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Published on: June 10, 2016
Transgenic overexpression of microRNA-30d in pancreatic beta-cells progressively regulates beta-cell function and
Yiping Mao1, Jacob Schoenborn1, Zhihong Wang1
1Department of Biological Sciences, Michigan Technological University, Houghton, MI, 49931, USA.
Abstract:
Abnormal microRNA functions are closely associated with pancreatic β-cell loss and dysfunction in type 2 diabetes. Dysregulation of miR-30d has been reported in the individuals with diabetes. To study how miR-30d affects pancreatic β-cell functions, we generated two transgenic mouse lines that specifically overexpressed miR-30d in β-cells at distinct low and high levels. Transgenic overexpressed miR-30d systemically affected β-cell function. Elevated miR-30d at low-level (TgL, 2-fold) had mild effects on signaling pathways and displayed no significant changes to metabolic homeostasis. In contrast, transgenic mice with high-level of miR-30d expression (TgH, 12-fold) exhibited significant diet-induced hyperglycemia and β-cell dysfunction. In addition, loss of β-cell identity was invariably accompanied with increased insulin/glucagon-double positive bihormonal cells and excess plasma glucagon levels. The transcriptomic analysis revealed that miR-30d overexpression inhibited β-cell-enriched gene expression and induced α-cell-enriched gene expression. These findings implicate that an appropriate miR-30d level is essential in maintaining normal β-cell identity and function.
Insights
MicroRNA-30d (miR-30d) dysregulation impacts pancreatic beta-cell function in type 2 diabetes. High miR-30d levels disrupt beta-cell identity and lead to hyperglycemia, underscoring its critical role.
Area of Science:
- Endocrinology
- Molecular Biology
- Diabetes Research
Background:
- Abnormal microRNA (miRNA) function is linked to pancreatic beta-cell loss and dysfunction in type 2 diabetes.
- Dysregulation of miR-30d has been observed in individuals with diabetes.
Purpose of the Study:
- To investigate the impact of miR-30d overexpression on pancreatic beta-cell function and identity.
- To determine the dose-dependent effects of miR-30d on metabolic homeostasis and beta-cell characteristics.
Main Methods:
- Generation of two transgenic mouse lines with distinct low (TgL) and high (TgH) levels of beta-cell-specific miR-30d overexpression.
- Assessment of metabolic homeostasis, beta-cell function, and beta-cell identity markers.
- Transcriptomic analysis to identify affected gene expression pathways.
Main Results:
- Low-level miR-30d overexpression (TgL) had minimal effects on signaling pathways and metabolic homeostasis.
- High-level miR-30d overexpression (TgH) resulted in diet-induced hyperglycemia, beta-cell dysfunction, and loss of beta-cell identity.
- TgH mice showed increased insulin/glucagon-double positive cells and elevated plasma glucagon.
- Transcriptomic analysis revealed inhibition of beta-cell genes and induction of alpha-cell genes.
Conclusions:
- Appropriate miR-30d levels are essential for maintaining normal pancreatic beta-cell identity and function.
- Elevated miR-30d disrupts beta-cell specific gene expression and promotes an alpha-cell phenotype.
- miR-30d is a critical regulator of beta-cell homeostasis and a potential therapeutic target in type 2 diabetes.
