BETATROPHIN FACES SCRUTINY

Islets of Langerhans are made of four different cell types. 
The majority are insulin-producing beta cells (shown in green)

A study published in Cell last year offered evidence that a hormone called betatrophin, or Angiopoietin-like protein 8 (ANGPTL8), could ramp up pancreatic β cell proliferation in a mouse model of insulin resistance. [1] The results made quite a splash; the study’s authors—led by Doug Melton at Harvard University—even wrote that betatrophin treatment “could augment or replace insulin injections by increasing the number of endogenous insulin-producing cells in diabetics.” [2]

Early this month, Melton and his colleagues report a complex recipe that can transform either human ES cells or iPS cells directly into functional β cells. The breakthrough is based on more than a decade of tenacious work in Melton’s lab. He and his colleagues have painstakingly studied the signals that guide pancreas development, applying what they and others have found to develop a method that turns stem cells into mature β cells. “There’s no magic to this,” Melton says. “It’s not a discovery so much as applied developmental biology.” The protocol “is reproducible, but it is tedious,” Melton adds. The stem cells are grown in flasks and require five different growth media and 11 molecular factors, from proteins to sugars, added in precise combinations over 35 days to turn them into β cells. On the bright side, Melton says, the technique can produce 200 million β cells in a single 500 ml flask—enough, in theory, to treat a patient. Melton says the protocol seems to work equally well with ES and iPS cell lines. [3]

But a follow-up study by an independent group of researchers found that the hormone is not required for β cell function or growth. “The lack of expansion of the beta cell area could theoretically be due to simultaneous increases in replication and apoptosis frequencies. However, even if this were the case, it would not change our observation that Angptl8 overexpression did not increase beta cell area, contrary to what was reported by Yi et al. (2013),” Viktoria Gusarova of Regeneron Pharmaceuticals and her colleagues wrote in a Cell paper published October 23. [2]

 Melton’s group redid its experiments to see what might have caused the discrepancy, finding the same result as Gusarova’s team. The problem appears to have been variability in how the mice responded to betatrophin. “Some mice respond strongly to ANGPTL8/betatrophin expression but many do not” Melton and his colleagues wrote in a response article accompanying Gusarova’s study [2]

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References

1 P. Yi  et al: Betatrophin: A hormone that controls pancreatic B cell proliferation,
Cell 153, 747-758 (5) (2013)  | doi: 10.1016/j.cell.2013.04.008

2 Diabetes 'Breakthrough' breaks up | The Scientist |27 October 2014 | ArticleTS

3 For diabetes, stem cell recipe offers new hope |Science | 9 October 2014 | ArticleSci

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