Insulin Resistance

What is Insulin Resistance?

Insulin resistance is when your body’s cells have a lowered response to the hormone insulin. Insulin is what allows our cells to use sugar (glucose) from carbohydrates in the food that we eat for energy or to store glucose for future use. All areas of your body that have insulin receptors, which receive and react to insulin, are prone to insulin resistance. However, the liver, muscles, and fat cells are the main places where insulin resistance happens. When insulin resistance occurs, it hampers the body’s ability to use glucose effectively. As a result, the cells that produce insulin (beta cells) step in to produce even more insulin – leading to a condition called hyperinsulinemia. Some recent studies suggest that hyperinsulinemia may even cause insulin resistance, indicating that overeating and the resulting hyperinsulinemia might lead to the harmful effects associated with insulin resistance. The resulting health issues from insulin resistance can include high blood sugar, high blood pressure, abnormal cholesterol levels, high uric acid levels, increased inflammation markers, poor endothelial function (which affects the insides of your blood vessels), and a state where your blood clots more easily. Over time, these conditions may lead to other health problems such as metabolic syndrome, non-alcoholic fatty liver disease (excess fat in your liver), and type 2 diabetes.

While insulin resistance typically results from having too much body fat, it can sometimes be caused by our genes too. However, it’s hard to define clinically because there isn’t a universally accepted test for it. Right now, doctors typically diagnose it by recognizing the symptoms associated with metabolic syndrome and insulin resistance syndrome. The most accurate method to measure insulin resistance is called the “hyperinsulinemic-euglycemic glucose clamp technique,” but it’s mainly used for research. In clinical practice, doctors often use other ways to measure insulin resistance, such as HOMA-IR, HOMA2, QUICKI, serum triglyceride, and the triglyceride/HDL ratio.

Type 2 diabetes is the main health problem resulting from insulin resistance. It usually develops a decade or a decade and a half after the onset of insulin resistance. This typically leads to faulty glucose uptake into the affected tissues, particularly skeletal muscle. So, when we eat food that’s high in calories, the body needs more insulin to use the glucose. This further increases insulin resistance, creating an unhealthy cycle. Over time, the insulin-producing cells in your pancreas can’t keep up with the increased insulin demand. The rising blood sugar levels eventually lead to type 2 diabetes. Insulin resistance has been observed even in people getting insulin treatment. Doctors generally consider someone as insulin-resistant if they need more than a unit of insulin per kilogram of body weight per day to keep their blood sugar levels in control.

Insulin resistance is associated with various health problems such as obesity, heart disease, non-alcoholic fatty liver disease, metabolic syndrome, and polycystic ovary syndrome. These conditions put significant strain on the healthcare system. The consequences of diabetes, such as nerve damage, eye disease, kidney disease, heart disease, and peripheral artery disease, place an even higher burden on healthcare costs.

When treating insulin resistance, the first step should always be changes to your lifestyle. Following a diet that reduces your calorie intake and avoids carbohydrates that trigger high insulin demand is crucial. Physical activity helps burn calories and can improve your muscle’s sensitivity to insulin. Medications can also enhance the body’s insulin response and lessen the demand for insulin.

What Causes Insulin Resistance?

Insulin resistance can come about due to different factors, and these can either be acquired (due to lifestyle or environmental influences), hereditary (passed on from parents), or a combination of both. However, the majority of people with insulin resistance have factors that are acquired rather than hereditary.

Acquired factors that can lead to insulin resistance include:

* Extra fat around the abdominal area. This is often due to fat that has moved over from under the skin.
* The aging process. As we get older, our chances of becoming insulin resistant increases.
* Lack of physical activity. Regular exercise can help our body use insulin more effectively.
* Unhealthy eating habits.
* Certain medications can interfere with our body’s ability to use insulin. They include steroids, antidepressants, antipsychotics, some insulin drugs, and others.
* Diets high in salt content.
* The damaging effect of too much blood sugar (glucose toxicity).
* The presence of excess fatty acids in the blood (lipotoxicity).

Apart from these acquired factors, genes that we inherit from our parents can also make us prone to insulin resistance. There are several genetic syndromes, unrelated to the acquired factors, that have insulin resistance as one of their symptoms.

Genetic conditions that can cause insulin resistance include:

* Myotonic dystrophy
* Ataxia-telangiectasia
* Alstom syndrome
* Rabson-Mendenhall syndrome
* Werner syndrome
* Lipodystrophy
* Polycystic ovarian syndrome
* Type-A insulin resistance: Severe insulin resistance due to a faulty insulin receptor gene. Symptoms include high blood sugar, masculine physical changes in females (virilization), and dark, thick skin patches (acanthosis nigricans).
* Type-B insulin resistance: Severe decrease in the action of insulin due to the presence of insulin receptor antibodies. This results in high blood sugar, excess male hormones in females (hyperandrogenism), and acanthosis nigricans.

Doctors can also categorize insulin resistance based on where the problem occurs. This classification system includes issues occurring before the insulin receptor (pre-receptor), at the insulin receptor, and after the insulin receptor (post-receptor).

Risk Factors and Frequency for Insulin Resistance

Insulin resistance is often studied in relation to how common metabolic syndrome or insulin resistance syndrome is. According to criteria put forward by the National Cholesterol Education Program Adult Treatment Panel III, insulin resistance syndrome is quite common.

An analysis of national health and nutrition data from 2003 showed that about 22% of US adults older than 20 years are affected by insulin resistance. Recent data from 2021 suggests that 40% of US adults aged 18 to 44 are insulin resistant, as measured by HOMA-IR tests. The sharp rise in this condition over the past 20 years can’t be linked to obesity alone. Other factors such as high blood pressure, abnormal cholesterol levels, and limited physical activity also contribute to insulin resistance.

Despite noticing a rapid increase in childhood obesity and type 2 diabetes, there’s no agreed-upon criteria to diagnose insulin resistance in children. It’s also key to point out that insulin resistance affects all races and ethnic groups, although the comparison between these groups is not entirely clear due to limited data.

Signs and Symptoms of Insulin Resistance

Insulin resistance can show up in many ways when a doctor examines a patient. The way it appears can depend on several factors. These include the kind of insulin resistance the person has, how long they’ve had it, how well their beta-cell function is, and whether they have any other related health conditions due to insulin resistance.

It is often linked with the following diseases:

• Non-alcoholic fatty liver disease (NAFLD)
• Metabolic syndrome
• Prediabetes or type 2 diabetes
• Polycystic ovarian syndrome (PCOS)
• Obesity
• Microvascular disease (issues with small blood vessels that can affect the eyes, nerves, or kidneys)
• Macrovascular disease (problems with larger blood vessels that can lead to stroke, peripheral artery disease, and coronary artery disease)

People with insulin resistance often have these symptoms:

• High blood pressure
• High cholesterol levels
• Increased waist size, depending on their gender and ethnicity
• Signs of PCOS such as irregular periods, excessive hair growth, acne, and hair loss
• A skin condition called acanthosis nigricans
• Signs of one of several genetic syndromes that involve insulin resistance
• Type A or type B insulin resistance syndrome

Testing for Insulin Resistance

Insulin resistance, a condition in which your body doesn’t respond properly to insulin, can be quite tricky to measure. An approach known as the hyperinsulinemic-euglycemic glucose clamp technique is considered the gold standard for measurement in research settings. In simpler terms, this test involves giving a fasting, non-diabetic individual a constant infusion of insulin while also regulating blood sugar levels using a dextrose solution. Keeping blood glucose at a normal range helps highlight how much external glucose your body needs to compensate for high insulin levels. The resulting data offers insights on insulin resistance related to body size.

However, due to risks and its complex process, this method isn’t practical for everyday use in clinics. Therefore, several alternative methods have been devised and tested. One commonly used is the homeostatic model assessment for insulin resistance (HOMA-IR), utilizing fasting glucose and fasting insulin levels. There are also formulas named HOMA2, the Glucose to Insulin Ratio (GIR), and the Quantitative Insulin Sensitivity Index (QUICKI), which are all based on fasting insulin levels. Other measures take into account insulin and blood sugar response after a glucose load, such as the Matsuda Index and Insulin Sensitivity Index (ISI).

Additionally, you’ll find markers that look at triglycerides alone or in relation to “good” cholesterol (HDL cholesterol). For example, people with prediabetes and high triglycerides (greater than or equal to 150 g/dL) are more likely to be insulin resistant. Moreover, if a person’s ratio of triglycerides to HDL cholesterol is greater than 3.0, it suggests insulin resistance. For males, a ratio over 3.5, and for females, over 2.5, also signal possible insulin resistance. These relationships, though, might not apply in the same way for people who identify as Black.

Given its complexity, insulin resistance is usually not diagnosed directly. Instead, its presence is inferred from signs and symptoms. Metabolic syndrome and insulin resistance syndrome (IRS) are seen as indicators of insulin resistance. Metabolic syndrome is diagnosed if you meet three or more of the following criteria: a certain range of waist circumference based on gender and ethnicity, elevated triglycerides, reduced HDL, high blood pressure, or high fasting glucose levels. IRS risk is associated with factors like glucose intolerance, abnormal uric acid metabolism, dyslipidemia (abnormal amount of blood fats), changes in blood pressure, prothrombotic factors (elements that promote clotting), signs of inflammation, and endothelial dysfunction (which affects blood vessel function).

Other risk factors include obesity (Body mass index (BMI) equal to or over 25 kg/m2), diagnosis of cardiovascular diseases (CVD), polycystic ovary syndrome (PCOS), non-alcoholic fatty liver disease (NAFLD), or acanthosis nigricans (dark, velvety skin), family history of type 2 diabetes, high blood pressure, or cardiovascular diseases, sedentary lifestyle, non-white ethnicity, or being over the age of 40.

Treatment Options for Insulin Resistance

Adopting a healthier lifestyle is a vital step in managing insulin resistance. Adjusting your diet to limit high-sugar carbohydrates and decrease your overall calorie intake, along with engaging in regular physical activity, can improve your body’s sensitivity to insulin and help burn extra calories.

People with insulin resistance are more likely to develop type 2 diabetes. However, research from studies like the Diabetes Prevention Program and its Outcomes Study (DPP & DPPOS) shows that lifestyle changes can significantly lower the risk of developing diabetes in high-risk adults.

These lifestyle changes can include eating a diet that is low in sodium and fats, reducing your calorie intake, and focusing on foods with a low glycemic index (which cause less of an increase in blood sugar). Understanding your condition, getting support, and tailoring a program specifically to your body and lifestyle is essential. A weight loss of just 7% can reduce the chances of developing type 2 diabetes by 58%. In these studies, they also tried a medicine called metformin which reduced the chances of developing diabetes by 31%.

Although there are no medications specifically approved to treat insulin resistance, your doctor might recommend some options. One of these is metformin, which is commonly used as an initial treatment for type 2 diabetes and PCOS (polycystic ovary syndrome). It may be combined with lifestyle changes, and this approach has been found to be beneficial and cost-effective. Despite worries about using metformin when kidney function is reduced, some organizations do recommend its use, if kidney function is not too impaired.

Other medications your doctor might recommend include GLP-1 (glucagon-like peptide one) receptor agonists. These medications stimulate a part of the pancreas to increase the release of insulin and decrease the output of glucagon, which raises blood sugar. They can cause weight loss, which can help lower insulin resistance. Some GLP-1 receptor agonists, like liraglutide and semaglutide, are FDA-approved to treat type 2 diabetes and obesity.

Another class of medications, SGLT2 (sodium-glucose cotransporter 2) inhibitors, work by increasing the amount of sugar removed in the urine. This action can lower blood glucose levels and lessen the need for insulin from outside the body. These medications can also lead to weight loss. However, they should be used with caution as they may lead to weight gain and retention of fluids, and these side effects can be problematic for some people.

In some cases, surgery may be an option. Procedures like gastric sleeves or bypass can lead to significant weight loss, which can improve the body’s response to insulin. Studies like the STAMPEDE trial support the benefits of these surgeries in treating type 2 diabetes.

What else can Insulin Resistance be?

Several health conditions can lead to abnormal body states. These conditions include:

• Lipodystrophy: This condition, which can be natural or acquired, involves the loss of body fat tissue. This fat can end up in unusual places like the liver or muscle tissue.
• Polycystic ovarian syndrome (PCOS)
• Obesity: This is a condition where a person has too much body weight. It’s categorized into four groups. ‘Overweight’ is a Body Mass Index (BMI) between 25 to 29.9. Class I obesity is a BMI of 30 to 34.9. Class II obesity is a BMI between 35.0-39.9. Class III obesity is a BMI over 40.
• Hypertension: This condition is also known as high blood pressure. The most recent diagnostic guidelines identify hypertension as having a systolic pressure of 130 mm Hg or above, or a diastolic pressure of 80 mm Hg or above.
• Hypertriglyceridemia: This is when the triglyceride (a type of fat) levels in your blood are higher than 150 mg/dL.
• Type 1 and Type 2 diabetes: These are different forms of a condition that affects how your body uses blood sugar.
• Other forms of glucose intolerance, like impaired fasting glucose, impaired glucose tolerance, and gestational diabetes.

What to expect with Insulin Resistance

The chances of getting better from insulin resistance can depend on many factors. These include the type and severity of the disease you have, how well your pancreas works, if your family has a history of complications due to insulin resistance, and how well you respond to treatment. The results can vary, from some who have mild insulin resistance and no symptoms, to those who suffer serious heart or brain events with significant health impacts and even death.

From a statistical point, heart disease is the number one cause of death in the United States, with diabetes ranking seventh. These two diseases often share a common root cause – insulin resistance. Insulin resistance can also lead to death through less common forms of the disease, which include genetic syndromes and diseases related to fatty deposits. Additionally, this condition can impair reproductive function and lead to problems like Polycystic Ovary Syndrome (PCOS), a hormonal disorder causing enlarged ovaries with small cysts on the outer edges.

But there is hope in managing this disease. Greater awareness among doctors can lead to early diagnosis and treatment. A better understanding of the disease can also lead to treatments that are more specific and effective. With efforts towards healthy weight management, better diet, and an active lifestyle, insulin resistance can be reduced and related complications prevented. If the general public becomes more aware of this, prevention would be more effective, and it could help reduce the epidemic levels of obesity and resulting insulin resistance.

Possible Complications When Diagnosed with Insulin Resistance

Most of the problems related to insulin resistance are linked to the development of vascular complications or issues with blood vessels.

Complications of smaller blood vessels, also known as microvascular disease, can show up as issues in several parts of the body. For instance, this problem can cause:

• Eye-related conditions like retinopathy (a disease of the retina), which can affect your vision
• Kidney diseases, including nephropathy (damage to the small blood vessels in your kidneys), leading to chronic kidney disease, kidney failure, and the requirement for dialysis
• Nerve damages in the peripherals, causing neuropathy

Additionally, if the microvascular disease affects the central nervous system, it can result in dementia, stroke, mood disturbances, and trouble maintaining balance while walking. Heart-related complications can include chest pain (angina), coronary artery spasms, and heart muscle disease (cardiomyopathy).

Complications involving larger blood vessels (macrovascular disease) can lead to Peripheral Arterial Disease (PAD), Coronary Artery Disease (CAD), and Cerebrovascular Accident (CVA or Stroke).

Another condition closely tied to insulin resistance is Non-alcoholic fatty liver disease (NAFLD), a condition where excess fat builds up in the liver. People with Type 2 diabetes (T2D) have twice the risk of developing NAFLD. This disease is increasingly prevalent worldwide, including among children, and should be a significant concern for clinicians treating patients with insulin resistance.

Preventing Insulin Resistance

When it comes to managing insulin resistance, there are three main strategies: primary, secondary, and tertiary prevention. Think of these as different steps for handling this health issue.

Primary prevention is all about getting everyone to understand the importance of regularly keeping tabs on their health. By eating a balanced diet and staying active, we can hold off or even prevent insulin resistance from developing. Insulin resistance, if left unchecked, can lead to a group of conditions known as the metabolic syndrome as well as diabetes, and these bring other health problems with them. So, making lifestyle changes like improving our diet and exercise habits are really vital not just to manage our weight, but to maintain our overall health in the long run.

Secondary prevention entails using medical tests to check for insulin resistance and diabetes. If detected early, insulin resistance can be managed more effectively. In fact, research studies “DPP” and “DPPOS” show that positive changes in lifestyle, along with a drug called metformin, can halt the progression from pre-diabetes (a condition where blood sugar levels are high, but not high enough to be classified as diabetes) to type 2 diabetes, which is a more severe condition.

Finally, tertiary prevention involves more aggressive medical treatments. This can include intensive medical therapies and even weight-loss surgery (also called bariatric surgery). These can significantly reduce the health issues arising from insulin resistance and as a result, can decrease illness and death rates linked to these conditions. The general public should be more accepting of these severe preventive measures as they can significantly improve a patient’s quality of life.