Insulin-Producing Intestinal K Cells Protect Nonobese Diabetic Mice From Autoimmune Diabetes

Mahdavi, Majid; Lam, Ada; Fujita, Yukihiro; Asadi, Ali; Grassl, Guntram A.; Dickie, Peter; Tan, Rusung; Cheung, Anthony; Kieffer, Timothy J.

doi:10.1053/j.gastro.2014.03.020

Cited by 8 publications

(7 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, diabetes incidence was significantly reduced in these mice. We have also observed that these K cells not only escape immune destruction, but that K cell insulin production appears to reduce the expected assault on pancreatic β‐cells in NOD mice, likely through the induction of immune tolerance to insulin.…”

Section: Targeting Gut Enteroendocrine Cellsmentioning

confidence: 62%

“…Our transgenic mice with insulin producing K cells showed high levels of insulin and proinsulin immunoreactivity, yet C‐peptide levels were comparable with non‐transgenic littermates. Further evaluation of the insulin produced by K cells, using insulin western blotting of intestinal lysates, suggested that the majority of the insulin immunoreactivity was proinsulin, although mature insulin was also produced (unpubl.…”

Section: Targeting Gut Enteroendocrine Cellsmentioning

confidence: 81%

“…Therefore, our group rationalized that K cells might be more suitable surrogates for β‐cells. We and others evaluated the feasibility of using these cells both in vitro , using a K cell line, and in vivo , using various transgenic mouse models. Moderately glucose‐responsive production of insulin was obtained from GIP‐expressing murine GTC‐1 cells (a derivative of STC‐1 cells) after transfection with a transgene comprised of a rat GIP promoter upstream of human preproinsulin.…”

Section: Targeting Gut Enteroendocrine Cellsmentioning

confidence: 99%

“…To explore the utility of endogenous K cells for insulin production, and avoid the issues encountered with transformed cell lines, our group generated transgenic mice in which human preproinsulin is coexpressed with GIP in gut K cells, and is secreted into the circulation in a meal‐dependent manner. These mice were protected from developing STZ‐induced diabetes and maintained normal glucose tolerance in the absence of exogenous insulin. To assess whether insulin‐producing K cells would be subjected to autoimmune attack similar to that which targets β‐cells in type 1 diabetes, we generated transgenic mice expressing murine insulin in K cells in the NOD mouse model of autoimmune diabetes.…”

Section: Targeting Gut Enteroendocrine Cellsmentioning

confidence: 99%

See 3 more Smart Citations

Engineering the gut for insulin replacement to treat diabetes

Mahdavi

Glavas

Kieffer

2016

J of Diabetes Invest

Self Cite

View full text Add to dashboard Cite

The gut epithelium's large surface area, its direct exposure to ingested nutrients, its vast stem cell population and its immunotolerogenic environment make it an excellent candidate for therapeutic cells to treat diabetes. Thus, several attempts have been made to coax immature gut cells to differentiate into insulin‐producing cells by altering the expression patterns of specific transcription factors. Furthermore, because of similarities in enteroendocrine and pancreatic endocrine cell differentiation pathways, other approaches have used genetically engineered enteroendocrine cells to produce insulin in addition to their endogenous secreted hormones. Several studies support the utility of both of these approaches for the treatment of diabetes. Converting a patient's own gut cells into meal‐regulated insulin factories in a safe and immunotolerogenic environment is an attractive approach to treat and potentially cure diabetes. Here, we review work on these approaches and indicate where we feel further advancements are required.

show abstract

Section: Targeting Gut Enteroendocrine Cellsmentioning

confidence: 62%

Section: Targeting Gut Enteroendocrine Cellsmentioning

confidence: 81%

Section: Targeting Gut Enteroendocrine Cellsmentioning

confidence: 99%

Section: Targeting Gut Enteroendocrine Cellsmentioning

confidence: 99%

See 2 more Smart Citations

Engineering the gut for insulin replacement to treat diabetes

Mahdavi

Glavas

Kieffer

2016

J of Diabetes Invest

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, from the therapeutic perspective, it may not be feasible to generate β cells by inhibiting Foxo1. Intestinal K cells have been engineered to produce insulin, which protect non-obese diabetic mice from autoimmune diabetes (Mojibian et al, 2014).…”

Section: Gastrointestinal Tissues To β Cell Reprogrammingmentioning

confidence: 99%

How to make insulin-producing pancreatic β cells for diabetes treatment

Lü

Xia

Zhou

2016

Sci. China Life Sci.

View full text Add to dashboard Cite

Around 400 million people worldwide suffer from diabetes mellitus. The major pathological event for Type 1 diabetes and advanced Type 2 diabetes is loss or impairment of insulin-secreting β cells of the pancreas. For the past 100 years, daily insulin injection has served as a life-saving treatment for these patients. However, insulin injection often cannot achieve full glucose control, and over time poor glucose control leads to severe complications and mortality. As an alternative treatment, islet transplantation has been demonstrated to effectively maintain glucose homeostasis in diabetic patients, but its wide application is limited by the scarcity of donated islets. Therefore, it is important to define new strategies to obtain functional human β cells for transplantation therapies. Here, we summarize recent progress towards the production of β cells in vitro from pluripotent stem cells or somatic cell types including α cells, pancreatic exocrine cells, gastrointestinal stem cells, fibroblasts and hepatocytes. We also discuss novel methods for optimizing β cell transplantation and maintenance in vivo. From our perspective, the future of β cell replacement therapy is very promising although it is still challenging to control differentiation of β cells in vitro and to protect these cells from autoimmune attack in Type 1 diabetic patients. Overall, tremendous progress has been made in understanding β cell differentiation and producing functional β cells with different methods. In the coming years, we believe more clinical trials will be launched to move these technologies towards treatments to benefit diabetic patients.

show abstract

In Vivo Reprogramming for Regenerating Insulin-Secreting Cells

Lü

Zhou

2017

In Vivo Reprogramming in Regenerative Medicine

View full text Add to dashboard Cite

Insulin-Producing Intestinal K Cells Protect Nonobese Diabetic Mice From Autoimmune Diabetes

Cited by 8 publications

References 33 publications

Engineering the gut for insulin replacement to treat diabetes

Engineering the gut for insulin replacement to treat diabetes

How to make insulin-producing pancreatic β cells for diabetes treatment

In Vivo Reprogramming for Regenerating Insulin-Secreting Cells

Contact Info

Product

Resources

About