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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
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AbstractAbstract PDFPubReader   ePub   
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.


Citations to this article as recorded by  
  • 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
  • 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
    Ben Niu, Lijing Ma, Lixuan Yao, Yating Zhang, Heng Su
    Endocrine.2023;[Epub]     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
    Biomedicines.2022; 11(1): 20.     CrossRef
Original Articles
Effect of Livingstone Potato (Plectranthus esculenthus N.E.Br) on Diabetes and Its Complications in Streptozotocin Induced Diabetes in Rats
Chinedum Ogbonnaya Eleazu, Kate Chinedum Eleazu, Adanma Ironkwe, Mercy Amarachi Iroaganachi
Diabetes Metab J. 2014;38(5):366-374.   Published online October 17, 2014
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  • 5 Web of Science
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AbstractAbstract PDFPubReader   

The effect of livingstone potato (Plectranthus esculenthus N.E.Br) on diabetes and its complications in Streptozotocin induced diabetic rats was investigated. The duration of the experiment was 4 weeks.


The blood glucose level of the rats was measured with a glucometer, the protein and glucose and specific gravity in the urine samples of the rats were measured using urine assay strips and urinometer respectively. The liver and kidney function parameters in the serum of the rats were determined using Biosystem Kits.


The diabetic rats given livingstonepotato incorporated feeds, had 129.7% decrease in their hyperglycemia with corresponding amelioration of their elevated urinary protein, sugars, specific gravity, renal growth, liver growth as well as 15.64% decrease in body weights compared with the nondiabetic rats that had 5.54% decrease in blood glucose and 20.39% increase in body weight unlike the diabetic control rats that had 18.34% decrease in blood glucose and 52.68% decrease in body weight. There were significant differences (P<0.05) in the relative liver, pancreas, and kidney weights of the diabetic rats given livingstone potato feeds compared with the diabetic control while there were no significant differences (P>0.05) in the relative heart weights of all the rats in the three different groups. In terms of liver and kidney function parameters, values obtained for the diabetic rats given livingstone potato incorporated feeds were not significantly different from that of the nondiabetic rats except for total bilurubin, aspartate transaminase, and creatinine (P>0.05) while they were significantly different from the values obtained for the diabetic control rats (P<0.05). In addition, the serum amylase of the diabetic control rats were significantly higher (P<0.05) than that of the nondiabetic and diabetic rats treated with livingstone potato incorporated feeds.


Results show the antidiabetic actions of livingstone potato and its ability to ameliorate glomerular complication and liver hypertrophy in diabetics.


Citations to this article as recorded by  
  • Plectranthus esculentus (Livingstone potato)

    CABI Compendium.2022;[Epub]     CrossRef
  • Biogenic Synthesis of Silver Nanoparticles Using Phagnalon niveum and Its In Vivo Anti-Diabetic Effect against Alloxan-Induced Diabetic Wistar Rats
    Muhammad Nisar Ul Haq, Ghulam Mujtaba Shah, Alia Gul, Ahmed Ibrahim Foudah, Mohammad Hamed Alqarni, Hasan Soliman Yusufoglu, Masroor Hussain, Huda Mohammed Alkreathy, Ihsan Ullah, Amir Muhammad Khan, Shahid Jamil, Mushtaq Ahmed, Rahmat Ali Khan
    Nanomaterials.2022; 12(5): 830.     CrossRef
  • Green Silver Nanoparticles Synthesized from Taverniera couneifolia Elicits Effective Anti-Diabetic Effect in Alloxan-Induced Diabetic Wistar Rats
    Muhammad Nisar Ul Haq, Ghulam Mujtaba Shah, Farid Menaa, Rahmat Ali Khan, Norah A. Althobaiti, Aishah E. Albalawi, Huda Mohammed Alkreathy
    Nanomaterials.2022; 12(7): 1035.     CrossRef
  • Nutrient Composition, Antioxidant Capacity and Natural Products in Livingstone Potato (Plectranthus esculentus )
    C.O. Eleazu, K.C. Eleazu
    Journal of Food Processing and Preservation.2015; 39(6): 3050.     CrossRef
Hypothalamic AMPK Activity in Diabetic Rats.
Churl Namkoong, Min Seon Kim, Woo Je Lee, Pil Geum Jang, Seong Min Han, Eun Hee Koh, Joong Yeol Park, Ki Up Lee
Korean Diabetes J. 2004;28(6):468-477.   Published online December 1, 2004
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AbstractAbstract PDF
AMP-activated protein kinase (AMPK) acts as a cellular energy sensor that is activated during states of low energy charge and it regulates the various metabolic pathways to reestablish the normal cellular energy balance. It has recently been demonstrated that AMPK activity is altered by the state of energy metabolism in the hypothalamic neurons and this mediates the feeding response. METHODS: Diabetes was induced by an intra-peritoneal injection of streptozotocin (STZ) in Sprague-Dawley rats. The diabetic rats were maintained for 3 weeks with or without insulin treatment. 3 weeks later, we collected hypothalamus and we then assayed the phosphorylation of AMPK and the activity of acetyl CoA carboxylase (ACC) and isoform-specfic AMPK. To determine the effect of hypothalamic AMPK inhibition on diabetic hyperphagia, we administered an AMPK inhibitor, compound C, into the third ventricle in the STZ-induced diabetic rats. RESULTS: Phosphorylation of AMPK, which is a marker of AMPK activation, increased in the hypothalamus of the STZ-induced diabetic rats (DR). Moreover, 2-AMPK activity, but not 1-AMPK activity, increased by 2-fold in hypothalamus of the DRs. Phosphorylation of hypothalamic acetyl CoA carboxylase (ACC), a key downstream enzyme of AMPK, also increased in the DRs and this caused a reduction in ACC activity. Insulin treatment completely reversed the diabetesinduced changes in the hypothalamic AMPK and ACC, suggesting that insulin deficiency was associated with the changes in hypothalamic AMPK and ACC. Inhibition of AMPK by an intracerebroventricular administration of AMPK inhibitor, compound C, attenuated the development of diabetic hyperphagia and reduced the blood glucose levels in DRs. CONCLUSION: We have demonstrated that hypothalamic AMPK activity increased in the DRs, and inhibition of hypothalamic AMPK activity attenuated the development of diabetic hyperphagia. These data indicate that the enhanced hypothalamic AMPK activity may contribute to the development of diabetic hyperphagia
Effect of Melatonin on the Diabetes Mellitus Induced by Streptozotocin in Rats.
Ri Ra Lee, You Hee Kim, Chun Sik Kwak, Mi Young Yeo, Kyo Cheol Mun
Korean Diabetes J. 2002;26(5):357-365.   Published online October 1, 2002
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AbstractAbstract PDF
Oxygen free radicals are related to the pathogenesis and development of diabetes mellitus. The effect of melatonin, a known powerful antioxidant, was studied diabetes mellitus induced by streptozotocin in male Sprague-Dawley rats. METHODS: Diabetes was induced by the intraperitoneal injection of streptozotocin at 65 mg per kg of body weight. To know the effects of melatonin, two doses of 10 mg of melatonin per kg of body weight were administered intraperitoneally, the first simultaneously with the streptozotocin, and the second after a further 72 hours. The rats were then sacrificed at the 7th day after the first injection. The parameters including the levels of blood glucose, hemoglobin A1C, malondialdehyde and antioxidant enzymes were analysed to evaluate the diabetic state and the degree of lipid peroxidation by oxygen free radicals. RESULTS: The injection of streptozotocin caused significant increases in the levels of blood glucose, hemoglobin A1C and malondialdehyde. The injection of melatonin significantly reduced the levels of blood glucose and malondialdehyde. CONCLUSION: These results suggest melatonin may have a protective effect on the oxidative damage in the diabetes induced by streptozotocin.
Effect of Probucol on the Apoptosis of Pancreatic Islet Cells in Multiple Low Dose Streptozotocin Induced Diabetic (LDSD) Mice.
Kyung Mook Choi, Dong Rim Kim, Nan Hee Kim, Chul Hwan Kim, Sei Hyun Baik, Dong Seop Choi
Korean Diabetes J. 2001;25(2):152-163.   Published online April 1, 2001
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AbstractAbstract PDF
Type 1 Diabetes Mellitus(DM) is consequence of pancreatic beta cell destruction by immune interactions of auto-reactive T cells and cytokines. In individuals with genetic predisposition, an environmental insult triggers immune reaction against beta cells to produce clinical type 1 DM. Since the capacity to form new beta cells from precursors and power of replication appear to be limited, the susceptibility of beta cell to death may be the major underlying variable influencing the occurrence of type 1 DM. However, the precise mechanism of beta cell death is not known. Apoptosis is a physiologic form of cell death and recent studies reported that it could play an important role in beta cell death in experimental diabetic animal models such as multiple low dose streptozotocin diabetic (LDSD) mice or non- obese diabetic (NOD) mice. Probucol is a hypocholesterolemic agent with antioxidant properties. Some studies reported that the probucol could reduce the blood glucose level in type 1 animal models but the mechanism was not known. Therefore, this study was performed to define whether the probucol could decrease the degree of hyperglycemia and the mechanism of its attenuation on the severity of pancreatic insulitis by reducing the degree of apoptosis in LDSD mice. METHODS: We performed an experimental study with male Charles-River CD-1 mice. Mice were divided into the 30 streptozotocin-induced diabetics, 30 probucol- treated streptozotocin-induced diabetics. At 1, 5, 10, 15, and 20 days after streptozotocin administration, the blood glucose level was measured and mice were sacrificed to determine the grade of insulitis and apoptosis. The numbers of apoptotic cells of pancreatic islets were compared using double staining immunohistochemical method (TUNEL and insulin antibody staining). RESULTS: The level of blood glucose and the severity of insulitis were decreased in the probucol treated LDSD mice group significantly when compared with the control LDSD mice group. The numbers of apoptotic cells of pancreatic islets were decreased in the probucol group. The appearance of apoptosis of beta cells preceded the development of insulitis in LDSD mice. CONCLUSION: Probucol can reduce blood glucose level and the severity of insulitis by the decrease of apoptosis in LDSD mice.
Alterations of Plasma Atrial Natriuretic Peptide and its mRNA in Non-insulin Dependent Diabetic Model of Rats.
Byeong Dae Yoo, Won Kyun Park, Young Su Hong, Dae Kyu Song, Jae Hoon Bae
Korean Diabetes J. 2000;24(4):421-430.   Published online January 1, 2001
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AbstractAbstract PDF
Diabetes mellitus has led to change in fluid and electrolyte balance and consequently affected blood volume and blood pressure. These changes can trigger the secretion and synthesis of atrial natriuretic peptide (ANP) from both atrial and extra-atrial tissues. ANP plays an important role in the regulations of body fluid balance and blood pressure. Therefore, this study was carried out to elucidate whether or not atrial and extra-atrial synthesis of ANP is influenced in experimental non-insulin dependent diabetes mellitus (NIDDM) rats. METHODS: Neonatal rats were induced into NIDDM rats by single injection of streptozotocin (80 mg/kg). Plasma ANP level was measured by the use of radioimmunoassay method and the ANP mRNA expressions from the right atrium, left ventricle, hypothalamus and kidney were analyzed by reverse transcription- polymerase chain reaction with [32P]-dCTP at 8 weeks after injection of streptozotocin or citrate buffer. RESULTS: Blood glucose was more significantly increased at 2 hours after glucose loading in NIDDM rats than control rats. Plasma concentration of ANP tended to significantly increase in NIDDM rats compared with control rats. The expressions of ANP mRNA from each tissue were observed in different patterns. Right atrial ANP mRNA expression revealed non-significant increasing trend in NIDDM rats, whereas left ventricular ANP mRNA did not have difference. However, both hypothalamic and renal ANP mRNA expressions in NIDDM rats were significantly increased. CONCLUSION: These results indicate that the enhanced expressions of hypothalamic and renal ANP mRNA act as an important regulator of electrolytes and body fluid volume in neonatally streptozotocin-induced NIDDM rats.
Effects of Insulin and Vitamin E on the Apoptosis of Pancreatic Islet Cells in Multiple Low dose Streptozotocin Induced Diabetic (LDSD) Mice.
Yong Hyun Kim, Jeong Hun Oh, Nan Hee Kim, Kyung Muk Choi, Sang Jin Kim, Sei Hyun Baik, Eung Seok Lee, Min Chul Lee, Dong Seop Choi
Korean Diabetes J. 1999;23(6):757-767.   Published online January 1, 2001
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AbstractAbstract PDF
Type 1 diabetes mellitus results from irreversible loss of beta cells in pancreatic islet. It is generally known that abnormal MHC expression and interaction of variable cytokines play a role in beta cell death, but the precise mechanism of beta cell death is unknown. Apoptosis is a physiological form of cell death and can play an important role in beta cell death in experimental diabetic animal models. Thus, in insulin and vitamin E treated LDSD mice and streptozotocin treated control mice. We attempted to comparing the levels of blood glucose (BG), the degree of insulitis, and number of apoptotic cells. Our study goal was to understand inhibition of apoptosis which thought to play an important mechanism in reducing the degree of hyperglycemia and insulitis. METHODS: In 3 LDSD mice groups (group 1: control group with streptozotocin only, group 2: streptozotocin plus insulin, group 3: streptozotocin plus vitamin E), the effects of insulin and vitamin E on the blood glucose levels and the degree of insulitis were evaluated. The number of apoptotic cells of pancreatic islet was compared using double staining immunohistochemical method. RESULT: The levels of BG, degree of insulitis and the rate of apoptosis of pancreatic islet cells were decreased in insulin and vitamin E treated groups when compared to the control group. There was no difference in number of apoptotic cells between insulin and vitamin E treated group, but levels of BG and degree of insulitis were higher in vitamin E treated group than insulin treated group as time elapsed. CONCLUSION: Insulin and vitamin E can decrease the elevation of BG and the degree of insulitis via inhibition of apoptosis in LDSD mice.
The Study of Alteration of Beta Cells in Pancreatic Islets, Glusoce Metabolism and Insulin Secretion in Low Dose Streptozotocin Indeced Type 2 Diabetic Rat Model.
Young Goo Shin, Hong Seung Kim, Mi Deok Lee, Young Uck Kim, Ho Suck Kang, Tae Sun Hwang, Choon Hee Chung
Korean Diabetes J. 1999;23(3):256-268.   Published online January 1, 2001
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AbstractAbstract PDF
Korean diabetes is different from western diabetes due to the racial differences in genetic factors and susceptability. It has recently been suggested that thrifty phenotype hypothesis is related to the recent increase in prevalence of Korean diabetes, but we have little evidence about that. We obtained basic materials in the animal model of type 2 diabetes mellitus and conducted a morphologic study of the beta cell change, insulin secreting capacity, and glucose metabolism. METHODS: To obtain the reference data of a non-insulin dependent diabetic animal model, we performed the intraperitoneal glucose tolerance test (IPGTT), hyperinsulinemic euglycemic clamp and immunobistochemical staining on the sacrificed pancreatic tissues on a Sprague-Dawley male rat into which streptozotocin (STZ) had been injected during the early neonatal period. The study groups consisted of a normal control group with citrate buffer injection, a group with injection of 50 ug STZ per kg of weight and a group with injection of 75 ug STZ per kg of weight. STZ was injected within 12 hours after birth. RESULTS: l. Although, STZ injected groups had lower body weight than the control group 7 weeks after birth, there were no differences during 14 weeks. 2. The IPGTT results showed that the average level of whole blood glucose concentration of the group with 50 ug STZ per kg of weight was higher than that of the control group at 7 and 14 weeks after birth. The mean serum insulin concentration of the 75 ug STZ per kg of weight injected group was lower than that of the control group at 7 weeks after birth, but it was higher than that of the control group at 14 weeks. 3. The hyperinsulinemic euglycemic clamp study showed that the average level of peripheral glucose disposal rate of the STZ injected groups was lower than the control group, but there were no differences in the study groups. 4. Pancreatic islet showed decreased beta cell mass and increased beta cell size in the STZ injected groups but the BrdU labelling index was not different between the control and study groups. CONCLUSION: STZ injection into neonatal Sprague-Dawley male rats may result in a diabetic status due to both decreased insulin secretion and increased insulin resistance, which gives us useful reference data for type 2 diabetes mellitus in the animal model.
The Effect of Cyclosporine on Insulin Sensitivity in Streptozotocin Induced Diabetic Rats.
Ju Seop Kang, Dong Sun Kim, Chang Beom Lee, Yong Soo Park, Woong Hwan Choi, Tae Wha Kim, Mok Hyun Kim
Korean Diabetes J. 1999;23(2):142-146.   Published online January 1, 2001
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AbstractAbstract PDF
Cyclosporine (CsA), being used as a immunosuppressant is known to have deleterious effects on the liver and kidney, but the harmful effect on glucose tolerance has not been clearly elucidated. This study was undertaken to determine whether the CsA affected peripheral insulin sensitivity in streptozotocin (STZ)-induced diabetic Sprague-Dawley rats. METHODS: After the daily treatment of CsA (10mg/kg, i.p.) for 2 weeks, glucose tolerance tests were carried out by the intraperitoneal administration of glucose alone or in conjunction with insulin (5 U/kg, s.c.). The glucose tolerance and peripheral insulin sensitivity were determined by measuring the deremental area under the time-lasma glucose concentration curve (AUC; mg-min/mL) according to the trapezoidal rule. The plasma glucose levels (mg/dL) were measured by a glucose analyzer at 0, 10, 30, 60, 90 and 120min after glucose load (2 g/kg). The STZ-diabetic rats were divided into thre groups (GLU- as control, INS+GLU- and CsA+INS+GLU-treated group, n 7 in each groups). RESULTS: In STZ-diabetic rats, the AUC 0-120 of the CsA+INS+GLU-treated group was significantly (p<0.01) lower than those of the control group (48.6% of control), but significantly (p<0.03) higher thain those of the INS+GLUtreated group (28.1% of control). CONCLUSIONS: These results suggest that intraperitoneal injection of CsA gives rise to a deterioration of glucose etabolism which is probably due to a decrease of insulin sensitivity of peripheral tissue in STZ-diabetic rats.

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