The first of a three-part webinar series on metabolic mechanisms presented by Dr Khosrow Adeli
This series is intended for faculty, students, and technologists involved in biological and molecular research. This series would also be of interest if you would like to gain a better understand of the pathophysiology and molecular mechanisms of obesity and diabetes.
About the Presenter
Dr Khosrow Adeli is currently a Senior Associate Scientist in the program in Molecular Structure and Function at the Hospital for Sick Children in the University of Toronto.
He is also the head and a full professor of Clinical Biochemistry at the Hospital for Sick Children, the Departments of Biochemistry, and Laboratory Medicine & Pathobiology at the University of Toronto, all in Canada.
Thank you for the very informative presentation on obesity and metabolic syndrome! Also Abcam is one of our favorite antibody companies! Thanks!”
- Epidemiology of obesity, metabolic syndrome, and diabetes
- Pathophysiology of visceral obesity and insulin resistance
- Links between obesity and metabolic syndrome
- Links between metabolic syndrome, diabetes, and cardiovascular disease
- Laboratory biomarkers of metabolic syndrome and diabetic complications
Hello and thank you for joining us for today's webinar: The Worldwide Epidemic of Obesity - Metabolic Syndrome in Diabetes. It is my pleasure to introduce today's presenter, Dr Khosrow Adeli. Dr Adeli is currently a Senior Associate Scientist in the program in Molecular Structure and Function at the Hospital for Sick Children at the University of Toronto. He is also the head and full professor of Clinical Biochemistry at the Hospital for Sick Children, and the Departments of Biochemistry, and Laboratory Medicine & Pathobiology at the University of Toronto in Canada.
Joining Dr Adeli today is Sambhav Dave, the Senior Associate in the Business Development team, with a primary focus on Neuroscience and Signal Transduction research areas. As Sandra just highlighted, if you have any questions throughout this presentation, we invite you to submit them on the right hand side of your screen in the Q&A panel. At this time, I'd like to hand the presentation over to Dr Adeli.
KA: Thank you, Sarah, and I'm pleased to be here to present on this very important topic of metabolic syndrome. I'll be discussing the pathophysiology of this very common condition at lab assessments, some of the research areas in this area of metabolic syndrome; and mechanisms, molecular mechanisms that lead to development of this condition.
Now, moving on to the second slide, this condition has been referred to, or defined in many different ways. In the literature you'll see it referred to as metabolic syndrome X, cardiometabolic syndrome, syndrome X, insulin resistance syndrome, or the Reavon's syndrome. They all really refer to a condition or a syndrome that includes a combination of a number of medical disorders. Together they increase the risk of developing cardiovascular disease and diabetes. As you know, cardiovascular disease and diabetes are right now the most common chronic diseases affecting humans and human populations around the world. Therefore, this condition has been identified as being very important in increasing the risk of developing these chronic conditions. It is a cluster of the most dangerous heart attack or cardiovascular risk factors, including pre-diabetes - which is basically a condition before development of full-blown diabetes - abdominal obesity, high cholesterol and high blood pressure, and a number of other abnormalities.
Now, on the next slide I have listed here the definitions provided by the WHO and NCEP, which is the National Cholesterol Education Panel in the US, and the World Health Organization. They typically regard the following components as factors involved in the development of metabolic syndrome, and that includes abdominal obesity, hypertension, high triglyceride - which is basically circulating fat being high - low HDL cholesterol, diabetes, impaired glucose tolerance, insulin resistance and microalbuminuria - which basically refers to presence of albumin in the urine, which is an indicator of early kidney damage. So these conditions and a number of others have been associated with this condition of metabolic syndrome.
On the next slide I actually share with you the definition that's now most commonly referred to, and that is by the IDF; IDF stands for International Diabetes Federation. This federation came up with the consensus definition for the metabolic syndrome, and that's shown here. According to IDF, the key defining condition in the metabolic syndrome is central obesity, largely meaning, abdominal obesity. So having too much fat tissue, adipose tissue in the abdominal cavity is referred to as central obesity. That, if it's present in a subject, plus two of the following four factors, then this patient is then regarded or diagnosed as having the metabolic syndrome. So if someone has central obesity which can be determined by just simply measuring waist circumference using a tape, one could then look at other risk factors. If someone has a central obesity, plus they're either high triglyceride, low HDL, high blood pressure and/or raised fasting plasma glucose, if any of the following two out of four, then that plus central obesity provides the definition of the metabolic syndrome. So this is the most commonly used definition currently worldwide in this area.
The next slide, I share with you some of the other biomarkers. I mentioned that the metabolic syndrome, other than some of the key risk factors, is also associated with a number of other abnormalities. Currently, there are a number of laboratory biomarkers that are being used to assess patients with the metabolic syndrome, and these are listed here. So these patients tend to have, for example, microalbuminuria, as I mentioned, it's an early sign of kidney failure and kidney disease; and that is measured, for example, or assessed using urine albumin and creatinine ratio. These patients tend to have subclinical inflammation, and that can be assessed by tests such as CRP; CRP standing for C-reactive protein, IL-6, IL-18 and others. These patients also have commonly problems with fibrinolytic system and impaired fibrinolysis, and that is assessed by PAI-1 and fibrinogen, and so on. There are a lot of other tests that I've listed here and these patients tend to have, commonly have non-alcoholic fatty liver disease; and this is assessed using enzymes such as ALT, ASP, GGT. These patients also tend to have dyslipidemia, and we've mentioned high triglyceride, but these patients also have small, dense LDL particles, which increases the risk of cardiovascular disease in these subjects. So a large number of biomarkers are being currently employed to assess patients and monitor their risk, or long-term risk of developing complications.
The next slide, I am showing you some of the statistics around this condition. As I mentioned initially, this is a worldwide issue with significantly increased problems in a number of societies around the world. Not only in developed countries, but in developing countries you see a large proportion of the population developing this condition called the metabolic syndrome. Currently, when you look at adults, about a quarter of adults, one in four adults around the world are regarded as having this metabolic syndrome. In some areas of the world, and that is even much higher and I will show you some of the statistics. People who have the metabolic syndrome have a five-fold greater risk of developing type II diabetes, and they also have a higher mortality risk; so twice as likely to die from and three times as likely to have a heart attack, or a stroke. If you look at the type II diabetes itself, which is associated with the metabolic syndrome, up to 80% of the 200 million people with diabetes globally, will actually die of cardiovascular disease. So these conditions are basically related. Developing the metabolic syndrome increases your risk of diabetes, which in turn increases the risk of cardiovascular disease. So these are, therefore, very common and chronic conditions affecting a large proportion of the populations worldwide. Now, I've also highlighted here that even though conditions such as HIV/AIDS have made a lot of news in terms of their effects on morbidity and mortality worldwide. In reality, conditions such as metabolic syndrome and diabetes are much more common, but not as well-recognized.
The next slide shows you data from the US and th is is from NHANES, which is a national survey in the US showing you the prevalence of metabolic syndrome in adults. As you can see, the prevalence increases rapidly as people age, well, both females and men are almost affected equally with the lowest rate in the younger adults, and the highest rates in the older seniors. You can see in seniors more than 60 years of age, you can see prevalence close to 5%; 40-50%, so very high prevalence in the older population. In the next slide, I show data based on various ethnic groups, again from the US, showing that certain ethnic groups appear to be particularly at risk, and this includes Mexican-Americans particularly appear to have the highest rate - if you look at both men and women - appear to have the highest rates. Particularly Mexican-American women having a rate of 36% based on this array and lowest in, for example, adult white populations was about 20-23%. Now, this rate has been going up actually since then - this is data from 2002, and the prevalence is probably higher in some of these populations.
The next slide shows you that this is not an issue just in the US, this is an issue around the world. Diabetes, which is the consequence of developing metabolic syndrome, so they're closely associated. The rate of diabetes has been also becoming epidemic in proportion, in the sense that worldwide there are now hundreds of millions of people living with diabetes, and projected over the next decade for this rate to increase significantly. So this is an issue around the world and not just simply in the US, or in North America.
The next slide I'm going to move on to some of the mechanisms. So we now have learned that this is a common condition and it develops in adults, and I didn't talk about children, but children do have so-called pediatric metabolic syndrome, but the rates are lower, fortunately, than adults, but it does exist in children. So presence of this condition, so the take-home message so far is that this condition significantly increases the risk of chronic diseases, such as diabetes and cardiovascular disease.
Now, we're going to turn into the mechanisms and pathophysiology. So what is causing the development of metabolic syndrome in the population? The next slide, I show a diagram showing that metabolic syndrome is really a constellation or cluster of a large number of conditions, and the most important conditions that are thought to be to cause the development of metabolic syndrome, are insulin resistance and obesity. Now, obesity you're all familiar with, it's becoming very common in the world population in North America and elsewhere, and obesity and overweight are some of the primary conditions that lead to metabolic syndrome. But it is also this condition called insulin resistance, which is resistance of tissues in the body to insulin action, and this would refer to insulin resistance. This condition actually can result from obesity or overweight, or can result from other genetic causes, but when it's present it can lead to also development of metabolic syndrome. So in most individuals, insulin resistance and obesity, so-called, go hand-in-hand and they contribute together to development of this condition. There is also a number of other conditions present such as inflammation, hypertension, dyslipidemia and others, as I've already mentioned.
The next slide, I'm going to just briefly talk about obesity, because the obesity phenomenon and epidemic that we have seen in the last 30, 40 years is actually the major cause of developing the metabolic syndrome. If you look at the global statistics, you can see that the rate of obesity has been going up around the world in both adults and children. I work actually in a children's hospital and we didn't used to have an obesity clinic in our hospital, but have recently opened one in the last several years, because the rate of pediatric obesity has been going up significantly.
So let's look at some of the data, if you look at the next slide shows global statistics and you can see this is actually in children, in teens between 10 and 16 years of age; school children. You can see that the rates are quite high in certain parts of the world, but it's been basically affecting populations around the world. Not only in the US, which has one of the highest rates, but in Canada and in Europe, and elsewhere in the world. So this is not simply a North American problem, it's really a worldwide issue. So this is a fact in both male and female children, and if you look at both overweight, which is a BMI of 25 to 29.9, or obesity which is a BMI of more than 30, both of these are going up, both overweight rates and obesity rates.
The next slide shows actually some of the statistics for in the US, because it has been best studied in the last few decades, and if you look at data in the 1990s versus '99 and then versus 2009. Actually, these are the slides that are available by CDC, the Center for Disease Control in the US and they can be downloaded, actually, those interested, and used for local lectures and presentations. These slides nicely use colors to show how the rates have changed, and you can see in the 1990s most states in the US had very low rates, less than 10% or less, between 10 and 14%. But then if you look at the 1999 and then 2009, you can see the rates have tremendously gone up, such that some states have more than 30%, and this is obesity and that is a BMI of more than 30, which is quite, much higher than it used to be. So this is a recent phenomenon really showing up within the last few decades, which has become quite worrisome to healthcare professionals and healthcare assistants around the world. Because these people develop all sorts of complications that can have a significant burden on healthcare expenditure, and healthcare costs around the world.
The next slide talks about why is the obesity increasing? Well, there are two major causes that can be identified. People working in this area define these as modifiable causes and non-modifiable causes. Modifiable causes are basically environmental factors, and some of our basically behavioral attitudes, whether it's a level of physical activity or sedentary lifestyle, socioeconomic status, eating habits and this is a major issue in a sense that food has become plentiful and more available than any time in history, and overconsumption of high calorie foods is definitely one major factor. Environmental exposures to also basically foods and advertisements in this area are becoming more and more common worldwide, which increases exposure, and therefore overconsumption of calories and high-density foods in terms of calories. But we should not forget that obesity can also have genetic causes, and these are called non-modifiable causes and there are a number of genes that have been identified that can lead to either very severe obesity, or milder forms of obesity.
So there are genetic causes, but since these high rates of obesity are relatively recent, and our genes really haven't changed in the last 30, 40 years, what likely is causing the recent phenomenon are the environmental changes. But, again, people respond differently to environmental factors, so genetic background and genetic factors do play a role.
The next slide just highlights the key problem in obesity that is particularly risky to have, and that is abdominal obesity, or also called as visceral obesity, and the presence of visceral fat in the abdominal cavity. So when we see obesity and obesity being an issue, it's largely referring to this form of obesity called visceral fat. This just shows you a MRI image showing the presence of visceral adipose tissue - AT as standing for adipose tissue - so visceral fat present in the abdominal cavity. This can be imaged by MRI very readily, and you can see when there is a tremendous amount of this fat present, this is thought to be very risky in terms of increasing risk of diabetes and cardiovascular disease. Now, there is a different form of fat called subcutaneous adipose tissue, and that is thought to be less risky in terms of chronic conditions. So more visceral adipose tissue and less subcutaneous fat is thought to increase risk.
The next slide compares an image, a MRI image of normal visceral fat, someone who has a normal amount of fat. There is always some fat in the abdominal cavity surrounding our tissues, but in an obese individual on the right you can see a massive increase in the amount of fat present. This is very common, and this can lead to a condition called insulin resistance, so when there is a loss of visceral fat this goes hand-in-hand with the development of the insulin-resistant state.
This next slide shows the correlation between abdominal fat and insulin sensitivity. So you can measure insulin sensitivity in the subject, and you can show that the greater amount of intra-abdominal fat, which is also visceral obesity, the lower the insulin sensitivity. If that person exercises and watches their diet, and decreases their abdominal fat that enhances insulin sensitivity, which is a good thing, that means it improves insulin resistance and helps the body metabolize calories from carbohydrates or fat much better. So this is a very fully established correlation that's been recorded in the literature for several years.
The next slide, going back to this condition called insulin resistance. So insulin resistance I've mentioned, is one of the key underlying factors in the development of the metabolic syndrome. Here, I'm showing that it can lead when you develop insulin resistance, it seems to then lead to all sorts of other abnormalities. The two most important that cause severe morbidity in the human populations around the world, are the type II diabetes and cardiovascular disease, which basically means eventually heart attacks. So insulin resistance is because there's an underlying factor in the development of type II diabetes, and other complications.
The next slide tries to define the insulin resistant state, and here I'm showing a diagram of a number of tissues in the body that have been shown to become resistant to insulin action. These are shown on the right muscle cells, adipose or fat cells, liver and intestine, as well as other tissues such as endothelial cells and others, have been shown to become resistant to insulin action in this condition of metabolic syndrome. That leads to this response by the pancreas, and the pancreas starts secreting more insulin, so the level of insulin in the circulation goes up; this gives you a condition called hyperinsulinemia. Now, this is a relatively transient state in the sense that the pancreas can keep up secreting more insulin for a number of years, but then eventually might fail. When it fails to produce enough insulin to fight this resistance through insulin action, this leads to your full-blown type II diabetes. So if the pancreas fails and insulin levels drop, now glucose levels increase and now you have a diagnosis of type II diabetes. So when somebody is diagnosed with type II diabetes, if they would have had to have insulin resistance for many years, possibly decades before they actually become diabetic. So this condition of insulin resistance, also referred to as pre-diabetic state is very important in understanding, because it is the underlying cause of developing the condition.
The next slide, I showed a progression of the various conditions, so if you look this can take years, so this is a period of years and sometimes decades, where a patient may have normal fasting glucose and, therefore, they're not diabetic, initially, and that sounds a laugh. As time passes they develop more insulin resistance, and reduce insulin secretion which eventually leads to higher circulating glucose levels, both in the fasting state and post-prandial state, which means following a meal. So you see high glucose levels under both conditions, and when there is more insulin resistance and less insulin secretion. So this is a chronic condition that develops over a number of years, and all of these can then lead to eventually these complications called macrovascular and microvascular complications, which lead to all sorts of diabetic complications and cardiovascular complications.
The next slide I show a number of tissues that are involved in this condition and are being studied currently, including the pancreas itself that secretes the insulin hormone; liver, which is a very important organ in sensitizing and secreting glucose. So hepatic glucose upward tends to go up in an insulin-resistant state, and actually one major reason for hyperglycaemia in these patients, is due to high production in the liver; so hepatic and glucose output increasing. These patients tend to have higher free fatty acids coming out of their fat cells, or adipose tissue. They also tend to have resistance to insulin action in the muscle, and the muscle doesn't take up enough glucose and, therefore, it contributes to hyperglycaemia.
The next slide, I introduced this hypothesis of linking basically fat metabolism and glucose metabolism, and this hypothesis or model has now been fully well-accepted around the world by scientists working this area, this condition called the ectopic fat model. This is what it is, is that when fat cannot be stored in the adipose tissue it tends to go to other tissues. So in the diagram on the left, you have a healthy individual where there is a minimal amount of abdominal fat, and this is stored in the adipose tissue and the other tissues are fully protected and healthy. Whereas when there is visceral obesity of a large amount of abdominal fat, the fat doesn't have a place to be stored because of the excess amount. This fat ends up going into other tissues, and the three tissues that are particularly problematic when they become fatty are the heart, so you get fatty heart; you also get fatty liver; you get fatty muscle. When these tissues become fatty, which means there is fat stored in these tissues, they become insulin-resistant and that is thought to be one of the initiating factors in the development of the metabolic syndrome.
We reviewed this more than ten years ago, the problems that are occurring at the fat tissue, and we have recent reviews there for those who are interested in looking at. But this review was published several years ago in endocrine reviews, talking about how adipose tissue becomes insulin-resistant. When they become insulin-resistant, they allow the free fatty acids to be released from the cells and into the blood. When fatty acids come into the circulation they can end up going into all these other tissues, and storing and causing issues.
The next slide, I actually basically re-emphasized this point that fatty acids, if they are redistributed from the adipose tissue to muscle, liver and heart, which is not shown here, it causes basically fatty heart, fatty liver, fatty muscle and eventually causing insulin resistance and metabolic syndrome.
The next slide, I talked about the liver a little bit more, because this condition is becoming very common in the human population, and the condition being the fatty liver. So, again, people with metabolic syndrome and diabetes tend to have fairly high rates of fatty liver, and what it is on the left I show a normal liver, on the right a fatty liver. Now, fatty liver can be quite problematic, initially can simply cause insulin resistance and some of the complications of that, but if it progresses - and, fortunately, it is not common - but if it progresses to steatohepatitis, it can cause inflammation and other severe complications. In some cases, can progress - again, in percentages it is relatively low - but it can progress to cirrhosis, which is basically loss of hepatocyte and the liver becoming severely damaged. If you look at obese subjects and people with metabolic syndrome, this is commonly seen, not so much cirrhosis, but fatty liver steatosis is pretty common.
So the next slide I talk about some of the mechanisms and this is just showing you how fatty acids and glucose interact in terms of metabolism. Randle proposed this cycle many years ago in the 1960s, and it's now fairly well accepted to be the case where a presence of free fatty acids coming from the adipose tissue, because of the high amount of abdominal fat, it can actually interfere with glucose metabolism. This is thought to be the reason for the development of the insulin resistant state. What is shown here is that some of the enzymes involved in this process, such as pyruvate dehydrogenase can be inhibited and causing the insulin-resistant state.
The next slide, this is just a study that was shown that if you take humans and infuse fatty acids; so if you infuse in their circulation fatty acids, you see a significant decrease in glucose uptake. So peripheral glucose uptake with glucose uptake in other tissues, and glucose uptake, including the liver, can go down significantly. But if you look at glucose production or output, it's increased. These are all signs of insulin resistance, so suggesting that free fatty acids can cause insulin resistance, which is, again, fairly now well accepted; so showing that abdominal fat can directly cause the insulin-resistant state.
The next slide, I'm going to end my presentation for the last five, six minutes talking about the role of the intestine and this is a relatively new area that has been highlighted in many publications recently, and I thought it's important to talk about that. The intestine generally is regarded as just the organ that absorbs dietary nutrients, and was not initially appreciated that this is a very important endocrine organ. Now, there is growing evidence that the intestine plays a really important role as an endocrine organ, and it also plays a critical role in development of insulin resistance, metabolic syndrome and type II diabetes. There's a lot of information coming out in the literature, and this slide here shows you some of the hormones that are secreted by various parts of the intestine. Now we know that there are over 100 different peptide hormones that are secreted by the intestine, so actually the intestine is now regarded as the largest endocrine organ in the body. Now there is revelations as to how important this organ is in regulating our glucose levels, and our diabetes states.
The next slide shows you this procedure that has been attempted in the last several years and is now becoming fairly routine, it's called bariatric surgery. This bariatric surgery initially was done for people who are obese and it was meant to reduce food absorption and, therefore, decrease body weight. This was started actually more than a decade ago for people who have a very high BMI; a BMI of more than 40 or a BMI of more than 50, who are severely obese. They noticed that after a few months of this surgery they could lose 30% of their body weight. But then, in the last five years or so, it's been noticed that not only does surgery cause a reduction in body weight, it also can actually almost resolve type II diabetes. So, as you know, many obese subjects also have diabetes, so what they notice is that their diabetes also goes away after surgery, which then highlighted the importance of the intestine. So all they were doing is they were changing the anatomy of the intestine through causing a bypass, so allowing the food to bypass most of the stomach and the duodenum, and enter directly into the lower part of the jejunum. This surgery, also referred to as Roux-en-Y gastric bypass, was shown to cause within days after surgery, people who had diabetes for many years or decades, and were taking insulin stopped needing insulin, and actually had their diabetes resolved. So this has led to a lot of interest in the link between the intestine and diabetes, and metabolic syndrome.
So the next slide I show some of the findings. So after the surgery, what you find is that patients with diabetes and obesity suddenly now have normal glycaemia, so they have normal glucose levels. They have increased insulin secretion, they have normal haemoglobin A1C, which is an important marker of diabetes and they discontinued the diabetes medication. This appears to be independent of weight loss, and the weight loss takes several months to take effect, but the diabetes can resolve within days of surgery, which suggests that it's independent of weight loss.
So the question is what are the mechanisms? So I wanted to highlight the role of an important hormone called GLP-1. So the next slide shows you some of the articles that have been published on the hormone secreted by the intestine, and now it is regarded as a metabolically-active organ that secretes a large number of peptides. One of these peptides here is called GLP-1; GLP-1 stands for Glucagon-like peptide-1, is a very interesting hormone that's secreted by the lower intestine, small intestine.
The next slide, I'll give you some more information about this hormone. It's an increasing hormone secreted by the jejunal and ileal L cells and responds to a meal; so after we consume a meal it gets triggered and secreted. Then, in turn, it stimulates insulin secretion and decreases glucagon secretion. That also leads to the slowing of gastric emptying, reduces fuel intake and actually reduces basically appetite, and increases satiety and improves insulin sensitivity, it increases better cell mass and, therefore, improves insulin secretion. So all of these are very beneficial effects, and this has led to GLP-1 becoming a major drug target and currently many pharmaceutical companies are marketing drugs that target this hormone.
This next slide just shows you where this comes from, and this hormone is secreted by these cells called enteroendocrine cells. Here, these cells actually lie between the enterocytes, and they are secreted into the circulation directly, or they can actually be sensed by some of the local neurons, which is enteric neurons and vagal neurons can sense these hormones such as GLP-1. So these are basically hormones secreted by cells that neighbor the absorbs of enterocytes. GLP-1, as I mentioned, has attracted a lot of attention and now we know that it can have effects on many tissues, and play a very important role in the insulin sensitization and metabolism. This has been reviewed by several groups, including ourselves, so I'd welcome you to look at some of the literature in this area.
The next slide, I just show the physiology of this hormone, so when we ingest a meal the intestine secretes this peptide, and this peptide increases insulin secretion and that's called an incretin action. But GLP-1 has a very short half-life, so it's degraded rapidly by an enzyme called DPP-4 and it's a protease. This inactivates GLP-1, so this an important regulatory mechanism. So GLP-1 is secreted, it acts and then is rapidly degraded by this enzyme. This has now been exploited by many pharmaceutical companies who develop compounds.
On the next slide I show some of the novel pharmacological anti-diabetic agents that have been developed. These are all based on GLP-1, so some are GLP-1 analogues, as shown here, such as exenatide and all these enzyme inhibitors called DPP-4 inhibitors. So those are now actually in the clinic, are being used to treat patients with type II diabetes. They've been used in some cases in patients with pre-diabetes and metabolic syndrome, and they are very effective in the sense that they can improve insulin secretion, and decrease insulin resistance. These are actually now multibillion dollar drugs and they are the most effective diabetic drugs available on the market. So they just highlight the importance of the intestinal peptides such as GLP-1, in regulating our metabolism and diabetes development.
The next slide - and I have a couple more slides before I conclude - this just shows you the mechanism of action, which basically I've already explained in the sense that GLP-1 increases insulin release, and that in turn lowers blood sugar. At the same time, it's been shown to inhibit glucagon release, and that also helps to lower blood glucose levels. This leads to a hyperglycaemic action that's exploited for type II diabetes treatment. I mentioned that the enzymes DPP-4 are really important, in the sense that they inactivate GLP-1, so inhibiting these enzymes can be a very important therapeutic approach.
This next slide shows you some of the recent data that is shown in patients who are taking the drug; patients who are diabetic, for example, on the right you can see a patient who is diabetic following over time without treatment, have a very high hemoglobin A1C levels. Hemoglobin A1C is a very good marker of diabetic control, or diabetes control and you can see this stays elevated at 8% or above. But with a linagliptin treatment, and this is a drug that's basically a DPP-4 inhibitor, it increases GLP-1 action and, as you see, within weeks it significantly lowers hemoglobin A1C level. So it just shows you that these drugs targeting GLP-1 are very effective diabetic treatments.
Finally, my last slide I wanted to just mention that we don't have time today, but I will talk about some of this in the next presentation, but this just highlights the importance of not only the intestine, but also the link between the intestine and the brain. There is a significant cross-talk between intestinal receptors and nutrient sensing in the intestine, and a number of pathways in the brain, in the hypothalamus and other parts of the brain that really regulate our metabolism. I would like to invite you to future presentations so that we can talk about this in more detail. So this brings this presentation to an end. Thank you for participating. I would like to introduce our next speaker who is going to give an Abcam presentation, Sambhav Dave, he's the Senior Business Development Associate at Abcam and will be giving you a presentation. Thank you.
SD: Thank you, Professor Adeli for this wonderful talk. I'd like to take a brief moment to tell you about Abcam. Abcam was founded in 1998 from a laboratory in Cambridge University, and since then our catalogue has grown to over 100,000 reagents. More than 47,000 reagents are available for metabolism research, so I'm quite confident that you can get the right product for your research. We have a range of primary antibodies, secondary antibodies, assays, ELISA kits and biochemicals. We also have a whole host of tools to help you with your work, including posters, pathway cards and video tutorials. If you want to access any of those, you can go to www.abcam.com/Metabolism.
We have a wide selection of primary antibodies for metabolism research. We have both polyclonal and monoclonal antibodies, and they are raised in rabbit, mouse, chicken, goat and sheep. Here's a selection of some of the antibodies that we have available for some of the biomarkers that Professor Adeli mentioned in his talk. All of our antibodies are highly validated and they've been tested in various DCs and applications. They've all been tested by the peers working on the reagents, and they've received AbReviews, and all our reagents are covered by the Abcam guarantee - the AbPromise. We also have a team of dedicated scientists that can help you if you have any problems or questions for all of our products.
We also offer a range of rabbit monoclonal antibodies; these are fairly new on our catalogue, and they are for the benefit of monoclonal with the specificity and robust rabbit immune system. Since these are raised in rabbit, there's no cross-reactivity when using mouse tissue, they have high affinity and specificity with a diverse epitope recognition, and our catalogue consists of more than 5,700 rabbit monoclonal antibodies.
We have a broad range of secondary antibodies to complement our primary antibodies as well with over 2,500 reagents, and are highly popular in extensively validated Alexa Fluor® secondary antibodies. These are a large selection of pre-adsorbed secondary antibodies with a whole host of Alexa Fluor® conjugates, and they have an excellent dilution range. So if you want more information on these Alexa Fluor® secondary antibodies, visit abcam.com/Alexa. Apart from our Alexa range, we also have biotinylated secondary antibodies, which can be used with avidin and streptavidin. AbGold conjugated secondaries, we use them in electron microscopy, as well as other fluorescent dyes like Chromeo Dylight.
We've recently launched secondary antibodies that are conjugated at three new Alexa Fluor® conjugates, Alexa Fluor® 405, Alexa Fluor® 568 and Alexa Fluor® 750. Alexa Fluor® 750 has an emission that is visible in the infrared spectra, but these can be used in instruments that can detect infrared signals.
Apart from antibodies, Abcam also offers convenient assay kits to study metabolism. The kit contains all reagents you would need to analyze metabolic processes. They come in a format of 96 well plate, and have both fluorometric and colorimetric section method, and they offer coverage over most biological pathways. Here are some of the examples of what you can measure. So as Professor Adeli mentioned, lipid formation you can measure adipogenesis, you can quantify and detect cholesterol and you can quantify free fatty acids. You can also look at insulin signaling pathways to detect glucose, and also to see uptake of glucose, and also lipid metabolism.
If you are interested in studying mitochondria, we have a range of reagents called MitoTox. The MitoTox range offers solution for mitochondrial safety analysis, and measurement of key parameters of mitochondrial function, such as screening of mitochondrial toxicity, investigating energy impairment, apoptosis and oxidative stress. All our products are listed at www.abcam.com/MitoTox, if you want to visit that page.
Apart from our assay kits, we also offer kits for rabbit quantification using ELISA. Our SimpleStep ELISA kit is specifically designed to make your life simple when performing ELISA. On the right hand side you can see when compared to traditional ELISA, SimpleStep takes less time and has greater sensitivity and efficiency. SimpleStep is compatible with the existing instrument and does not require any additional training. So it is really time-efficient, it saves you more than two hours in your experiment time, it is extremely accurate and reduces handling time. The kit contains capture and detection antibody that captures the analyte. This entire complex is then immobilized to the antibody conjugated on the well, which then can be detected using the color solution. In this slide, I have just pointed out a few of the kits that are available for metabolism research, and especially some of the biomarkers that Professor Adeli has mentioned in his talk. Example: fibrinogen, ICAM-1 and leptin. At the bottom we have a review from one of the academics from the University of Florida, and she said this kit was very easy to use and the fastest ELISA that she had ever performed, with an excellent dynamic range.
Finally, our future upcoming webinars are Epigenetic Mechanisms in Early Mitochondrial Mammalian Development on 21st January; An Investigation of Glutamate Receptors using Immunochemical Techniques on 5th February, 2014. I'd like to thank you all for listening in, and I'll hand over to Professor Adeli to answer the questions you have submitted. If you have any questions about the products I've talked about in this presentation, or any other products, I'll be happy to answer these questions too.
KA: Thank you very much, Sambhav. Now, I'm happy to answer any questions that might be posed. Actually, I have prepared a couple of questions that normally are asked when I present at different conferences. A couple of questions of which I can try to go through and answer. One common question is: Is the metabolic syndrome a condition that's reversible? The answer is yes, certainly development of these complications that are associated, the components of metabolic syndrome, such as high blood pressure, high lipids, abdominal obesity, these are all reversible initially through a simple means such as lifestyle changes, improved physical activity, reduced intake of high-density, high calorie-dense foods. Basically, increasing energy expenditure and reducing energy intake has been shown in a number of human studies to reverse many of the complications of metabolic syndrome, and make someone insulin-sensitive and reduce the degree of insulin resistance. So these are really conditions that are reversible and in most cases drugs are not needed, and lifestyle changes are sufficient.
The next question that is commonly asked is: In the development of metabolic syndrome and diabetes, what comes first, is it obesity or is it insulin resistance, and which one comes first? The answer is actually rather complicated in the sense that it depends on the individual. Many individuals appear to develop obesity or overweight first before insulin resistance takes hold. So overweight and increased abdominal fat appears to initiate the insulin resistance, and then development of metabolic syndrome and diabetes. But there are cases where lean individuals who are not obese have insulin resistance, and this is thought to be partly genetically caused, which then can lead to complications and development of other complications. So I would say the most common observation is that obesity and overweight comes first before you see significant insulin resistance developing, but there are cases where that is not the case. So those are the two main questions I wanted to address, so thank you very much for participating. I look forward to giving the second presentation in January.