Inactivation of specific β cell transcription factors in type 2 diabetes

Abstract

Type 2 diabetes (T2DM) commonly arises from islet β cell failure and insulin resistance. Here, we examined the sensitivity of key islet-enriched transcription factors to oxidative stress, a condition associated with β cell dysfunction in both type 1 diabetes (T1DM) and T2DM. Hydrogen peroxide treatment of β cell lines induced cytoplasmic translocation of MAFA and NKX6.1. In parallel, the ability of nuclear PDX1 to bind endogenous target gene promoters was also dramatically reduced, whereas the activity of other key β cell transcriptional regulators was unaffected. MAFA levels were reduced, followed by a reduction in NKX6.1 upon development of hyperglycemia in db/db mice, a T2DM model. Transgenic expression of the glutathione peroxidase-1 antioxidant enzyme (GPX1) in db/db islet β cells restored nuclear MAFA, nuclear NKX6.1, and β cell function in vivo. Notably, the selective decrease in MAFA, NKX6.1, and PDX1 expression was found in human T2DM islets. MAFB, a MAFA-related transcription factor expressed in human β cells, was also severely compromised. We propose that MAFA, MAFB, NKX6.1, and PDX1 activity provides a gauge of islet β cell function, with loss of MAFA (and/or MAFB) representing an early indicator of β cell inactivity and the subsequent deficit of more impactful NKX6.1 (and/or PDX1) resulting in overt dysfunction associated with T2DM.

MafA is critical for maintenance of the mature beta cell phenotype in mice

“…4a, b) and it was more sensitive to glucotoxic change than PDX1 (ESM Fig. 4c, d) as previously described [25,26,37]. In db/db mice, the beta to alpha cell ratio was reduced and hormone-negative cells were increased in the islets (ESM Fig.…”

“…The ectopic expression of MafA (Mafa), pancreatic and duodenal homeobox 1 (PDX1 [Pdx1]) and neurogenic differentiation 1 (NeuroD1 [Neurod1]) or neurogenin 3 (Ngn3, also known as Neurog3) converts adult pancreatic acinar cells or liver cells into insulin-expressing cells [11,24]. In addition, reduced MafA expression is a harbinger of beta cell dysfunction in human type 2 diabetes [25,26]. In the present study, we examined the role of MafA in the plasticity and homeostasis of beta cells in mice.…”

Selective and sequential loss of transcriptional factors: A hallmark of β‐cell failure in type 2 diabetes?

“…Translocation of FOXO1 from the cytosol to the nucleus was an earlier event than inactivation of MAFA, NKX6.1 and PDX1 during the course of development of β‐cell failure in db / db mice3. Both oxidative stress and ER stress induced translocation and retention of FOXO1 in the nucleus.…”

“…While MAFB is thought to play a role in the development of both α‐ and β‐cells, and its expression is also implicated in β‐cell adaptation during pregnancy in mice, the role of MAFB in human islets still remains unclear. MAFB expression was downregulated in the β‐cells of humans with type 2 diabetes, but not in the α‐cells3. However, as aforementioned, the physiological role of MAFB in adult human islet cells still remains unclear.…”

“…These FOXO1‐deficient β‐cells had lost the expressions of PDX1, MAFA and insulin, and instead expressed the progenitor markers neurogenin 3 (NEUROG3), v‐myc avian myelocytomatosis viral oncogene lung carcinoma‐derived homolog (MYCL), nanog homeobox (NANOG) and POU class 5 homeobox 1 (1 POU5F1). Meanwhile, according to one study, the expressions of NEUROG3, MYCL, NANOG and POU5F1 are unchanged in human diabetic islets3. Hence, the conversion of cell fate between α‐cells and β‐cells in human diabetic islets is still controversial.…”