An interview with Dr. George Fantus
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Dr. George Fantus is principal investigator of a New Emerging Team studying the effects of high glucose on diabetes complications. Dr. Fantus is Clinician-Scientist, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and Division of Cellular and Molecular Biology, Toronto General Research Institute. |
For a person with diabetes, the key to long term-health and well-being is regulation of blood glucose. Yet this can be difficult, with effects that can lead to life-threatening complications if left untreated. Dr. George Fantus, principal investigator of an III New Emerging Team, is working with team members to counteract those effects.
The metabolic disease in its various forms hinges on insulin, a hormone that aids the conversion of sugar and starch into energy by easing the entry of glucose from the circulating bloodstream into cells. The amount of insulin produced is normally controlled by the amount of glucose in the bloodstream.
Type 1 diabetes, previously known as Insulin Dependent Diabetes Mellitus (IDDM) or juvenile onset diabetes, is an autoimmune disease which most commonly manifests in childhood or adolescence.
The immune system attacks and destroys the pancreatic insulin-producing beta cells with the result that insulin production declines and eventually ceases. However, the overwhelming majority of people with diabetes (about 90 per cent), suffer from Type 2 diabetes.
Type 2 diabetes, or non-insulin-dependent diabetes, is characterized by insulin resistance: although the amount of insulin produced may be normal, the body doesn't respond to it normally. Most are over 40 years of age, although the current obesity trend is creating younger age brackets for this disease.
The theme of the team's research is to learn more about how high bloodstream glucose levels characteristic of diabetes affect various cells and tissues. Periodically high levels of glucose in the bloodstream are characteristic of diabetes of any type and are known to have detrimental or "toxic" effects. "The message from the clinical point of view is to keep the glucose as close to normal as possible," says Fantus. It is already known that high glucose levels, if untreated, can injure the eyes, kidneys, nerves and blood vessels, and can alter metabolism in fat and muscle cells. High glucose is toxic to the pancreatic beta cells, and in the case of Type 2 diabetes can lead to a further decrease of insulin production and increased insulin resistance, in effect exacerbating the condition.
This New Emerging Team grant has brought together an interdisciplinary team in search of commonalities, which is a new approach in this area. For example, investigators who study islet cells would not study the kidney, and vice versa. Fantus used the New Emerging Team (NET) funding tool creatively to ensure this collaboration. While training is only one objective of the NET program, the funding has been targeted mainly for support of postdoctoral fellows and students. Each trainee must be supervised by a minimum of two, but preferably three members of the team to guarantee an interdisciplinary experience.
How glucose harms
Altered patterns of gene expression due to high levels of glucose have been observed in tissues including the kidney, retina and pancreatic beta cells. The team will delve into these effects to learn if there is a common subset of genes regulated by high glucose that mediate changes in cell function. "Basically what we want to define is how glucose changes cell signalling," says Fantus.
Microarrays will be used to pinpoint changes in gene expression in the various cell types. "Once we can define some of these genes and proteins, then we can look in vivo and try to find out which ones are the most important in terms of causing the problems," says Fantus. The team expects to find that a number of key signals, which either initiate or are a result of altered gene expression, are shared.
There is evidence indicating that all glucose toxicity may at some level be influenced by oxidative stress (an overabundance of reactive oxygen species) caused by high glucose. It's hypothesized that the combination of oxidative stress and several other signals resulting from high glucose work together to mediate changes in gene expression and cell function. Humans are always producing reactive oxygen species. During normal mitochondrial respiration, a small amount is produced. It follows that a higher concentration of glucose entering the mitochondria leads to more reactive oxygen species. "Usually they're mopped up. In the cell we have all kinds of antioxidant defence mechanisms, because too much will damage protein, DNA and lipids," says Fantus.
Another theory being pursued by the team involves a new metabolic pathway that may contribute to these effects. The reactive oxygen intermediates block metabolism by glycolysis, causing glucose to enter other metabolic pathways, which may mediate some of the toxic effects. "One of the pathways that I'm particularly interested in is called the hexosamine biosynthesis pathway. It is increased in the presence of high glucose," says Fantus. The team has already published data showing that the pathway is one factor that alters gene expression in the kidney.
Hope for new treatments
Current management of diabetes includes cholesterol and blood pressure control. The team is working to target new avenues for treating and preventing complications, and expects to move into clinical applications within the NET's five-year funding period. The team is seeking commonalities between different glucose toxic effects which would allow a point for interruption. "Right now we're looking at the oxidative stress story and different antioxidants," says Fantus.
One point of interest is the disparity in diabetes pathology among different patients. Fantus points out that complications aren't seen in all diabetes sufferers. "For example, 30 per cent will develop renal failure - end-stage renal disease that requires dialysis or transplantation - but it's only 30 to 40 per cent." Others develop mild renal disease, and others hardly develop any complications at all. The team hopes their research will shed light on the reasons for these disparities; for example, whether some people have better antioxidant mechanisms or different pathways of glucose metabolism.
Optimism aside, Fantus points out that ultimately, different drugs might be required to treat different target tissues. "Everyone would like to think that there will be a magic bullet, that's everybody's dream, to solve all the problems, but it doesn't always work that way."
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NEW EMERGING TEAM Glucose toxicity: Prevention of diabetes complications and preservation of pancreatic ß-cell function | ||
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Sponsors: Juvenile Diabetes Research Foundation, CIHR Institute of Infection and Immunity, CIHR Institute of Nutrition, Metabolism and Diabetes, CIHR Institute of Human Development, Child and Youth Health | ||
| Investigator | Host institution | Role |
| FANTUS, I. George(Principal Investigator) | Samuel Lunenfeld Research Institute (Toronto) | Mechanisms of insulin resistance at cellular and molecular level |
| CHAN, John | Centre Hosp. de l'Université de Montréal (CHUM) | Gene expression in kidney proximal tubular cells |
| GIACCA, Adria | Department of Physiology,University of Toronto | High glucose effects on insulin secretion and resistance in vivo (animal models) |
| LEWIS, Gary | Department of Medicine,University Health Network (Toronto) | Insulin secretion effects and insulin resistance in vivo (human subjects) |
| WHEELER, Michael | Department of Physiology, University of Toronto | Molecular research on islet cells |
| WHITESIDE, Catharine | Department of Medicine, University of Toronto | Cell biology and signalling of kidney mesangial and retinal cells |
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Diabetes Quick Facts
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