The findings will be published online Sept. 15 in two articles in Nature Medicine.
The studies, done in mice, identify a previously unexpected link between a low-oxygen condition called hypoxia and the ability of cells in the liver to respond to insulin. The drug, aflibercept (marketed as Eylea or Zaltrap), is used to treat metastatic colorectal cancer and a form of macular degeneration. Aflibercept is a member of a family of proteins that inhibit the vascular endothelial growth factor, or VEGF, pathway. It works by blocking the growth of the blood vessels into tumors and starving them of oxygen.
The lab of Calvin Kuo, MD, PhD, professor of medicine, identified a series of protein interactions that link VEGF inhibitors and blood glucose levels. "We were surprised to find that this drug currently used in patients for cancer treatment had beneficial effects on diabetes in laboratory mice and could, potentially, in humans," said Kuo, senior author of one of the Nature Medicine papers.
Amato Giaccia, PhD, the Jack, Lulu and Sam Willson Professor of Cancer Biology, is senior author of the other paper. "Proteins involved in this pathway could also be targeted for the development of new diabetes therapies," said Giaccia, who also is a professor and director of radiation oncology. His laboratory has identified a protein called PhD3 that could be a particularly attractive target.
The lead author of the Giaccia paper is Cullen Taniguchi MD, PhD, a radiation oncology resident at Stanford; former graduate students Kevin Wei, MD, PhD, and Lisa McGinnis, MD, PhD, and postdoctoral scholar Stephanie Piecewicz, PhD, are lead authors of the Kuo paper.
Together, the studies explain an observation made several years ago by Kuo and his lab members that VEGF inhibitors, such as aflibercept, could lower blood glucose levels in mice. There have been intriguing hints that these inhibitors could function in a similar way in humans, but human studies have not been formally conducted.
"Anecdotally, there have been reports that diabetic patients who have been prescribed VEGF inhibitors to treat their cancer are better able to control their diabetes," Kuo said.
The liver is commonly known as the organ responsible for removing toxins from our blood. But it also serves as the body's energy warehouse. After a meal, blood glucose levels rise and insulin triggers cells in the liver to squirrel away the glucose in long, branching chains of a substance called glycogen (imagine an ever-growing Lego structure, where each block is a glucose molecule). When we are asleep or fasting, the liver breaks down that Lego structure unit by unit to deliver glucose into the blood for cells to use as an energy source until the next meal.
When this process goes awry, blood glucose levels can become dangerously high. This can happen when the body either can't make insulin (in the case of type-1, or juvenile, diabetes) or when it can't respond appropriately to the insulin the body does make (type-2 diabetes).
The liver's critical function requires that most of its cells have ready access to blood, which carries both glucose and oxygen. Oxygen diffuses as a gradient outward from blood vessels; those cells that are more removed have less oxygen and can become hypoxic. Hypoxic cells naturally produce certain proteins to enable them to live and function under these more severe conditions.
Wei, McGinnis and Piecewicz, in Kuo's lab, found that one protein induced by hypoxia, HIF-2alpha, activates the expression of insulin receptor substrate 2. IRS2 enhances the ability of the cells to respond to insulin. Treatment of normal and diabetic laboratory mice with a variety of VEGF inhibitors, including aflibercept, causes regression of blood vessels and increases the number of hypoxic cells in the liver. As a result, HIF-2alpha levels increase, IRS2 expression rises and the animals become better able to tolerate increases in blood-glucose levels.
The researchers found that deletion of HIF-2alpha blocked the effect of the VEGF inhibitors, while liver-specific induction of HIF-2alpha expression also significantly improved the animals' glucose tolerance.
"Much work remains to translate these mouse studies to human patients, but it will be interesting to explore VEGF inhibitors or drugs that can stabilize HIF-2alpha, such as prolyl hydroxylase inhibitors, for diabetes treatment, possibly in combination with pre-existing therapies to minimize toxicities," Kuo said.
Taniguchi, in Giaccia's lab, focused on the biology of HIF-2alpha. He and his colleagues found that blocking the expression of a protein called Phd3 specifically taps into the pathway identified by the Kuo group, stabilizing the HIF-2alpha protein and prolonging its effect on IRS2 expression. Laboratory mice missing Phd3 are more sensitive to insulin and exhibit improved glucose tolerance.
The specificity of the effect of Phd3 on HIF-2alpha is important. Because it doesn't appear to regulate other proteins in the HIF family in the liver, it's possible a diabetes treatment could be designed that would avoid unwanted or dangerous side effects that could occur by blocking the production of a more broadly acting protein.
"Targeting the Phd3/HIF-2 pathway represents a new therapeutic approach for the treatment of diabetes with little toxicity," said Giaccia. "These studies indicate that Phd specific inhibitors, especially Phd3, should be more widely developed for clinical development."
Additional Stanford authors of the papers were research assistant David Kuo; basic life sciences research associates Jenny Yuan and Mario Vallon; assistant professor of medicine Justin Annes, MD, PhD; and postdoctoral scholars Elizabeth Finger, PhD, Colleen Wu, PhD, Anh Diep, VMD, and Edward LaGory, PhD.
Funding for the studies was provided by the National Institutes of Health (grants R01HL074267, R01NS064517, R01CA158528, 1R01HL074267, RO1DK043748, P60DK020593, U24DK059637 CA67166 and CA88480); the National Cancer Institute (grant CA121940); Radiological Society of North America Resident Research Grants; the Canadian Institutes of Health and Research; the National Institute of General Medical Sciences (grants GM104936 and GM007365); the Sydney Frank Foundation; Stanford's Medical Scientist Training Program; and Stanford training-program grants in comparative animal medicine, cardiovascular medicine, molecular and cellular immunobiology, and molecular endocrinology.
Regeneron Pharmaceuticals, Sanofi and Genentech provided reagents for the Kuo study. Three co-authors of the Kuo study are employees at Regeneron, which manufactures aflibercept.
The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://mednews.stanford.edu. The medical school is part of Stanford Medicine, which includes Stanford Hospital & Clinics and Lucile Packard Children's Hospital. For information about all three, please visit http://stanfordmedicine.org/about/news.html.Print media contact: Krista Conger at (650) 725-5371 (firstname.lastname@example.org)
Krista Conger | EurekAlert!
Cystic fibrosis alters the structure of mucus in airways
28.06.2017 | University of Iowa Health Care
Mice provide insight into genetics of autism spectrum disorders
28.06.2017 | University of California - Davis
An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.
Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
28.06.2017 | Physics and Astronomy
28.06.2017 | Physics and Astronomy
28.06.2017 | Health and Medicine