Overexpression of kinase-dead mTOR impairs glucose homeostasis by regulating insulin secretion and not β-cell mass

Emilyn U. Alejandro, Nadejda Bozadjieva, Manuel Blandino Rosano, Michelle Ann Wasan, Lynda Elghazi, Suryakiran Vadrevu, Leslie Satin, Ernesto Bernal Mizrachi

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Abstract

Regulation of glucose homeostasis by insulin depends on β-cell growth and function. Nutrients and growth factor stimuli converge on the conserved protein kinase mechanistic target of rapamycin (mTOR), existing in two complexes, mTORC1 and mTORC2. To understand the functional relevance of mTOR enzymatic activity in β-cell development and glucose homeostasis, we generated mice overexpressing either one or two copies of a kinase-dead mTOR mutant (KD-mTOR) transgene exclusively in β-cells. We examined glucose homeostasis and β-cell function of these mice fed a control chow or highfat diet. Mice with two copies of the transgene [RIPCre; KD-mTOR (Homozygous)] develop glucose intolerance due to a defect in β-cell function without alterations in β-cell mass with control chow. Islets from RIPCre;KDmTOR (Homozygous) mice showed reduced mTORC1 and mTORC2 signaling along with transcripts and protein levels of Pdx-1. Islets with reduced mTORC2 signaling in their β-cells (RIPCre;Rictorfl/fl) also showed reduced Pdx-1. When challenged with a high-fat diet, mice carrying one copy of KD-mTOR mutant transgene developed glucose intolerance and β-cell insulin secretion defect but showed no changes in β-cell mass. These findings suggest that the mTOR-mediated signaling pathway is not essential to β-cell growth but is involved in regulating β-cell function in normal and diabetogenic conditions.

Original languageEnglish (US)
Pages (from-to)2150-2162
Number of pages13
JournalDiabetes
Volume66
Issue number8
DOIs
StatePublished - Aug 1 2017

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Sirolimus
Homeostasis
Phosphotransferases
Insulin
Glucose
Transgenes
Glucose Intolerance
High Fat Diet
Growth
Protein Kinases
Intercellular Signaling Peptides and Proteins
Diet
Food

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Overexpression of kinase-dead mTOR impairs glucose homeostasis by regulating insulin secretion and not β-cell mass. / Alejandro, Emilyn U.; Bozadjieva, Nadejda; Blandino Rosano, Manuel; Wasan, Michelle Ann; Elghazi, Lynda; Vadrevu, Suryakiran; Satin, Leslie; Bernal Mizrachi, Ernesto.

In: Diabetes, Vol. 66, No. 8, 01.08.2017, p. 2150-2162.

Research output: Contribution to journalArticle

Alejandro, Emilyn U. ; Bozadjieva, Nadejda ; Blandino Rosano, Manuel ; Wasan, Michelle Ann ; Elghazi, Lynda ; Vadrevu, Suryakiran ; Satin, Leslie ; Bernal Mizrachi, Ernesto. / Overexpression of kinase-dead mTOR impairs glucose homeostasis by regulating insulin secretion and not β-cell mass. In: Diabetes. 2017 ; Vol. 66, No. 8. pp. 2150-2162.
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