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Mutations in SLC2A2 gene reveal hGLUT2 function in pancreatic β cell development
Aurélien Michau1, Ghislaine Guillemain, Alexandra Grosfeld
1From the INSERM UMRS872, Cordeliers Research Center, Université Pierre et Marie Curie, 75006 Paris, France.
The Journal of Biological Chemistry
|August 30, 2013
Summary
Investigating human glucose transporter 2 (hGLUT2) mutations reveals critical roles in insulin secretion and beta cell development. Some mutations enhance function, acting as receptors to trigger signaling pathways independently of glucose transport.
Area of Science:
- Molecular biology
- Endocrinology
- Cell biology
Background:
- The human glucose transporter 2 (hGLUT2), encoded by SLC2A2, plays a vital role in glucose transport and sensing in pancreatic beta cells.
- Understanding structure-function relationships of hGLUT2 is crucial for elucidating its impact on insulin secretion and beta cell differentiation.
Purpose of the Study:
- To investigate the structure-function relationships of hGLUT2 and its impact on insulin secretion and beta cell differentiation.
- To characterize naturally occurring and engineered mutations in hGLUT2, including those associated with Fanconi-Bickel syndrome.
Main Methods:
- Characterization of naturally occurring SLC2A2 variants (SNPs and Fanconi-Bickel syndrome mutations) and engineered mutations.
- Assay of sugar transport function in Xenopus oocytes.
- Evaluation of protein localization at the plasma membrane.
- Assessment of insulin secretion and beta cell differentiation in cultured rat embryonic pancreas.
Main Results:
- Single-nucleotide polymorphisms (P68L, T110I) did not affect sugar transport.
- Fanconi-Bickel syndrome mutations either prevented membrane targeting (G20D, S242R) or abolished transport capacity (P417L, W444R).
- Engineered mutations, while retaining membrane localization and transport, exhibited modified kinetics and gain-of-function properties.
- Specific mutations (G20S, L368P) increased insulin secretion independently of glucose and promoted beta cell differentiation.
- The F295Y mutation induced beta cell differentiation even without glucose, suggesting a glucose-transport-independent receptor function.
Conclusions:
- This study identifies the first gain-of-function mutations for hGLUT2.
- Results highlight the dual role of hGLUT2 as both a transporter and a receptor in pancreatic beta cell function and development.
- The receptor function of hGLUT2 can trigger signaling pathways crucial for insulin secretion and beta cell differentiation, independent of its transport activity.
Keywords:
Carbohydrate MetabolismFanconi-Bickel SyndromeGLUT2Glucose TransportInsulin SecretionMutantPancreatic IsletsXenopusMore Related Videos
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