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A Novel Rat Model of Type 2 Diabetes: The Zucker Fatty Diabetes Mellitus ZFDM Rat.

ABSTRACT: The Zucker fatty (ZF) rat harboring a missense mutation (fatty, fa) in the leptin receptor gene (Lepr) develops obesity without diabetes; Zucker diabetic fatty (ZDF) rats derived from the ZF strain exhibit obesity with diabetes and are widely used for research on type 2 diabetes (T2D). Here we establish a novel diabetic strain derived from normoglycemic ZF rats. In our ZF rat colony, we incidentally found fa/fa homozygous male rats having reproductive ability, which is generally absent in these animals. During maintenance of this strain by mating fa/fa males and fa/+ heterozygous females, we further identified fa/fa male rats exhibiting diabetes. We then performed selective breeding using the fa/fa male rats that exhibited relatively high blood glucose levels at 10 weeks of age, resulting in establishment of a diabetic strain that we designated Hos:ZFDM-Lepr(fa) (ZFDM). These fa/fa male rats developed diabetes as early as 10 weeks of age, reaching 100% incidence by 21 weeks of age, while none of the fa/+ male rats developed diabetes. The phenotypic characteristics of this diabetic strain are distinct from those of normoglycemic ZF rats. ZFDM rat strain having high reproductive efficiency should serve as a more useful animal model of T2D.

SUBMITTER: Yokoi N

PROVIDER: S-EPMC3647587 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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A Novel Rat Model of Type 2 Diabetes: The Zucker Fatty Diabetes Mellitus ZFDM Rat.

Yokoi Norihide N Hoshino Masayuki M Hidaka Shihomi S Yoshida Eri E Beppu Masayuki M Hoshikawa Ritsuko R Sudo Katsuko K Kawada Akihiko A Takagi Sadaaki S Seino Susumu S

Journal of diabetes research 20130226

The Zucker fatty (ZF) rat harboring a missense mutation (fatty, fa) in the leptin receptor gene (Lepr) develops obesity without diabetes; Zucker diabetic fatty (ZDF) rats derived from the ZF strain exhibit obesity with diabetes and are widely used for research on type 2 diabetes (T2D). Here we establish a novel diabetic strain derived from normoglycemic ZF rats. In our ZF rat colony, we incidentally found fa/fa homozygous male rats having reproductive ability, which is generally absent in these ...[more]

PMID: 23671847

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Project description:Background: Although substantial efforts have been made to link the gut microbiota to type 2 diabetes, dynamic changes in the fecal microbiome under the pathological conditions of diabetes have not been investigated. Methods: Four male Zucker diabetic fatty (ZDF) rats received Purina 5008 chow [protein = 23.6%, Nitrogen-Free Extract (by difference) = 50.3%, fiber (crude) = 3.3%, ash = 6.1%, fat (ether extract) = 6.7%, and fat (acid hydrolysis) = 8.1%] for 8 weeks. A total of 32 stool samples were collected from weeks 8 to 15 in four rats. To decipher the microbial populations in these samples, we used a 16S rRNA gene sequencing approach. Results: Microbiome analysis showed that the changes in the fecal microbiome were associated with age and disease progression. In all the stages from 8 to 15 weeks, phyla Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria primarily dominated the fecal microbiome of the rats. Although Lactobacillus and Turicibacter were the predominant genera in 8- to 10-week-old rats, Bifidobacterium, Lactobacillus, Ruminococcus, and Allobaculum were the most abundant genera in 15-week-old rats. Of interest, compared to the earlier weeks, relatively greater diversity (at the genus level) was observed at 10 weeks of age. Although the microbiome of 12-week-old rats had the highest diversity, the diversity in 13-15-week-old rats was reduced. Spearman's correlation analysis showed that F/B was negatively correlated with age. Random blood glucose was negatively correlated with Lactobacillus and Turicibacter but positively correlated with Ruminococcus and Allobaculum and Simpson's diversity index. Conclusion: We demonstrated the time-dependent alterations of the abundance and diversity of the fecal microbiome during the progression of diabetes in ZDF rats. At the genus level, dynamic changes were observed. We believe that this work will enhance our understanding of fecal microbiome development in ZDF rats and help to further analyze the role of the microbiome in metabolic diseases. Furthermore, our work may also provide an effective strategy for the clinical treatment of diabetes through microbial intervention.

Project description:BackgroundThe incidence of diabetes-associated cognitive dysfunction (DACD) is increasing; however, few clinical intervention measures are available for the prevention and treatment of this disease. Research has shown that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, particularly SBC-115076, have a protective effect against various neurodegenerative diseases. However, their role in DACD remains unknown. In this study, we aimed to explore the impact of PCSK9 inhibitors on DACD.MethodsMale Sprague-Dawley (SD) rats were used to establish an animal model of type 2 diabetes mellitus (T2DM). The rats were randomly divided into three groups: the Control group (Control, healthy rats, n = 8), the Model group (Model, rats with T2DM, n = 8), and the PCSK9 inhibitor-treated group (Treat, T2DM rats treated with PCSK9 inhibitors, n = 8). To assess the spatial learning and memory of the rats in each group, the Morris water maze (MWM) test was conducted. Hematoxylin-eosin staining and Nissl staining procedures were performed to assess the structural characteristics and functional status of the neurons of rats from each group. Transmission electron microscopy was used to examine the morphology and structure of the hippocampal neurons. Determine serum PCSK9 and lipid metabolism indicators in each group of rats. Use qRT-PCR to detect the expression levels of interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) in the hippocampal tissues of each group of rats. Western blot was used to detect the expression of PCSK9 and low-density lipoprotein receptor (LDLR) in the hippocampal tissues of rats. In addition, a 4D label-free quantitative proteomics approach was used to analyse protein expression in rat hippocampal tissues. The expression of selected proteins in hippocampal tissues was verified by parallel reaction monitoring (PRM) and immunohistochemistry (IHC).ResultsThe results showed that the PCSK9 inhibitor alleviated cognitive dysfunction in T2DM rats. PCSK9 inhibitors can reduce PCSK9, total cholesterol (TC), and low-density lipoprotein (LDL) levels in the serum of T2DM rats. Meanwhile, it was found that PCSK9 inhibitors can reduce the expression of PCSK9, IL-1β, IL-6, and TNF-α in the hippocampal tissues of T2DM rats, while increasing the expression of LDLR. Thirteen potential target proteins for the action of PCSK9 inhibitors on DACD rats were identified. PRM and IHC revealed that PCSK9 inhibitors effectively counteracted the downregulation of transthyretin in DACD rats.ConclusionThis study uncovered the target proteins and specific mechanisms of PCSK9 inhibitors in DACD, providing an experimental basis for the clinical application of PCSK9 inhibitors for the potential treatment of DACD.

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A Novel Rat Model of Type 2 Diabetes: The Zucker Fatty Diabetes Mellitus ZFDM Rat.

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A Novel Rat Model of Type 2 Diabetes: The Zucker Fatty Diabetes Mellitus ZFDM Rat.

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