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Rfx6 directs islet formation and insulin production in mice and humans.

ABSTRACT: Insulin from the beta-cells of the pancreatic islets of Langerhans controls energy homeostasis in vertebrates, and its deficiency causes diabetes mellitus. During embryonic development, the transcription factor neurogenin 3 (Neurog3) initiates the differentiation of the beta-cells and other islet cell types from pancreatic endoderm, but the genetic program that subsequently completes this differentiation remains incompletely understood. Here we show that the transcription factor Rfx6 directs islet cell differentiation downstream of Neurog3. Mice lacking Rfx6 failed to generate any of the normal islet cell types except for pancreatic-polypeptide-producing cells. In human infants with a similar autosomal recessive syndrome of neonatal diabetes, genetic mapping and subsequent sequencing identified mutations in the human RFX6 gene. These studies demonstrate a unique position for Rfx6 in the hierarchy of factors that coordinate pancreatic islet development in both mice and humans. Rfx6 could prove useful in efforts to generate beta-cells for patients with diabetes.

SUBMITTER: Smith SB

PROVIDER: S-EPMC2896718 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Rfx6 directs islet formation and insulin production in mice and humans.

Smith Stuart B SB Qu Hui-Qi HQ Taleb Nadine N Kishimoto Nina Y NY Scheel David W DW Lu Yang Y Patch Ann-Marie AM Grabs Rosemary R Wang Juehu J Lynn Francis C FC Miyatsuka Takeshi T Mitchell John J Seerke Rina R Désir Julie J Vanden Eijnden Serge S Abramowicz Marc M Kacet Nadine N Weill Jacques J Renard Marie-Eve ME Gentile Mattia M Hansen Inger I Dewar Ken K Hattersley Andrew T AT Wang Rennian R Wilson Maria E ME Johnson Jeffrey D JD Polychronakos Constantin C German Michael S MS

Nature 20100201 7282

Insulin from the beta-cells of the pancreatic islets of Langerhans controls energy homeostasis in vertebrates, and its deficiency causes diabetes mellitus. During embryonic development, the transcription factor neurogenin 3 (Neurog3) initiates the differentiation of the beta-cells and other islet cell types from pancreatic endoderm, but the genetic program that subsequently completes this differentiation remains incompletely understood. Here we show that the transcription factor Rfx6 directs isl ...[more]

PMID: 20148032

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Project description:Islet transplantation is a promising potential therapy for patients with type 1 diabetes. The outcome of islet transplantation depends on the transplantation of a sufficient amount of ?-cell mass. However, the initial loss of islets after transplantation is problematic. We hypothesized the hyperglycemic status of the recipient may negatively affect graft survival. Therefore, in the present study, we evaluated the effect of insulin treatment on islet transplantation involving a suboptimal amount of islets in Akita mice, which is a diabetes model mouse with an Insulin 2 gene missense mutation. Fifty islets were transplanted under the left kidney capsule of the recipient mouse with or without insulin treatment. For insulin treatment, sustained-release insulin implants were implanted subcutaneously into recipient mice 2 weeks before transplantation and maintained for 4 weeks. Islet transplantation without insulin treatment did not reverse hyperglycemia. In contrast, the group that received transplants in combination with insulin treatment exhibited improved fasting blood glucose levels until 18 weeks after transplantation, even after insulin treatment was discontinued. The group that underwent islet transplantation in combination with insulin treatment had better glucose tolerance than the group that did not undergo insulin treatment. Insulin treatment improved graft survival from the acute phase (i.e., 1 day after transplantation) to the chronic phase (i.e., 18 weeks after transplantation). Islet apoptosis increased with increasing glucose concentration in the medium or blood in both the in vitro culture and in vivo transplantation experiments. Expression profile analysis of grafts indicated that genes related to immune response, chemotaxis, and inflammatory response were specifically upregulated when islets were transplanted into mice with hyperglycemia compared to those with normoglycemia. Thus, the results demonstrate that insulin treatment protects islets from the initial rapid loss that is usually observed after transplantation and positively affects the outcome of islet transplantation in Akita mice.

Dataset Information

Rfx6 directs islet formation and insulin production in mice and humans.

Publications

Rfx6 directs islet formation and insulin production in mice and humans.

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