Artemether Does Not Turn α Cells into β Cells

Meulen, Talitha van der; Lee, Sharon; Noordeloos, Els; Donaldson, Cynthia J.; Adams, Michael W. W.; Noguchi, Glyn M.; Mawla, Alex M.; Huising, Mark O.

doi:10.1016/j.cmet.2017.10.002

Cited by 88 publications

(63 citation statements)

References 33 publications

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“…Li et al (20) reported that artemisinin can drive a cells into functional b-like cells through enhanced GABA signaling. But 2 subsequent papers failed to replicate this finding (21,22). These discrepancies could be due to several reasons.…”

Section: Discussionmentioning

confidence: 99%

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Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL‐4—producing T cells and regulatory T cells

Shi

Liu

et al. 2019

FASEB j.

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Type 1 diabetes (T1D) is an autoimmune disease characterized by the immune‐mediated destruction of insulin‐producing β cells. Recent studies showed that in addition to malaria, artemisinin and its derivative, artesunate (AS), could alleviate several autoimmune diseases. However, whether AS has a role in the prevention or treatment of T1D is still unknown. Therefore, in this study we administrated AS or DMSO in the drinking water of nonobese diabetic (NOD) mice, a mouse model of T1D. We found that AS administration significantly prevented the incidence of T1D. The frequency of IL‐4—producing CD4+ single‐positive T cells and CD8+ T cells was significantly elevated, and IFN‐γ—producing T cells were reduced in the spleen and pancreatic lymph nodes. In the pancreas, the skewing to IL‐4—producing T cells was also observed. In addition, more regulatory T cells were found in the pancreas. mRNA levels of proinflammatory cytokines, including TNF‐α and IL‐6, were decreased. In addition, AS administration promoted the functional maturity of β cells in vitro. Our findings demonstrate that AS administration can prevent T1D in NOD mice mainly by reducing autoimmune T cells and increasing protective T cells. Our data constitute the first functional study of AS in T1D, which may provide a new rationale for future translational studies.—Li, Z., Shi, X., Liu, J., Shao, F., Huang, G., Zhou, Z., Zheng, P. Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL‐4—producing T cells and regulatory T cells. FASEB J. 33, 8241–8248 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

“…In addition to the immune system, Li et al (20) reported that AS might have a role in promoting the transdifferentiation of a to b cells. However, this finding has been challenged (21,22).…”

mentioning

confidence: 99%

Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL‐4—producing T cells and regulatory T cells

Shi

Liu

et al. 2019

FASEB j.

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“…This leads to activation of the PI3K/Akt pathway and the enhancement of b-cell replication and survival (11,22,27,75,76). The increased b-cells are unlikely to arise from the transdifferentiation of human islet a-cells into b-cells because 1) that was observed only after long-term GABA treatment (2-3 mo, as opposed to the 10-d treatment period in our xenograft studies) (66,67), and 2) those observations have been called into question by others (77,78) as well as by our observations in mice given combination therapy (discussed above).…”

Section: Discussionmentioning

confidence: 73%

Homotaurine Treatment Enhances CD4+ and CD8+ Regulatory T Cell Responses and Synergizes with Low-Dose Anti-CD3 to Enhance Diabetes Remission in Type 1 Diabetic Mice

et al. 2019

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Immune cells express g-aminobutyric acid receptors (GABA-R), and GABA administration can inhibit effector T cell responses in models of autoimmune disease. The pharmacokinetic properties of GABA, however, may be suboptimal for clinical applications. The amino acid homotaurine is a type A GABA-R (GABA A-R) agonist with good pharmacokinetics and appears safe for human consumption. In this study, we show that homotaurine inhibits in vitro T cell proliferation to a similar degree as GABA but at lower concentrations. In vivo, oral homotaurine treatment had a modest ability to reverse hyperglycemia in newly hyperglycemic NOD mice but was ineffective after the onset of severe hyperglycemia. In severely diabetic NOD mice, the combination of homotaurine and low-dose anti-CD3 treatment significantly increased 1) disease remission, 2) the percentages of splenic CD4 + and CD8 + regulatory T cells compared with anti-CD3 alone, and 3) the frequencies of CD4 + and CD8 + regulatory T cells in the pancreatic lymph nodes compared with homotaurine monotherapy. Histological examination of their pancreata provided no evidence of the largescale GABA A-R agonist-mediated replenishment of islet b-cells that has been reported by others. However, we did observe a few functional islets in mice that received combined therapy. Thus, GABA A-R activation enhanced CD4 + and CD8 + regulatory T cell responses following the depletion of effector T cells, which was associated with the preservation of some functional islets. Finally, we observed that homotaurine treatment enhanced b-cell replication and survival in a human islet xenograft model. Hence, GABA A-R agonists, such as homotaurine, are attractive candidates for testing in combination with other therapeutic agents in type 1 diabetes clinical trials. ImmunoHorizons, 2019, 3: 498-510.

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“…The authors purported that artemisinins, including artemether, increase GABA signaling and prevent glucagon secretion by α-cells, resulting in their consequent loss of identity and transdifferentiation to a βlike phenotype, with associated increased insulin content and improvement in GSIS assessments [76]. However, follow up reports challenged these results, showing that neither artemisinins nor GABA directly cause α-to β-cell conversion [77,78].…”

Section: The Genetic Makeup Of β-Cells Defines Their Functionmentioning

confidence: 99%

Islet Identity in Transplantation Procedures: The Intersection of Cellular Maturity and Function

Beamish

Sabek²

2018

obm transplant

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Pancreatic islet transplantation holds promise for patients with insulin-dependent diabetes, but is severely limited by a shortage of cadaveric donor islets, and more so because of stringent inclusion criteria for organ donation including donor metabolic function, age, and comorbidities. The impact of these diverse factors on islet health has led to a broad investigation of global influences on islet biology, not least of all, characterization of mature, functional cellular identity and maintenance of appropriate endocrine lineage. This review will present the current knowledge on β-cell heterogeneity and inherent plasticity, and the role of cellular dedifferentiation of islets and β-cells in the normal and pathophysiological states, including aging, diabetes subtypes, and islet transplantation. Examination of potential strategies for reduction of metabolic stress by endogenous and exogenous modes is further discussed.

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Artemether Does Not Turn α Cells into β Cells

Cited by 88 publications

References 33 publications

Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL‐4—producing T cells and regulatory T cells

Artesunate prevents type 1 diabetes in NOD mice mainly by inducing protective IL‐4—producing T cells and regulatory T cells

Homotaurine Treatment Enhances CD4+ and CD8+ Regulatory T Cell Responses and Synergizes with Low-Dose Anti-CD3 to Enhance Diabetes Remission in Type 1 Diabetic Mice

Islet Identity in Transplantation Procedures: The Intersection of Cellular Maturity and Function

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