A rare benign tumor may hold the key to understanding how to regenerate insulin-producing beta cells and consequently lead to the development of novel drugs for patients with diabetes, the results of a new US study indicate.
The researchers performed a series of analyses on insulinomas, rare pancreatic tumors that secrete too much insulin, and discovered a complex network of changes relative to normal beta cells that not only illuminate previous research on the regeneration of beta cells but point to a series of new pathways.
The work was published online in Nature Communications on October 3.
“For the first time, we have a genomic recipe, an actual wiring diagram in molecular terms that demonstrates how beta cells replicate,” commented coauthor Andrew Stewart, MD, director of the Diabetes, Obesity, and Metabolism Institute at the Icahn School of Medicine at Mount Sinai, New York, in a press release from his institution.
“The real innovation here is that we collected benign tumors that don’t metastasize and don’t cause great harm, and we’re trying to use these — that have beta-cell regeneration going on in them — as the only reasonable source of genomic information on how to make beta cells regenerate.”
Coauthor Dennis S Charney, MD, Anne and Joel Ehrenkranz Dean, Icahn School of Medicine at Mount Sinai, added: “We are excited and gratified by these remarkable results, which reveal an extraordinary array of new and validated pathways for diabetes drug development. In a very short time, we have made terrific progress.”
Knowing How to Look as Well as Where to Look
It is well-known that autoimmune-related loss of beta cells, which produce insulin, is associated with the development of type 1 diabetes, while the development of type 2 diabetes is linked to the deficiency of functioning beta cells in the pancreas.
Consequently, there has been a great deal of interest in the development of drugs that can increase the number of healthy, functioning beta cells.
Indeed, one class of compounds, harmine analogues, were previously shown by the same group of researchers to induce beta-cell proliferation, increase islet mass, and improve glycemic control in mice models of human diabetes (Nat Med. 2015;21:383-388).
In the current work, to better understand the process of beta-cell expansion and identify potential therapeutic pathways, the team studied 38 human insulinomas, rare slowly proliferating pancreatic beta-cell adenomas, and compared the findings with those from purified beta cells from 22 donors of normal cadaveric islets.
In the era of big data, knowing how to look, as well as where to look, is very important, explained coauthor Carmen Argmann, PhD, associate professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai.
“We looked at millions of data points collected in rare human insulinomas to try to find an answer to a common disease, diabetes. We then computationally created two molecular pictures from that data, one from the insulinoma and one for the normal beta cell, and identified the critical differences that will hopefully lead to new ways to expand beta-cell mass in diabetes patients,” she noted.
Holy Grail: How to Increase Number of Functioning Beta Cells
The new results did confirm that harmine is one pathway to beta-cell regeneration but also suggested a number of new routes that could potentially be targeted by therapeutics.
Interestingly, the researchers found that the strongest recurrent mutational signal among the insulinomas was related to the multiple endocrine neoplasia type 1 (MEN1) gene, despite the researchers attempting to exclude MEN1-associated tumors.
There were also 3709 differentially expressed protein-coding genes between insulinomas and normal beta cells, of which 2125 were upregulated and 1584 were downregulated in insulinomas.
Further analysis revealed that the upregulated genes were associated with biological processes such as immunity, vascular development, and cell proliferation.
Moreover, the team found that the same group of 2000 genes that are repressed in normal beta cells and related pancreatic and endocrine cells were overexpressed in insulinomas.
They also demonstrated that insulinomas contained a number of genetic alterations that were potentially related to cell proliferation.
Developing adenoviruses to over- or underexpress candidate proliferation drivers in human beta cells, the team found that the combination of EZH2 overexpression and CDKN1C silencing was the most effective at inducing human beta-cell replication, at rates similar to those seen in insulinomas.
“Altogether, these observations clearly illustrate that ‘insulinoma data mining’ can yield beta-cell regenerative targets,” they say.
Further studies involving a variety of genomic analyses and comparing malignant and nonmalignant insulinomas “will deepen the description of the proliferating human beta cell and provide additional opportunities for therapeutic drug discovery,” they summarize.
The research was supported by National Institute of Diabetes and Digestive and Kidney Diseases grants. It was also supported by the New Jersey–based Foundation for Diabetes Research and by the National Institute of Health. The authors report no relevant financial relationships.
Nature Commun. Published online October 3, 2017. Article
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