Betatrophin Versus Bitter-Trophin and the Elephant in the Room: Time for a New Normal in β-Cell Regeneration Research

  1. Andrew F. Stewart
  1. Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
  1. Corresponding author: Andrew F. Stewart, andrew.stewart{at}

The purpose of studying pancreatic β-cells in nonhuman species is to learn how to protect and regenerate the supply of residual endogenous β-cells in the face of the immunologic attack of type 1 diabetes, and the glucolipotoxic, inflammatory, endoplasmic reticulum- and oxidative stress–inducing environment of type 2 diabetes. β-Cell replication was unimaginable 20 years ago, when many believed that β-cells were irrevocably, terminally differentiated or senescent, and could never reenter the cell cycle. Enormous progress has been made over the past two decades. There are now many, many agonists that induce β-cells to replicate and expand. The agonists have included nutrients, growth factors, intracellular signaling molecules, small molecules discovered in high-throughput screens, proteins discovered in similar screens, or transgenic mouse models. Examples of these agonists are shown in Table 1, some of which are derived from work in the author’s group. Importantly, most of the β-cell replication and expansion resulting from these agonists has been observed in β-cells from mice, rats, pigs, and zebra fish. Surprisingly few induce human β-cells to replicate at therapeutically meaningful rates. Demonstration of human β-cell replication is an unspoken “elephant in the room” that is avoided in most reports.

View this table:
Table 1

Example of small molecules, growth factors, hormones, and nutrients that induce robust β-cell replication in rodents, but not in adult humans

One recent case in point is a report by Yi et al. (1) that attracted considerable attention both in the diabetes research community and in the lay media. Very briefly, Yi et al. described a novel …

| Table of Contents