Discoveries and Innovations
Alexandre Caron, Type 2 Diabetes, Obesity and Nervous System
Researcher in obesity-metabolism, principal investigator in determining the role the autonomic nervous system has in the development of metabolic diseases .
The brain is playing an essential role in maintaining energy homoeostasis. It is through a network of neurons and nerves that the brain successfully communicates important information and instructions to the different body’s organs in order to keep us alive. Many messengers, called neurotransmitters, ensure this communication. Specific receptors for each messenger are expressed by various organs, thus helping to integrate and amplify signals from the brain in order to maintain, among other things, body weight and glycemia. So obviously, disturbances in this elaborate communication system could lead to severe consequences. A lot of data indeed indicate that cardiometabolic diseases, such as obesity and type 2 diabetes, are associated with an impaired brain-to-organ communication. Type 2 diabetes, as an example, is closely related to peripheral neuropathy. Also genetic manipulations in specific brain regions are sufficient to affect the energy metabolism and blood glucose levels. Dr. Alexandre Caron’s works, chairholder of the Canada Research Chair in Neurometabolic Pharmacology, aims to elucidate the pathophysiological mechanisms leading to communication problems between the brain and the organs. They are designed as well to identify new molecular and pharmacological targets in the brain and peripheral organs for the treatment of cardiometabolic diseases. This work is based on the innovative premise that obesity and type 2 diabetes are diseases of the nervous system. To achieve this, the research team is using cutting-edge tools, including chemogenetics and transgenesis, in order to find out how receptors that are targeted by the nervous system influence the biology of adipose tissues and the liver.
We recently received generous financial support from the IUCPQ Foundation, the Réseau québécois de recherche sur les médicaments (RQRM) as well as the Cardiometabolic Health, Diabetes and Obesity Research Network (CMDO) in order to identify the receptors and signalling pathways involved in brain-to-organ communication. These projects are particularly focusing on the sympathetic nervous system, one of the greatest communication systems in the brain, and its associated receptors, the adrenergic receptors.
So we are able to develop tools available to control the activation of particular receptors in adipocytes and hepatocytes. We are currently busy working on to determine how these receptors influence metabolism, from the cell to the organ, and from the organ to the organism. By combining in vitro, ex vivo and in vivo studies, this approach provides an overall appreciation of the mechanisms by which neurotransmitters end up influencing the activity metabolic organs has. It has also allowed us, for example, to discover unexpected signalling pathways that control hepatic glucose production, a phenomenon which may become out of hand in people with type 2 diabetes. We are in the process of defining how these pathways are impaired under obesogenic conditions. We are trying as well to define the set of receptors involved as well as the potential to target these to prevent the chronic hyperglycemia that characterizes diabetes and can lead to cardiovascular diseases.
Our general objectives are consequently to understand the mechanisms that ensure an effective communication between the brain and the metabolic organs, to determine how this is affected in contexts of cardiometabolic diseases and ultimately to come up with drug solutions available to restore it. Our discoveries will help to define the importance of the nervous system in the development, but also in the treatment of these diseases.
Neurometabolism and pharmacology are emerging fields that will have major impacts on health research. We are proud and privileged to be able to develop our research program and participate in the discovery of new targets involved in the pathophysiology of cardiometabolic diseases, here at the Institute, an enabling environment for interdisciplinary collaboration.
Dr. Marie-Annick Clavel, Aortic Stenosis in Women
Researcher in cardiology, principal investigator in identifying gender differences in physiopathology, presentation, treatment and outcomes in patients with aortic stenosis.
Our heart consists of four valves which allow blood passage, but prevent it from flowing back the wrong way. Apart from not functioning normally, each of our valves can either leak and it is regurgitation, which therefore causes blood to flow in the wrong direction, or becomes rigid and difficult to open and it is stenosis that puts a barrier on the normal fluid flow. These cardiac valve diseases affect approximately 800,000 Canadians (2.5% of the population) and about as many men as women. These diseases are directly responsible for about 2,500 deaths and 15,000 cardiac surgeries and procedures per year in Canada. The mechanisms by which cardiac valve diseases develop remain unclear and there is no medical treatment to slow their course, however, assessment, clinical management and surgical or catheter-based interventions are well described and applied. It is unfortunate the studies that led to develop practice guides for the treatment of these diseases were essentially conducted in men or with an overwhelming majority of men. The same is true for fundamental studies carried out to elucidate the development mechanisms of cardiac valve diseases, which included only males or in great majority. So we have very little data on these diseases in women.
Several recent studies from Dr. Clavel’s laboratory showed that women’s stenotic aortic valves do not have the same lesions as men’s. Men have indeed valves with a large majority of calcium deposits while that of women with aortic stenosis have less calcium and more fibrosis. We confirmed this difference in a murine model and highlighted certain male-specific pathways for calcification and for which females seemed to be protected. We are seeking, in collaboration with Drs. Yohan Bossé and Sébastien Thériault, to understand the genetic bases within these differences between men and women, in the pathophysiology of aortic stenosis. The ultimate goal of uncovering these genetic differences is the possibility of finding new biomarkers available to predict the disease progression in a given patient, but more importantly to identify novel gender-specific molecules that could prevent the disease to progress and develop.
We recently demonstrated that, for example, with Dr. Philippe Pibarot’s team, an increased systolic blood pressure is a predisposing factor to more rapid progression of aortic stenosis. Also certain hypertension drugs have a component that fights against the production of fibrosis. So we are in the process of conducting, with Drs. Beaudoin, Pibarot and Poirier (IUCPQ-ULaval) and Drs. Dahl, Dweck, and Newby in Europe, a randomized, controlled, double-blind study in order to test this drug in patients with aortic stenosis (grant from the Canadian Institutes of Health Research).
We also showed that women with cardiac valve diseases have a higher mortality than men, despite a more favourable risk profile at first presentation. This increased mortality would appear to be related to delayed treatment (surgical or catheter-based intervention). This delay in treatment comes from the fact practice guides are proposing directives that were overwhelmingly tested in men and do not take into account the patient’s gender. The indicators of severity in valvular lesions, damage in heart muscle, or others that must lead to the decision for intervention are indeed unique and frequently not indexed to the patient’s size, so they are associated with more advanced illnesses in women, who are smaller and whose cardiac remodeling differs. Symptoms play at last a major role in the decision to intervene on a cardiac valve disease. But women will experience symptoms that are different from those of men and often more simple-minded.
The development of large clinical databases allowed us to redefine certain thresholds for the severity of the aortic stenosis in women to facilitate the clinical decision-making and avoid a potentially fatal delay in management for many of them. The use of tomography, with the thresholds we proposed, was recently included in the European and American practice guides for the management of patients with a cardiac valve disease. In this regard Dr. Clavel set up a core lab here that is standardizing the evaluation of CT exams obtained in more than 20 hospitals around the world within the context of clinical trials.
Dr. Yves Lacasse, Nocturnal Desaturation
Respirologist, principal investigator of the INOX trial.
The Institute’s Research Centre is considered an enabling environment for important work of interest to the international scientific and medical community.
Dr. Yves Lacasse’s research team was getting in 2009 a grant of $5.5M from the Canadian Institutes of Health Research (CIHR) in order to do a clinical trial of nocturnal oxygen for chronic obstructive pulmonary disease (COPD). This event marked the start of a true journey.
Getting this grant represented the completion of few years in preliminary works aimed at better understanding the epidemiology, mechanisms and consequences of a phenomenon frequently met in the clinic: nocturnal desaturation, i.e. the lowering of arterial blood oxygen levels during sleep in patients who have COPD. As this issue was not well known at the time, clinicians long believed that supplemental oxygen while sleeping was sufficient to reduce the impacts of this process. So in 2010, 20% of patients receiving home oxygen, under the supervision of the Regional Specialized Home Respiratory Care Service in the Quebec City region, were treated only during sleep. This situation was not unique to the Quebec City area. Similar statistics were also reported in international literature. .
No evidence of effectiveness nevertheless supported this expensive practice. Proven effectiveness of supplemental oxygen at home is, moreover, still limited to the results of two small clinical trials conducted more than 40 years ago. These studies focused on more severely ill patients who required almost permanent supplemental oxygen. These obviously did not show that the oxygen “cures” COPD. In fact there is no cure for COPD. It is an illness that can be prevented by stopping smoking. Once the disease is established, it progresses more or less rapidly. Treatments provided are then targeted to slow its progression, prevent complications, improve quality of life and extend the life of people affected. If the pandemic taught the citizens of this world anything, it is that oxygen is fundamental for life.
If oxygen prolongs the life of patients with COPD who also displayed a severe and permanent reduction in blood oxygen levels, what about when desaturation occurs only at night? Does supplemental oxygen while asleep have a real impact on the life and fate of COPD patients? If so, which one? Does nocturnal oxygen extend their life? Or even does it slow down the disease progression? Does it reduce its complications?
Only a randomized clinical trial comparing nocturnal oxygen to a placebo could answer these questions. The INOX (International Nocturnal Oxygen) study took place in Canada, Portugal, Spain and France, evidence that Institute’s researchers are capable of international collaborations.
INOX showed that nocturnal oxygen does not change the fate of patients who also have COPD with a significant nocturnal desaturation. Physicians usually refer to these studies as negative. “Eleven years of work to get to this point?” some will say.
The results of negative studies are typically difficult to publish. Scientific journals and their readers often seek good news. Negative studies are also frequently subject to criticism from those who believed in the benefits the intervention being studied has. These works nevertheless add to medical and scientific knowledge. They lead to the avoidance of intervening futilely, and better use human and financial resources by allocating them to really effective interventions. They may not lead to cure some people, but they do help to provide better care for others. INOX results were certainly noticed, enough to be published in the very prestigious New England Journal of Medicine in September 2020.