Diabetes & Metabolism Journal

Review

Complications
Peripheral Neuropathy Phenotyping in Rat Models of Type 2 Diabetes Mellitus: Evaluating Uptake of the Neurodiab Guidelines and Identifying Future Directions: Md Jakir Hossain, Michael D. Kendig, Meg E. Letton, Margaret J. Morris, Ria Arnold; Diabetes Metab J. 2022;46(2):198-221. Published online March 24, 2022; DOI: https://doi.org/10.4093/dmj.2021.0347

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Diabetic peripheral neuropathy (DPN) affects over half of type 2 diabetes mellitus (T2DM) patients, with an urgent need for effective pharmacotherapies. While many rat and mouse models of T2DM exist, the phenotyping of DPN has been challenging with inconsistencies across laboratories. To better characterize DPN in rodents, a consensus guideline was published in 2014 to accelerate the translation of preclinical findings. Here we review DPN phenotyping in rat models of T2DM against the ‘Neurodiab’ criteria to identify uptake of the guidelines and discuss how DPN phenotypes differ between models and according to diabetes duration and sex. A search of PubMed, Scopus and Web of Science databases identified 125 studies, categorised as either diet and/or chemically induced models or transgenic/spontaneous models of T2DM. The use of diet and chemically induced T2DM models has exceeded that of transgenic models in recent years, and the introduction of the Neurodiab guidelines has not appreciably increased the number of studies assessing all key DPN endpoints. Combined high-fat diet and low dose streptozotocin rat models are the most frequently used and well characterised. Overall, we recommend adherence to Neurodiab guidelines for creating better animal models of DPN to accelerate translation and drug development.

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SIRT3 alleviates painful diabetic neuropathy by mediating the FoxO3a‐PINK1‐Parkin signaling pathway to activate mitophagy
Jing Yang, Zhuoying Yu, Ye Jiang, Zixian Zhang, Yue Tian, Jie Cai, Min Wei, Yanhan Lyu, Dongsheng Yang, Shixiong Shen, Guo‐Gang Xing, Min Li
CNS Neuroscience & Therapeutics.2024;[Epub] CrossRef
Long-term sensorimotor changes after a sciatic nerve block with bupivacaine and liposomal bupivacaine in a high-fat diet/low-dose streptozotocin rodent model of diabetes
Susanna C. Byram, Krista M. Lotesto, Michael Volyanyuk, Jacob E. Exline, Elizabeth A. Sager, Eileen M. Foecking
Frontiers in Anesthesiology.2024;[Epub] CrossRef
The impact of gut microbial dysbiosis on the atrophy of the hippocampus and abnormal metabolism of N-acetyl aspartate in type 2 diabetic rats
Zhenyang Zhu, Qingqing Chen, Gege Jiang, Yuan Liang, Jing Shen, Jianlin Wu
Heliyon.2024; 10(12): e33152. CrossRef
Advances in the treatment of diabetic peripheral neuropathy by modulating gut microbiota with traditional Chinese medicine
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World Journal of Diabetes.2024; 15(8): 1712. CrossRef
Compound Qiying Granules alleviates diabetic peripheral neuropathy by inhibiting endoplasmic reticulum stress and apoptosis
Yan Hu, Chen Chen, Zhengting Liang, Tao Liu, Xiaoling Hu, Guanying Wang, Jinxia Hu, Xiaolin Xie, Zhiyan Liu
Molecular Medicine.2023;[Epub] CrossRef
HCV affects KATP channels through GnT-IVa-mediated N-glycosylation of GLUT2 on the surface of pancreatic β-cells leading to impaired insulin secretion
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Endocrine.2023; 84(2): 427. CrossRef
Multimodal Comparison of Diabetic Neuropathy in Aged Streptozotocin-Treated Sprague–Dawley and Zucker Diabetic Fatty Rats
Annalisa Canta, Valentina A. Carozzi, Alessia Chiorazzi, Cristina Meregalli, Norberto Oggioni, Virginia Rodriguez-Menendez, Barbara Sala, Roberto Cosimo Melcangi, Silvia Giatti, Raffaella Lombardi, Roberto Bianchi, Paola Marmiroli, Guido Cavaletti
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Sulwon Lecture 2020

Pathophysiology
Rho-Kinase as a Therapeutic Target for Nonalcoholic Fatty Liver Diseases: Inês Sousa-Lima, Hyun Jeong Kim, John Jones, Young-Bum Kim; Diabetes Metab J. 2021;45(5):655-674. Published online September 30, 2021; DOI: https://doi.org/10.4093/dmj.2021.0197

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Nonalcoholic fatty liver disease (NAFLD) is a major public health problem and the most common form of chronic liver disease, affecting 25% of the global population. Although NAFLD is closely linked with obesity, insulin resistance, and type 2 diabetes mellitus, knowledge on its pathogenesis remains incomplete. Emerging data have underscored the importance of Rho-kinase (Rho-associated coiled-coil-containing kinase [ROCK]) action in the maintenance of normal hepatic lipid homeostasis. In particular, pharmacological blockade of ROCK in hepatocytes or hepatic stellate cells prevents the progression of liver diseases such as NAFLD and fibrosis. Moreover, mice lacking hepatic ROCK1 are protected against obesity-induced fatty liver diseases by suppressing hepatic de novo lipogenesis. Here we review the roles of ROCK as an indispensable regulator of obesity-induced fatty liver disease and highlight the key cellular pathway governing hepatic lipid accumulation, with focus on de novo lipogenesis and its impact on therapeutic potential. Consequently, a comprehensive understanding of the metabolic milieu linking to liver dysfunction triggered by ROCK activation may help identify new targets for treating fatty liver diseases such as NAFLD.

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Fares E.M. Ali, Mustafa Ahmed Abdel-Reheim, Emad H.M. Hassanein, Mostafa K. Abd El-Aziz, Hanan S. Althagafy, Khalid S.A. Badran
Life Sciences.2024; 347: 122642. CrossRef
Targeting of G-protein coupled receptor 40 alleviates airway hyperresponsiveness through RhoA/ROCK1 signaling pathway in obese asthmatic mice
Xixi Lin, Like Wang, Xiaojie Lu, Yuanyuan Zhang, Rongying Zheng, Ruijie Chen, Weixi Zhang
Respiratory Research.2023;[Epub] CrossRef
Selectivity matters: selective ROCK2 inhibitor ameliorates established liver fibrosis via targeting inflammation, fibrosis, and metabolism
Alexandra Zanin-Zhorov, Wei Chen, Julien Moretti, Melanie S. Nyuydzefe, Iris Zhorov, Rashmi Munshi, Malavika Ghosh, Cindy Serdjebi, Kelli MacDonald, Bruce R. Blazar, Melissa Palmer, Samuel D. Waksal
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Insight Into Rho Kinase Isoforms in Obesity and Energy Homeostasis
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Paeoniflorin alleviates liver injury in hypercholesterolemic rats through the ROCK/AMPK pathway
Tong Liu, Ning Zhang, Lingya Kong, Sijie Chu, Ting Zhang, Guangdi Yan, Donglai Ma, Jun Dai, Zhihong Ma
Frontiers in Pharmacology.2022;[Epub] CrossRef
Fasudil Increased the Sensitivity to Gefitinib in NSCLC by Decreasing Intracellular Lipid Accumulation
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Original Articles

Basic Research
Carnitine Orotate Complex Ameliorates Insulin Resistance and Hepatic Steatosis Through Carnitine Acetyltransferase Pathway: Jung-Hee Hong, Moon-Kyu Lee; Diabetes Metab J. 2021;45(6):933-947. Published online August 19, 2021; DOI: https://doi.org/10.4093/dmj.2020.0223

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Background
Carnitine orotate complex (Godex) has been shown to decrease glycated hemoglobin levels and improve steatosis in patients with type 2 diabetes mellitus with non-alcoholic fatty liver disease. However, the mechanisms of Godex in glucose metabolism remain unclear.
Methods
Male C57BL/6J mice were divided into four groups: normal-fat diet, high-fat diet, a high-fat diet supplemented with intraperitoneal injection of (500 mg or 2,000 mg/kg/day) Godex for 8 weeks. Computed tomography, indirect calorimetry, and histological analyses including electron microscopy of the liver were performed, and biochemical profiles and oral glucose tolerance test and insulin tolerance test were undertaken. Expressions of genes in the lipid and glucose metabolism, activities of oxidative phosphorylation enzymes, carnitine acetyltransferase, pyruvate dehydrogenase, and acetyl-coenzyme A (CoA)/CoA ratio were evaluated.
Results
Godex improved insulin sensitivity and significantly decreased fasting plasma glucose, homeostatic model assessment for insulin resistance, steatosis, and gluconeogenesis, with a marked increase in fatty acid oxidation as well as better use of glucose in high-fat diet-fed mice. It preserved mitochondrial function and ultrastructure, restored oxidative phosphorylation enzyme activities, decreased acetyl-CoA/CoA ratio, and increased carnitine acetyltransferase content and pyruvate dehydrogenase activity. Carnitine acetyltransferase knockdown partially reversed the effects of Godex in liver and in vitro.
Conclusion
Godex improved insulin resistance and steatosis by regulating carnitine acetyltransferase in liver in high-fat diet-fed mice.

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Impact of l-Carnitine Supplementation on Liver Enzyme Normalization in Patients with Chronic Liver Disease: A Meta-Analysis of Randomized Trials
Hyunwoo Oh, Chan Hyuk Park, Dae Won Jun
Journal of Personalized Medicine.2022; 12(7): 1053. CrossRef
Prolonged Use of Carnitine-Orotate Complex (Godex®) Is Associated with Improved Mortality: A Nationwide Cohort Study
Kye-Yeung Park, Sangmo Hong, Kyung-Soo Kim, Kyungdo Han, Cheol-Young Park
Journal of Personalized Medicine.2022; 12(12): 1970. CrossRef
The Role of Carnitine Orotate Complex in Fatty Liver
Hyon-Seung Yi
Diabetes & Metabolism Journal.2021; 45(6): 866. CrossRef

Basic Research
The Effects of Exercise and Restriction of Sugar-Sweetened Beverages on Muscle Function and Autophagy Regulation in High-Fat High-Sucrose-Fed Obesity Mice: Didi Zhang, Ji Hyun Lee, Hyung Eun Shin, Seong Eun Kwak, Jun Hyun Bae, Liang Tang, Wook Song; Diabetes Metab J. 2021;45(5):773-786. Published online March 25, 2021; DOI: https://doi.org/10.4093/dmj.2020.0157

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Background
Autophagy maintains muscle mass and healthy skeletal muscles. Several recent studies have associated sugar-sweetened beverage (SSB) consumption with diseases. We investigated whether muscle dysfunction due to obesity could be restored by SSB restriction (SR) alone or in combination with exercise (EX) training.
Methods
Obese mice were subjected to SR combined with treadmill EX. Intraperitoneal glucose tolerance test, grip strength test, hanging time test, and body composition analysis were performed. Triglyceride (TG) and total cholesterol (TC) serum concentrations and TG concentrations in quadriceps muscles were analyzed. Western blot and reverse transcription-quantitative polymerase chain reaction helped analyze autophagy-related protein and mRNA expression, respectively.
Results
SR alone had no significant effect on fasting blood glucose levels, glucose tolerance, and muscle function. However, it had effect on serum TC, serum TG, and BCL2 interacting protein 3 expression. SR+EX improved glucose tolerance and muscle function and increased serum TC utilization than SR alone. SR+EX reduced P62 levels, increased glucose transporter type 4 and peroxisome proliferator-activated receptor γ coactivator-1α protein expression, and improved grip strength relative to the high-fat and high-sucrose liquid (HFHS) group, and this was not observed in the HFHS+EX group.
Conclusion
SR induced mitophagy-related protein expression in quadriceps, without affecting muscle function. And, the combination of SR and EX activated mitophagy-related proteins and improved muscle function.

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Association between sugar-sweetened beverage consumption frequency and muscle strength: results from a sample of Chinese adolescents
Yunjie Zhang, Pan Xu, Yongjing Song, Nan Ma, Jinkui Lu
BMC Public Health.2023;[Epub] CrossRef
Muscle strength and prediabetes progression and regression in middle‐aged and older adults: a prospective cohort study
Shanhu Qiu, Xue Cai, Yang Yuan, Bo Xie, Zilin Sun, Duolao Wang, Tongzhi Wu
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O.M. Voloshchuk, Н.P. Kopylchuk
Fiziolohichnyĭ zhurnal.2022; 68(4): 48. CrossRef

Review

Regulation of Muscle Pyruvate Dehydrogenase Complex in Insulin Resistance: Effects of Exercise and Dichloroacetate: Dumitru Constantin-Teodosiu; Diabetes Metab J. 2013;37(5):301-314. Published online October 17, 2013; DOI: https://doi.org/10.4093/dmj.2013.37.5.301

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Abstract PDF PubReader

Since the mitochondrial pyruvate dehydrogenase complex (PDC) controls the rate of carbohydrate oxidation, impairment of PDC activity mediated by high-fat intake has been advocated as a causative factor for the skeletal muscle insulin resistance, metabolic syndrome, and the onset of type 2 diabetes (T2D). There are also situations where muscle insulin resistance can occur independently from high-fat dietary intake such as sepsis, inflammation, or drug administration though they all may share the same underlying mechanism, i.e., via activation of forkhead box family of transcription factors, and to a lower extent via peroxisome proliferator-activated receptors. The main feature of T2D is a chronic elevation in blood glucose levels. Chronic systemic hyperglycaemia is toxic and can lead to cellular dysfunction that may become irreversible over time due to deterioration of the pericyte cell's ability to provide vascular stability and control to endothelial proliferation. Therefore, it may not be surprising that T2D's complications are mainly macrovascular and microvascular related, i.e., neuropathy, retinopathy, nephropathy, coronary artery, and peripheral vascular diseases. However, life style intervention such as exercise, which is the most potent physiological activator of muscle PDC, along with pharmacological intervention such as administration of dichloroacetate or L-carnitine can prove to be viable strategies for treating muscle insulin resistance in obesity and T2D as they can potentially restore whole body glucose disposal.

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Cell Reports.2014; 7(6): 2042. CrossRef

Original Article

Balsamic Vinegar Improves High Fat-Induced Beta Cell Dysfunction via Beta Cell ABCA1: Hannah Seok, Ji Young Lee, Eun Mi Park, Se Eun Park, Jae Hyuk Lee, Seungtaek Lim, Byung-Wan Lee, Eun Seok Kang, Hyun Chul Lee, Bong Soo Cha; Diabetes Metab J. 2012;36(4):275-279. Published online August 20, 2012; DOI: https://doi.org/10.4093/dmj.2012.36.4.275

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Background

The aim of this study was to investigate the effects of balsamic vinegar on β-cell dysfunction.

Methods

In this study, 28-week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats were fed a normal chow diet or a high-fat diet (HFD) and were provided with tap water or dilute balsamic vinegar for 4 weeks. Oral glucose tolerance tests and histopathological analyses were performed thereafter.

Results

In rats fed both the both chow diet and the HFD, the rats given balsamic vinegar showed increased insulin staining in islets compared with tap water administered rats. Balsamic vinegar administration also increased β-cell ATP-binding cassette transporter subfamily A member 1 (ABCA1) expression in islets and decreased cholesterol levels.

Conclusion

These findings provide the first evidence for an anti-diabetic effect of balsamic vinegar through improvement of β-cell function via increasing β-cell ABCA1 expression.

Citations

Citations to this article as recorded by

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