Nrf2 Regulates β-Cell Mass by Suppressing β-Cell Death and Promoting β-Cell Proliferation

Abstract

Finding therapies that can protect and expand functional β-cell mass is a major goal of diabetes research. Here we generated β-cell-specific conditional knockout and gain-of-function mouse models and used human islet transplant experiments to examine how manipulating Nrf2 levels affects β-cell survival, proliferation and mass. Depletion of Nrf2 in β-cells results in decreased glucose-stimulated β-cell proliferation ex vivo and decreased adaptive β-cell proliferation and β-cell mass expansion after a high fat diet in vivo. Nrf2 protects β-cells from apoptosis after a high fat diet. Nrf2 loss-of-function decreases Pdx1 abundance and insulin content. Activating Nrf2 in a β-cell-specific manner increases β-cell proliferation and mass and improves glucose tolerance. Human islets transplanted under the kidney capsule of immunocompromised mice and treated systemically with CDDO-Me, an Nrf2 activator, display increased β-cell proliferation. Thus, by managing ROS levels, Nrf2 regulates β-cell mass and is an exciting therapeutic target for expanding and protecting β-cell mass in diabetes.

Deletion of Thioredoxin Reductase Disrupts Redox Homeostasis and Impairs β-Cell Function

“…Indeed, Nrf2 expression is increased in islets in response to high fat diet, a condition that stimulates β-cell mass expansion. 80 Mouse islets depleted of Nrf2 have blunted replication in response to high glucose ex vivo , and β-cell mass expansion in response to high fat diet is impaired when Nrf2 is deleted. 80 Further, Nrf2-regulated S100a6, which is significantly increased in Txnrd1 -deficient β-cells, plays a role in stem cell renewal.…”

“… 80 Mouse islets depleted of Nrf2 have blunted replication in response to high glucose ex vivo , and β-cell mass expansion in response to high fat diet is impaired when Nrf2 is deleted. 80 Further, Nrf2-regulated S100a6, which is significantly increased in Txnrd1 -deficient β-cells, plays a role in stem cell renewal. 81 Additional studies are necessary to determine the mechanism utilized by Txnrd1 -knockout β-cells to establish and maintain mass.…”

Regulation of Pdx1 by oxidative stress and Nrf2 in pancreatic beta-cells

“…Additionaly, type-2 diabetic rodent models, such as db/db mice as well as mice and rats fed on high fat diet (HFD), display reduced Pdx1 mRNA and/or protein expression as well as decreased PDX1 nuclear localization ( 53 , 70 – 72 ). Similarly, beta-cell specific deletion of Nrf2 in mice fed on HFD results in increased oxidative stress, reduced Pdx1 mRNA levels and inhibition of PDX1 translocation into the nucleus ( 11 ). Conversely, treatment of obese diabetic C57BL/KsJ-db/db mice or Zucker diabetic rats with antioxidant agents restores PDX1 nuclear localization and PDX1 transcriptional activity ( 73 , 74 ).…”

“…Therefore, and perhaps as a compensatory mechanism, beta-cells protect themselves against oxidative stress by activating the nuclear factor erythroid 2-related factor ( Nrf2 ) antioxidant signaling pathway. This activation is performed by ROS which oxidize critical cysteine in the NRF2 inhibitor, KEAP1, thus inhibiting NRF2 degradation ( 7 , 11 ). Remarkably, apart from providing protection against oxidative stress, NRF2 regulates beta-cell mitochondrial biogenesis and activity, provides anti-inflammatory effects, promotes beta-cell function and stimulates beta-cell proliferation ( 7 , 11 ).…”

“…This activation is performed by ROS which oxidize critical cysteine in the NRF2 inhibitor, KEAP1, thus inhibiting NRF2 degradation ( 7 , 11 ). Remarkably, apart from providing protection against oxidative stress, NRF2 regulates beta-cell mitochondrial biogenesis and activity, provides anti-inflammatory effects, promotes beta-cell function and stimulates beta-cell proliferation ( 7 , 11 ).…”