What is Insulin Resistance and What is the Effect on the Body?

Insulin resistance is a common metabolic dysfunction that gives rise to many chronic illnesses, such as type 2 diabetes, cardiovascular disease, and obesity. Recent studies show that at least 25% of adults in the United States who don’t have diabetes are insulin-resistant. 

Insulin resistance occurs when cells fail to respond to insulin. This causes more and more insulin to be produced, leading to chronically high insulin levels. This article will discuss how insulin resistance develops and its negative impacts on the body.

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What is Insulin Resistance?

Insulin is a hormone released by the pancreas in response to a rise in blood glucose. When carbohydrates are consumed and metabolism begins, blood glucose rises, signaling the body to release insulin. Insulin functions in two ways: to reduce blood glucose and to act as a signaling molecule for different cells. 

Insulin resistance indicates a disruption of metabolism occurring when cells fail to respond to insulin. In turn, the pancreas releases more insulin to overcome this blunted response. Eventually, blood glucose remains consistently elevated, resulting in type 2 diabetes mellitus. A chronically elevated insulin level perpetuates inflammation and disease progression. 

Causes of Insulin Resistance

Lifestyle Factors: 

Lifestyle factors play a significant role in the development of insulin resistance.

• Diets high in processed foods, including added sugars, refined carbohydrates, and processed meats, can cause increased pancreatic insulin secretion and a proinflammatory state, increasing the risk of insulin resistance. 
• Physical inactivity is a risk factor for developing insulin resistance. 
• Weight gain leading to obesity independently increases the risk of insulin resistance.

Genetic Factors: 

In addition to lifestyle factors, genetic predispositions can also increase the risk of insulin resistance. Variations in genes coding for insulin signaling or other genetic factors affecting lipid metabolism, mitochondrial activity, and inflammatory mediators are genetic factors that can increase the risk of insulin resistance.

Examples of genetic markers that increase the risk for insulin resistance include these:

• PTB1
• LEPR
• RETN
• SLC2A4

Hormonal Imbalances: 

Imbalances of neuroendocrine hormones can significantly increase insulin resistance. Dysregulated glucagon-like peptide-1, glucose-dependent insulinotropic peptide (GIP), ghrelin, peptide YY, and others can affect insulin release from the pancreas. 

Hormone imbalances in disease states like polycystic ovarian syndrome (PCOS) predispose to elevated insulin levels and decreased activity of insulin on organs, further increasing the risk of weight gain and type 2 diabetes mellitus.

Mechanisms of Insulin Resistance

Understanding insulin resistance requires a biochemical explanation of actions at the cellular level. 

Excess accumulation of adipose tissue is a significant risk factor for developing insulin resistance. Adipose tissue (particularly visceral or abdominal fat) secretes pro-inflammatory cytokines and adipokines, which disrupt insulin signaling pathways, thus promoting insulin resistance. In addition, elevated levels of free fatty acids in obesity further exacerbate insulin resistance by interfering with insulin action in the peripheral tissues. 

Finally, insulin is a pro-inflammatory hormone, and obesity is a pro-inflammatory state. Both are associated with energy storage rather than energy burning, representing a continuous cycle of weight gain and metabolic dysfunction.

Effects of Insulin Resistance on the Body

Insulin resistance increases the risk of developing diseases of metabolic dysfunction and is a core component of metabolic syndrome, which is a constellation of several adverse metabolic conditions: 

• Central obesity
• Low high-density lipoprotein levels
• Elevated triglycerides
• Hypertension
• Impaired glucose metabolism

Metabolic syndrome is a state of chronic inflammation, increasing the risk of the development of inflammatory-mediated diseases, such as cardiovascular disease and type 2 diabetes. Type 2 diabetes mellitus can lead to end-organ complications, such as chronic kidney disease, neuropathy, and blindness.

Insulin resistance increases the risk of atherosclerosis and endothelial dysfunction, raising the risk of hyperlipidemia, coronary artery disease, stroke, and peripheral artery disease. Obesity also causes systemic inflammation, which independently increases cardiovascular risk.

Insulin resistance promotes the storage of glucose as fat in the liver and the formation of triglycerides, leading to the development of non-alcoholic fatty liver disease (NAFLD). As NAFLD progresses, it results in increased liver inflammation, fibrosis, and, ultimately, cirrhosis.

Diagnosing Insulin Resistance

Insulin resistance develops gradually and exists on a spectrum. Therefore, diagnosing it requires assessing various biomarkers related to glucose metabolism.

Serum insulin levels should be tested in a fasting state and also after eating a carbohydrate-containing meal. A fasting blood glucose and an oral glucose tolerance test should be performed alongside insulin levels as an integrated test like HOMA-IR to understand how insulin levels correspond with serum glucose levels. Elevated fasting glucose levels (>100 mg/dL) indicate impaired fasting glucose and may suggest underlying insulin resistance when correlated with insulin levels. 

The hemoglobin A1c (HbA1c) test measures the average blood glucose levels over the life of the hemoglobin molecule, which is generally about three months. Higher HbA1c levels (>5.7%) indicate chronically impaired glucose metabolism.

Physical findings of insulin resistance include the development of skin tags in areas like the axilla or neck. Acanthosis nigricans, which are dark, velvety appearing areas on the back of the neck, is a common presentation of insulin resistance. Central obesity (adipose tissue heavily located in the abdomen) is commonly associated with insulin resistance. 

Managing and Treating Insulin Resistance

Lifestyle Modifications to Improve Insulin Sensitivity

Lifestyle interventions are integral in managing insulin resistance and obesity, providing effective strategies for improving metabolic health and reducing the risk of associated complications. 

Diet is one of the most significant drivers of insulin sensitivity and requires balancing energy intake with optimal macronutrient composition. 

• Focusing on a diet of whole, nutrient-dense foods while minimizing refined sugars and processed foods helps regulate blood glucose and aids in maintaining a healthy weight.
• Prioritizing healthy fats, like omega-3 fatty acids, has been shown to reduce inflammation. 
• Emphasizing high-fiber foods like fruits, vegetables, legumes, and whole grains helps control insulin release and promotes insulin sensitivity.

Regular physical activity improves overall metabolic health, including insulin sensitivity. 

• Cardiovascular exercise enhances insulin sensitivity by increasing glucose uptake and utilization in muscles. It also helps promote a healthy weight by increasing energy expenditure and promoting fat oxidation. 
• Strength training, including weight lifting and bodyweight exercise, improves insulin sensitivity by increasing muscle mass and glucose uptake into muscles. Strength training helps increase and preserve lean body mass, which supports long-term weight management by increasing resting energy expenditure. 

Medications and Other Treatments

Several medical treatments and surgical interventions can be used when lifestyle modifications do not sufficiently improve insulin resistance. 

• Metformin is a commonly used medication for type 2 diabetes, often prescribed to enhance insulin sensitivity and reduce hepatic gluconeogenesis. Metformin also helps manage a healthy weight by reducing appetite and helping with mild weight loss. 
• Glucagon-like-peptide-1 receptor agonists (GLP-1 RA), including liraglutide, semaglutide, and the dual agonist tripeptide, improve insulin secretion and slow gastric emptying, leading to better glycemic control and clinically significant weight loss. 
• Other medications used for diabetes include sodium-glucose cotransporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, sulfonylureas, alpha-glucosidase inhibitors, and others.

In cases of severe obesity or when lifestyle interventions and pharmacotherapy are insufficient, bariatric surgery may provide an option for long-term weight loss success and improved metabolic health. Bariatric surgical techniques like sleeve gastrectomy and Roux-en-Y gastric bypass can lead to substantial weight loss and even the resolution of conditions like obesity, type 2 diabetes, hypertension, and dyslipidemia. 

Bariatric surgery and the loss of notable amounts of excess fatty tissue lead to hormonal changes that improve insulin sensitivity, leading to sustainable weight loss and metabolic health benefits.

Monitoring and Prevention Strategies

Early identification of insulin resistance is important to help delay the onset of type 2 diabetes, cardiovascular disease, and other metabolic dysregulations. It also allows for treatment with lifestyle interventions first. 

Preventing insulin resistance starts with preventing obesity and optimizing healthy lifestyles, including nutrition, regular physical activity, stress management, and adequate sleep. This requires a multifaceted approach focused on patient education and implementing healthy individual lifestyle choices. 

Using personalized approaches will provide effective patient-centered care to improve overall health outcomes. 

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Key Takeaways

• Insulin resistance is a common metabolic disruption that increases the risk of other diseases, like obesity, type 2 diabetes mellitus, and cardiovascular disease.
• Modifications to diet, physical activity, and, in some cases, medications can prevent and treat insulin resistance.
• In cases of severe obesity, insulin resistance can be reversed by bariatric surgery.
• A personalized approach to holistic health can help reduce the risk of insulin resistance.