Amino Acids-Rab1A Nutrient Signaling in the Regulation of Glucose Homeostasis

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Amino acids (AAs) are basic building blocks and fuels of life. They are also increasingly appreciated as chemical signals that regulate growth and metabolic processes. Accumulating evidence clearly show that AA sensing and signaling play a critical role in health and diseases. mTOR is a master regulator of AA sensing and signaling. Recent progress has led to some basic understanding of how AA activates mTOR. Rag, a heterodimeric small GTPase anchored on the lysosomes, was shown to activate mTOR in response to AA stimulation. Surprisingly, we and others found that AAs can still activate mTOR in Rag-knockout yeast and mice, indicating that an alternative AA signaling mechanism exists. In a recently published study, we carried out a yeast genetic screening and identified Rab1A, a small GTPase localized on the ER/Golgi, represents a novel, conserved mediator of AA signaling upstream of mTOR in yeast and mammals (Thomas et al., Cancer Cell 26:754). To date, the physiological functions of AA-Rab1A signaling are not known. Therefore, we generated tamoxifen- induced whole body Rab1A knockout in young adult mice. Rab1A knockout animals were relatively normal except exhibiting hyperglycemia and glucose intolerance. Further analysis showed that the mutant animals had significantly smaller β-cell mass and their β-cells underwent trans-differentiation to α-cells. Moreover, both insulin mRNA and protein expression were markedly reduced in Rab1A knockout pancreatic β-cells. Consistently, we further showed that AA-Rab1A signaling regulated insulin transcription in β-cell lines. Based on these preliminary results, we propose to test the hypothesis that β-cell-autonomous AA-Rab1A signaling controls glucose homeostasis by regulating insulin transcription, β-cell proliferation and maintenance in mammals. We will dissect the basic mechanisms and significance under normal physiological and pathological conditions using cell and genetically engineered mouse models. If successful, this project will enhance the basic knowledge on how nutrients control whole body’s glucose homeostasis. It could also lead to new opportunities for nutritional and/or therapeutic intervention for diabetes, cancer and other related diseases.