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Metabolic disorders: Betatrophin boosts β-cells
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Although the underlying causes of type 1 and type 2 diabetes differ, reduced insulin-producing pancreatic β-cell mass is a central feature of both forms of the disease. Restoring functional β-cell mass is therefore a key goal of diabetes therapy. Now, writing in Cell, Melton and col- leagues report a novel liver-secreted hormone named betatrophin that promotes β-cell proliferation and improves glucose tolerance in mice. Several reports have shown that various systemic and circulating factors can regulate β-cell mass and function, but the therapeutic manipulation of these genes and hormones has been limited by their lack of specificity and modest effects. Therefore, with the aim of identifying new potential therapeutic strategies, the authors set out to identify novel factors that may be involved in the regulation of β-cell mass. As a compensatory increase in β-cell proliferation occurs in situations of insulin resistance, the authors first developed a new pharmacological model of severe insulin resistance. They infused adult mice with S961, a 43-amino-acid peptide that binds to the insulin receptor and antagonizes insulin signalling, and found it to rapidly induce glucose intolerance, insulin resistance, β-cell proliferation and the expansion of β-cell mass. Next, to understand the mecha- nism by which S961 induced β-cell proliferation, the authors directly applied the peptide to β-cells in vitro. They saw no effect, which suggested that S961 was acting indirectly. Analysis of the effects of S961 in metabolically active tissues revealed that the expression of one gene, which they named betatrophin, was significantly upregulated in the liver and white adipose tissue of mice. Betatrophin mRNA expression was also upregulated in the liver of two different mouse models of diabetes (ob/ob and db/db mice), which exhibit an increased pancreatic β-cell mass. In humans, they found betatrophin to be predominantly expressed in the liver. Sequence analysis of the 198-amino-acid betatrophin protein showed a predicted secretion signal at the amino terminus. Furthermore, when plasmids expressing beta- trophin were used to transfect liver cells in vitro or express betatrophin in the mouse liver, betatrophin protein was found in vesicle-like structures and detected in the supernatant or plasma, respectively, as would be expected for a secreted protein. In addition, betatrophin was detected in human plasma, which demonstrates that endogenous beta- trophin is a secreted protein in vivo. Finally, they confirmed whether betatrophin affected pancreatic β-cell proliferation. The use of hydrodynamic tail vein injection to deliver betatrophin expression constructs to the liver of mice resulted in a striking 17-fold increase in the rate of β-cell proliferation compared to control mice. After just 8 days, this translated into a threefold higher pancreatic β-cell area in the treated mice, in conjunction with improved β-cell function; the treated mice had lower fasting glucose levels and improved glucose tolerance. Importantly, the effect on proliferation was specific for β-cells. The identification of betatrophin as a hormone that can control β-cell replication opens a new door to a possible future diabetes therapy. Evotec and Johnson & Johnson have rights to the molecule and plan to turn it into a preclinical type 2 diabetes candidate this year. Sarah Crunkhorn METABOLIC DISORDERS Betatrophin boosts β-cells ORIGINAL RESEARCH PAPER Yi, P. et al. Betatrophin: a hormone that controls pancreatic β cell proliferation. Cell 153, 747–758 (2013) Romantiche/Alamy RESEARCH HIGHLIGHTS NATURE REVIEWS | DRUG DISCOVERY VOLUME 12 | JULY 2013 Nature Reviews Drug Discovery | AOP, published online 21 June 2013; doi:10.1038/nrd4058 © 2013 Macmillan Publishers Limited. All rights reserved
Transcript of Metabolic disorders: Betatrophin boosts β-cells
Although the underlying causes of type 1 and type 2 diabetes differ, reduced insulin-producing pancreatic β-cell mass is a central feature of both forms of the disease. Restoring functional β-cell mass is therefore a key goal of diabetes therapy. Now, writing in Cell, Melton and col-leagues report a novel liver-secreted hormone named betatrophin that promotes β-cell proliferation and improves glucose tolerance in mice.
Several reports have shown that various systemic and circulating factors can regulate β-cell mass and function, but the therapeutic manipulation of these genes and hormones has been limited by their lack of specificity and modest effects. Therefore, with the aim of identifying new potential therapeutic strategies, the authors set out to identify novel factors that may be involved in the regulation of β-cell mass.
As a compensatory increase in β-cell proliferation occurs in situations of insulin resistance, the authors first developed a new pharmacological model of severe insulin resistance. They infused adult mice with S961, a 43-amino-acid peptide that binds to the insulin receptor and antagonizes insulin signalling, and found it to rapidly induce glucose intolerance, insulin resistance, β-cell proliferation and the expansion of β-cell mass.
Next, to understand the mecha-nism by which S961 induced β-cell proliferation, the authors directly applied the peptide to β-cells in vitro. They saw no effect, which suggested that S961 was acting indirectly. Analysis of the effects of S961 in metabolically active tissues revealed that the expression of one gene, which they named betatrophin, was significantly upregulated in the liver and white adipose tissue of mice.
Betatrophin mRNA expression was also upregulated in the liver of two different mouse models of diabetes (ob/ob and db/db mice), which exhibit an increased pancreatic β-cell mass. In humans, they found beta trophin to be predominantly expressed in the liver.
Sequence analysis of the 198-amino-acid betatrophin protein showed a predicted secretion signal at the amino terminus. Furthermore, when plasmids expressing beta-trophin were used to transfect liver cells in vitro or express betatrophin in the mouse liver, betatrophin protein was found in vesicle-like structures and detected in the supernatant or plasma, respectively, as would be expected for a secreted protein. In addition, betatrophin was detected in human plasma, which demonstrates that endogenous beta-trophin is a secreted protein in vivo.
Finally, they confirmed whether betatrophin affected pancreatic β-cell proliferation. The use of
hydro dynamic tail vein injection to deliver betatrophin expression constructs to the liver of mice resulted in a striking 17-fold increase in the rate of β-cell proliferation compared to control mice. After just 8 days, this translated into a threefold higher pancreatic β-cell area in the treated mice, in conjunction with improved β-cell function; the treated mice had lower fasting glucose levels and improved glucose tolerance. Importantly, the effect on proliferation was specific for β-cells.
The identification of betatrophin as a hormone that can control β-cell replication opens a new door to a possible future diabetes therapy. Evotec and Johnson & Johnson have rights to the molecule and plan to turn it into a preclinical type 2 diabetes candidate this year.
Sarah Crunkhorn
M E TA B O L I C D I S O R D E R S
Betatrophin boosts β-cells
ORIGINAL RESEARCH PAPER Yi, P. et al. Betatrophin: a hormone that controls pancreatic β cell proliferation. Cell 153, 747–758 (2013)
Rom
anti
che/
Ala
my
R E S E A R C H H I G H L I G H T S
NATURE REVIEWS | DRUG DISCOVERY VOLUME 12 | JULY 2013
Nature Reviews Drug Discovery | AOP, published online 21 June 2013; doi:10.1038/nrd4058
© 2013 Macmillan Publishers Limited. All rights reserved
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