OBESITY IS A WORLDWIDE EPIDEMIC
30% Obesity Rate Worldwide
According to a report from the McKinsey Global Institute in 2014, more than 2.1 billion people – approximately 30% of the world population – are classified as overweight or obese by the World Health Organization. This is an unprecedented trend never seen before in history. Projections show the prevalence of obesity increasing to about half of the world’s population by 2030 with the current trajectory. 5% of all deaths annually are said to be obesity related. It is estimated to have cost the global economy in 2012 $2.0 trillion, or 2.8% of the global GDP, based on direct costs (i.e. healthcare) and indirect costs (i.e. lost productivity). Obesity costs the US economy almost $700 billion annually.
The Health Risks Associated with Obesity
Being overweight or obese is not merely a cosmetic problem. The risks of developing the following health problems are greatly increased by being overweight or obese:
– Coronary heart disease including angina, heart attack, and heart failure.
– High blood pressure.
– Type 2 diabetes, which itself is a leading cause of early death, coronary heart disease, stroke, kidney disease, and blindness.
– Abnormal blood fats including high levels of triglycerides and low density lipoprotein (“bad cholesterol”) and low levels of high density lipoprotein (“good cholesterol”), which increase the risk of coronary heart disease.
– Cancer, in particular colon, breast, endometrial, and gallbladder.
– Sleep apnea.
– Reproductive problems.
Current Drug Treatments are not Optimal
Almost all marketable drugs used to treat obesity today are appetite suppressants, which work by acting on the brain’s satiety center. However, this action can lead to depression due to close proximity to the brain’s pleasure centers. Other drugs (e.g. exenatide and liraglutide) can also delay emptying of the stomach to create a false sense of fullness, although frequently this comes at the price of feeling nauseous. Clinical research has shown that these drugs do work in a laboratory setting, but lead to a great deal of discomfort in the process due to the undesirable side effects.
Insulin is the Answer
Insulin is known as an “efficiency hormone.” It is the most potent hormone known to promote the synthesis and storage of carbohydrates and lipids, while inhibiting their breakdown. This makes it not only an instrumental component in maximizing energy storage and survival, but also a key factor in development of obesity and related diseases. Historically food was scarce, and organisms needed to adapt in order to obtain and store as much nutrient when it was available in order to survive. Insulin provided this function, but life today is different as food is now plentiful. Also, our diets have changed, we live more sedentary lifestyles, and consequently we no longer need the ability to efficiently break down and store as much food as possible.
A landmark study published in 1964 in Lancet observed the effects of oral and intravenous (IV) glucose on plasma insulin and glucose. It showed that insulin release was approximately 3 times greater when oral glucose was given to humans compared to IV glucose. Blood glucose levels were found to be similar. Thus, something in the intestine was determined to be responsible for the effect seen. The responsible agents, which at that time were unidentified, are now known to be incretin hormones that promote insulin release.
GIP is an Incretin Hormone
Gastric inhibitory polypeptide (GIP) is a 42-amino acid hormone found in the upper small intestine. It is released into blood by lipids and carbohydrates, and by stomach acid entering the small intestine. Its role was initially unknown but was suggested to suppress acid secretion and increase insulin release (i.e. an incretin hormone). Confirmation was found with development of GIP peptide antagonist in the lab of our founder, Dr M Michael Wolfe.
Structurally, GIP peptide antagonist is similar to GIP – the only difference is that it is missing a portion of itself. Therefore GIP peptide antagonist functions as an antagonist to GIP, or a block to GIP activity. By testing the effect of GIP peptide antagonist on plasma insulin and serum glucose levels, it was found that insulin levels decreased by ⅔ while glucose only had a very minor decrease. These results describe the unknown observations seen in the 1964 Lancet study.
Many further studies were performed to better understand GIP. A summary of the results reveals that overnutrition leads to an increase in GIP release that leads to higher glucose uptake from the intestine coupled with insulin release. This results in increased glucose uptake into fat cells and conversion into fat stores. With GIP peptide antagonist however, glucose uptake is decreased from the intestine, thereby decreasing insulin release. This then leads to a reduction in glucose uptake into fat cells and conversion. Ultimately, these effects result in weight loss, or the prevention of weight gain.
Putting it all Together
We have developed a humanized monoclonal antibody (mAb) that binds specifically to GIP (anti-GIP mAb). Anti-GIP does not affect appetite at all, but rather, it blocks obesity at its roots making us less efficient eaters by decreasing both nutrient absorption from the intestine and nutrient storage. It is designed to prevent GIP from binding to its receptor, therefore preventing GIP activity similar to the effect of GIP peptide antagonist. Due to the nature of a monoclonal antibody, it is highly specific in binding only to GIP and nothing else. This makes it a highly safe and practical method for development. By acting at the source of where metabolic activity occurs, we can use our anti-GIP mAb to effectively treat obesity.
Currently, anti-GIP is being prepared for human clinical testing. Early results in a mouse model have already shown great promise. In an obesity prevention study where mice were fed a high fat/high carbohydrate diet, anti-GIP treatment resulted in a dramatic 46.5% decrease in weight gain (similar to the calorie controlled diet control group) versus mice that were not treated. MRI scans and subsequent dissection of these mice also reveal a large reduction in abdominal cavity fat. Furthermore, mice that were left untreated were found to have developed type 2 diabetes while those that were treated did not. This implies a further protective effect of anti-GIP against obesity and related diseases.