 Okay, good morning everybody. Thank you for being here. My name is Rand Akashay. I am from the University of Illinois at Chicago. I study basically how diseases occur. It's a field we call pathophysiology. And I'm gonna discuss the role of insulin in today's most prevalent chronic diseases. The title is the role of hyperinsulinemia, meaning increased insulin levels in the circulation and how they are related to chronic diseases. What's insulin anyway to start with the basics? This hormone is secreted by the pancreas. This organ that sits kind of lower to the stomach and it's a peptide hormone. It's produced by the cleavage of a longer peptide and goes to the circulation and it has a very complicated and various functions that are conveyed through signalling pathway. This is what happens inside our cells and this is rather a simplified version of it. But what insulin does is that it binds to a receptor as we see here and then it triggers a cascade of biochemical reactions which classically would lead to the transportation of the glucose channel to the cell membrane so glucose can get inside the cell. In addition to that, insulin is known to be an anabolic hormone so it stops lipolysis or lipid release, fatty acid release. It stops proteolysis. It triggers fatty acid synthesis, the accumulation of fat in the adipose tissue, the production of lipids in the liver and their export glycogen synthesis in the muscle, in the liver. It also blocks gluconeogenesis which is the production of glucose in the liver and ketogenesis. So it's basically an anabolic hormone. We think about it as an anabolic hormone but also it has a vital role in driving all nutrients not just glucose, amino acids and fatty acids inside the cells so the cells can utilize them and it kind of moves the glucose through glycolysis so it can be further burnt into ATP and energy production. We also have a system of anti-insulin hormones. We call them the counter-regulatory hormones and these would be glucagon, growth hormone, cortisol and epinephrine. They do the exact opposite. So their job is to function in the absence of fuel. They kick in, they increase blood glucose, they kind of create homeostasis with insulin in order to keep fuel available in the circulation but if these also get over secreted, so for example if you have too much cortisol for a very long time, this by itself can promote adipocyte formation, lipid accumulation, obesity, diabetes on the long term. So it's all about balance. Before we speak about hyperinsulinemia, I want to speak about insulin deficiency and the history of it. This is a child that had type one diabetes and it's among the first cases that were treated of insulin with insulin and recovered. Before that, children would just die with type one diabetes because it has vital functions in growth, in maintenance, in cell proliferation and we already know that if insulin receptor is absent in mice, they just don't survive. So it is certainly a vital hormone and ever since insulin's discovery since 1923, much work has been done to understand its functions until we also further understood how it works in type two diabetes and many Nobel prizes were granted to scientists for their work on insulin. But how about insulin excess? So this is like the other end of the spectrum which is what we call hyperinsulinemia. This also is problematic because it is associated with insulin resistance, type two diabetes, obesity, cancer, chronic inflammation, hypertension, atherosclerosis and I will show that the evidence suggests that it's not just an association, it can actually be a causal factor in these diseases. What's hyperinsulinemia anyway? At least by medical textbooks and most medical references, you're gonna see a fasting insulin of less than 25 million units per liter is what's considered to be normal even though some studies suggest that lower level can be more beneficial but not lower than two. Other studies also looked at post-prane-del insulin and the importance of its return to the baseline which is less than 25 after two to three hours of a meal ingestion or glucose loss. And here we're looking at a big number of studies that looked at the correlation between hyperinsulinemia and various conditions like central obesity, diabetes, renal failure, non-alcoholic fatty liver disease, polycystic ovarian syndrome, sleep apnea, you can name it, metabolic syndrome, all of these chronic diseases that in the study populations, most of the study population actually in those studies had hyperinsulinemia versus the studies that did not show hyperinsulinemia are actually rather rare. So, and that's pretty significant. And I'm gonna talk a little bit about the connection to metabolic syndrome. And the criteria to diagnose metabolic syndrome has been evolving through the history of research. It had been focused more on the WASER conference on triglyceride levels if elevated LDL, HDL, cholesterol, BMI, all of these factors. But now we're seeing that organizations like World Health Organization and a European group for study of insulin resistance have actually added insulin resistance and it's related issues like hyperinsulinemia and periphasic glucose as a criteria for the diagnosis, as one of the criteria for the diagnosis of metabolic syndrome, if not to be a necessary criteria for its diagnosis. But still not all organizations would consider that. As a matter of fact, in some of the studies that report hyper triglyceridemia, for example, the study population, 95% of it would have hyperinsulinemia. So, and that says something about it. What causes hyperinsulinemia in general? That's a critical question and I'm gonna spend some time explaining those factors. Factors can be quite direct that involve insulin administration, of course. Insulin secretagogues like cell phone ureas, insulinomas, which are tumors in the pancreas that oversecrete insulin. We have congenital hyperinsulinism or autoimmunity to insulin or the insulin receptor where we see the insulin-like bound to its antibodies in the circulation, which delays its clearance. In addition to that, we have severe liver disease and liver congestion with heart disease. All of that can lead to reduced insulin clearance and this would lead to hyperinsulinemia and may or not lead to hypoglycemia depending on how strong the compensatory insulin secretion is. And then we have conditions that are rather associated because they're chronic. We like to call them associated with hyperinsulinemia and these would be obesity. Steroid administration like glucocorticoids because there's a counter-regulatory hormones, the induced insulin resistance, drive insulin secretion, acromiglialy, Cushing syndrome, insulin receptor mutations which are rare of course and last but not least, type two diabetes. And of course, obesity and type two diabetes are the most prevalent causes or related factors to hyperinsulinemia. What are the consequences of hyperinsulinemia? Let's study the pattern and the relationship with obesity and diabetes. So we see here in normal and lean individuals insulin levels are high, these are fasting insulin levels and then they start rising with obesity, impaired obesity, non-incident dependent diabetes and in later stages it's even higher. So insulin definitely correlates, positively correlates with body weight and diabetes status. And if we look at the natural history of diabetes, untreated diabetes, how does it go? You're gonna see interestingly that insulin in some studies come before impaired glucose tolerance by 25 years in some studies or 22 years and this had been consistent. So despite that, there is still resistance by physician to test insulin levels. So a lot of scientists now are saying that testing insulin is important if excessive body weight is there, if other risk factors are there because it is a very strong predictor of type two diabetes. As we can see here, insulin level would rise, correlates with insulin resistance and at the peak, this is when we start seeing impaired fasting glucose and then diabetes at the exact diagnosis of diabetes when beta cell failure occurs, this is when hyperglycemia occur. So in diabetes and insulin resistance, the first event is hyperinsulinemia. Of course, the prevalence of diabetes in the USA and in the world as a matter of fact is very high and had been rising since the 1980s through 2010 and now it's even higher. So here we have 22 million people with diabetes. It has dramatic complications that affect quality of life in addition to the cost that come with it. So its prevention is really very important for the well-being of populations. And hyperinsulinemia isn't just about diabetes. It's also about heart disease, which actually we know that cardiovascular events and complications are the main complications that come with diabetes. So we're looking here at a study that looked at risk of cardiovascular event, new cardiovascular events and heart disease people. And we're looking here at multiple risk factors like hypertension, age, smoking, everything. Many factors are correlated of course, but with analysis they revealed that insulin of more than 10 units per ML leads to a relative risk increase by 1.7, which is like 70% increase in relative risk. And they did further analysis in this population. What they did is they took this population, they split them into two, diabetic and non-diabetic. And guess what happened to the relative risk here or the odds ratio of having cardiovascular event? Here's the log insulin. And here we see that odds ratio is 6.7 for all patients, even not diabetic. And for a non-diabetic patients it's 4.9. So that said, hyperinsulinemia is a very, very strong risk for cardiovascular events in the absence of hyperglycemia. And that is very important, especially that these numbers statistically imply kind of or suggest a causative relationship. Because in the world of epidemiology, a relative risk or odds ratio of six and four, this is very high. This is like 600% increase in the risk. In addition to that, hyperinsulinemia is also a risk factor for many neurological disorders, including Alzheimer's disease. You can watch my AHS 16 presentation on Alzheimer's disease and I have focused most of that talk on the role of insulin and insulin resistance in Alzheimer's disease. And for that, we talk about obesity being associated with hyperinsulinemia We still, scientists kind of are trying to figure out what is the first event that triggers hyperinsulinemia. And for that, various research models have been developed to study where the problem starts. And the classical model of obesity is that it goes from obesity to insulin resistance and from there we go to a compensatory increase in insulin secretion. So your cells are not accepting insulin. The pancreas would compensate by secreting more insulin. And how do we test that in the lab? We give, for example mice, caloric dense diet or high-fat diets, they gain a lot of weight. And as we study their adipose tissue biology, we see that increased inflammatory cytokines happen with weight gain. And this would invite and tell the macrophages surrounding the adipocytes to secrete more cytokines. Not only that, they would invite more immune cells from the circulation. This will drive more inflammation. And we know that inflammatory factors disrupt insulin signaling. That big pathway I just showed, it gets disrupted when inflammation is there. So this is the model. We have excessive calorie intake, obesity, insulin resistance, hyperinsulinemia. But does it go the other way round? So can we say that insulin leads to obesity, for example? And there's a group of researcher that have been doing a significant amount of work in that direction. So here, for example, they suggest that insulin level goes up and with that adipocytes goes up and later glycemia or hyperglycemia occur with further insulin resistance and beta cell dysfunction. And with that, if we start with a certain number of overweight people, like 1,900 million, some will go to pre-diabetes and few, not few. Less than those will go to type two diabetes. So the insulin obesity model is gaining more attraction now because evidence suggests that moderate reduction in insulin levels in obese people can help in weight loss. And insulin resistance, so this is kind of the evidence for this model. That weight gain and insulin resistance can occur following insulin administration in type one diabetes. If excessive insulin is administered to these people, they eventually will become insulin resistant and obese. So here we know that increased insulin is what started the issue. People with insulinoma or increased insulin secretion because of tumors also can develop insulin resistant and obesity because of that. And there has been very neat animal work, animal-like mouse models that insert genetically modified the mouse and insert the human insulin gene into the mouse. And if this insulin gene is simply overexpressed, it will leave these mice to be more insulin resistant and more obese compared to the control mice that didn't have an over-activation of this gene. So further evidence that the problem can start with hyperinsulinemia. And insulin administration by itself in mice induces weight gain despite their caloric restriction. That means it's not all about caloric restriction. Excess insulin can actually oppose the attempt to lose weight. Addition to that, hyperinsulinemia occurs before weight gain in mice that are prone to obesity. Like these mice are known to be prone to obesity and diabetes like C57 black six mice and leptin deficient mice. It was shown that hyperinsulinemia comes before their weight gain. Hyperinsulinemia also leads to insulin resistance in drosophila and that's because just like many hormones, if you overexpose the cells to them, these cells get desensitized. And it's true for so many hormones, for so many medications. So this is like the kind of the summary of the insulin obesity models. We know that hyperinsulinemia in observational study is strongly correlated with not just obesity but with many other diseases. And we have free clinical evidence like on animals that would support that. And then we have clinical evidence, some studies on clinical evidence that would suggest this true. And we have one or two studies that would kind of don't agree with that say the reduction of calories kind of matter more than the focus on hyperinsulinemia. And that was the insulin obesity model. And this had led some scientists to think maybe it's carbohydrates that are driving the insulin and therefore the obesity. And so for the conventional model, as I said, the scope of the disease is that overeating would lead to, and along with reduced energy expenditure and reduced physical activity would lead to increased body weight. And this would lead to increased fat storage. And as I said, then insulin resistant, then hyperinsulinemia, and then all the diseases. But the carbohydrate insulin obesity model says that carbohydrate consumption would lead to overeating. So as a major cause of overeating. And because insulin is an metabolic hormone, this would increase fat storage. And then this will drive the rest of the problems that come with hyperinsulinemia and obesity. But this hasn't yet gained much acceptance in the scientific community. And I will present the pro, the for and the against arguments for this model. Because it's rather new. So the evidence for is that rodents on high versus low glycemic index diet develop hyperinsulinemia before weight gain. So high glycemic load will lead hypothetically to more insulin and then this will lead to weight gain. Also people who have certain like variants in their insulin receptor promoters that would typically lead to increased insulin secretion. These people are more prone to obesity during adolescence, so early in life. There are also two trials, the diogenes and the direct clinical trials, which found greater weight loss on low versus high glycemic load diet. And we also have that carbohydrate restriction was superior to fat restriction in reducing this lipidemia in multiple studies, especially actually hyperlyseridemia. What's the evidence against? We have actually a well-designed clinical trial, the diet fits, which reported no significant differences in weight loss between participants on low carbohydrate versus low fat diet over a 12 months intervention. And the baseline insulin did not seem to predict the degree of weight loss. So that's kind of the evidence against. Typically, as I have went through so many studies, I've seen that on low carbohydrate diets, the initial weight loss is faster than the low fat diet, but eventually the rate will level off and after a long period of intervention, you're gonna see that the rate of weight loss is the same. And that's likely because insulin is not the only factor that affects anabolism and catabolism inside the cells. Because at the end of the day, the fate of fuels inside the cell would depend on ATP sensors, like molecules whose job is to sense how much ATP and energy is inside the cells. While this is affected by insulin, it can be affected by so many other things. And that's why insulin is not the only player. It is definitely a strong contributor to the complications of diabetes and obesity, but certainly not the only one. And it appears that so far, most studies will indicate that caloric restriction tends to be the winner, at least in terms of body weight. So in conclusion, hyperinsulinemia is a strong risk factor for multiple chronic diseases with many studies pointing to a causal relationship, as I showed. Screening for insulin levels must become a routine in the clinical practice for early intervention. We can capture these diseases way before we have to give any medication. And we have very successful intervention in reducing insulin. One is weight loss. Weight loss on any diet would be expected to reduce body weight, reduce insulin, and this would be beneficial. And fasting, of course, low carbohydrate diets are, of course, the most effective in reducing insulin. That is because insulin is the carbohydrates or glucose, the strongest secretagog. And, of course, exercise and sleep are important, but I didn't talk much about also glycemic load and the glycemic index. So if carbohydrates are gonna be ingested, certainly simple carbohydrates like sugars, refined flowers, all of that, these are risk factors for diabetes by themselves, independent of anything. So definitely simple carbohydrates. If we're gonna blame carbohydrates, a big part of the problem would be simple carbohydrates, while complex carbohydrates, in many, at least observational studies, would show that people can be healthy without diabetes while eating those. So, yep, thank you.