Pancreatic β cell-inferred exosomal miR-29s control glucose homeostasis

Overview

• Post By : Kumar Jeetendra


• Source: Nanjing University School of Life Sciences


• Date: 24 Jan,2021

In a new study published in Journal of Extracellular Vesicles, Chen-Yu Zhang’s team at Nanjing University, School of Life Sciences, and Antonio Vidal-Puig’s group at University of Cambridge report that pancreatic β cells secrete miR-29 family members (miR-29s) via exosomes in reaction to high levels of free fatty acids (FFAs).

Formerly, Chen-Yu Zhang’s team identified biomedical miRNA as a new form of cell-to-cell communication. They are one of the first that reported that the selective secretion of miRNAs under different physiological or pathological states; additionally, the uptake and function of secreted miRNAs in recipient cells. In the past decade, intensive research have shown the role of extracellular miRNAs in a range of biological processes. Thus, as a newly-emerged secretory, more insightful studies have to further reveal its significance to more physiological progresses and ailments.

Pancreatic islet has long been identified as crucial secretory tissue in term of its function in maintaining glucose homeostasis by releasing conventional hormones, such as glucagon and insulin. Since pancreatic islet is a classic secretory organ, study to identify its secreted miRNAs and their functional implications in the regulation of glucose homeostasis is quite needed.

In the current study, they show that elevated levels of FFAs can induce the secretion of miR-29s from cultured pancreatic β cells. In vivo study revealed both physiological (fasting)-and pathological (obese)-related high levels of FFAs induce the secretion of miR-29s from pancreatic β cells.

Likewise, miR-29s are also increased in the plasma of obese human compared to normal human. Intriguingly, they found that exosomal miR-29s administrated intravenously can cause impaired insulin sensitivity. They used a combination of genetic modification animals to further confirm the functional role of secreted miR-29s.

Consistently, these mice show impaired insulin sensitivity. By tracking the distribution of mutant miR-29a, they found β cell-derived mutant miR-29a could be taken up by liver.

Mechanism dissections revealed that β cell-derived miR-29s negatively regulate insulin signaling pathway via targeting p85 α (regulatory subunit of PI3K), and then attenuate the suppression of insulin on glucose output. Finally, miR-29s lack in β cell considerably improves the insulin sensitivity in mice fed on HFD. This study not only describes a new secretory variable from pancreatic β cells, but also elucidates an alternative mechanism which underlies β cell-controlled glucose homeostasis.

This work is important for the following reasons:

1. We demonstrate pancreatic islets secrete not only canonical hormones, but also exosomal miRNAs, which is largely extended our understanding of islet function;
2.We identify a new secretory that play a role in regulation of glucose homeostasis.
3.We reveal a mechanism underlying obesity/FFAs-induced insulin resistance and type 2 diabetes. Obesity or high levels of FFA may not only directly affect liver, skeletal muscle and white adipose tissue and cause insulin resistance, but regulate exogenous secreted miRNA to indirectly result in pathophysiology as well. More importantly, the secreted miR-29s is increased prior to the onset of insulin resistance in ob/ob mice, indicating secreted miR-29s may be the factors that initiate the development of insulin resistance.
4.We provide further evidence for the selectivity of secreted miRNAs under certain physiological or pathological context.