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TBC1D1, a Rab‐GTPase Activating Protein, is Critical for Maintaining β‐cell Mass and Glucose Homeostasis
Author(s) -
Paglialunga Sabina,
Simnett Genevieve,
Robson Holly,
Houad Jacy,
Jain Swati,
Herbst Eric,
Snook Laelie,
Arkell Alicia,
Pillai Renjitha,
Dyck Davide,
Simpson Jeremy,
Bonen Arend,
Joseph Jamie,
Holloway Graham
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.958.5
Subject(s) - medicine , endocrinology , glucose homeostasis , rab , islet , glut4 , insulin , biology , glucose uptake , microbiology and biotechnology , insulin resistance , gtpase
Understanding the mechanisms regulating islet function is crucial for establishing novel therapeutic modalities to combat diabetes. TBC1D1, a Rab‐GTPase activating protein involved in skeletal muscle GLUT4 trafficking events, was recently identified withinβ‐cells and implicated in cell proliferation. However, the in vivo function of TBC1D1 remains to be elucidated. Therefore, we addressed the role of TBC1D1 in the pancreas utilizing a rat knockout (KO) model. Wild‐type and TBC1D1 KO rats were maintained on a chow or high‐fat diet. We demonstrated that TBC1D1 KO rats were glucose intolerant and displayed reduced insulin levels during a glucose challenge, suggesting that their phenotype prominently manifests within the pancreas. Next, we examined islet function and β‐cell mass. While, glucose‐stimulated insulin secretion from harvested islets was increased in TBC1D1 KO rats, we observed an overall decrease in β‐cell mass by ~30%. In addition, consumption of a high‐fat diet did not influence these changes observed in the KO rats. Altogether, our data suggests that in vivo impaired glucose homeostasis observed in TBC1D1 KO rats is a consequence of altered islet mass, thereby establishing a fundamental in vivo role for TBC1D1 in maintaining β‐cell mass. Therefore, pancreatic TBC1D1 may represent an attractive target to improve β‐cell function and stability to treat and prevent diabetes.