Pioglitazone/microRNA‑141/FOXA2: A novel axis in pancreatic β‑cells proliferation and insulin secretion

Abstract

MicroRNAs (miRs) are considered to be effective, post‑transcriptional regulators in the pathophysiology of type 2 diabetes (T2D) and promising treatment targets. However, the function of miR‑141 remains to be elucidated. In the present study, upregulation of miR‑141 was demonstrated in diabetic mice and elderly diabetic patients. Using reverse transcriptase‑quantitative polymerase chain reaction, luciferase reporter assays and western blotting, forkhead box A2 (FOXA2) was identified as a direct target gene of miR‑141. The potential role of miRNA‑141 or FOXA2 was evaluated by overexpressing or silencing miR‑141 or FOXA2, respectively. The increased expression of miR‑141 resulted in impaired glucose‑stimulated insulin secretion (GSIS) and INS‑1 β cell proliferation. In addition, miR‑141 silencing in MIN6 pseudoislets or INS‑1 β cells led to reduced T2D‑associated damage. Furthermore, the expression of miR‑141 may be corrected by treatment with pioglitazone, which is widely used for insulin resistance therapy. The present study also demonstrated the mechanism by which miR‑141 regulated GSIS and proliferation through FOXA2. Overexpression of FOXA2 in MIN6 pseudoislets increased the effect of the miR‑141 inhibitor on GSIS. FOXA2 effectively reversed the effect of miR‑141 overexpression on β cell proliferation. In conclusion, the results of the present study indicate that the pioglitazone/miR‑141/FOXA2 axis may represent a promising target mechanism for T2D treatment.

Overexpression of miR-297b-5p protects against stearic acid-induced pancreatic β-cell apoptosis by targeting LATS2

“…Additionally, miR-34a was shown to contribute to lipotoxicity in palmitic or stearic acid-induced ␤-cell injury (25). Furthermore, an increased level of miR-141 can result in impaired glucose-stimulated insulin secretion in diabetic mice and elderly diabetic patients (47). miR-297, which often acts as a tumor suppressor, has been implicated in various physiological and pathological conditions, such as carcinoma (43,49), meiosis (44), and cardiac hypertrophy (3,50).…”

FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

“…[23][24][25][26][27] Glucose-induced DNA methylation in the promoter region and miRNAs such as miR-141, miR-124a, and miR-342 inhibit FOXA2 expression in pancreatic β cells. [28][29][30] In pancreatic α cells, memin interacts with FOXA2 to repress its transcriptional activity. 31 In the islets of type 2 diabetic animals and humans, nuclear FOXA2 distribution was decreased.…”

“…Transcription factor forkhead box protein A2 (FOXA2), also known as hepatocyte nuclear factor 3‐beta (HNF‐3β), is also critical for maintaining pancreatic cell functions by regulating PDX1 expression . Glucose‐induced DNA methylation in the promoter region and miRNAs such as miR‐141, miR‐124a, and miR‐342 inhibit FOXA2 expression in pancreatic β cells . In pancreatic α cells, memin interacts with FOXA2 to repress its transcriptional activity .…”

Insulin Resistance and Endometrial Cancer: Emerging Role for microRNA

“…Therefore, there should be a role for miR-200 in EMT. Upregulation of miR-141 has been demonstrated in IR, as well as in EC [169,170,196]. The increased expression of miR-141 resulted in impaired glucose-stimulated insulin secretion and pancreatic β-cell proliferation.…”

“…In addition, a positive correlation was observed in diabetic patients between miR-141 expression and blood glucose concentration. Forkhead box A2 (FOXA2) was identified as a direct miR-141 target gene [170]. Separate work demonstrated that FOXA2 must be important in tumorigenesis based on its role in the inhibition of EMT in cancer [203,204].…”