Loss of islet beta cells and/or impaired beta cell function cause type 1 or type 2 diabetes - diseases that are increasing at an alarming rate to reach epidemic levels worldwide. The overarching goal of our research is to investigate mechanisms responsible for maintaining beta cell function and to devise new strategies for enhancing beta-cell fitness and function to prevent or treat diabetes.

Current Projects

  1. Investigating mechanisms and processes for maintaining beta cell functionality

During the early phase of diabetes development, there is a gradual decline of beta cell function leading to impaired insulin secretion and glucose tolerance. As the disease progress, beta cell function and mass continue to decline to a point where the amount of released insulin no longer meets the metabolic demand – causing glucose to rise to a level at which symptoms occur and diabetes can be diagnosed. Investigating how beta cells maintain their fitness and functionality to achieve a sufficient and sustainable insulin secretion is essential for understanding how beta cell fails in diabetes and for inventing new therapies to restore beta cell function.

To this end, we asked the question whether, in vivo, there are subpopulations of islet beta cells exhibiting distinct functional states, for instance, beta cells that maintain (or could be restored to) a robust insulin secretion activity in response to secretagogue stimulation; and, if there is such a pool of functional islet beta cells, do they degenerate similarly or differently from other beta cells? Using a combination of methods including activity-dependent cell tagging, cell sorting, RNA-Seq and differential gene expression analysis, and cell lineage tracing, we have recently identified a subpopulation of islet beta cells with a distinct gene expression profile, glucose responsivity, and insulin secretion. We are currently performing detailed analysis of these cells to characterize their functional properties and to analyze their contributions to euglycemia control. (Read more)

Mouse islet immunolabelled for insulin (red), glucagon (blue), and somatostatin (green). This confocal image reconstruction of the cells at the exterior of the islet demonstrates the network of δ-cells and their proximity to α- and β-cells. Scale, 20 µm.
  1. Functional analysis of ZnT8 and zinc signaling in islet cells

Zn2+ is an important metal ion playing essential roles in diverse biological processes. Malfunction of cellular Zn2+ homeostasis is implicated in a number of human diseases including diabetes. Recent genome-wide association studies have uncovered that mutations of a Zn2+ transporter, ZnT8 (Slc30a8 gene), were associated with the risk of type 2 diabetes. ZnT8 is almost exclusively expressed in islet cells. Remarkably, haploinsufficiency of Slc30a8 is protective against diabetes, yet the underlying mechanism remains elusive. Using genetically engineered mouse models, we are investigating how variations in ZnT8 expression may affect diabetes susceptibility.

Immunofluorescence of human islet showing insulin in blue, ZnT8 in magenta, somatostatin in green and glucagon in red
  1. Probe development and targeted drug delivery

We combine the techniques of molecular engineering, chemistry, and genetics to develop probes for studying islet biology in vitro and in vivo. Currently, we are focusing on crafting fluorescent Zn2+ sensors for monitoring Zn2+ activity in various cellular compartments as a part of our efforts of studying Zn2+ signaling and ZnT8 in islet cells. To explore the translational potential of our research in islet biology, we are developing strategies to enable selective delivery of therapeutic agents to islet cells. 

Insulin granules within MIN-6 beta cells revealed by granule-specific fluorescent Zn(II) sensor.
  1. MicroRNA targets identification

MicroRNAs are small non-coding RNAs acting as posttranscriptional repressors of gene expression. Malfunction of microRNA production or regulation has been implicated in numerous human diseases including diabetes and cancer. Identifying mRNA targets of a given miRNA are essential for the functional analysis of a miRNA. We have developed a new experimental approach, TargetLink, that applied locked nucleic acid as the affinity probe to enrich target genes of a specific microRNA in intact cells. We are improving and applying TargetLink to define the role of miR-21 and other microRNAs in physiology or pathophysiology.

Workflow of TargetLink illustrated with miR-21 as an example. (Xu et al., RNA biology 2017, 259)