Summary

Insulin resistance is a metabolic condition that results from a diet high in processed foods. It’s incredible to imagine that every function in our bodies, including what we eat, requires gene activation; every morsel of food has a purpose. Our bodies metabolize following gene signals released in preparation and response to the intake. The hormone insulin works with glucose absorbed from our intestines, moving it out of the bloodstream and into cells to be used for energy. Adipose tissues stores the glucose as triacylglycerols, and releases it back into the blood during starvation states.

A diet high in carbohydrates leads to the increase in fat stores. Insulin levels go up and lead to physical changes and disease states in the body. This article will inform the reader about insulin resistance, with which conditions it is associated, and how someone can prevent or address it on their health journey.

Introduction

Most people think that elevated blood glucose is the cause of the damage seen in diabetes. Well, that is only partly correct. Hormone dysregulation, such as higher insulin levels, plays a role in the development of diabetes and can even contribute to significant harm in patients without diabetes. This condition is known as insulin resistance and requires attention because of its association with metabolic syndrome, polycystic ovarian syndrome (PCOS), fatty liver, and cancer development.

What is Insulin resistance?

Insulin resistance (IR) is defined as the inability of a known quantity of insulin to increase glucose uptake and utilization. Both insulin produced by the body (endogenous) and externally administered (exogenous) can have impaired function. We will go through how this occurs in the next section [1].  

Insulin resistance is a disease state related to the decreased response of tissues to insulin. Consequently, this results in higher insulin levels and raised blood glucose levels caused by increased hepatic glucose outflow. [8] In a nutshell, your muscles, fat, and liver don’t respond well to insulin with this condition. Insulin secretion by the normally functioning pancreas has to increase to accommodate the energy needs of the body. 

What causes insulin resistance?

Insulin resistance is likely related to a combination of factors. However, excess fat stores (adipose tissue) make the most significant impact. Lebovitz (2001) broke it down into these three categories:

(1) Genetic abnormalities of one or more proteins of the insulin action cascade.

(2) Fetal malnutrition. Children that are born with a lower birth weight have a higher odds of becoming diabetic as adults; scientists refer to this as the “thrifty phenotype hypothesis.”

(3) Visceral adiposity.  Obesity is a significant cause of insulin resistance. Contrary to popular thought, adipose tissue is more than insulation and potential energy. It is an active endocrine organ. When fat stores around the internal organs (i.e. visceral fat) are in excess, immune cells found in this tissue lead to inflammation, blocking insulin’s activity, leading to insulin resistance [1].

How do you know if you have insulin resistance?

1. The Body Mass Index, a tool using weight and height, can be an indicator of insulin resistance, when used in conjunction with other measurements. Although BMI is less specific, a greater body mass index correlates with increased insulin resistance as shown one study. “Overweight” represents a BMI greater than 25; A BMI of greater than or equal to 30 corresponds with “Obesity.” Studies have shown that insulin resistance can be seen in visceral obesity in Asians at lower BMI than their white counterpoints. In Asians, a BMI of >23-27.5 is considered overweight and >27.5 is obese. You can calculate your BMI here.

2. Adipose tissue location is a stronger predictor to IR than the BMI. A marker of central obesity and IR is waist circumference. Your risk increases as your waist increases. As a general ballpark figure, a waist circumference of under 39 inches in both men and women usually means that IR is minimal or unlikely. But make sure you are measuring around the abdomen at about the level of the umbilicus and not the hips (also, pants size does not necessary equate to waist circumference.)

3. A physical examination may also reveal findings that are associated with higher levels of insulin. A skin condition known as acanthosis nigricans (AN), appearing as dark, velvety soft patches, is a finding of insulin resistance. They occur along the neck, under the arm, and elbows. Acrochordons, or skin tags, are small skin growths seen usually along the neck line or axillae. Hair loss, known as androgenetic alopecia, in both men and women can be another finding. It is associated with androgen excess. Hirsutism (secondary hair on the face) and acne are also seen in women with the insulin resistant state of PCOS.

4. Glucose levels may be elevated in the setting of insulin resistance. Around 50% patients with insulin resistance were found to have elevated glucose >100 mg/dl. Another way to check for glucose management and insulin resistance is with a dynamic test, such as the 2-hour 75-g oral glucose tolerance test (OGTT). A person is given a high-sugar drink and then glucose measurements (and sometimes insulin levels) are taken at the beginning and in increments of 30 minutes afterward. In the OGTT (here is a description), a normal glucose is lower than 140 mg/dl. Impaired glucose tolerance, or prediabetes, is associated with a glucose between 140 and 199 ng/dl; anything higher than 200 mg/dl may indicate diabetes.

5. Low HDL (good) cholesterol levels and high triglycerides are two other markers strongly associated with this condition. These are findings described in the metabolic syndrome.

6. In research, the homeostasis model assessment-estimated insulin resistance (HOMA-IR), developed by Matthews et al. [11], has been widely used to estimate insulin resistance. One determines this by multiplying fasting plasma insulin (FPI) by fasting plasma glucose (FPG), then dividing by the constant 22.5, i.e., HOMA-IR = (FPI×FPG)/22.5 [10].

Implications of raised insulin levels: too much of a good thing?

Along with other hormones like glucagon and somatostatin, insulin contributes to maintaining glucose homeostasis by shifting it out of the bloodstream and into tissues like muscle and fat. In excess (hyperinsulinemia), insulin can be detrimental due to its anabolic nature. 

The implications of insulin resistance are as follows:

1. Insulin is a growth hormone, and an excess of this hormone leads to the promotion of protein synthesis, de novo lipogenesis, and cell proliferation.
2. Insulin excess inhibits lipolysis, preventing the autophagy of cells that remove old or damaged tissue, and reduces the antioxidant action of nuclear factor E2-related factor-2. [2]

Because of the largely unrestricted insulin signaling, hyperinsulinemia, whether endogenous or exogenous, increases the risk of obesity, type 2 diabetes, and cardiovascular disease and decreases health span and life expectancy. In epidemiological studies, high-dose insulin therapy correlates to an increased risk of cardiovascular disease. 

Metabolic syndrome 

Metabolic syndrome (MS) is a set of cardiometabolic circumstances that occur together. These include obesity, insulin resistance, high triglycerides, high blood pressure, and dyslipidemia. Type 2 diabetes and cardiovascular disease may follow. [5] In adults, it is well known that abdominal obesity measured by waist circumference (WC) is associated with an increased risk of cardiovascular disease, dyslipidemia, and type 2 diabetes.

Metabolic syndrome is becoming increasingly common, found in up to one-third of American adults. It is closely related to being overweight or obese, inactivity, and insulin resistance. If you have metabolic syndrome or any of its components, active lifestyle changes can delay or even prevent the development of severe health problems.

The following factors increase your chances of developing metabolic syndrome [7] :

• Age. Greater age comes with a higher likelihood of insulin resistance.
• Ethnicity. Hispanic women and Asian Americans appear to be at the greater risk for Metabolic syndrome, even in lower BMI ranges. 
• Overweight or Obesity. Overweight equates to a BMI of 25.0 – 29.9, and obesity is a BMI greater than 30.0.
• Diabetes. Diabetes during pregnancy (gestational diabetes) or if a family history of type 2 diabetes exists.
• Other diseases. Your risk of metabolic syndrome is higher if you’ve ever had nonalcoholic fatty liver disease, polycystic ovary syndrome, or sleep apnea.

Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) result from metabolic syndrome. They are directly related to insulin resistance: studies have found a correlation between higher HOMA-IR levels (above) and fatty liver. The process is fueled by the excess dietary intake of sugars, leading to glucose conversion to free fatty acids (triglycerides). These fatty acids exert an inflammatory effect on liver cells.

In the setting of the obesity epidemic, fatty liver has become the most common cause of liver disease in the US. About one-quarter of US adults have NAFLD, and up to 6.5% of US adults have NASH. The result of liver inflammation and damage from NASH is cirrhosis. Click here for more on the liver from YHF.

Polycystic Ovary Syndrome (PCOS) and Insulin resistance

Polycystic ovary syndrome (PCOS) is a hormonal disorder common among women of reproductive age. Women with PCOS may have infrequent or prolonged menstrual periods or excess male hormone (androgen) levels. The ovaries may develop numerous small collections of fluid (follicles) and fail to release eggs regularly. [4]

The exact cause of PCOS is unknown. Early diagnosis and treatment and weight loss may reduce the risk of long-term complications such as type 2 diabetes and heart disease. [4] Insulin resistance and the associated compensatory hyperinsulinemia are common in women with PCOS and may play a vital role in this condition. [3] 

Signs and symptoms of PCOS vary. A diagnosis of PCOS corresponds to at least two of these findings:

• Irregular periods. Infrequent, irregular, or prolonged menstrual cycles are the most common sign of PCOS. 
• Excess androgen leads to increased facial and body hair (hirsutism) and occasionally severe acne and male-pattern baldness.
• Polycystic ovaries. In PCOS, the ovaries might become enlarged and contain numerous follicles that surround the eggs. As a result, the ovaries may fail to function regularly.
• PCOS signs and symptoms are typically more severe if you’re obese. [3] 

Complications of PCOS include:

• Infertility
• Gestational diabetes or pregnancy-induced high blood pressure
• Miscarriage or premature birth
• Nonalcoholic steatohepatitis 
• Metabolic syndrome 
• Prediabetes and Type 2 Diabetes mellitus
• Sleep apnea
• Depression, anxiety, and eating disorders
• Abnormal uterine bleeding
• Cancer of the uterine lining (endometrial cancer)
• Increased cardiovascular disease risk

Insulin Resistance and Cancer

Epidemiological studies have consistently demonstrated the association of insulin resistance with higher cancer rates, including breast, colorectal, liver, and pancreas. 

(1) Chronically high levels of insulin increase cancer risk. Insulin shows cancer potential. This is because it stimulates cell mechanisms (cell signaling pathways) that increase cell number (growth-factor-dependent cell proliferation). This condition also directly affects cell metabolism and promotes cancer. Persistent high glucose levels and cell damage from it (oxidative stress) also contribute to cancer risk. [9]

(2) Insulin increases the activity of factors that reduce typical cell control systems to prevent cancer. Insulin triggers liver cells to produce a growth factor out of check with other proteins. (More information: this factor is known as insulin-like-growth-factor-one (IGF-I) and it is without the inhibitory hepatic protein production of the insulin-like growth factor binding proteins 1 (IGFBP-1) and 2 (IGFBP-2)). Consequently, IGF-1 is left out of control leading to the risk of cancer. [9]

(3) Insulin reduces Steroid Hormone Binding Globulin levels and increases estrogen bioavailability, increasing breast cancer risk. [9]

(4) Obesity is increasingly recognized as a low-grade inflammatory state in which overproduction of specific molecules can play a role in malignant transformation and cancer progression. These molecules include free fatty acids, interleukin6 (IL-6), adiponectin, leptin, tumor necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1, and monocyte chemoattractant protein (MCP-1), [9]

What are Ways to Reduce Insulin Resistance?

If you have features of insulin resistance, now is the time to act. Here are 9 ways to counteract it and return your body to a state of more optimal health:

1. Regular Exercise may be the single-most accessible way to improve insulin sensitivity with effects that are almost immediate. Physical activity has a beneficial impact on insulin sensitivity in normal as well as insulin-resistant populations. Better than a pill, a single dose of exercise can increase insulin sensitivity after at least 16 hours in healthy and diabetic subjects. This response could relate to how exercise increases insulin-stimulated Glucose Transporter type 4 (GLUT4), which contributes to improved insulin sensitivity [12]. 

2. Optimal Diet

Since food intake led to insulin resistance, a change in intake can improve it. “Waist loss” is important for addressing metabolic syndrome. This can be accomplished by reduced sugar intake, a diet of natural, high fiber foods, and fish oils. Reduce sugar intake. Try to reduce your intake of added sugars, especially from sugar-sweetened beverages, and white bread. Carbonated drinks and packaged fruit juices contain large amounts of sugar. It would help if you swapped them for healthier options like green tea, water, and eating whole fruits ( with the added benefit of boosting your fiber intake).

Saturated and trans fats can also boost insulin resistance. Nuts and fatty fish can be a good source of healthy oils, such as Omega-3 fatty acids. These oils may reduce insulin resistance and lower blood triglycerides. Indeed, fish oil reduces insulin response to oral glucose without altering the glycemic response, decreases the activation of sympathetic activity during mental stress, and decreases plasma triglycerides. [14]

3. Caloric Reduction vs. Intermittent Fasting Strategy? Caloric reduction can certainly support a reduction of weight and insulin resistance. A switch to whole foods includes a much larger amount of fiber and lower amount of concentrated glucose. This requires less production of insulin and allows the body to regulate its needs by releasing glucagon to cause adipose tissue stores to break down.

Intermittent fasting (IF) may allow for improved insulin sensitivity. One study found weight loss of 2.5 to 9.9% of total body weight loss and fat mass loss in subjects with a feeding window of 8 hours and fasting window of 16 hours. Both caloric restriction and IF result in weight loss and reduced insulin levels, but further research is needed to determine if intermittent fasting should be a part of clinical recommendations.

4. Quit smoking. Tobacco smoking has metabolic consequences and causes insulin resistance and may contribute to type 2 diabetes. It reduces insulin sensitivity in muscle tissue. A common metabolic finding in smoking is an elevated triglyceride level and low High Density-lipoprotein (HDL), a finding similar to metabolic syndrome. Smoking can contribute to the development of insulin resistance and the risk of cardiovascular disease. [13]

5. Ensure Optimal Sleep. Some evidence suggests that poor sleep causes insulin resistance, so improving sleep quality should help. Short-sleepers had higher insulin levels and insulin resistance rates than Long-Sleepers. Difficulty with either getting to sleep or staying asleep requires an investigation into causes. Check out these YHF posts for further information (Insomnia; Sleep Hygiene; Sleep General Overview; Sleep Apnea).

6. Reduce stress. A stress response requires the body’s adaptive mechanisms to deal with the increased metabolic demand. The adrenal hormone cortisol reduces insulin sensitivity leading to higher glucose levels in the blood. The same action is seen with steroids taken by mouth. Try to manage your stress levels if you easily get overwhelmed. Meditation may be beneficial in reducing insulin resistance in some studies.

7. Are you looking for other ways to reduce insulin resistance? Donate blood because it improves insulin sensitivity. In case you want to learn more, check out this link. A high level of iron in your blood may affect the pancreas and cause insulin resistance and diabetes. This may explain why diabetes results from iron-overload states such as hemochromatosis.

Thanks to Dr. Ishita Ray for the literature review and assisting in the writing of the PCOS section.

References 

1. Insulin resistance: definition and consequences
2. Insulin: too much of a good thing is bad
3. Insulin Resistance and Polycystic Ovary Syndrome
4. Polycystic ovary syndrome (PCOS) – Symptoms and causes
5. Metabolic syndrome and insulin resistance: underlying causes and modification by exercise training
6. Waist circumference, blood pressure, and lipid components of the metabolic syndrome
7. Metabolic syndrome – Symptoms and causes
8. The Role of Ceramides in Insulin Resistance
9. Insulin Resistance and Cancer Risk: An Overview of the Pathogenetic Mechanisms
10. The Definition of Insulin Resistance Using HOMA-IR for Americans of Mexican Descent Using Machine Learning
11. Insulin and Insulin Resistance — Ultimate Guide
12. Exercise and insulin sensitivity: a review
13. Smoking induces insulin resistance–a potential link with the insulin resistance syndrome
14. N-3 long chain polyunsaturated fatty acids: a nutritional tool to prevent insulin resistance associated to type 2 diabetes and obesity?
15. Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: evidence from a case-control study
16. Ziemke F, Mantzoros C. Adiponectin in insulin resistance: lessons from translational research. Am Journ Clin Nutri. 2009. Jan. 258S-261S. doi.org/10.3945/ajcn.2009.28449C
17. Gonzalez-Saldivar G, et. al., Skin Manifestations of Insulin Resistance: From a Biochemical Stance to a Clinical Diagnosis and Management. Dermatol Ther (Heidelb). 2017. Mar; 7(1): 37-51. doi: 10.1007/s13555-016-0160-3.
18. Stockman M-C, et. al. Intermittent Fasting: Is the Wait Worth the Weight? Cur Obes Rep. 2018. Jun 7(2): 172-185. doi: 10.1007/s13679-018-0308-9