Novel murine model of congenital diabetes: The insulin hyposecretion mouse

Nakano, Kenta; Yanobu–Takanashi, Rieko; Takahashi, Yuki; Sasaki, Hayato; Shimizu, Yukiko; Okamura, Tadashi; Sasaki, Nobuya

doi:10.1111/jdi.12895

Cited by 4 publications

(12 citation statements)

References 41 publications

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“…Based on our in vitro data showing approximately 0.05% relative affinity for the IR, we decided to use 0.3 μmol/kg (50x higher concentration than insulin) of GIV and SGIV dcVILPs in male mice. Consistent with previous studies [ 9 , 45 ], insulin caused a 60% decrease in blood glucose in 60 min, after which glucose started to increase. Surprisingly, injection with 50x GIV or SGIV dcVILPs led to very severe hypoglycemia, which required termination of the experiment in 30 min by injecting glucose to save the animals ( Figure 3 A).…”

Section: Resultssupporting

confidence: 93%

Characterization of viral insulins reveals white adipose tissue-specific effects in mice

Marchand

Noh

Páníková

et al. 2021

Molecular Metabolism

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Objective Members of the insulin/insulin-like growth factor (IGF) superfamily are well conserved across the evolutionary tree. We recently showed that four viruses in the Iridoviridae family possess genes that encode proteins highly homologous to human insulin/IGF-1. Using chemically synthesized single-chain (sc), i.e., IGF-1-like, forms of the viral insulin/IGF-1-like peptides (VILPs), we previously showed that they can stimulate human receptors. Because these peptides possess potential cleavage sites to form double chain (dc), i.e., more insulin-like, VILPs, in this study, we have characterized dc forms of VILPs for Grouper iridovirus (GIV), Singapore grouper iridovirus (SGIV) and Lymphocystis disease virus-1 (LCDV-1) for the first time. Methods The dcVILPs were chemically synthesized. Using murine fibroblast cell lines overexpressing insulin receptor (IR-A or IR-B) or IGF1R, we first determined the binding affinity of dcVILPs to the receptors and characterized post-receptor signaling. Further, we used C57BL/6J mice to study the effect of dcVILPs on lowering blood glucose. We designed a 3-h dcVILP in vivo infusion experiment to determine the glucose uptake in different tissues. Results GIV and SGIV dcVILPs bind to both isoforms of human insulin receptor (IR-A and IR-B) and to the IGF1R, and for the latter, show higher affinity than human insulin. These dcVILPs stimulate IR and IGF1R phosphorylation and post-receptor signaling in vitro and in vivo. Both GIV and SGIV dcVILPs stimulate glucose uptake in mice. In vivo infusion experiments revealed that while insulin (0.015 nmol/kg/min) and GIV dcVILP (0.75 nmol/kg/min) stimulated a comparable glucose uptake in heart and skeletal muscle and brown adipose tissue, GIV dcVILP stimulated 2-fold higher glucose uptake in white adipose tissue (WAT) compared to insulin. This was associated with increased Akt phosphorylation and glucose transporter type 4 (GLUT4) gene expression compared to insulin in WAT. Conclusions Our results show that GIV and SGIV dcVILPs are active members of the insulin superfamily with unique characteristics. Elucidating the mechanism of tissue specificity for GIV dcVILP will help us to better understand insulin action, design new analogs that specifically target the tissues and provide new insights into their potential role in disease.

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Section: Resultssupporting

confidence: 93%

Characterization of viral insulins reveals white adipose tissue-specific effects in mice

Marchand

Noh

Páníková

et al. 2021

Molecular Metabolism

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show abstract

“…Based on our in vitro data showing about 0.05 % relative affinity for the IR, we decided to use 0.3 µmol/kg (50x higher concentration than insulin) GIV and SGIV dcVILPs in male mice. Consistent with previous studies 9,40 , insulin caused ~ 60% decrease in blood glucose in 60 minutes, after which glucose started to increase. Surprisingly, injection with 50x GIV or SGIV dcVILPs led to very severe hypoglycemia such that we needed to terminate the experiment in 30 minutes by injecting glucose to save the animals (Fig.…”

Section: Giv and Sgiv Dcvilps Are Active In Vivo And Stimulate Glucossupporting

confidence: 92%

Characterization of Viral Insulins Reveals White Adipose Tissue Specific Effects in Mice

Marchand

Noh

Páníková

et al. 2020

Preprint

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Members of the insulin/IGF superfamily are well conserved across the evolutionary tree. We recently showed that four viruses in the Iridoviridae family possess genes that encode proteins highly homologous to human insulin/IGF-1. Using chemically synthesized single chain (sc), i.e. IGF-1-like, forms of the viral insulin/IGF-1 like peptides (VILPs), we previously showed that they can stimulate human receptors. Because these peptides possess potential cleavage sites to form double chain (dc), i.e. more insulin-like, VILPs, in this study, we have characterized dc forms of VILPs for Grouper iridovirus (GIV), Singapore grouper iridovirus (SGIV) and Lymphocystis disease virus-1 (LCDV-1). GIV and SGIV dcVILPs bind to both isoforms of human insulin receptor (IR-A, IR-B) and to the IGF1R, and for the latter show higher affinity than human insulin. These dcVILPs stimulate IR and IGF1R phosphorylation and post-receptor signaling in vitro and in vivo. Both GIV and SGIV dcVILPs stimulate glucose uptake in mice. In vivo infusion experiments in awake mice revealed that while insulin (0.015 nmol/kg/min) and GIV dcVILP (0.75nmol/kg/min) stimulated a comparable glucose uptake in heart, skeletal muscle and brown adipose tissue, GIV dcVILP stimulated ~2 fold higher glucose uptake in white adipose tissue (WAT) compared to insulin. This was associated with increased Akt phosphorylation and glucose transporter type 4 (GLUT4) gene expression compared to insulin. Taken together, these results show that GIV and SGIV dcVILPs are active members of the insulin superfamily with unique characteristics. Elucidating the mechanism of tissue specificity for GIV dcVILP will help us to better understand insulin action, design new analogues that specifically target the tissues, and provide new insights into their potential role in disease.

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“…RT-qPCR analyses were performed as previously described, with minor modifications (Nakano et al 2018 ). Briefly, total RNAs from the kidneys and livers of 14-week-old male BN and LEA/Tohm rats were extracted as described above, and cDNA was prepared with ReverTra Ace (Toyobo).…”

Section: Methodsmentioning

confidence: 99%

A deletion in the Ctns gene causes renal tubular dysfunction and cystine accumulation in LEA/Tohm rats

et al. 2018

Self Cite

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The Long-Evans Agouti (LEA/Tohm) rat has recently been established as a new rat model of type 2 diabetes. The onset of diabetes mellitus was observed only in male LEA/Tohm rats; however, urinary glucose appeared before the onset of diabetes. To clarify the genetic basis of urinary glucose, we performed genetic linkage analysis using (BN × LEA) F 2 intercross progeny. A recessively acting locus responsible for urinary glucose excretion ( ugl ) was mapped to a 7.9 Mb region of chromosome 10, which contains the cystinosin ( Ctns ) gene. The Ctns gene encodes the cystine transporter, which transports cystine out of the lysosome and is responsible for nephropathic cystinosis in humans. Sequence analysis identified a 13-bp deletion in the Ctns gene, leading to a truncated and loss-of-function protein, which cause cystine accumulation in various tissues. We also developed a novel congenic rat strain harboring the Ctns ugl mutation on the F344 genetic background. Phenotypic analysis of F344- Ctns ugl rats indicated that the incidence of urinary glucose was 100% in both males and females at around 40 weeks of age, and marked cystine accumulation was observed in the tissues, as well as remarkable renal lesions and cystine crystals in the lysosomes of the renal cortex. Furthermore, treatment with cysteamine depleted the cystine contents in F344- Ctns ugl rat embryonic fibroblasts. These results indicated that the F344- Ctns ugl rat provides a novel rat model of cystinosis, which allows not only a better understanding of the pathogenesis and pathophysiology of cystinosis but will also contribute to the development of new therapies. Electronic supplementary material The online version of this article (10.1007/s00335-018-9790-3) contains supplementary material, which is available to authorized users.

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Novel murine model of congenital diabetes: The insulin hyposecretion mouse

Abstract: The ihs mouse provides a novel murine model of congenital diabetes that shows insulin secretion failure. This model allows not only an analysis of the progression of diabetes, but also the identification of unknown genes involved in insulin secretion.

Cited by 4 publications

References 41 publications

Characterization of viral insulins reveals white adipose tissue-specific effects in mice

Characterization of viral insulins reveals white adipose tissue-specific effects in mice

Characterization of Viral Insulins Reveals White Adipose Tissue Specific Effects in Mice

A deletion in the Ctns gene causes renal tubular dysfunction and cystine accumulation in LEA/Tohm rats

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