ABSTRACT
Preservation and expansion of ß-cell mass is a therapeutic goal for diabetes. Here we show that the hyperactive isoform of carbohydrate response-element binding protein (ChREBPß) is a nuclear effector of hyperglycemic stress occurring in ß-cells in response to prolonged glucose exposure, high-fat diet, and diabetes. We show that transient positive feedback induction of ChREBPß is necessary for adaptive ß-cell expansion in response to metabolic challenges. Conversely, chronic excessive ß-cell-specific overexpression of ChREBPß results in loss of ß-cell identity, apoptosis, loss of ß-cell mass, and diabetes. Furthermore, ß-cell "glucolipotoxicity" can be prevented by deletion of ChREBPß. Moreover, ChREBPß-mediated cell death is mitigated by overexpression of the alternate CHREBP gene product, ChREBPα, or by activation of the antioxidant Nrf2 pathway in rodent and human ß-cells. We conclude that ChREBPß, whether adaptive or maladaptive, is an important determinant of ß-cell fate and a potential target for the preservation of ß-cell mass in diabetes.
Subject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Insulin-Secreting Cells , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , Feedback , Glucose/metabolism , Humans , Insulin-Secreting Cells/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolismABSTRACT
We present an innovative technique which allows the simultaneous measurement of the dielectric constant of a material at many frequencies, spanning a four orders of magnitude range chosen between 10(-2) Hz and 10(4) Hz. The sensitivity and accuracy are comparable to those obtained using standard single frequency techniques. The technique is based on three new and simple features: (a) the precise real time correction of the amplification of a current amplifier, (b) the specific shape of the excitation signal and its frequency spectrum, and (c) the precise synchronization between the generation of the excitation signal and the acquisition of the dielectric response signal. This technique is useful in the case of relatively fast dynamical measurements when the knowledge of the time evolution of the dielectric constant is needed.