Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure

Abstract

Preservation and expansion of β-cell mass is a therapeutic goal for diabetes. Here we show that the hyperactive isoform of carbohydrate response-element binding protein (ChREBPβ) is a nuclear effector of hyperglycemic stress occurring in β-cells in response to prolonged glucose exposure, high-fat diet, and diabetes. We show that transient positive feedback induction of ChREBPβ is necessary for adaptive β-cell expansion in response to metabolic challenges. Conversely, chronic excessive β-cell-specific overexpression of ChREBPβ results in loss of β-cell identity, apoptosis, loss of β-cell mass, and diabetes. Furthermore, β-cell “glucolipotoxicity” can be prevented by deletion of ChREBPβ. Moreover, ChREBPβ-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 β-cells. We conclude that ChREBPβ, whether adaptive or maladaptive, is an important determinant of β-cell fate and a potential target for the preservation of β-cell mass in diabetes.

Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity.

“…By contrast, following exposure to high glucose for 30 min, ChREBPα no longer interacted with 14-3-3, but the interaction was restored after 2 h ( Fig 5a ). These observations are consistent with our previous study showing that ChREBPα transiently enters the nucleus to begin the feed-forward induction of ChREBPβ (42). Remarkably, in the presence of 43 , the interaction between 14-3-3 and ChREBPα remained unchanged at high glucose concentrations, thus confirming that 43 stabilized the interaction between 14-3-3 and ChREBPα in high glucose.…”

“…S13f ). This result was consistent with our previous findings that a modest induction of ChREBPβ is required for adaptive β-cell expansion (14, 42, 43). Considering molecular glues as a potential therapeutic, it is likely that preservation of β-cell mass is more clinically relevant compared to the loss of an extremely low proliferation rate of human β-cells (90, 91).…”

“…Indeed, clinical trials have been launched with compounds that inhibit the induction of TXNIP in T1D (87–89). We recently described the destructive feed-forward production of ChREBPβ in β-cells in the context of prolonged hyperglycemia and diabetes (42, 87–89). Importantly, we found that deletion of the ChREBPβ isoform, using the Lox/Cre system, completely rescued β-cells from glucolipotoxicity.…”

“…Cells were washed with PBS and fixed in 4% paraformaldehyde. Immunolabeling was performed as previously described (ref) with primary antibodies directed against N-terminus ChREBP [1:250, (42)], C-terminus ChREBP (Novus, 1:250), Pdx1 (Abcam, 1:500), and Insulin (Fisher, 1:1000)…”

“…1a) (17,(37)(38)(39). ChREBPβ lacks this N-terminal domain, resulting in a nuclear, constitutively active, hyper-potent TF (40)(41)(42)(43). In healthy conditions, glucose flux leads to dissociation of CHREBPα from 14-3-3 resulting in its translocation to the nucleus and induction of ChREBPβ transcription, ultimately leading to glucose-stimulated β-cell proliferation to meet the demand for insulin (Fig.…”