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Updated: Feb 20, 2026
Generation of a Humanized Mouse Liver Using Human Hepatic Stem Cells
Published on: August 29, 2016
Elevated mouse hepatic betatrophin expression does not increase human β-cell replication in the transplant setting
Yang Jiao1, John Le Lay, Ming Yu
1Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
Abstract:
The recent discovery of betatrophin, a protein secreted by the liver and white adipose tissue in conditions of insulin resistance and shown to dramatically stimulate replication of mouse insulin-producing β-cells, has raised high hopes for the rapid development of a novel therapeutic approach for the treatment of diabetes. At present, however, the effects of betatrophin on human β-cells are not known. Here we use administration of the insulin receptor antagonist S961, shown to increase betatrophin gene expression and stimulate β-cell replication in mice, to test its effect on human β-cells. Although mouse β-cells, in their normal location in the pancreas or when transplanted under the kidney capsule, respond with a dramatic increase in β-cell DNA replication, human β-cells are completely unresponsive. These results put into question whether betatrophin can be developed as a therapeutic approach for treating human diabetes.
Insights
Betatrophin dramatically stimulates mouse beta-cell replication, but not human beta-cells. This finding questions betatrophin
Area of Science:
- Endocrinology
- Diabetes Research
- Cell Biology
Background:
- Betatrophin, a protein from liver and adipose tissue, stimulates mouse insulin-producing beta-cell replication.
- High hopes exist for betatrophin as a novel diabetes therapeutic.
- Effects of betatrophin on human beta-cells remain unknown.
Purpose of the Study:
- To investigate the effects of betatrophin on human beta-cells.
- To determine if betatrophin can be a viable therapeutic for human diabetes.
Main Methods:
- Administration of insulin receptor antagonist S961 to induce betatrophin expression.
- Testing the effect of S961-induced betatrophin on mouse and human beta-cells in vitro and in vivo (transplanted under kidney capsule).
Main Results:
- Mouse beta-cells showed a dramatic increase in DNA replication in response to betatrophin.
- Human beta-cells were completely unresponsive to betatrophin.
- S961 administration increased betatrophin gene expression and stimulated beta-cell replication in mice.
Conclusions:
- Betatrophin does not stimulate human beta-cell replication.
- The therapeutic potential of betatrophin for human diabetes is questionable.
- Further research is needed to understand species-specific responses to betatrophin.
