences, Moscow, 119334 Russia
- Lomonosov Moscow State University, Faculty of Biology, Moscow, 119234 Russia
| | - E. A. Vorotelyak
- Institute of Developmental Biology, Russian Academy of Sciences, Moscow, 119334 Russia
- Lomonosov Moscow State University, Faculty of Biology, Moscow, 119234 Russia
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13
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Jesmin S, Shima T, Soya M, Takahashi K, Omura K, Ogura K, Koizumi H, Soya H. Long-term light and moderate exercise intervention similarly prevent both hippocampal and glycemic dysfunction in presymptomatic type 2 diabetic rats. Am J Physiol Endocrinol Metab 2022; 322:E219-E230. [PMID: 34957860 DOI: 10.1152/ajpendo.00326.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A prediabetic population has an increased risk of cognitive decline and type 2 diabetes mellitus (T2DM). This study investigated whether the progression of memory dysfunction and dysregulated brain glycogen metabolism is prevented with 4 mo of exercise intervention from the presymptomatic stage in a T2DM rat model. Memory function and biochemical and molecular profiles were assessed in the presymptomatic stage of Otsuka-Long-Evans-Tokushima fatty (OLETF) rats, a T2DM model, with Long-Evans Tokushima (LETO) rats as genetic control. These rats were subjected to light- or moderate-intensity treadmill running for 4 mo with repetition of the same experiments. Significant hippocampal-dependent memory dysfunction was observed in the presymptomatic stage of OLETF rats, accompanied by downregulated levels of hippocampal monocarboxylate transporter 2 (MCT2), a neuronal lactate-transporter, without alteration in hippocampal glycogen levels. Four months of light or moderate exercise from the presymptomatic stage of T2DM normalized glycemic parameters and hippocampal molecular normalization through MCT2, glycogen, and brain-derived neurotrophic factor (BDNF) levels with the improvement of memory dysfunction in OLETF rats. A 4-mo exercise regimen from the presymptomatic stage of T2DM at a light and moderate intensities contributed to the prevention of the development of T2DM and the progression of cognitive decline with hippocampal lactate-transport and BDNF improvement.NEW & NOTEWORTHY Type 2 diabetes mellitus is an independent risk factor for hippocampal memory dysfunction, which would progress since the prediabetic stage. We found that 4 mo of exercise both at the light and moderate intensity prevented the progression of memory dysfunction with an improvement of hippocampal MCT2 expression in presymptomatic diabetes, implying that light intensity exercise could be a therapeutic approach, and the alteration of hippocampal MCT2 would be a therapeutic target of memory dysfunction from presymptomatic diabetes.
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Affiliation(s)
- Subrina Jesmin
- Laboratory of Exercise Biochemistry and Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Japan
- Sport Neuroscience Division, Advanced Research Initiative for Human High Performance (ARIHHP), University of Tsukuba, Tsukuba, Japan
| | - Takeru Shima
- Laboratory of Exercise Biochemistry and Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Japan
- Department of Health and Physical Education, Cooperative Faculty of Education, Gunma University, Maebashi, Japan
| | - Mariko Soya
- Laboratory of Exercise Biochemistry and Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Japan
- Sport Neuroscience Division, Advanced Research Initiative for Human High Performance (ARIHHP), University of Tsukuba, Tsukuba, Japan
- Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kanako Takahashi
- Laboratory of Exercise Biochemistry and Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Japan
- Sport Neuroscience Division, Advanced Research Initiative for Human High Performance (ARIHHP), University of Tsukuba, Tsukuba, Japan
| | - Koki Omura
- Laboratory of Exercise Biochemistry and Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Japan
| | - Kasane Ogura
- Sport Neuroscience Division, Advanced Research Initiative for Human High Performance (ARIHHP), University of Tsukuba, Tsukuba, Japan
| | - Hikaru Koizumi
- Laboratory of Exercise Biochemistry and Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Japan
- Sport Neuroscience Division, Advanced Research Initiative for Human High Performance (ARIHHP), University of Tsukuba, Tsukuba, Japan
| | - Hideaki Soya
- Laboratory of Exercise Biochemistry and Neuroendocrinology, Faculty of Health and Sport Sciences, University of Tsukuba, Tsukuba, Japan
- Sport Neuroscience Division, Advanced Research Initiative for Human High Performance (ARIHHP), University of Tsukuba, Tsukuba, Japan
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14
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Enli L, Moronuki Y, Yamada T, Kose H. Examination of Niddm20 candidate genes of OLETF rats in Drosophila melanogaster using inducible GeneSwitch GAL4 system. J Genet 2022. [DOI: 10.1007/s12041-021-01356-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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15
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Godoy-Lugo JA, Thorwald MA, Hui DY, Nishiyama A, Nakano D, Soñanez-Organis JG, Ortiz RM. Chronic angiotensin receptor activation promotes hepatic triacylglycerol accumulation during an acute glucose challenge in obese-insulin-resistant OLETF rats. Endocrine 2022; 75:92-107. [PMID: 34327606 PMCID: PMC8763929 DOI: 10.1007/s12020-021-02834-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/18/2021] [Indexed: 11/01/2022]
Abstract
PURPOSE Angiotensin receptor blockers (ARBs) can ameliorate metabolic syndrome (MetS)-associated dyslipidemia, hepatic steatosis, and glucose intolerance, suggesting that angiotensin receptor (AT1) over-activation contributes to impaired lipid and glucose metabolism, which is characteristic of MetS. The aim of this study was to evaluate changes in the lipid profile and proteins of fatty acid uptake, triacylglycerol (TAG) synthesis, and β-oxidation to better understand the links between AT1 overactivation and non-alcoholic fatty liver disease (NAFLD) during MetS. METHODS Four groups of 25-week-old-rats were used: (1) untreated LETO, (2) untreated OLETF, (3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 weeks) and (4) OLETF ± ARB (MINUS; 10 mg olmesartan/kg/d × 4 weeks, then removed until dissection). To investigate the dynamic shifts in metabolism, animals were dissected after an oral glucose challenge (fasting, 3 and 6 h post-glucose). RESULTS Compared to OLETF, plasma total cholesterol and TAG remained unchanged in ARB. However, liver TAG was 55% lesser in ARB than OLETF, and remained lower throughout the challenge. Basal CD36 and ApoB were 28% and 29% lesser, respectively, in ARB than OLETF. PRDX6 abundance in ARB was 45% lesser than OLETF, and it negatively correlated with liver TAG in ARB. CONCLUSIONS Chronic blockade of AT1 protects the liver from TAG accumulation during glucose overload. This may be achieved by modulating NEFA uptake and increasing TAG export via ApoB. Our study highlights the contributions of AT1 signaling to impaired hepatic substrate metabolism and the detriments of a high-glucose load and its potential contribution to steatosis during MetS.
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Affiliation(s)
- Jose A Godoy-Lugo
- School of Natural Sciences, University of California, Merced, CA, USA.
| | - Max A Thorwald
- School of Natural Sciences, University of California, Merced, CA, USA
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA
| | - David Y Hui
- Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, OH, USA
| | - Akira Nishiyama
- Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan
| | - Daisuke Nakano
- Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan
| | - Jose G Soñanez-Organis
- Universidad de Sonora, Departamento de Ciencias Químico Biológicas y Agropecuarias, Navojoa, Sonora, Mexico
| | - Rudy M Ortiz
- School of Natural Sciences, University of California, Merced, CA, USA
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16
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Jaquenod De Giusti C, Palomeque J, Mattiazzi A. Ca 2+ mishandling and mitochondrial dysfunction: a converging road to prediabetic and diabetic cardiomyopathy. Pflugers Arch 2022; 474:33-61. [PMID: 34978597 PMCID: PMC8721633 DOI: 10.1007/s00424-021-02650-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 11/17/2021] [Accepted: 12/03/2021] [Indexed: 12/16/2022]
Abstract
Diabetic cardiomyopathy is defined as the myocardial dysfunction that suffers patients with diabetes mellitus (DM) in the absence of hypertension and structural heart diseases such as valvular or coronary artery dysfunctions. Since the impact of DM on cardiac function is rather silent and slow, early stages of diabetic cardiomyopathy, known as prediabetes, are poorly recognized, and, on many occasions, cardiac illness is diagnosed only after a severe degree of dysfunction was reached. Therefore, exploration and recognition of the initial pathophysiological mechanisms that lead to cardiac dysfunction in diabetic cardiomyopathy are of vital importance for an on-time diagnosis and treatment of the malady. Among the complex and intricate mechanisms involved in diabetic cardiomyopathy, Ca2+ mishandling and mitochondrial dysfunction have been described as pivotal early processes. In the present review, we will focus on these two processes and the molecular pathway that relates these two alterations to the earlier stages and the development of diabetic cardiomyopathy.
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Affiliation(s)
- Carolina Jaquenod De Giusti
- Centro de Investigaciones Cardiovasculares, CCT-La Plata-CONICET, Facultad de Cs. Médicas, UNLP, La Plata, Argentina
| | - Julieta Palomeque
- Centro de Investigaciones Cardiovasculares, CCT-La Plata-CONICET, Facultad de Cs. Médicas, UNLP, La Plata, Argentina
| | - Alicia Mattiazzi
- Centro de Investigaciones Cardiovasculares, CCT-La Plata-CONICET, Facultad de Cs. Médicas, UNLP, La Plata, Argentina.
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17
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Madhu SV, Mishra BK, Mannar V, Aslam M, Banerjee B, Agrawal V. TCF7L2 gene associated postprandial triglyceride dysmetabolism- a novel mechanism for diabetes risk among Asian Indians. Front Endocrinol (Lausanne) 2022; 13:973718. [PMID: 36263318 PMCID: PMC9573951 DOI: 10.3389/fendo.2022.973718] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 08/31/2022] [Indexed: 11/25/2022] Open
Abstract
AIM TCF7L2 gene is believed to increase the risk of T2DM by its effects on insulin secretion. However, the exact mechanism of this enhanced risk is not clearly known. While TCF7L2 gene has been shown to affect lipid metabolism, these effects have remained largely unexplored in the context of diabetes risk. METHODS Postprandial lipid responses to a standardized fat challenge test were performed in 620 Asian Indian subjects (310 with NGT and 310 with T2DM/prediabetes) and compared between the risk and wild genotypes of the rs7903146 TCF7L2 gene. In 30 subjects scheduled to undergo abdominal surgery (10 each with NGT, Prediabetes and T2DM), adipocyte TCF7L2 gene expression was also performed by real time qPCR and confirmed by protein expression in western blot. RESULTS T allele of rs7903146 TCF7L2 gene was confirmed as the risk allele for T2DM (OR=1.8(1.2-2.74), p=0.005). TT+CT genotypes of rs7903146 TCF7L2 gene showed significantly higher 4hrTg (p<0.01), TgAUC (p<0.01), peakTg (p<0.01) as well as higher postprandial plasma glucose (p=.006) levels and HOMA-IR (p=0.03) and significantly lower adiponectin levels (p=0.02) as compared to CC genotype. The expression of TCF7L2 gene in VAT was 11-fold higher in prediabetes group as compared to NGT (P<0.01) and 5.7-fold higher in T2DM group as compared to NGT group(P=0.003) and was significantly associated with PPTg and glucose levels. CONCLUSION There is significant PPTg dysmetabolism associated with the risk allele of rs7903146 polymorphism as well as adipocyte expression of TCF7L2 gene. Significant upregulation of TCF7L2 gene expression in VAT that correlates with PPTg and glycaemia is also seen in Asian Indians with glucose intolerance. Modulation of PPTg metabolism by TCF7L2 gene and the resultant PPHTg may be a novel mechanism that contributes to its diabetes risk in them.
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18
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Yang X, Jiang W, Cheng J, Hao J, Han F, Zhang Y, Xu J, Shan C, Wang J, Yang Y, Yang J, Chang B. Reductions in Intestinal Taurine-Conjugated Bile Acids and Short-Chain Fatty Acid-Producing Bacteria Might be Novel Mechanisms of Type 2 Diabetes Mellitus in Otsuka Long-Evans Tokushima Fatty Rats. Exp Clin Endocrinol Diabetes 2021; 130:237-247. [PMID: 34929746 DOI: 10.1055/a-1643-1689] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
BACKGROUND The pathogenesis of spontaneously diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, among the best models for human type 2 diabetes mellitus (T2DM), remains poorly defined. Therefore, we investigated the dynamic changes in taurine-conjugated bile acids (T-BAs) and intestinal microbiota during T2DM development in OLETF rats. METHODS OLETF rats and corresponding diabetes-resistant Long Evans Tokushima Otsuka (LETO) rats were fed a normal baseline diet. The progress of T2DM was divided into four phases, including normal glycemia-normal insulinemia (baseline), normal glycemia-hyperinsulinemia, impaired glucose tolerance, and DM. Body weight, liver function, blood lipids, fasting plasma glucose, fasting plasma insulin, fasting plasma glucagon-like peptide (GLP)-1 and GLP-2, serum and fecal T-BAs, and gut microbiota were analyzed during the entire course of T2DM development. RESULTS There were reductions in fecal T-BAs and short-chain fatty acids (SCFAs)-producing bacteria including Phascolarctobacterium and Lactobacillus in OLETF rats compared with those in LETO rats at baseline, and low levels of fecal T-BAs and SCFAs-producing bacteria were maintained throughout the whole course of the development of T2DM among OLETF rats compared with those in corresponding age-matched LETO rats. Fecal taurine-conjugated chenodeoxycholic acid correlated positively with Phascolarctobacterium. Fecal taurine-conjugated deoxycholic acid correlated positively with Lactobacillus and fasting plasma GLP-1 and inversely with fasting plasma glucose. CONCLUSION The fecal BAs profiles and microbiota structure among OLETF rats were different from those of LETO rats during the entire course of T2DM development, indicating that reductions in intestinal T-BAs and specific SCFA-producing bacteria may be potential mechanisms of T2DM in OLETF rats.
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Affiliation(s)
- Xiaoyun Yang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.,Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China
| | - Wenhui Jiang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.,Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine of Hebei Province, Hebei Province, China
| | - Jingli Cheng
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Jintong Hao
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Fei Han
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Yi Zhang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Jie Xu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Chunyan Shan
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Jingyu Wang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Yanhui Yang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Juhong Yang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Baocheng Chang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
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19
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Rodriguez R, Lee AY, Godoy-Lugo JA, Martinez B, Ohsaki H, Nakano D, Parkes DG, Nishiyama A, Vázquez-Medina JP, Ortiz RM. Chronic AT 1 blockade improves hyperglycemia by decreasing adipocyte inflammation and decreasing hepatic PCK1 and G6PC1 expression in obese rats. Am J Physiol Endocrinol Metab 2021; 321:E714-E727. [PMID: 34658252 PMCID: PMC8782654 DOI: 10.1152/ajpendo.00584.2020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 10/04/2021] [Accepted: 10/07/2021] [Indexed: 11/22/2022]
Abstract
Inappropriate activation of the renin-angiotensin system decreases glucose uptake in peripheral tissues. Chronic angiotensin receptor type 1 (AT1) blockade (ARB) increases glucose uptake in skeletal muscle and decreases the abundance of large adipocytes and macrophage infiltration in adipose. However, the contributions of each tissue to the improvement in hyperglycemia in response to AT1 blockade are not known. Therefore, we determined the static and dynamic responses of soleus muscle, liver, and adipose to an acute glucose challenge following the chronic blockade of AT1. We measured adipocyte morphology along with TNF-α expression, F4/80- and CD11c-positive cells in adipose and measured insulin receptor (IR) phosphorylation and AKT phosphorylation in soleus muscle, liver, and retroperitoneal fat before (T0), 60 (T60) and 120 (T120) min after an acute glucose challenge in the following groups of male rats: 1) Long-Evans Tokushima Otsuka (LETO; lean control; n = 5/time point), 2) obese Otsuka Long Evans Tokushima Fatty (OLETF; n = 7 or 8/time point), and 3) OLETF + ARB (ARB; 10 mg olmesartan/kg/day; n = 7 or 8/time point). AT1 blockade decreased adipocyte TNF-α expression and F4/80- and CD11c-positive cells. In retroperitoneal fat at T60, IR phosphorylation was 155% greater in ARB than in OLETF. Furthermore, in retroperitoneal fat AT1 blockade increased glucose transporter-4 (GLUT4) protein expression in ARB compared with OLETF. IR phosphorylation and AKT phosphorylation were not altered in the liver of OLETF, but AT1 blockade decreased hepatic Pck1 and G6pc1 mRNA expressions. Collectively, these results suggest that chronic AT1 blockade improves obesity-associated hyperglycemia in OLETF rats by improving adipocyte function and by decreasing hepatic glucose production via gluconeogenesis.NEW & NOTEWORTHY Inappropriate activation of the renin-angiotensin system increases adipocyte inflammation contributing to the impairment in adipocyte function and increases hepatic Pck1 and G6pc1 mRNA expression in response to a glucose challenge. Ultimately, these effects may contribute to the development of glucose intolerance.
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Affiliation(s)
- Ruben Rodriguez
- Department of Molecular & Cellular Biology, University of California, Merced, California
| | - Andrew Y Lee
- Department of Molecular & Cellular Biology, University of California, Merced, California
| | - Jose A Godoy-Lugo
- Department of Molecular & Cellular Biology, University of California, Merced, California
| | - Bridget Martinez
- Department of Molecular & Cellular Biology, University of California, Merced, California
| | - Hiroyuki Ohsaki
- Department of Medical Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Daisuke Nakano
- Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan
| | | | - Akira Nishiyama
- Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan
| | | | - Rudy M Ortiz
- Department of Molecular & Cellular Biology, University of California, Merced, California
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20
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Liu XY, Zhang N, Zhang SX, Xu P. Potential new therapeutic target for Alzheimer's disease: Glucagon-like peptide-1. Eur J Neurosci 2021; 54:7749-7769. [PMID: 34676939 DOI: 10.1111/ejn.15502] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 10/06/2021] [Accepted: 10/07/2021] [Indexed: 12/13/2022]
Abstract
Increasing evidence shows a close relationship between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Recently, glucagon-like peptide-1 (GLP-1), a gut incretin hormone, has become a well-established treatment for T2DM and is likely to be involved in treating cognitive impairment. In this mini review, the similarities between AD and T2DM are summarised with the main focus on GLP-1-based therapeutics in AD.
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Affiliation(s)
- Xiao-Yu Liu
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Ni Zhang
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Sheng-Xiao Zhang
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China.,Key laboratory of Cellular Physiology, Shanxi Medical University, Ministry of Education, Shanxi, China
| | - Ping Xu
- Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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21
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Yang S, Liu Y, Huang S, Jin F, Qi F. Sevoflurane and isoflurane inhibit KCl-induced, Rho kinase-mediated, and PI3K-participated vasoconstriction in aged diabetic rat aortas. BMC Anesthesiol 2021; 21:212. [PMID: 34470604 PMCID: PMC8408970 DOI: 10.1186/s12871-021-01425-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 08/08/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The mechanism of volatile anesthetics on vascular smooth muscle (VSM) contraction in the setting of diabetes mellitus (DM) remains unclear. The current study was designed to determine the effects of sevoflurane (SEVO) and isoflurane (ISO) on phosphoinositide 3-kinase (PI3K) and Rho kinase (ROCK) mediated KCl-induced vasoconstriction in aged type 2 diabetic rats. METHODS KCl-induced (60 mM) contractions were examined in endothelium-denuded aortic rings from aged T2DM Otsuka Long-Evans Tokushima Fatty (OLETF) rats (65-70 weeks old), control age-matched nondiabetic Long-Evans Tokushima Otsuka (LETO) rats and young Wistar rats (6-8 weeks old). The effects of SEVO or ISO (1-3 minimum alveolar concentration, MAC) on KCl-induced vasoconstriction, as well as those of LY294002 (PI3K inhibitor) and Y27632 (ROCK inhibitor) were measured in aortic rings from the three groups using an isometric force transducer. RESULTS KCl induced rapid and continuous contraction of aortic smooth muscle in the three groups, and the contraction was more obvious in OLETF rats. SEVO and ISO inhibited KCl-induced vasoconstriction in a concentration-dependent manner and were suppressed by LY294002 (10 µM) and Y27632 (1 µM). SEVO had a stronger inhibitory effect on the aortas of young Wistar rats than ISO, especially at 2 MAC and 3 MAC (P < 0.05). In aged rats, the inhibitory effect of ISO was stronger than that of SEVO, especially OLETF rats. There was no significant difference in the effects of different concentrations of ISO on arterial contraction among the three groups (P > 0.05). The effects of 1 MAC SEVO on Wistar rats and 3 MAC SEVO on OLETF rats, however, were noticeably and significantly different (P < 0.05). Compared with the control condition, LY294002 and Y27632 had the most noticeable effect on the KCl-induced contraction of aortic rings in OLETF rats (P < 0.01). CONCLUSION SEVO (3 MAC), ISO (1, 2, 3 MAC), LY294002 and Y27632 have more significant inhibitory effect on the contraction of vascular smooth muscle in aged T2MD rats. The mechanism of SEVO and ISO in vascular tension in T2DM is partly due to changes in PI3K and/or Rho kinase activity.
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Affiliation(s)
- Shaozhong Yang
- Department of Anesthesiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107, Wenhua West Road, Jinan, 250012, Shandong, China
| | - Yu Liu
- Department of Anesthesiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107, Wenhua West Road, Jinan, 250012, Shandong, China
| | - Shanshan Huang
- Department of Anesthesiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107, Wenhua West Road, Jinan, 250012, Shandong, China
| | - Feihong Jin
- Department of Anesthesiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107, Wenhua West Road, Jinan, 250012, Shandong, China
| | - Feng Qi
- Department of Anesthesiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107, Wenhua West Road, Jinan, 250012, Shandong, China.
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Barakat M, DiPietro LA, Chen L. Limited Treatment Options for Diabetic Wounds: Barriers to Clinical Translation Despite Therapeutic Success in Murine Models. Adv Wound Care (New Rochelle) 2021; 10:436-460. [PMID: 33050829 PMCID: PMC8236303 DOI: 10.1089/wound.2020.1254] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 10/12/2020] [Indexed: 12/15/2022] Open
Abstract
Significance: Millions of people worldwide suffer from diabetes mellitus and its complications, including chronic diabetic wounds. To date, there are few widely successful clinical therapies specific to diabetic wounds beyond general wound care, despite the vast number of scientific discoveries in the pathogenesis of defective healing in diabetes. Recent Advances: In recent years, murine animal models of diabetes have enabled the investigation of many possible therapeutics for diabetic wound care. These include specific cell types, growth factors, cytokines, peptides, small molecules, plant extracts, microRNAs, extracellular vesicles, novel wound dressings, mechanical interventions, bioengineered materials, and more. Critical Issues: Despite many research discoveries, few have been translated from their success in murine models to clinical use in humans. This massive gap between bench discovery and bedside application begs the simple and critical question: what is still missing? The complexity and multiplicity of the diabetic wound makes it an immensely challenging therapeutic target, and this lopsided progress highlights the need for new methods to overcome the bench-to-bedside barrier. How can laboratory discoveries in animal models be effectively translated to novel clinical therapies for human patients? Future Directions: As research continues to decipher deficient healing in diabetes, new approaches and considerations are required to ensure that these discoveries can become translational, clinically usable therapies. Clinical progress requires the development of new, more accurate models of the human disease state, multifaceted investigations that address multiple critical components in wound repair, and more innovative research strategies that harness both the existing knowledge and the potential of new advances across disciplines.
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Affiliation(s)
- May Barakat
- Center for Wound Repair and Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Luisa A. DiPietro
- Center for Wound Repair and Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Lin Chen
- Center for Wound Repair and Tissue Regeneration, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, USA
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Ueno T, Tanaka N, Imoto H, Maekawa M, Kohyama A, Watanabe K, Motoi F, Kamei T, Unno M, Naitoh T. Mechanism of Bile Acid Reabsorption in the Biliopancreatic Limb After Duodenal-Jejunal Bypass in Rats. Obes Surg 2021; 30:2528-2537. [PMID: 32291708 DOI: 10.1007/s11695-020-04506-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Bile acids (BAs) are important in the metabolic effects of bariatric surgery. Most BAs are reabsorbed in the ileum and recycled back to the liver. We have reported that this enterohepatic circulation was shortened by duodenal-jejunal bypass (DJB), and the biliopancreatic (BP)-limb plays an important role in reabsorption of BAs. However, the mechanism of BA reabsorption in BP-limb remains uncertain. We aimed to investigate the mechanisms of BA reabsorption after DJB, especially focusing on carrier-mediated transport of BAs and the impact of the presence or absence of lipids on BA reabsorption. METHODS Otsuka-Long-Evans-Tokushima fatty rats or Sprague-Dawley rats were assigned to a control group and DJB group. BA levels in the divided small intestine were quantified with liquid chromatography-mass spectrometry. Labeled BA was injected and perfused with BA transporter inhibitors or mixture of lipids in the isolated BP-limb, and bile was sampled and analyzed. RESULTS Conjugated BA levels in the BP-limb were significantly higher than that of the control group. BA absorption tended to decrease by the apical sodium-dependent BA transporter inhibitor and was significantly decreased by the organic anion-transporting peptide (OATP) inhibitor. BA absorption tended to increase in the absence of lipid solutions compared with that in the presence of lipid solutions. CONCLUSION We attributed the increased BA reabsorption in the BP-limb to lack of food in the BP-limb, which contains concentrated BAs and no lipids. OATP played an important role in BA reabsorption in the BP-limb. Therefore, BAs would be reabsorbed in different manners after DJB.
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Affiliation(s)
- Tomotaka Ueno
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Naoki Tanaka
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.
| | - Hirofumi Imoto
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Masamitsu Maekawa
- Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Atsushi Kohyama
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Kazuhiro Watanabe
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Fuyuhiko Motoi
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
| | - Takeshi Naitoh
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1, Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan
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Sexual hormones and diabetes: The impact of estradiol in pancreatic β cell. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021. [PMID: 33832654 DOI: 10.1016/bs.ircmb.2021.02.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/13/2023]
Abstract
Diabetes is one of the most prevalent metabolic diseases and its incidence is increasing throughout the world. Data from World Health Organization (WHO) point-out that diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation and estimated 1.6 million deaths were directly caused by it in 2016. Population studies show that the incidence of this disease increases in women after menopause, when the production of estrogen is decreasing in them. Knowing the impact that estrogenic signaling has on insulin-secreting β cells is key to prevention and design of new therapeutic targets. This chapter explores the role of estrogen and their receptors in the regulation of insulin secretion and biosynthesis, proliferation, regeneration and survival in pancreatic β cells. In addition, delves into the genetic animal models developed and its application for the specific study of the different estrogen signaling pathways. Finally, discusses the impact of menopause and hormone replacement therapy on pancreatic β cell function.
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Ishiyama S, Kimura M, Nakagawa T, Fujimoto Y, Uchimura K, Kishigami S, Mochizuki K. Development of the Diabetic Kidney Disease Mouse Model Culturing Embryos in α-Minimum Essential Medium In Vitro, and Feeding Barley Diet Attenuated the Pathology. Front Endocrinol (Lausanne) 2021; 12:746838. [PMID: 34867790 PMCID: PMC8634848 DOI: 10.3389/fendo.2021.746838] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 10/07/2021] [Indexed: 01/17/2023] Open
Abstract
Diabetic kidney disease (DKD) is a critical complication associated with diabetes; however, there are only a few animal models that can be used to explore its pathogenesis. In the present study, we established a mouse model of DKD using a technique based on the Developmental Origins of Health and Disease theory, i.e., by manipulating the embryonic environment, and investigated whether a dietary intervention could ameliorate the model's pathology. Two-cell embryos were cultured in vitro in α-minimum essential medium (MEM; MEM mice) or in standard potassium simplex-optimized medium (KSOM) as controls (KSOM mice) for 48 h, and the embryos were reintroduced into the mothers. The MEM and KSOM mice born were fed a high-fat, high-sugar diet for 58 days after they were 8 weeks old. Subsequently, half of the MEM mice and all KSOM mice were fed a diet containing rice powder (control diet), and the remaining MEM mice were fed a diet containing barley powder (barley diet) for 10 weeks. Glomerulosclerosis and pancreatic exhaustion were observed in MEM mice, but not in control KSOM mice. Renal arteriolar changes, including intimal thickening and increase in the rate of hyalinosis, were more pronounced in MEM mice fed a control diet than in KSOM mice. Immunostaining showed the higher expression of transforming growth factor beta (TGFB) in the proximal/distal renal tubules of MEM mice fed a control diet than in those of KSOM mice. Pathologies, such as glomerulosclerosis, renal arteriolar changes, and higher TGFB expression, were ameliorated by barley diet intake in MEM mice. These findings suggested that the MEM mouse is an effective DKD animal model that shows glomerulosclerosis and renal arteriolar changes, and barley intake can improve these pathologies in MEM mice.
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Affiliation(s)
- Shiori Ishiyama
- Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi, Kofu, Japan
| | - Mayu Kimura
- Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi, Kofu, Japan
| | | | - Yuka Fujimoto
- Advanced Biotechnology Center, University of Yamanashi, Kofu, Japan
| | - Kohei Uchimura
- Division of Nephrology, Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Kofu, Japan
| | - Satoshi Kishigami
- Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi, Kofu, Japan
- Faculty of Life and Environmental Sciences, University of Yamanashi, Kofu, Japan
| | - Kazuki Mochizuki
- Department of Integrated Applied Life Science, Integrated Graduate School of Medicine, Engineering, and Agricultural Sciences, University of Yamanashi, Kofu, Japan
- Faculty of Life and Environmental Sciences, University of Yamanashi, Kofu, Japan
- *Correspondence: Kazuki Mochizuki,
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Bioactive Agent Discovery from the Natural Compounds for the Treatment of Type 2 Diabetes Rat Model. Molecules 2020; 25:molecules25235713. [PMID: 33287318 PMCID: PMC7731446 DOI: 10.3390/molecules25235713] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/27/2020] [Accepted: 11/27/2020] [Indexed: 12/16/2022] Open
Abstract
Diabetes mellitus is a well-known chronic metabolic disease that poses a long-term threat to human health and is characterized by a relative or absolute lack of insulin, resulting in hyperglycemia. Type 2 diabetes mellitus (T2DM) typically affects many metabolic pathways, resulting in β-cell dysfunction, insulin resistance, abnormal blood glucose levels, inflammatory processes, excessive oxidative reactions, and impaired lipid metabolism. It also leads to diabetes-related complications in many organ systems. Antidiabetic drugs have been approved for the treatment of hyperglycemia in T2DM; these are beneficial for glucose metabolism and promote weight loss, but have the risk of side effects, such as nausea or an upset stomach. A wide range of active components, derived from medicinal plants, such as alkaloids, flavonoids, polyphenol, quinones, and terpenoids may act as alternative sources of antidiabetic agents. They are usually attributed to improvements in pancreatic function by increasing insulin secretions or by reducing the intestinal absorption of glucose. Ease of availability, low cost, least undesirable side effects, and powerful pharmacological actions make plant-based preparations the key player of all available treatments. Based on the study of therapeutic reagents in the pathogenesis of humans, we use the appropriate animal models of T2DM to evaluate medicinal plant treatments. Many of the rat models have characteristics similar to those in humans and have the advantages of ease of genetic manipulation, a short breeding span, and access to physiological and invasive testing. In this review, we summarize the pathophysiological status of T2DM rat models and focus on several bioactive compounds from herbal medicine with different functional groups that exhibit therapeutic potential in the T2DM rat models, in turn, may guide future approach in treating diabetes with natural drugs.
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27
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Mahmoud M, Kokozidou M, Auffarth A, Schulze-Tanzil G. The Relationship between Diabetes Mellitus Type II and Intervertebral Disc Degeneration in Diabetic Rodent Models: A Systematic and Comprehensive Review. Cells 2020; 9:cells9102208. [PMID: 33003542 PMCID: PMC7600368 DOI: 10.3390/cells9102208] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/22/2020] [Accepted: 09/23/2020] [Indexed: 12/13/2022] Open
Abstract
The number of diabetic patients grows constantly worldwide. Many patients suffer simultaneously from diabetes mellitus type 2 (T2DM) and intervertebral disc disease (IVDD), suggesting a strong link between T2DM and IVDD. T2DM rodent models provide versatile tools to study this interrelation. We hypothesized that the previously achieved studies in rodents approved it. Performing a search in the publicly available electronic databases according to our inclusion (e.g., experimental study with clearly outlined methods investigating IVDD in diabetic rodent models) and exclusion (e.g., non-experimental) criteria, we included 23 studies from 1992 to 2020 analyzing different aspects of IVDD in diabetic rodents, such as on pathogenesis (e.g., effects of hyperglycemia on IVD cells, sirtuin (SIRT)1/p53 axis in the interrelation between T2DM and IVDD), risk factors (e.g., high content of advanced glycation end-products (AGEs) in modern diets), therapeutical approaches (e.g., insulin-like growth factor (IGF-I)), and prophylaxis. Regarding their quality, 12 studies were classified as high, six as moderate, and five as low. One strong, 18 moderate, and three mild evidences of the link between DM and IVDD in rodents were found, while only one study has not approved this link. We concluded that T2DM has a devastating effect on IVD, particularly in advanced cases, which needs to be further evaluated.
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Affiliation(s)
- Mohamed Mahmoud
- Department of Anatomy Paracelsus Medical University, Nuremberg and Salzburg, 90419 Nuremberg, Germany; (M.M.); (M.K.)
| | - Maria Kokozidou
- Department of Anatomy Paracelsus Medical University, Nuremberg and Salzburg, 90419 Nuremberg, Germany; (M.M.); (M.K.)
| | - Alexander Auffarth
- Department of Orthopedics and Traumatology, Paracelsus Medical University, 5020 Salzburg, Austria;
| | - Gundula Schulze-Tanzil
- Department of Anatomy Paracelsus Medical University, Nuremberg and Salzburg, 90419 Nuremberg, Germany; (M.M.); (M.K.)
- Correspondence: ; Tel.: +49-(0)-911-398-6772
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28
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1-Kestose supplementation mitigates the progressive deterioration of glucose metabolism in type 2 diabetes OLETF rats. Sci Rep 2020; 10:15674. [PMID: 32973311 PMCID: PMC7515885 DOI: 10.1038/s41598-020-72773-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 09/02/2020] [Indexed: 02/07/2023] Open
Abstract
The fructooligosaccharide 1-kestose cannot be hydrolyzed by gastrointestinal enzymes, and is instead fermented by the gut microbiota. Previous studies suggest that 1-kestose promotes increases in butyrate concentrations in vitro and in the ceca of rats. Low levels of butyrate-producing microbiota are frequently observed in the gut of patients and experimental animals with type 2 diabetes (T2D). However, little is known about the role of 1-kestose in increasing the butyrate-producing microbiota and improving the metabolic conditions in type 2 diabetic animals. Here, we demonstrate that supplementation with 1-kestose suppressed the development of diabetes in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, possibly through improved glucose tolerance. We showed that the cecal contents of rats fed 1-kestose were high in butyrate and harbored a higher proportion of the butyrate-producing genus Anaerostipes compared to rats fed a control diet. These findings illustrate how 1-kestose modifications to the gut microbiota impact glucose metabolism of T2D, and provide a potential preventative strategy to control glucose metabolism associated with dysregulated insulin secretion.
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29
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De Paoli M, Werstuck GH. Role of Estrogen in Type 1 and Type 2 Diabetes Mellitus: A Review of Clinical and Preclinical Data. Can J Diabetes 2020; 44:448-452. [DOI: 10.1016/j.jcjd.2020.01.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/17/2019] [Accepted: 01/06/2020] [Indexed: 02/06/2023]
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30
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Exercise and Curcumin in Combination Improves Cognitive Function and Attenuates ER Stress in Diabetic Rats. Nutrients 2020; 12:nu12051309. [PMID: 32375323 PMCID: PMC7284733 DOI: 10.3390/nu12051309] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 04/27/2020] [Accepted: 04/30/2020] [Indexed: 12/13/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disease associated with chronic low-grade inflammation that is mainly associated with lifestyles. Exercise and healthy diet are known to be beneficial for adults with T2DM in terms of maintaining blood glucose control and overall health. We investigated whether a combination of exercise and curcumin supplementation ameliorates diabetes-related cognitive distress by regulating inflammatory response and endoplasmic reticulum (ER) stress. This study was performed using male Otsuka Long-Evans Tokushima Fatty (OLETF) rats (a spontaneous diabetes Type 2 model) and Long-Evans Tokushima Otsuka (LETO) rats (LETO controls) by providing them with exercise alone or exercise and curcumin in combination. OLETF rats were fed either a diet of chow (as OLETF controls) or a diet of chow containing curcumin (5 g/kg diet) for five weeks. OLETF rats exercised with curcumin supplementation exhibited weight loss and improved glucose homeostasis and lipid profiles as compared with OLETF controls or exercised OLETF rats. Next, we examined cognitive functions using a Morris water maze test. Exercise plus curcumin improved escape latency and memory retention compared to OLETF controls. Furthermore, OLETF rats exercised and fed curcumin had lower IL6, TNFα, and IL10 levels (indicators of inflammatory response) and lower levels of ER stress markers (BiP and CHOP) in the intestine than OLETF controls. These observations suggest exercise plus curcumin may offer a means of treating diabetes-related cognitive dysfunction.
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31
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Sato T, Mito K, Ishii H. Relationship between impaired parasympathetic vasodilation and hyposalivation in parotid glands associated with type 2 diabetes mellitus. Am J Physiol Regul Integr Comp Physiol 2020; 318:R940-R949. [PMID: 32209022 DOI: 10.1152/ajpregu.00016.2019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We examined the relationship between hemodynamics in the three major salivary glands and salivary secretion in urethane-anesthetized and sympathectomized type 2 diabetic and nondiabetic rats via laser speckle imaging and by collecting the saliva. Lingual nerve stimulation elicited rapid increases in glandular blood flow and induced salivary secretion from the three glands in both diabetic and nondiabetic rats. In the parotid gland, the magnitude of blood flow increase and salivary secretion was significantly lower in the diabetic rats when compared with the nondiabetic rats; however, this was not observed in the other glands. Although the intravenous administration of acetylcholine increased blood flow in the parotid gland in a dose-dependent manner, the response was significantly lower in the diabetic rats when compared with the nondiabetic rats. Similarly, mRNA expression levels of M1 and M3 muscarinic acetylcholine receptors in the parotid gland were relatively lower in the diabetic rats compared with the nondiabetic rats. Our results indicate that type 2 diabetes impairs parasympathetic vasodilation and salivary secretion in the parotid gland and suggest that disturbances in the cholinergic vasodilator pathway may contribute to the underlying mechanisms involved in the disruption of parasympathetic nerve-mediated glandular vasodilation.
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Affiliation(s)
- Toshiya Sato
- Division of Physiology, Department of Oral Biology, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan
| | - Kohei Mito
- Division of Physiology, Department of Oral Biology, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan
| | - Hisayoshi Ishii
- Division of Physiology, Department of Oral Biology, School of Dentistry, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, Japan
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32
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Lorberbaum DS, Docherty FM, Sussel L. Animal Models of Pancreas Development, Developmental Disorders, and Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1236:65-85. [PMID: 32304069 DOI: 10.1007/978-981-15-2389-2_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The pancreas is a glandular organ responsible for diverse homeostatic functions, including hormone production from the endocrine islet cells to regulate blood sugar levels and enzyme secretion from the exocrine acinar cells to facilitate food digestion. These pancreatic functions are essential for life; therefore, preserving pancreatic function is of utmost importance. Pancreas dysfunction can arise either from developmental disorders or adult onset disease, both of which are caused by defects in shared molecular pathways. In this chapter, we discuss what is known about the molecular mechanisms controlling pancreas development, how disruption of these mechanisms can lead to developmental defects and disease, and how essential pancreas functions can be modeled using human pluripotent stem cells. At the core of understanding of these molecular processes are animal model studies that continue to be essential for elucidating the mechanisms underlying human pancreatic functions and diseases.
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Affiliation(s)
- David S Lorberbaum
- Barbara Davis Center, University of Colorado Anschutz Medical Center, Aurora, CO, USA
| | - Fiona M Docherty
- Barbara Davis Center, University of Colorado Anschutz Medical Center, Aurora, CO, USA
| | - Lori Sussel
- Barbara Davis Center, University of Colorado Anschutz Medical Center, Aurora, CO, USA.
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Khatun MA, Sato S, Konishi T. Obesity preventive function of novel edible mushroom, Basidiomycetes-X (Echigoshirayukidake): Manipulations of insulin resistance and lipid metabolism. J Tradit Complement Med 2020; 10:245-251. [PMID: 32670819 PMCID: PMC7340980 DOI: 10.1016/j.jtcme.2020.03.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 03/09/2020] [Accepted: 03/18/2020] [Indexed: 01/04/2023] Open
Abstract
Echigoshirayukidake is an edible mushroom found in Uonuma, Japan in 1994. It was assigned to a new species of Basidiomycetes (BDM-X) but is uniquely defect of forming bashidium. The high antioxidant activity and β-glucan content of BDM-X suggest possible functions preventing type 2 diabetes. In the present study, anti-obesity and insulin resistance preventive functions of BDM-X were examined using genetically defined obese model rat, OLETF (Otsuka Long Evans Tokushima Fatty) by feeding regular diet with and without supplementation of 5% dried BDM-X powder (BDMP) for 15 weeks. BDMP supplementation to the diet significantly (p < 0.01) suppressed the body weight gain and also visceral fat accumulation during the feeding period compared to control diet. Simultaneously, the insulin resistance and the plasma levels of adiponectin and triglycerides were significantly (p = 0.003) ameliorated in the BDMP supplemented diet group. A statistical multivariate analysis showed the weight of three types of adipose tissue (epididymal, retroperirenal, and mesenteric fat) positively correlated with HOMA-IR (Homeostasis Model Assessment of Insulin Resistance), and negatively correlated with plasma adiponectin. These results indicate BDM-X is a new resource applicable to the functional foods or the complementary biomedicines to prevent metabolic syndromes leading to type 2 diabetes.
A new mushroom, Echigoshirayukidake (BDM-X), ameliorates postprandial sugar and insulin spike enhancing insulin sensitivity. BDM-X prevented body weight gain, hyperlipidemia, NEFA, and visceral fat deposition. HOMA-IR was improved by BDM-X. Anti-metabolic syndrome effect of BDM-X could be related to increase of adiponectin level.
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Affiliation(s)
- Mst Afifa Khatun
- Faculty of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata, 956-8603, Japan.,Food Safety and Quality Analysis Division, Institute of Food and Radiation Biology, Atomic Energy Research Establishment, Savar, Dhaka, 1000, Bangladesh
| | - Shinji Sato
- Faculty of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata, 956-8603, Japan
| | - Tetsuya Konishi
- Faculty of Applied Life Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Akiha-ku, Niigata, 956-8603, Japan.,Office HALD Food Function Research, Yuzawa, Minami-Uonuma City, Niigata, 949-6103, Japan
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Effect of the Sodium-Glucose Cotransporter 2 Inhibitor, Dapagliflozin, on Genitourinary Infection in an Animal Model of Type 2 Diabetes. Int Neurourol J 2020; 24:21-28. [PMID: 32252183 PMCID: PMC7136444 DOI: 10.5213/inj.1938220.110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 02/11/2020] [Indexed: 01/11/2023] Open
Abstract
Purpose To investigate the effect of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, on inflammatory cytokines of urogenital tissue in a rat model of type 2 diabetes (T2DM) to infer pharmaceutical influence of dapagliflozin on genitourinary infection or inflammation. Methods Study animals were divided into the following 4 groups of 10 animals each: (1) the Otsuka Long-Evans Tokushima Fatty (OLETF)-DA group treated with dapagliflozin at 1.0 mg/kg/day, (2) the OLETF-VO group treated with voglibose at 0.6 mg/kg/day, (3) the control group (OLETF-CO) given water, and (4) the Long-Evans Tokushima Otsuka (LETO) rats were included as nondiabetic control group. Changes in blood glucose, 24-hour urine volume, and urine glucose were measured. The interleukin-1β (IL-1β) and interleukin-18 (IL-18) levels in the bladder and the urethra were quantified, respectively. Results The urine glucose level and the 24-hour urine volume at 12 weeks of treatment were significantly higher in the OLETF-DA group than that in any other group (P<0.05). The cytokine analysis of the bladder and urethra showed higher IL-18 and IL-1β in the OLETF-DA and the OLETF-CO groups than that in the OLETF-VO and LETO groups (P<0.05). The cytokine levels did not differ between the OLETF-DA and the OLETF-CO groups, and the level of IL-18 in the OLETF-DA group was higher in the urethra than in the bladder. Conclusions This study revealed that dapagliflozin increased the urine glucose concentration, resulting in an inflammatory response remain in the urogenital tract as the untreated diabetic rats. Therefore, when treating patients with T2DM with dapagliflozin, careful attention should be paid to genitourinary infection or inflammation.
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Yang Y, Kim J, Park H, Lee E, Yoon K. Pancreatic stellate cells in the islets as a novel target to preserve the pancreatic β-cell mass and function. J Diabetes Investig 2020; 11:268-280. [PMID: 31872946 PMCID: PMC7078117 DOI: 10.1111/jdi.13202] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 12/02/2019] [Accepted: 12/06/2019] [Indexed: 12/17/2022] Open
Abstract
There are numerous lines of clinical evidence that inhibition of the renin-angiotensin system (RAS) can prevent and delay the development of diabetes. Also, the role of RAS in the pathogenesis of diabetes, including insulin resistance and β-cell dysfunction, has been extensively investigated. Nevertheless, this role had not yet been fully shown. A variety of possible protective mechanisms for RAS blockers in the regulation of glucose homeostasis have been suggested. However, the direct effect on pancreatic islet fibrosis has only recently been spotlighted. Various degrees of islet fibrosis are often observed in the islets of patients with type 2 diabetes mellitus, which can be associated with a decrease in β-cell mass and function in these patients. Pancreatic stellate cells are thought to be deeply involved in this islet fibrosis. In this process, the activation of RAS in islets is shown to transform quiescent pancreatic stellate cells into the activated form, stimulates their proliferation and consequently leads to islet fibrotic destruction. In this article, we introduce existing clinical and experimental evidence for diabetes prevention through inhibition of RAS, and review the responsible local RAS signaling pathways in pancreatic stellate cells. Finally, we propose possible targets for the prevention of islet fibrosis.
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Affiliation(s)
- Yeoree Yang
- Division of Endocrinology and MetabolismDepartment of Internal MedicineCollege of MedicineSeoul St. Mary’s HospitalThe Catholic University of KoreaSeoulKorea
| | - Ji‐Won Kim
- Division of Endocrinology and MetabolismDepartment of Internal MedicineCollege of MedicineSeoul St. Mary’s HospitalThe Catholic University of KoreaSeoulKorea
| | - Heon‐Seok Park
- Division of Endocrinology and MetabolismDepartment of Internal MedicineCollege of MedicineSeoul St. Mary’s HospitalThe Catholic University of KoreaSeoulKorea
| | - Eun‐Young Lee
- Division of Endocrinology and MetabolismDepartment of Internal MedicineCollege of MedicineSeoul St. Mary’s HospitalThe Catholic University of KoreaSeoulKorea
| | - Kun‐Ho Yoon
- Division of Endocrinology and MetabolismDepartment of Internal MedicineCollege of MedicineSeoul St. Mary’s HospitalThe Catholic University of KoreaSeoulKorea
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Cornejo MA, Nguyen J, Cazares J, Escobedo B, Nishiyama A, Nakano D, Ortiz RM. Partial Body Mass Recovery After Caloric Restriction Abolishes Improved Glucose Tolerance in Obese, Insulin Resistant Rats. Front Endocrinol (Lausanne) 2020; 11:363. [PMID: 32587574 PMCID: PMC7298117 DOI: 10.3389/fendo.2020.00363] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 05/11/2020] [Indexed: 11/13/2022] Open
Abstract
Caloric restriction, among other behavioral interventions, has demonstrated benefits on improving glycemic control in obesity-associated diabetic subjects. However, an acute and severe intervention without proper maintenance could reverse the initial benefits, with additional metabolic derangements. To assess the effects of an acute caloric restriction in a metabolic syndrome model, a cohort of 15-week old Long Evans Tokushima Otsuka (LETO) and Otsuka Long Evans Tokushima Fatty (OLETF) rats were calorie restricted (CR: 50% × 10 days) with or without a 10-day body mass (BM) recovery period, along with their respective ad libitum controls. An oral glucose tolerance test (oGTT) was performed after CR and BM recovery. Both strains had higher rates of mass gain during recovery vs. ad lib controls; however, the regain was partial (ca. 50% of ad lib controls) over the measurement period. Retroperitoneal and epididymal adipose masses decreased 30% (8.8 g, P < 0.001) in OLETF; however, this loss only accounted for 11.5% of the total BM loss. CR decreased blood glucose AUC 16% in LETO and 19% in OLETF, without significant decreases in insulin. Following CR, hepatic expression of the gluconeogenic enzyme, PEPCK, was reduced 55% in OLETF compared to LETO, and plasma triglycerides (TG) decreased 86%. Acute CR induced improvements in glucose tolerance and TG suggestive of improvements in metabolism; however, partial recovery of BM following CR abolished the improvement in glucose tolerance. The present study highlights the importance of proper maintenance of BM after CR as only partial recovery of the lost BM reversed benefits of the initial mass loss.
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Affiliation(s)
- Manuel A. Cornejo
- School of Natural Sciences, University of California, Merced, Merced, CA, United States
- *Correspondence: Manuel A. Cornejo
| | - Julie Nguyen
- School of Natural Sciences, University of California, Merced, Merced, CA, United States
| | - Joshua Cazares
- School of Natural Sciences, University of California, Merced, Merced, CA, United States
| | - Benny Escobedo
- School of Natural Sciences, University of California, Merced, Merced, CA, United States
| | - Akira Nishiyama
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Daisuke Nakano
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Rudy M. Ortiz
- School of Natural Sciences, University of California, Merced, Merced, CA, United States
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Shakya A, Chaudary SK, Garabadu D, Bhat HR, Kakoti BB, Ghosh SK. A Comprehensive Review on Preclinical Diabetic Models. Curr Diabetes Rev 2020; 16:104-116. [PMID: 31074371 DOI: 10.2174/1573399815666190510112035] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 02/20/2019] [Accepted: 04/22/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Preclinical experimental models historically play a critical role in the exploration and characterization of disease pathophysiology. Further, these in-vivo and in-vitro preclinical experiments help in target identification, evaluation of novel therapeutic agents and validation of treatments. INTRODUCTION Diabetes mellitus (DM) is a multifaceted metabolic disorder of multidimensional aetiologies with the cardinal feature of chronic hyperglycemia. To avoid or minimize late complications of diabetes and related costs, primary prevention and early treatment are therefore necessary. Due to its chronic manifestations, new treatment strategies need to be developed, because of the limited effectiveness of the current therapies. METHODS The study included electronic databases such as Pubmed, Web of Science and Scopus. The datasets were searched for entries of studies up to June, 2018. RESULTS A large number of in-vivo and in-vitro models have been presented for evaluating the mechanism of anti-hyperglycaemic effect of drugs in hormone-, chemically-, pathogen-induced animal models of diabetes mellitus. The advantages and limitations of each model have also been addressed in this review. CONCLUSION This review encompasses the wide pathophysiological and molecular mechanisms associated with diabetes, particularly focusing on the challenges associated with the evaluation and predictive validation of these models as ideal animal models for preclinical assessments and discovering new drugs and therapeutic agents for translational application in humans. This review may further contribute to discover a novel drug to treat diabetes more efficaciously with minimum or no side effects. Furthermore, it also highlights ongoing research and considers the future perspectives in the field of diabetes.
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Affiliation(s)
- Anshul Shakya
- Department of Pharmaceutical Sciences, School of Science and Engineering, Dibrugarh University, Dibrugarh - 786 004, Assam, India
| | - Sushil Kumar Chaudary
- Department of Pharmacology, University of the Free State, Bloemfontein 9300, South Africa
| | - Debapriya Garabadu
- Institute of Pharmaceutical Research, GLA University, Mathura - 281406, Uttar Pradesh, India
| | - Hans Raj Bhat
- Department of Pharmaceutical Sciences, School of Science and Engineering, Dibrugarh University, Dibrugarh - 786 004, Assam, India
| | - Bibhuti Bhusan Kakoti
- Department of Pharmaceutical Sciences, School of Science and Engineering, Dibrugarh University, Dibrugarh - 786 004, Assam, India
| | - Surajit Kumar Ghosh
- Department of Pharmaceutical Sciences, School of Science and Engineering, Dibrugarh University, Dibrugarh - 786 004, Assam, India
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Pérez-López L, Boronat M, Melián C, Brito-Casillas Y, Wägner AM. Animal Models and Renal Biomarkers of Diabetic Nephropathy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1307:521-551. [PMID: 32329028 DOI: 10.1007/5584_2020_527] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Diabetes mellitus (DM) is the first cause of end stage chronic kidney disease (CKD). Animal models of the disease can shed light on the pathogenesis of the diabetic nephropathy (DN) and novel and earlier biomarkers of the condition may help to improve diagnosis and prognosis. This review summarizes the most important features of animal models used in the study of DN and updates the most recent progress in biomarker research.
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Affiliation(s)
- Laura Pérez-López
- Institute of Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gran Canaria, Spain
| | - Mauro Boronat
- Institute of Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gran Canaria, Spain
- Department of Endocrinology and Nutrition, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain
| | - Carlos Melián
- Institute of Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gran Canaria, Spain
- Department of Animal Pathology, Veterinary Faculty, University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Arucas, Las Palmas, Spain
| | - Yeray Brito-Casillas
- Institute of Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gran Canaria, Spain
| | - Ana M Wägner
- Institute of Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria (ULPGC), Las Palmas de Gran Canaria, Spain.
- Department of Endocrinology and Nutrition, Complejo Hospitalario Universitario Insular Materno-Infantil, Las Palmas de Gran Canaria, Spain.
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Den Hartogh DJ, Gabriel A, Tsiani E. Antidiabetic Properties of Curcumin II: Evidence from In Vivo Studies. Nutrients 2019; 12:nu12010058. [PMID: 31881654 PMCID: PMC7019668 DOI: 10.3390/nu12010058] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 12/19/2019] [Accepted: 12/24/2019] [Indexed: 12/14/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a growing metabolic disease characterized by insulin resistance and hyperglycemia. Current preventative and treatment approaches to insulin resistance and T2DM lack in efficacy, resulting in the need for new approaches to prevent and treat the disease. In recent years, epidemiological studies have suggested that diets rich in fruits and vegetables have beneficial health effects, including protection against insulin resistance and T2DM. Curcumin, a polyphenol found in turmeric, and curcuminoids have been reported to have antioxidant, anti-inflammatory, hepatoprotective, nephroprotective, neuroprotective, immunomodulatory and antidiabetic properties. The current review (II of II) summarizes the existing in vivo studies examining the antidiabetic effects of curcumin.
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Affiliation(s)
- Danja J. Den Hartogh
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada; (D.J.D.H.); (A.G.)
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
| | - Alessandra Gabriel
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada; (D.J.D.H.); (A.G.)
| | - Evangelia Tsiani
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada; (D.J.D.H.); (A.G.)
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
- Correspondence: ; Tel.: +1-905-688-5550 (ext. 3881)
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Ato S, Kido K, Sato K, Fujita S. Type 2 diabetes causes skeletal muscle atrophy but does not impair resistance training-mediated myonuclear accretion and muscle mass gain in rats. Exp Physiol 2019; 104:1518-1531. [PMID: 31328833 PMCID: PMC6790689 DOI: 10.1113/ep087585] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Accepted: 07/19/2019] [Indexed: 12/12/2022]
Abstract
New Findings
What is the central question of this study? Type 2 diabetes mellitus (T2DM) causes skeletal muscle atrophy; does it affect resistance training (RT)‐mediated molecular adaptations and subsequent muscle hypertrophy? What is the main finding and its importance? Although skeletal muscle mass and regulation were not preserved under conditions of T2DM, the response of RT‐induced skeletal muscle hypertrophy was not impaired in T2DM rat skeletal muscle. These findings suggest that the capacity of RT‐mediated muscle mass gain is not diminished in the T2DM condition. Abstract Type 2 diabetes mellitus (T2DM) is known to cause skeletal muscle atrophy. However, it is not known whether T2DM affects resistance training (RT)‐mediated molecular adaptations and subsequent muscle hypertrophy. Therefore, we investigated the effect of T2DM on response of skeletal muscle hypertrophy to chronic RT using a rat resistance exercise mimetic model. T2DM and healthy control rats were subjected to 18 bouts (3 times per week) of chronic RT on unilateral lower legs. RT significantly increased gastrocnemius muscle mass and myonuclei in both T2DM and healthy control rats to the same extent, even though T2DM caused muscle atrophy in the resting condition. Further, T2DM significantly reduced mechanistic target of rapamycin complex 1 (mTORC1) activity (phosphorylation of p70S6KThr389 and 4E‐BP1Thr37/46) to insulin stimulation and the number of myonuclei in the untrained basal condition, but RT‐mediated adaptations were not affected by T2DM. These findings suggested that although the skeletal muscle mass and regulation were not preserved under basal conditions of T2DM, the response of RT‐induced skeletal muscle hypertrophy was not impaired in T2DM rat skeletal muscle.
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Affiliation(s)
- Satoru Ato
- Graduate School of Sport and Health Science, Ritsumeikan University, Kusatsu, Japan
| | - Kohei Kido
- Graduate School of Sport and Health Science, Ritsumeikan University, Kusatsu, Japan
| | - Koji Sato
- Faculty of Human Development, Kobe University, Kobe, Japan
| | - Satoshi Fujita
- Graduate School of Sport and Health Science, Ritsumeikan University, Kusatsu, Japan
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Han F, Li X, Yang J, Liu H, Zhang Y, Yang X, Yang S, Chang B, Chen L, Chang B. Salsalate Prevents β-Cell Dedifferentiation in OLETF Rats with Type 2 Diabetes through Notch1 Pathway. Aging Dis 2019; 10:719-730. [PMID: 31440379 PMCID: PMC6675521 DOI: 10.14336/ad.2018.1221] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 12/21/2018] [Indexed: 11/30/2022] Open
Abstract
A strategic approach is urgently needed to curb the growing global epidemic of diabetes. In this study, we investigated the effects and mechanisms of salsalate (SAL), an anti-inflammatory drug with anti-diabetic properties, assessing its potential to prevent diabetes in Otsuka Long-Evans Tokushima Fatty rats (OLETF). All animals in our placebo group developed diabetes, whereas none in the SAL test group did so, and only 25% of SAL-treated rats displayed impaired glucose tolerance (IGT). SAL lowered levels of glucagon and raised levels of insulin in plasma, while improving both insulin sensitivity and β-cell function. The protective effect of SAL is likely due to diminished β-cell dedifferentiation, manifested as relative declines in Neurogenin 3+/insulin- cells and synaptophysin+/islet hormone- cells and increased expression of β-cell-specific transcription factor Foxo1. Both Notch1-siRNA and N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butyl ester (DAPT; an indirect inhibitor of the Notch1 pathway) were shown to prevent β-cell dedifferentiation. Similar to DAPT, SAL effectively reduced β-cell dedifferentiation, significantly suppressing Notch1 pathway activation in INS-1 cells. The inhibitory role of SAL in β-cell dedifferentiation may thus be attributable to Notch1 pathway suppression.
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Affiliation(s)
- Fei Han
- 1NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Xiaochen Li
- 1NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Juhong Yang
- 1NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Haiyi Liu
- 1NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Yi Zhang
- 1NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Xiaoyun Yang
- 2Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Shaohua Yang
- 1NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Bai Chang
- 1NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Liming Chen
- 1NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin, China
| | - Baocheng Chang
- 1NHC Key Laboratory of Hormones and Development (Tianjin Medical University), Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin, China
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Kanemoto N, Okamoto T, Tanabe K, Shimada T, Minoshima H, Hidoh Y, Aoyama M, Ban T, Kobayashi Y, Ando H, Inoue Y, Itotani M, Sato S. Antidiabetic and cardiovascular beneficial effects of a liver-localized mitochondrial uncoupler. Nat Commun 2019; 10:2172. [PMID: 31092829 PMCID: PMC6520346 DOI: 10.1038/s41467-019-09911-6] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Accepted: 04/08/2019] [Indexed: 12/11/2022] Open
Abstract
Inducing mitochondrial uncoupling (mUncoupling) is an attractive therapeutic strategy for treating metabolic diseases because it leads to calorie-wasting by reducing the efficiency of oxidative phosphorylation (OXPHOS) in mitochondria. Here we report a safe mUncoupler, OPC-163493, which has unique pharmacokinetic characteristics. OPC-163493 shows a good bioavailability upon oral administration and primarily distributed to specific organs: the liver and kidneys, avoiding systemic toxicities. It exhibits insulin-independent antidiabetic effects in multiple animal models of type I and type II diabetes and antisteatotic effects in fatty liver models. These beneficial effects can be explained by the improvement of glucose metabolism and enhancement of energy expenditure by OPC-163493 in the liver. Moreover, OPC-163493 treatment lowered blood pressure, extended survival, and improved renal function in the rat model of stroke/hypertension, possibly by enhancing NO bioavailability in blood vessels and reducing mitochondrial ROS production. OPC-163493 is a liver-localized/targeted mUncoupler that ameliorates various complications of diabetes.
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Affiliation(s)
- Naohide Kanemoto
- Department of Lead Discovery Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan.
| | - Takashi Okamoto
- Department of Lead Discovery Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan
| | - Koji Tanabe
- Department of CNS Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan
| | - Takahiro Shimada
- Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan
| | - Hitomi Minoshima
- Pharmaceutical Planning Group, Otsuka Pharmaceutical Co., Ltd., 2-16-4 Shinagawa Grand Central Tower Minatominami Minato-ku, Tokyo, 108-8242, Japan
| | - Yuya Hidoh
- Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan
| | - Masashi Aoyama
- Biology and Translational Research Unit, Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan
| | - Takashi Ban
- Department of Renal and Cardiovascular Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan
| | - Yusuke Kobayashi
- Department of Lead Discovery Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan
| | - Hikaru Ando
- Department of Lead Discovery Research, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan
| | - Yuki Inoue
- Department of Drug Safety Research, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan
| | - Motohiro Itotani
- Quality Assurance Section (Tokushima Wajiki Factory), Quality Assurance Department, Headquarters for Product Safety and Quality Assurance, Otsuka Pharmaceutical Co., Ltd., 306-2 Otsubo Koniu aza Naka-cho Naka-gun, Tokushima, 771-5209, Japan
| | - Seiji Sato
- Medicinal Chemistry Research Laboratories, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno Kawauchi-cho, Tokushima, 771-0192, Japan
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Ise I, Tanaka N, Imoto H, Maekawa M, Kohyama A, Watanabe K, Motoi F, Unno M, Naitoh T. Changes in Enterohepatic Circulation after Duodenal–Jejunal Bypass and Reabsorption of Bile Acids in the Bilio-Pancreatic Limb. Obes Surg 2019; 29:1901-1910. [DOI: 10.1007/s11695-019-03790-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Kawabeta K, Hase-Tamaru S, Yuasa M, Suruga K, Sugano M, Koba K. Dietary β-Conglycinin Modulates Insulin Sensitivity, Body Fat Mass, and Lipid Metabolism in Obese Otsuka Long-Evans Tokushima Fatty (OLETF) Rats. J Oleo Sci 2019; 68:339-350. [DOI: 10.5650/jos.ess18232] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Koji Kawabeta
- Graduate School of Human Health Science, University of Nagasaki
| | - Shizuka Hase-Tamaru
- Faculty of Nursing and Nutrition, University of Nagasaki
- Department of Life, Environment and Materials Science, Fukuoka Institute of Technology
| | - Masahiro Yuasa
- Faculty of Nursing and Nutrition, University of Nagasaki
| | - Kazuhito Suruga
- Graduate School of Human Health Science, University of Nagasaki
- Faculty of Nursing and Nutrition, University of Nagasaki
| | - Michihiro Sugano
- Professor Emeritus, Kyushu University and Prefectural University of Kumamoto
| | - Kazunori Koba
- Graduate School of Human Health Science, University of Nagasaki
- Faculty of Nursing and Nutrition, University of Nagasaki
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Aoi W, Zou X, Xiao JB, Marunaka Y. Body Fluid pH Balance in Metabolic Health and Possible Benefits of Dietary Alkaline Foods. EFOOD 2019. [DOI: 10.2991/efood.k.190924.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
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Bu Y, Shih KC, Kwok SS, Chan YK, Lo ACY, Chan TCY, Jhanji V, Tong L. Experimental modeling of cornea wound healing in diabetes: clinical applications and beyond. BMJ Open Diabetes Res Care 2019; 7:e000779. [PMID: 31803484 PMCID: PMC6887488 DOI: 10.1136/bmjdrc-2019-000779] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 10/06/2019] [Accepted: 11/03/2019] [Indexed: 12/11/2022] Open
Abstract
Diabetes mellitus is the most common cause of blindness in working age populations worldwide. While much of the focus for public health has been on secondary prevention in sight-threatening diabetic retinopathy, the cornea, including its epithelium and nerves, represents a major site of damage by chronic hyperglycemia. On injury, the diabetic cornea exhibits a delayed wound-healing response, as well as an altered ocular surface immune response. This suggests a potential association between the dysfunctional wound healing response and altered inflammation on the ocular surface. However, the presence of potential confounders makes this association difficult to investigate in human epidemiological studies. Thus, we turn to animal diabetic models for a better understanding. In this review, 20 original studies, published between 2008 and 2018, describe in vivo and in vitro models of diabetic cornea disease. We compared different models of diabetic cornea wound healing and discussed the relative strengths and drawbacks of each model. A number of molecular and cellular components involved in the corneal wound healing response that are altered in the presence of diabetes have been identified in the reviewed studies. Particularly, altered corneal epithelial protein concentrations of lumician and occludin were detected in diabetic eyes compared with controls. Additionally, the importance of IL-1β in modulating the inflammatory response after corneal injury in patients with diabetes and controls was further elucidated. Meanwhile, abnormal P2×7 receptor localization and decreased corneal sub-basal nerve density in diabetic eyes were shown to contribute to altered corneal nerve signaling after injury and thus affecting the wound healing response. Finally, the discovery of the therapeutic effects of topically administered aloe vera, Serpine 1, Resolvin D1 (RvD1), pigment epithelium-derived factor (PEDF) and Pro-His-Ser-Arg-Asn in diabetic animal models of cornea epithelial and nerve injury provide encouraging evidence for the future availability of effective treatment for diabetic keratopathy.
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Affiliation(s)
- Yashan Bu
- Department of Ophthalmology, University of Hong Kong, Hong Kong
| | | | - Sum Sum Kwok
- Department of Ophthalmology, University of Hong Kong, Hong Kong
| | - Yau Kei Chan
- Department of Ophthalmology, University of Hong Kong, Hong Kong
| | | | | | - Vishal Jhanji
- Department of Ophthalmology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Louis Tong
- Department of Ophthalmology, Singapore National Eye Centre, Singapore
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Abstract
The laboratory rat, Rattus norvegicus, has been used in biomedical research for more than 150 years, and in many cases remains the model of choice for studies of physiology, behavior, and complex human disease. This book provides detailed information on a number of methodologies that can be used in rat. This chapter gives an introduction to rat as a species and as a biomedical model, providing historical information, a brief introduction to the current state of rat research, and a perspective on the future of rat as a model for human disease.
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Affiliation(s)
- Jennifer R Smith
- Department of Biomedical Engineering, Rat Genome Database, Medical College of Wisconsin, Milwaukee, WI, USA.
| | - Elizabeth R Bolton
- Department of Biomedical Engineering, Rat Genome Database, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Melinda R Dwinell
- Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, USA
- Department of Physiology, Rat Genome Database, Medical College of Wisconsin, Milwaukee, WI, USA
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CB1 receptor blockade ameliorates hepatic fat infiltration and inflammation and increases Nrf2-AMPK pathway in a rat model of severely uncontrolled diabetes. PLoS One 2018; 13:e0206152. [PMID: 30365523 PMCID: PMC6203369 DOI: 10.1371/journal.pone.0206152] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 10/08/2018] [Indexed: 12/26/2022] Open
Abstract
Previous studies have shown that the CB1 receptor antagonist reverses steatohepatitis and its related features of metabolic syndrome, such as obesity and type 2 diabetes. However, the beneficial effects of CB1 receptor blockade on hepatic steatosis and inflammation have not been investigated independently of its effects on body weight and glycemic control. At 32 weeks of age, OLETF rats were administered with rimonabant (10 mg·kg−1·day−1) by oral gavage for 6 weeks. No significant changes in body weight, OGTT, and serum glucose were observed in spite of rimonabant-decreased food intake. Moreover, there was a significant difference between initial and final body weight, regardless of rimonabant administration, indicating that OLETF rats were severely diabetic rats. Rimonabant administration significantly decreased serum liver enzyme levels such as ALT and AST, hepatic fat accumulation, lipid peroxidation, and cell death as demonstrated by the number of TUNEL-positive cells in severely uncontrolled diabetic OLETF rats. Significant decreases in hepatic gene expression of proinflammatory cytokines (CD11b, F4/80, MCP1, and TNFα), negative inflammatory mediators (SOCS1 and SOCS3), and fibrosis-related proteins (TGFβ, collagen 1, and TIMP1) were found in rimonabant-treated OLETF rats. Six-week administration of rimonabant significantly upregulated mRNA levels of CPT1α and PPARα related to β-oxidation. Moreover, significant increases in Nrf2 gene expression and its downstream genes, NQO1, GSAT, HO-1, and TXNRD1 along with increased AMPK phosphorylation were noted in uncontrolled diabetic rats treated with rimonabant. The observed potent inhibitory effects of CB1 receptor blockade on hepatic fat infiltration and cellular death in severely uncontrolled diabetic rats indicate that CB1 receptor is a possible therapeutic target. Increased Nrf2 and AMPK phosphorylation may play a role in the mechanism of rimonabant action.
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Rodriguez R, Lee A, Mathis KW, Broome HJ, Thorwald M, Martinez B, Nakano D, Nishiyama A, Ryan MJ, Ortiz RM. Angiotensin receptor and tumor necrosis factor-α activation contributes to glucose intolerance independent of systolic blood pressure in obese rats. Am J Physiol Renal Physiol 2018; 315:F1081-F1090. [PMID: 29993275 DOI: 10.1152/ajprenal.00156.2018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Pathological activation of the renin-angiotensin system and inflammation are associated with hypertension and the development of metabolic syndrome (MetS). The contributions of angiotensin receptor type 1 (AT1) activation, independent of blood pressure, and inflammation to glucose intolerance and renal damage are not well defined. Using a rat model of MetS, we hypothesized that the onset of glucose intolerance is primarily mediated by AT1 activation and inflammation independent of elevated systolic blood pressure (SBP). To address this hypothesis, we measured changes in SBP, adiposity, plasma glucose and triglyceride levels, and glucose tolerance in six groups of rats: 1) lean, strain control Long-Evans Tokushima Otsuka (LETO; n = 5), 2) obese Otsuka Long-Evans Tokushima Fatty (OLETF; n = 8), 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg; n = 8), 4) OLETF + tumor necrosis factor-α (TNF-α) inhibitor (ETAN; 1.25 mg etanercept/kg; n = 6), 5) OLETF + TNF-α inhibitor + angiotensin receptor blocker (ETAN+ARB; 1.25 mg etanercept/kg + 10 mg olmesartan/kg; n = 6), and 6) OLETF + calcium channel blocker (CCB; 5 mg amlodipine/kg; n = 7). ARB and ETAN+ARB were most effective at decreasing SBP in OLETF, and ETAN did not offer any additional reduction. Glucose tolerance improved in ARB, ETAN, and ETAN+ARB compared with OLETF, whereas CCB had no detectable effect. Furthermore, all treatments reduced adiposity, whereas ETAN alone normalized urinary albumin excretion. These results suggest that AT1 activation and inflammation are primary factors in the development of glucose intolerance in a setting of MetS and that the associated increase in SBP is primarily mediated by AT1 activation.
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Affiliation(s)
- Ruben Rodriguez
- Department of Molecular and Cellular Biology, University of California, Merced, California
| | - Andrew Lee
- Department of Molecular and Cellular Biology, University of California, Merced, California
| | - Keisa W Mathis
- Department of Physiology and Anatomy, University of North Texas Health Science Center , Fort Worth, Texas
| | - Hanna J Broome
- Department of Biological Sciences, Mississippi College , Clinton, Mississippi
| | - Max Thorwald
- Department of Molecular and Cellular Biology, University of California, Merced, California
| | - Bridget Martinez
- Department of Molecular and Cellular Biology, University of California, Merced, California.,School of Medicine, St. George's University , St. George's , Grenada.,Department of Physics and Engineering, Los Alamos National Laboratory , Los Alamos, New Mexico
| | - Daisuke Nakano
- Department of Pharmacology, Faculty of Medicine, Kagawa University , Takamatsu , Japan
| | - Akira Nishiyama
- Department of Pharmacology, Faculty of Medicine, Kagawa University , Takamatsu , Japan
| | - Michael J Ryan
- Department of Physiology and Biophysics, University of Mississippi Medical Center , Jackson, Mississippi.,G.V. (Sonny) Montgomery Veterans Affairs Medical Center , Jackson, Mississippi
| | - Rudy M Ortiz
- Department of Molecular and Cellular Biology, University of California, Merced, California
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Brown SM, Meuth AI, Davis JW, Rector RS, Bender SB. Mineralocorticoid receptor antagonism reverses diabetes-related coronary vasodilator dysfunction: A unique vascular transcriptomic signature. Pharmacol Res 2018; 134:100-108. [PMID: 29870805 DOI: 10.1016/j.phrs.2018.06.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 06/01/2018] [Accepted: 06/01/2018] [Indexed: 01/09/2023]
Abstract
Coronary microvascular dysfunction predicts and may be a proximate cause of cardiac dysfunction and mortality in diabetes; however, few effective treatments exist for these conditions. We recently demonstrated that mineralocorticoid receptor (MR) antagonism reversed cardiovascular dysfunction in early-stage obesity/insulin resistance. The mechanisms underlying this benefit of MR antagonism and its relevance in the setting of long-term obesity complications like diabetes; however, remain unclear. Thus, the present study evaluated the impact of MR antagonism on diabetes-related coronary dysfunction and defines the MR-dependent vascular transcriptome in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat recapitulating later stages of human diabetes. OLETF rats were treated with spironolactone (Sp) and compared to untreated OLETF and lean Long-Evans Tokushima Otsuka rats. Sp treatment attenuated diabetes-associated adipose and cardiac inflammation/fibrosis and improved coronary endothelium-dependent vasodilation but did not alter enhanced coronary vasoconstriction, blood pressure, or metabolic parameters in OLETF rats. Further mechanistic studies using RNA deep sequencing of OLETF rat aortas revealed 157 differentially expressed genes following Sp including upregulation of genes involved in the molecular regulation of nitric oxide bioavailability (Hsp90ab1, Ahsa1, Ahsa2) as well as novel changes in α1D adrenergic receptors (Adra1d), cyclooxygenase-2 (Ptgs2), and modulatory factors of these pathways (Ackr3, Acsl4). Further, Ingenuity Pathway Analysis predicted inhibition of upstream inflammatory regulators by Sp and inhibition of 'migration of endothelial cells', 'differentiation of smooth muscle', and 'angiogenesis' biological functions by Sp in diabetes. Thus, this study is the first to define the MR-dependent vascular transcriptome underlying treatment of diabetes-related coronary microvascular dysfunction by Sp.
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Affiliation(s)
- Scott M Brown
- Research Service, Harry S Truman Memorial Veterans Hospital, Columbia, MO, USA; Biomedical Sciences, University of Missouri, Columbia, MO, USA
| | - Alex I Meuth
- Research Service, Harry S Truman Memorial Veterans Hospital, Columbia, MO, USA; Biomedical Sciences, University of Missouri, Columbia, MO, USA
| | - J Wade Davis
- MU Informatics Institute, University of Missouri, Columbia, MO, USA; Health Management and Informatics, University of Missouri, Columbia, MO, USA; Statistics, University of Missouri, Columbia, MO, USA
| | - R Scott Rector
- Research Service, Harry S Truman Memorial Veterans Hospital, Columbia, MO, USA; Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, USA; Medicine-Division of Gastroenterology and Hepatology, University of Missouri, School of Medicine, Columbia, MO, USA
| | - Shawn B Bender
- Research Service, Harry S Truman Memorial Veterans Hospital, Columbia, MO, USA; Biomedical Sciences, University of Missouri, Columbia, MO, USA; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA.
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