5th Annual GNF-JDRF Diabetes Research Symposium

April 23, 2014; San Diego, CA Full Commentary - Draft

Executive Highlights

Hello from sunny San Diego where we attended yesterday’s 5th Annual Diabetes Research Symposium hosted by the Genomics Institute of the Novartis Research Foundation (GNF) and the JDRF. The theme for this year’s meeting was “New Frontiers in Beta Cell Biology” and it drew about fifty academic and industry researchers (many from GNF) to GNF’s headquarters. 

As background, in late 2009, the GNF and JDRF began collaborating on work to cure type 1 diabetes. In his introduction to the meeting, Dr. Richard Insel (JDRF, New York City, NY) explained that two of the goals of the Symposium are to i) be transparent in the work the JDRF and GNF are conducting; and ii) catalyze partnerships between GNF and academia. Dr. Insel highlighted GNF’s extensive resources and encouraged the academic community to take advantage of them.

The meeting included approximately five hours of scientific presentations, which dug into topics ranging from how adiponectin influences beta cell function, to the role of certain transcription factors in beta cell function. We have detailed our top five learnings from these presentations below. Additionally, at the end of the meeting Dr. Insel provided a valuable recap of the day, synthesizing eight points:

1. The beta cell is part of a system, and one must think about the context and connections within which it exists and interacts.

2. Not all humans are the same; they have different numbers of beta cells and islets. (Dr. Al Powers commented that beta cell mass in healthy people can vary by as much as six- fold.) Additionally, Dr. Insel highlighted that not all type 1 diabetes is the same. As an example, he emphasized that a child diagnosed with type 1 diabetes before the age of five years, likely has a different disease pathogenesis than a person diagnosed over 30 years old.

3. Human beta cells are not equivalent to rodent beta cells, and yet researchers need to translate between these two. (An example of this difference presented during the meeting was delivered by Dr. Alvin Powers [Vanderbilt University, Nashville, TN]: a mouse islet is comprised of 75% beta cells, 19% alpha cells, and 6% delta cells, whereas, a human islet contains 54% beta cells, 35% alpha cells, and 11% delta cells.)

4. When trying to promote beta cell survival, researchers need to target non-adaptive endoplasmic reticulum stress induced death pathways, such as mediated by TXNIP, rather than adaptive pathways.  

5. Human beta cell proliferation can be induced with low molecular weight compounds.

6. Beta cell dedifferentiation needs to be taken into account and appears to be a cause of beta cell failure in T2D. There is plasticity of dedifferentiated beta cells with the ability to convert to alpha or delta cells

7. Thioredoxin-interacting protein (TXNIP) deficiency can protect against diabetes, and improves beta cell survival, function, and insulin production.

8. One can boost the “efficiency” (i.e., level insulin secretion in a glucose sensitive manner) of residual beta cells using SNARE proteins (which the secretion of insulin) or decreasing beta cell stress.


Top Five Highlights

1. One of the encouraging points of the meeting for us was the improved tools for the study of beta cell function that are becoming available – though slowly. For example, Dr. Raphael Scharfmann (INSERM U1016 Institute Cochin, Paris, France) walked through the work he has been doing since 1999 on developing human beta cell lines so that researchers would not be as dependent on rodent models. In 2011, his lab derived a human beta cell line (EndoC-betaH1) by targeted oncogenesis (tumor induction) of a human fetal pancreas. As of September 2013, more than 60 labs worldwide had received EndoC-betaH1 cells, which expresses beta cell markers and secretes insulin. However, unlike true beta cells EndoC-betaH1 continue to proliferate. Earlier this year, Dr. Scharfmann’s group published a paper on a new generation of the cell line, EndoC-betaH2, whose proliferation is markedly decreased, enabling them to answer more questions with the cells (Scharfmann et al., J Clin Invest 2014). Notably, in his closing comments Dr. Insel also mentioned rumors that mature beta cells derived from human embryonic stem cell lines may become available to researchers in the near future. This would further open the research possibilities for investigators due to the likely close resemblance between these cells and true beta cells. Additionally, depending on their functionality they could serve as a new source for islet transplantation.

2. Despite the progress being made on the tools available for investigating beta cell function, it continues to be an area that slows overall advancement of innovative, new type 1 and type 2 diabetes treatments. During Q&A sessions, speakers often remarked that proposed research questions cannot be answered at this point due to lacking technologies. In particular, speakers stressed the desperate need for biomarkers in type 1 and type 2 diabetes. Dr. Domenico Accili (Columbia University, New York City, NY) characterized biomarker development as being as important for future type 2 diabetes therapies as the discovery of therapeutic targets. Similarly, Dr. Insel pressed that the dearth of biomarkers in type 1 diabetes “is haunting us.” Dr. Insel encouraged public and private players to partner on this research area and not use it for competitive advantage. It is our understanding that biomarkers are one of the focuses of the Novo Nordisk Type 1 Diabetes R&D Center – we hope the center has success and will publicize its findings so that the entire research community – and in the end patients ­– can benefit from them. Another tool Dr. Insel suggested was the development of more predictive animal models with human elements (e.g., a rodent induced to express a human immune system and with human islets).

  • Dr. Insel also underscored the need for beta cell targeting technologies (e.g., aptamers [molecules that bind to a specific target], antibodies, peptides, etc.). Such technologies would improve the risk/benefit of beta cell regeneration therapies by reducing an agent’s systemic effects. Dr. Insel expressed his dismay with that it appears as a lack of pharmaceutical activities around such.

3. Dr. Domenico Accili (Columbia University, New York City, NY) argued that dedifferentiation, not apoptosis, is the main cause of beta cell failure in type 2 diabetes. He presented evidence showing that after a beta cell has dedifferentiated (such that it no longer secretes insulin), it is prone to converting into a different kind of an endocrine cell (i.e., an alpha or a delta cell). Dr. Accili believes that the transformation of beta cells into alpha cells, in particular, could help explain the hyperglucagonemia seen in type 2 diabetes. Dr. Accili concluded that novel type 2 diabetes treatments should aim to restore beta cell differentiation (i.e., cause undifferentiated beta cells to return to secreting insulin in a glucose sensitive manner).

4. Dr. Byran Laffitte (GNF, San Diego, CA) described how GNF has the potential to identify the first disease altering therapy for type 1 diabetes. He presented preclinical evidence that the GNF has identified the first highly effective low molecular weight regulators of beta cell proliferation. Overall, the GNF has identified five novel beta cell proliferators using this technique, two of which he discussed: GNF4156 and GNF4877. These preclinical agents have been found to robustly stimulate rat and human beta cell proliferation in islets. This leads to an expansion of human islet mass with the retention of function. In rodents, these candidates have also been associated with an improvement in glucose tolerance. These agents’ key mechanism of action is the inhibition of Dyrk1a, which is thought to be help regulate cell proliferation.  

5. A theme underscoring many presentations, and noted by Dr. Insel in his closing statement, was that in order to have a nuanced understanding of the beta cell’s function – or dysfunction in diabetes – we must account for the context within which it exists: its local microenvironment (i.e., the nearby vasculature and innervation) and its interactions with other cell types (e.g., alpha cells, adipocytes, etc.). This point was particularly emphasized by Dr. Alvin Powers (Vanderbilt University, Nashville, TN) who noted that the human pancreatic islet is one of the most vascularized organs in the body. He also explained that beta cell proliferation is likely modulated by the infiltration of macrophages and not soluble factors from the pancreas or islet. Looking more at type 2 diabetes, Dr. Philipp Scherer (University of Texas Southwestern, Dallas, TX) detailed how dysfunctional adipocytes can negatively lead to dysfunctional beta cells, via ectopic lipid accumulation and insulin resistance. On the flip side, adiponectin has been shown to be protective of the beta cells, and its overexpression has been found to restore beta cell function.


--by Hannah Deming and Kelly Close