The Foundation of Our Approach
Targeting cellular energy to treat chronic disease
Therapeutic interventions aimed at restoring the cellular bioenergetics balance are promising approaches to metabolic diseases, in particular, treat type 2 diabetes and non-alcoholic steatohepatitis (NASH), among others. We have focused our research strategy on two targets, both of which are important in the regulation of the cellular bioenergetics:
- The mitochondria
- The AMP-activated protein kinase (AMPK)
Mitochondria - The Energy Center of the Cell
Mitochondria are the power stations of the body's cells, contributing to the regulation of energy balance and metabolism. As such, mitochondria play an essential role in the pathophysiology of metabolic diseases, as they are responsible for the production of energy in the form of an adenosine tri-phosphate (ATP) molecules through the oxidization of nutrients such as glucose and fatty acids from food. In diabetes pathophysiology, for example, metabolic imbalance creates a pressure on the mitochondria, which leads to their dysfunction, reduction of oxidative capacity and subsequently, to the accumulation of lipids in insulin-sensitive tissues and, lastly, to insulin resistance and diabetes. Mitochondrial dysfunction also plays a key role in non-alcoholic steatohepatitis. The generation of reactive oxygen species (ROS) through a deficient respiratory chain in a lipid-enriched environment causes toxic oxidative stress in the liver which can result in apoptosis or necrosis of liver cells.
The AMPK Enzyme - An Important Energy Sensor
The AMPK enzyme is an energy sensor whose role is to maintain cellular energy homeostasis. Depending on the cellular bioenergetics status, AMPK activation enhances catabolic processes and down-regulates anabolic pathways. Based on its central metabolic role, targeting AMPK offers the opportunity to pursue a wide range of indications to treat chronic metabolic diseases, such as NASH. For NASH, targeting AMPK is important because it has the potential to trigger benefits on the three key pathophysiology processes involved in disease development: liver steatosis, inflammation and fibrosis. AMPK activation also has the potential to also treat NASH comorbidities, specifically targeting cardiovascular risk factors, such as hyperglycemia, insulin resistance, dyslipidemia, inflammation and obesity.
Metabolic Disorders associated with mitochondrial dysfunction
Type 2 Diabetes
How is Type 2 Diabetes Characterized?
Type 2 diabetes pathophysiology is characterized by a deregulation of the body's metabolic and cellular bioenergetics balances. This is linked to high food supply and low energy demand due to a sedentary lifestyle of diabetic patients and leads to mitochondrial dysfunction.
In diabetes pathophysiology, metabolic misbalance creates a pressure onto the mitochondria, which leads to their dysfunction, overproduction of reactive oxygen species (ROS), reduction of oxidative capacity, and subsequently to the accumulation of lipids in insulin-sensitive tissues and, lastly, to insulin resistance and diabetes.
What's Going on Inside the Body of a Type 2 Diabetes Patient?
Recent scientific investigations support the concept that type 2 diabetes is fundamentally tied to changes in mitochondrial content or oxidative capacity in insulin-sensitive tissues (liver, muscle, adipose tissue) and in the pancreas of insulin-resistant patients. Studies have demonstrated that this oxidation failure and inappropriate lipid storage in the tissues can be correlated with a decline in both insulin sensitivity and metabolic flexibility, due to a defect in insulin signaling.
Non-Alcoholic Steatohepatitis (NASH)
Non-alcoholic steatohepatitis (NASH) is a metabolic disease with no clear disease origin that is quickly becoming a worldwide epidemic. It is characterized by the accumulation of fat in the liver causing inflammation and fibrosis. The disease can be silent for a long period of time, but may progress towards severe damage and liver fibrosis, which ultimately can even result in liver failure and/or liver cancer. Typical risk factors for NASH include obesity, elevated levels of blood lipids (such as cholesterol and triglycerides) and diabetes. Currently no curative or specific therapies are available.