Delayed bone regeneration and low bone mass in a rat model of insulin-resistant type 2 diabetes mellitus is due to impaired osteoblast function

Patients with diabetes mellitus have an impaired bone metabolism; however, the underlying mechanisms are poorly understood. Here, we analyzed the impact of type 2 diabetes mellitus on bone physiology and regeneration using Zucker diabetic fatty (ZDF) rats, an established rat model of insulin-resistant type 2 diabetes mellitus. ZDF rats develop diabetes with vascular complications when fed a Western diet. In 21-wk-old diabetic rats, bone mineral density (BMD) was 22.5% (total) and 54.6% (trabecular) lower at the distal femur and 17.2% (total) and 20.4% (trabecular) lower at the lumbar spine, respectively, compared with nondiabetic animals. BMD distribution measured by backscattered electron imaging postmortem was not different between diabetic and nondiabetic rats, but evaluation of histomorphometric indexes revealed lower mineralized bone volume/tissue volume, trabecular thickness, and trabecular number. Osteoblast differentiation of diabetic rats was impaired based on lower alkaline phosphatase activity (−20%) and mineralized matrix formation (−55%). In addition, the expression of the osteoblast-specific genes bone morphogenetic protein-2, RUNX2, osteocalcin, and osteopontin was reduced by 40–80%. Osteoclast biology was not affected based on tartrate-resistant acidic phosphatase staining, pit formation assay, and gene profiling. To validate the implications of these molecular and cellular findings in a clinically relevant model, a subcritical bone defect of 3 mm was created at the left femur after stabilization with a four-hole plate, and bone regeneration was monitored by X-ray and microcomputed tomography analyses over 12 wk. While nondiabetic rats filled the defects by 57%, diabetic rats showed delayed bone regeneration with only 21% defect filling. In conclusion, we identified suppressed osteoblastogenesis as a cause and mechanism for low bone mass and impaired bone regeneration in a rat model of type 2 diabetes mellitus.

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Role of TLR4/MyD88/NF-κB signaling in heart and liver-related complications in a rat model of type 2 diabetes mellitus

Journal of International Medical Research ◽

10.1177/0300060521997590 ◽

2021 ◽

Vol 49 (3) ◽

pp. 030006052199759

Author(s):

Jiajia Tian ◽

Yanyan Zhao ◽

Lingling Wang ◽

Lin Li

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Signaling Pathway ◽

Rat Model ◽

Fasting Blood Glucose ◽

Diabetic Rats ◽

Primary Response ◽

Monocyte Chemoattractant Protein 1

Aims To analyze expression of members of the Toll-like receptor (TLR)4/myeloid differentiation primary response 88 (MyD88)/nuclear factor (NF)-κB signaling pathway in the heart and liver in a rat model of type 2 diabetes mellitus (T2DM). Our overall goal was to understand the underlying pathophysiological mechanisms. Methods We measured fasting blood glucose (FBG) and insulin (FINS) in a rat model of T2DM. Expression of members of the TLR4/MyD88/NF-κB signaling pathway as well as downstream cytokines was investigated. Levels of mRNA and protein were assessed using quantitative real-time polymerase chain reaction and western blotting, respectively. Protein content of tissue homogenates was assessed using enzyme-linked immunosorbent assays. Results Diabetic rats had lower body weights, higher FBG, higher FINS, and higher intraperitoneal glucose tolerance than normal rats. In addition, biochemical indicators related to heart and liver function were elevated in diabetic rats compared with normal rats. TLR4 and MyD88 were involved in the occurrence of T2DM as well as T2DM-related heart and liver complications. TLR4 caused T2DM-related heart and liver complications through activation of NF-κB. Conclusions TLR4/MyD88/NF-κB signaling induces production of tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1, leading to the heart- and liver-related complications of T2DM.

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Establishment of a rat model of bone regeneration in type 2 diabetes mellitus

Bone ◽

10.1016/j.bone.2010.04.203 ◽

2010 ◽

Vol 47 ◽

pp. S97-S98

Author(s):

C. Hamann ◽

C. Goettsch ◽

J. Mettelsiefen ◽

V. Henkenjohann ◽

U. Hempel ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Bone Regeneration ◽

Rat Model

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Exenatide inhibits JAK1/STAT1 expression and B cell apoptosis in insulin resistant rat model of type 2 diabetes mellitus

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2010.01189 ◽

2010 ◽

Vol 30 (11) ◽

pp. 1189-1192

Author(s):

Qi-jin WANG ◽

Da-jin ZOU ◽

Jian-qing TIAN ◽

Wei DING ◽

Chang-hua DING ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

B Cell ◽

Rat Model ◽

Cell Apoptosis ◽

Insulin Resistant

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The Biological Impacts of Sitagliptin on the Pancreas of a Rat Model of Type 2 Diabetes Mellitus: Drug Interactions with Metformin

Biology ◽

10.3390/biology9010006 ◽

2019 ◽

Vol 9 (1) ◽

pp. 6 ◽

Cited By ~ 1

Author(s):

Lamiaa M. Shawky ◽

Ahmed A. Morsi ◽

Eman El Bana ◽

Safaa Masoud Hanafy

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Rat Model ◽

Cell Damage ◽

Diabetic Rats ◽

Male Rats ◽

Control Group ◽

Dipeptidyl Peptidase 4

Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is a beneficial class of antidiabetic drugs. However, a major debate about the risk of developing pancreatitis is still existing. The aim of the work was to study the histological and immunohistochemical effects of sitagliptin on both endocrine and exocrine pancreases in a rat model of type 2 diabetes mellitus and to correlate these effects with the biochemical findings. Moreover, a possible synergistic effect of sitagliptin, in combination with metformin, was also evaluated. Fifty adult male rats were used and assigned into five equal groups. Group 1 served as control. Group 2 comprised of untreated diabetic rats. Group 3 diabetic rats received sitagliptin. Group 4 diabetic rats received metformin. Group 5 diabetic rats received both combined. Treatments were given for 4 weeks after the induction of diabetes. Blood samples were collected for biochemical assay before the sacrification of rats. Pancreases were removed, weighed, and were processed for histological and immunohistochemical examination. In the untreated diabetic group, the islets appeared shrunken with disturbed architecture and abnormal immunohistochemical reactions for insulin, caspase-3, and inducible nitric oxide synthase (iNOS). The biochemical findings were also disturbed. Morphometrically, there was a significant decrease in the islet size and islet number. Treatment with sitagliptin, metformin, and their combination showed an improvement, with the best response in the combined approach. No evidence of pancreatic injury was identified in the sitagliptin-treated groups. In conclusion, sitagliptin had a cytoprotective effect on beta-cell damage. Furthermore, the data didn’t indicate any detrimental effects of sitagliptin on the exocrine pancreas.

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The Hepatoprotective Effect of Jaboticaba Peel Powder in a Rat Model of Type 2 Diabetes Mellitus Involves the Modulation of Thiol/Disulfide Redox State through the Upregulation of Glutathione Synthesis

Journal of Nutrition and Metabolism ◽

10.1155/2018/9794629 ◽

2018 ◽

Vol 2018 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Andréia Quatrin ◽

Lisiane Conte ◽

Dariane Trivisiol da Silva ◽

Cassieli Gehlen Figueiredo ◽

Sabrina Somacal ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Rat Model ◽

Antioxidant Properties ◽

Redox Balance ◽

Diabetic Rats ◽

Hepatic Damage ◽

Glutathione Synthesis

Jaboticaba peel powder (JPP) is rich in bioactive compounds, mainly soluble and insoluble polyphenols with great antioxidant properties. The aim of this study is to evaluate the effects of JPP supplementation on the oxidative stress and hepatic damage in a rat model of type 2 diabetes mellitus (T2DM). Diabetic rats received vehicle or JPP at 2.7 (JPP-I), 5.4 (JPP-II), or 10.8 (JPP-III) g/L in drinking water during 8 weeks. JPP-III attenuated hyperglycaemia and dyslipidemia increased by 86% the liver content of nonprotein thiol groups and by 90% the GSH/GSSG ratio by activating glutathione synthesis. Accordingly, JPP supplementation prevented the loss of activity of the sulfhydryl-dependent enzymeδ-aminolaevulinic acid dehydratase and attenuated hepatic injury assessed by the reduction of serum aspartate aminotransferase activity and liver hypertrophy. Our results support that JPP supplementation to T2DM rats decreases hepatic damage most likely by increasing glutathione synthesis and modulating the thiol/disulfide redox balance.

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