Understanding Insulin Resistance and Its Impact on Diabetes and Obesity

The key word that I want to stress here is insulin resistance. I want to spend a little bit of time on this so that your only take-home point will be this. This terminology is key in understanding the pathophysiology of obesity. Insulin resistance results in several metabolic disorders, especially metabolic syndrome and diabetes.

So, how does this insulin work? Insulin gets to the receptor on the cell and unlocks the glucose channel, helping to open up the transporter, which we call the glucose channel, so that glucose can enter the cell. Insulin resistance is a subnormal glucose response to endogenous or exogenous insulin. That means the insulin that is produced inside the body or the insulin given as an injection from outside.

If you see here, the insulin is there but it’s not letting the glucose come into the cell. It can happen for a couple of reasons: one, the receptor for the insulin might not work, or two, the receptor works and accepts the insulin, but the intracellular signaling mechanism that helps to open up the glucose channel might not work. These two mechanisms are the fundamental basis for insulin resistance.

What happens when the glucose doesn’t get into the cell? It stays in the blood. When it stays in the blood, it goes all over and starts affecting every tissue and organ. If it goes to the liver, it converts into fat, and that fat is released into the blood and then tries to go all over the body. When the fat goes and deposits in and around the organs, we call it visceral fat. At the same time, when the glucose is not entering because the insulin is providing some resistance and the insulin is also not working, the excess insulin in the bloodstream will stimulate the ovaries to produce excess androgens, which will be converted into estrogen and progesterone. This hormonal imbalance is a key mechanism for polycystic ovarian disease.

So, what does this insulin resistance do to us? The excess fat that is produced in the liver gets into the bloodstream and starts getting deposited all over the body—in the liver, in and around the heart, in and around the pancreas, and even around the skeletal muscle. As it deposits, it starts affecting their important functions. When it surrounds the heart, it affects the heart’s function and results in heart failure. If it goes to the pancreas, it messes up with their functions. If it goes to the kidneys, it results in high blood pressure.

This is an easy picture to understand how obesity can impact several organs. It can present in various ways depending on the underlying etiology and severity. As I mentioned, obesity is only one among the reasons for insulin resistance. There are many other reasons, such as inactivity, medications, and stress.

What are the consequences of this insulin resistance? As I mentioned before, it’s an array of metabolic disorders that it can cause. How do you explain those metabolic disorders? We put all these things into a cluster and call it metabolic syndrome. It can cause obesity, metabolic syndrome, high blood pressure, diabetes, and polycystic ovary syndrome. We will try to address them one by one very slowly so that you can understand.

From the beginning, I’ve been mentioning insulin resistance. How do you know if a person has insulin resistance? What are the signs and symptoms we can look into? Impaired glucose tolerance, skin tags, infertility, or high blood pressure are symptoms that we can look for. Currently, there is no acceptable test for measuring insulin resistance, so what we go by are the symptoms and signs, like skin tags and infertility. We corroborate and incorporate all these with waist circumference, BMI, blood glucose, and blood cholesterol levels to quantify and diagnose insulin resistance and metabolic syndrome.

This is a cluster of metabolic disorders that influence the risk of cardiovascular disease linked with insulin resistance. There are five traits we need to look into for each person to see whether they have insulin resistance: abdominal obesity (defined by waist circumference, like 40 inches in men and 35 in women; for the Asian population, it’s different: 35 inches for men and 31 for women), serum triglycerides more than 150, fasting plasma glucose more than 100, blood pressure more than 130/85, and HDL cholesterol less than 40. We take all these parameters into consideration, in addition to the signs and symptoms, to identify insulin resistance.

After identifying, we will do the risk stratification. If anyone has three out of five, then we will say this person has metabolic syndrome. One of the important metabolic disorders caused by insulin resistance and obesity is diabetes. As I mentioned before, diabetes and obesity go hand in hand. We call it diabetes—a dual epidemic. If obesity is present, you are at a high risk—seven-fold for men and 15-fold for women—of having diabetes. Given this high risk, which will have some influence over cardiovascular disease, HbA1c is the marker that we use for diabetes. An HbA1c of 6.5 or more, fasting plasma glucose of 126 or more, or random glucose of 200 or more with symptoms indicates diabetes. Prediabetes, which is very commonly seen, has an HbA1c of 5.7 to 6.4.

These are the markers that we use to identify who has diabetes. There are 11 pathways that can result in hyperglycemia, and insulin resistance is just one among the mechanisms for hyperglycemia. Given that today's topic is obesity, we will focus on insulin resistance. How do we prevent and manage obesity? Weight loss is key. It should be sustained, and it should be as little as five percent. I will explain why they chose five percent. Diet, exercise, and behavioral therapy are essential to keep it sustainable. A sustained, modest weight loss of five percent will definitely improve glycemic control and reduce the need for diabetic medications. A weight loss of more than five percent improves the lipid profile as well as the blood pressure status in those at risk. A weight loss reduction of seven percent or more over a period of three to six months is ideal.

Next comes lifestyle modification. I know there will be a lot of questions on diet, which is a very popular topic when it comes to obesity. I will try to explain it in a way that you can understand and customize according to your dietary patterns. Several studies evaluating the effect of various popular diets on weight loss have revealed, after reviewing all those studies, that the current trend favors a low-carb, low-glycemic index Mediterranean diet.

However, no optimal dietary strategy exists for patients with obesity and diabetes. More research is needed, especially for these high-risk people. This term I want you to get familiar with: medical nutrition. Even with the wide range of choices we have, the best thing is to customize it based on your dietary preferences, energy needs, and health status. Medical nutrition therapy and a multidisciplinary lifestyle approach are key in preventing weight gain following successful short-term weight loss. We are all very good at achieving short-term weight loss, which I will try to explain a little more about later. We try to prevent weight gain following weight loss. For that, you need some sort of rehabilitation in the form of cognitive behavior therapy, which is a type of behavioral therapy.

Medical nutrition therapy is very effective within the first year of diagnosis of diabetes, as it is associated with a 0.5 to 2 percent decrease in HbA1c levels, which is very significant. You cannot underestimate that. I told you it’s all based on your dietary preferences, energy needs, and health status. You might ask, what kind of energy levels are we talking about? It varies from person to person. The energy expenditure can be calculated using a simple formula: for men, it’s ten times the kilograms plus nine hundred, and for women, seven times the kilogram plus eight hundred. Multiply the result by 1.2, and it will give you how many calories you need. From that, you can have a deficit of 500 to 1000 kilocalories per day to achieve a reasonable weight loss of five percent.

However, I want to mention here that you have to consume at least 800 kilocalories per day to avoid electrolyte imbalance and metabolic disturbances from starvation, which we have seen in very low-calorie diets adopted by individuals who are very enthusiastic but don’t understand how it works. They will be on SlimFast or Optifast, using synthetic food substitutes to follow a very low-calorie diet, and they end up having some electrolyte as well as metabolic disturbances, which is very dangerous. So, try to avoid very low-calorie diets; at least you need 800 kilocalories per day.

As I mentioned before, several studies have been reviewed, and the summary was given for each and every diet. They analyzed the low-glycemic diet. I will go through only the key points: HbA1c reduction of 0.5 percent. Weight regain couldn’t be unfound because when you say some diet is determined, we need to take into account that these studies are done over a five-year period, and there are so many rate-limiting factors in the study, like dropout rates and other things. That is why they couldn’t find the weight regains.

Low-fat diets allow taking less than 30 percent of the calories from fat, avoiding all the saturated and trans fats. The Mediterranean diet, which I’ve been mentioning from the beginning, focuses mainly on unsaturated fats. That is the key point why it is on the top of the ladder for the last seven to ten years, according to studies. If you see, the weight loss is 7.4 kilograms in a year, and HbA1c reduction is 0.4 to 0.6 percent.

Protein-sparing modified fasting diet, which you all call a ketogenic diet, is a low-carb ketogenic diet with very low calories. What it means is taking fat and protein and avoiding carbohydrates. Studies have proven that it is not sustainable; there are more challenges in the study because if you see the weight regain, most people return to baseline by five years. It is very challenging and very difficult to sustain this, and people find it very difficult to follow after two years, as per the study outcomes.

A vegetarian diet shows an HbA1c reduction of 0.6%. This one slide will explain how important it is to compare the Mediterranean diet versus the Western diet. Sustainability is the key word that I want you to take home, apart from the insulin resistance. Whatever you do, we have to make sure it is sustainable. In the Mediterranean diet, they found fewer chronic diseases and fewer comorbidities, and it is more sustainable compared to the Western diet.

Then comes exercise. Thirty minutes or more, at least five days a week, totaling 150 minutes per week. The point I'm trying to mention here is attainable goals, measurable goals. Whatever we identify, we try to measure and track it. That is the only way we can improve the outcomes. So set smart goals and try to track them with all these novel devices we have right now. This will help you achieve the target, which is weight loss. Studies have found that a combination of different exercises gives the best outcome rather than just doing aerobics. Resistance, flexibility, and balance exercises all help. Just sticking to one aspect of exercise is not enough.

You can ask me how to start with the prescription: it could be FITT—Frequency, Intensity, Time, and Type. How many days you can work in a week, how intense you want to be depends on how motivated you are, how much time you want to spend per session when you do the exercise, and how much endurance you have. For sedentary beginners, three days a week, moderate intensity for 30 minutes; for non-sedentary active people, four days a week, moderate intensity for 30 minutes, brisk walking plus squats or planks.

You can see the benefits of doing regular physical activity. The most important thing is the lower risk of all-cause mortality, which is what we are aiming for. Try to reduce the risk of cardiovascular disease linked with insulin resistance from obesity. This is very important.

Behavioral and cognitive techniques will be used for a short period of time, and then we will rebound with the making. There are ways to come around this. This is an important part of medical nutrition therapy, which is another term I want you to remember. Not only will they educate you on what to eat and how to make it sustainable on a long-term basis by giving you some counseling, but also keep a food diary. You can go through all these things like simple attributes: do nothing else while eating, leave the table after eating. These are simple things that we can do in day-to-day life activities.

Lastly, anti-obesity therapies are used only if the patient is very motivated and shows at least a five percent body weight loss over a period of three to six months. They are only for people whose BMI is more than 30 or more than 27 with comorbidities like diabetes, hypertension, heart attack, or kidney problems. Before we start the medications, we always try to rule out other causes of obesity, like any thyroid problems or if the patient is on any medications causing weight gain. Based on this, we classify obesity like neuroendocrine obesity or dietary obesity, and we try to rule out other causes before we get into the therapy for obesity.

These are the medications associated with weight gain, with steroids being number one on the list. There are several medications that can be used for obesity control. The most commonly used ones are Orlistat, liraglutide, and phentermine with bupropion. In the metabolic clinic, the phentermine combination has produced significant weight loss when tested over a period of two months.

Since diabetes and obesity go hand in hand, are there any diabetic medications that can be used to reduce weight while controlling diabetes? There are several mechanisms that can cause diabetes, and one of the mechanisms is insulin resistance. There are some medications that can work on that. The medications that we normally use in obese patients are metformin, DPP-4 inhibitors, and GLP-1 agonists. These are all medications that can be used for obese patients.

Watching this link will provide you more wholesome information https://www.youtube.com/watch?v=sPzGflwtz4A&t=1482s