KEYWORDS:
Insulin gene transcription factor and pancreatic β-cell failure
The hallmark of type 2 diabetes is pancreatic β-cell failure and insulin resistance in various insulin target tissues such as the liver, skeletal muscle and adipose tissues. Intact β-cells compensate for insulin resistance by augmenting insulin biosynthesis and secretion, but when β-cells are chronically exposed to hyperglycemia, β-cells fail to compensate insulin resistance, which leads to the aggravation of diabetes.[Citation1,Citation2] Such phenomena are well known as pancreatic β-cell glucose toxicity which is often observed in type 2 diabetes in practical medicine. It has been shown that oxidative stress is involved in such glucose toxicity. Oxidative stress is induced under diabetic conditions through the glycation reaction and electron transport chain in mitochondria and such oxidative stress leads to suppression of insulin gene expression and deterioration of β-cell function, which is accompanied by reduced expression of pancreatic transcription factors v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA) and pancreatic and duodenal homeobox factor-1 (PDX-1).[Citation3,Citation4] It is noted that MafA and PDX-1 are very important transcription factors for insulin gene in mature β-cells.[Citation3–Citation12] Furthermore, antioxidant treatment protects β-cells from glucose toxicity in various diabetic model animals; β-cell mass and insulin content are preserved by antioxidant treatment.[Citation13,Citation14] In addition, expression levels of MafA and PDX-1 are decreased by oxidative stress and those expression levels are preserved by antioxidant treatment. These data suggest that oxidative stress and reduction of insulin gene transcription factors such as MafA and PDX-1 are involved in β-cell glucose toxicity found in type 2 diabetes. It is noted, however, that there are many studies showing no effect or the opposite effect of oxidative stress and that small amounts of oxidative stress are thought to bring out beneficial effects.[Citation15,Citation16] Furthermore, it was recently reported that in pancreatic β-cell-specific MafA overexpressing diabetic db/db mice which can overexpress MafA in only β-cells upon tamoxifen treatment, β-cell function was preserved and blood glucose levels were significantly lower compared to untreated diabetic db/db mice.[Citation12] Therefore, it is likely that the down-regulation of MafA expression is particularly involved in the suppression of insulin biosynthesis and secretion and thereby is involved in β-cell glucose toxicity found in type 2 diabetes.
Incretin signaling and pancreatic β-cell failure
In response to ingestion of food, incretins such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released by the gastrointestinal tract, both of which stimulate insulin secretion. GLP-1 and GIP bind to each receptor in β-cell membrane, which facilities insulin secretion, suppresses β-cell apoptosis and increases β-cell growth. It is well known, however, that the action of incretin hormones is markedly reduced under diabetic conditions. It has been reported that expression levels of incretin receptors are down-regulated under diabetic conditions.[Citation17–Citation19] Therefore, it is likely that down-regulation of incretin receptors is involved in the impaired incretin effects and the β-cell failure observed in type 2 diabetes. Transcription factor 7-like 2 (TCF7L2) is a transcription factor acting for the wingless-type integration site family/β-catenin signaling pathway. It is known that common genetic variations of TCF7L2 are associated with type 2 diabetes [Citation20] and that TCF7L2 plays a crucial role in the maintenance of β-cell function.[Citation21–Citation23] Furthermore, it has been recently reported that the inactivation or deficiency of TCF7L2 in β-cells leads to down-regulation of incretin receptor expression.[Citation22,Citation23] Therefore, it is likely that TCF7L2 plays an important role in β-cells for glucose metabolism and decreased expression of TCF7L2 is, at least in part, involved in the down-regulation of incretin receptor expression.
Conclusion
Down-regulation of insulin gene transcription factors (MafA and PDX-1) and/or incretin receptors (GLP-1 receptor and GIP receptor) are likely involved in pancreatic β-cell failure, which is often observed in type 2 diabetes. Therefore, it is important to explore the methods to preserve such factors which would lead to the protection of β-cell function.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Additional information
Notes on contributors
Hideaki Kaneto
References
- Paper of special note have been highlighted as:
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