Insulin Resistance

Insulin resistance is a metabolic and vascular disorder in which the body’s cells no longer respond effectively to insulin, the hormone produced by the pancreas that enables glucose (sugar) to enter cells for energy. When this signaling fails, glucose accumulates in the bloodstream, forcing the pancreas to release increasing amounts of insulin to compensate. This state of chronic hyperinsulinemia not only disrupts glucose metabolism but also damages the vascular endothelium, alters blood flow, and promotes a prothrombotic environment. Over time, these combined metabolic and vascular effects lead to sustained hyperglycemia, microvascular injury, and heightened risk for prediabetes, type 2 diabetes, and thrombotic events if left unaddressed.

Overview

What is insulin resistance?

Under normal conditions, insulin acts as the body’s metabolic “key,” unlocking cells in the muscles, liver, and adipose tissue so glucose can be used or stored for energy. With insulin resistance, these cells become less sensitive to insulin’s signal, forcing the pancreas to work harder to regulate blood sugar. Over time, this imbalance disrupts multiple systems—not just glucose metabolism, but also vascular, hormonal, and inflammatory pathways.

As resistance progresses, glucose that should be fueling cells remains trapped in the bloodstream. This triggers a chain reaction: insulin levels rise, fat storage increases, and inflammation worsens—creating a self-perpetuating cycle that links insulin resistance to nearly every major chronic disease.

Persistent insulin resistance is associated with:

Obesity

Chronic insulin resistance promotes visceral fat accumulation, the metabolically active fat surrounding the abdominal organs that releases inflammatory cytokines, free fatty acids, and clot-promoting proteins such as plasminogen activator inhibitor-1 (PAI-1). This biochemical environment sustains endothelial injury and suppresses fibrinolysis, creating ideal conditions for thrombosis. Women with central obesity face greater vascular risk than men at the same BMI due to estrogen-related differences in coagulation. Studies published in Thrombosis and Haemostasis (2023) show that individuals with high visceral fat have a fivefold greater risk of deep vein thrombosis (DVT) than those with lower visceral fat, underscoring its pro-coagulant effect.

Cardiovascular Disease

Persistent hyperinsulinemia damages the vascular endothelium, depletes nitric oxide, and accelerates atherothrombosis by promoting platelet aggregation and vascular smooth muscle proliferation. These mechanisms double the risk of heart attack and ischemic stroke, even among people without diabetes. In women, insulin resistance contributes significantly to the sharp rise in cardiovascular events after menopause, when estrogen’s vascular protection diminishes. Recent findings from Circulation (2024) reveal that nearly 40% of first-time myocardial infarctions occur in individuals with previously undiagnosed insulin resistance, highlighting its silent but destructive role in thrombosis.

Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD)

Formerly known as fatty liver disease, MASLD affects up to 70% of individuals with insulin resistance. Excess hepatic fat drives overproduction of fibrinogen and coagulation factors VII, VIII, and IX, fueling a systemic hypercoagulable state. This connection links liver dysfunction directly to thrombotic vascular risk. Women with PCOS or gestational insulin resistance are especially vulnerable, as they exhibit higher rates of hepatic fibrosis and endothelial dysfunction. Evidence from Hepatology (2023) shows that people with MASLD face a threefold higher risk of venous thromboembolism (VTE) compared with those without liver involvement.

Metabolic Syndrome

Characterized by abdominal obesity, dyslipidemia, hypertension, and glucose intolerance, metabolic syndrome represents a convergence of vascular and metabolic injury. Chronic inflammation increases tissue factor and adhesion molecule expression on the endothelium, heightening the likelihood of clot formation and arterial stiffness. The European Heart Journal (2024) reports that patients with metabolic syndrome experience twice the rate of fatal pulmonary embolism as those without it, even after controlling for obesity, making it a major yet overlooked thrombotic driver.

Polycystic Ovary Syndrome (PCOS)

In women, hyperinsulinemia increases ovarian androgen production and decreases sex hormone–binding globulin (SHBG), disrupting hormonal balance while promoting vascular inflammation and platelet activation. Elevated PAI-1 levels and increased thrombin generation make PCOS a pro-thrombotic endocrine disorder as well as a reproductive one. Research in The Journal of Clinical Endocrinology & Metabolism (2023) found that women with PCOS have a fourfold increased risk of venous thrombosis compared with women without PCOS—even when controlling for age, weight, and contraceptive use.

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High-Risk Populations

Who is most at risk for insulin resistance?

Insulin resistance can develop in anyone, regardless of weight or diabetes status, and may be temporary or chronic. Short-term resistance can occur with certain medications, such as corticosteroids, or during acute illness, pregnancy, or periods of stress. Chronic resistance, however, is most often linked to excess visceral fat, physical inactivity, poor sleep, and genetic predisposition.

Individuals with a family history of prediabetes, type 2 diabetes, or PCOS are at higher risk. People living with prediabetes or type 2 diabetes almost always exhibit insulin resistance, while those with type 1 diabetes may develop it secondarily, a condition known as double diabetes.

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Symptoms

What are the signs of insulin resistance?

Insulin resistance develops gradually and often without obvious warning signs. In its early stages, the pancreas compensates by producing more insulin to maintain normal blood glucose levels. Over time, this compensation begins to fail, and elevated insulin and glucose start to damage the inner lining of blood vessels—the endothelium. This process triggers vascular inflammation and alters the blood’s natural balance between clotting and dissolution. The result is not only a metabolic disturbance but also a prothrombotic state that increases the risk of deep vein thrombosis (DVT), coronary artery disease, and stroke, often years before diabetes is diagnosed.

Visible and dermatologic indicators often include:

Acanthosis Nigricans

This dark, velvety thickening of the skin typically appears on the neck, underarms, or groin and represents one of the earliest visible markers of insulin resistance. Chronic hyperinsulinemia stimulates keratinocyte and fibroblast growth, producing this distinctive discoloration and texture. Acanthosis nigricans is present in up to 60% of individuals with insulin resistance and is especially common among women with polycystic ovary syndrome (PCOS), adolescents with obesity, and adults with prediabetes or Type 2 diabetes.

Skin Tags (Acrochordons)

These small, benign growths develop on the neck, chest, eyelids, or underarms and are associated with chronically elevated insulin and growth factor signaling. Skin tags occur in approximately 50–70% of patients with metabolic syndrome and are more prevalent among individuals with central obesity and impaired glucose tolerance. Their presence strongly correlates with higher fasting insulin levels and increased risk of Type 2 diabetes and atherothrombosis.

Central Adiposity

This pattern of fat accumulation around the abdomen and internal organs (visceral fat) is a defining feature of metabolic syndrome and one of the strongest predictors of insulin resistance and vascular inflammation. Central adiposity affects nearly one in three adults worldwide, and its prevalence rises sharply with age and sedentary lifestyle. Unlike subcutaneous fat, visceral adipose tissue releases inflammatory cytokines (IL-6, TNF-α) and free fatty acids directly into portal circulation, promoting endothelial dysfunction, platelet activation, and a prothrombotic state that increases the risk of both arterial and venous clot formation.

Metabolic and systemic symptoms often include:

Fatigue

The body’s inability to effectively transport glucose into muscle and liver cells leaves tissues deprived of energy despite adequate food intake. This persistent fatigue is one of the most frequently reported symptoms, affecting an estimated 60–70% of individuals with insulin resistance. The constant cycle of hyperinsulinemia and fluctuating blood glucose levels also impairs mitochondrial efficiency, compounding exhaustion even at rest.

Polydipsia and Polyuria

As blood glucose rises, excess sugar draws fluid from surrounding tissues, leading to dehydration and increased urination. This osmotic effect causes frequent urination (polyuria) followed by excessive thirst (polydipsia). These symptoms occur in approximately 40–50% of individuals with advanced insulin resistance or prediabetes, often signaling a progression toward hyperglycemia and impaired kidney glucose reabsorption.

Polyphagia (Increased Hunger)

When insulin cannot effectively transport glucose into cells, the brain interprets this as energy deprivation, triggering intense, persistent hunger. Polyphagia is observed in nearly half of adults with hyperinsulinemia or early Type 2 diabetes, reflecting the body’s attempt to compensate for cellular energy deficiency despite sufficient or even excessive caloric intake.

Unexplained Weight Loss

In later stages of insulin resistance, declining pancreatic function and reduced insulin signaling cause the body to metabolize stored fat and muscle tissue for fuel. Though more common in the transition from prediabetes to Type 2 diabetes, unintentional weight loss affects roughly 15–20% of patients and may occur alongside muscle wasting and increased fatigue.

Blurred Vision

Rapid fluctuations in blood glucose alter the osmotic balance within the lens of the eye, temporarily changing its shape and affecting focus. Transient blurred vision is reported by up to 40% of individuals with impaired glucose tolerance and is one of the earliest ocular signs of metabolic instability preceding diabetic retinopathy.

Recurrent Yeast Infections

Elevated glucose levels in the bloodstream and tissues create an optimal environment for Candida overgrowth, especially in the genital and oral regions. These infections occur in approximately 30–40% of women with insulin resistance or early diabetes and often recur due to persistently high glucose and impaired immune response. Chronic hyperglycemia also alters local pH balance, further increasing susceptibility to infection.

What many people don't realize is that Insulin resistance is not only a metabolic condition, but a vascular disorder with thrombotic implications. Chronically elevated insulin and glucose impair endothelial function, reducing nitric oxide (NO) production and disrupting normal vascular tone. This promotes platelet activation, increased fibrinogen concentration, and suppressed fibrinolysis, creating a circulatory environment prone to clot formation.

Clinical and subclinical vascular effects may include:

Leg Pain, Swelling, or Tenderness

Possible signs of deep vein thrombosis (DVT), particularly in those with central obesity or prolonged immobility. Studies in Circulation (2023) show insulin-resistant individuals face a two to threefold higher risk of venous thromboembolism (VTE), even in the absence of diabetes.

Microvascular Changes

Cold hands or feet, delayed wound healing, and sensory changes due to capillary basement membrane thickening and reduced endothelial perfusion. These same mechanisms contribute to peripheral artery disease and early microangiopathy.

Atherothrombosis

Chronic endothelial injury accelerates plaque formation and instability, predisposing to myocardial infarction and ischemic stroke. According to The Lancet Diabetes & Endocrinology (2024), nearly 40% of first-time heart attacks occur in individuals with undiagnosed insulin resistance, despite normal fasting glucose levels.

Subclinical Hypercoagulability

Elevated D-dimer, plasminogen activator inhibitor-1 (PAI-1), and circulating endothelial microparticles have been observed in insulin-resistant patients, indicating ongoing microscopic clot formation and endothelial stress.

Insulin resistance, once viewed as a hormonal or metabolic imbalance, is now recognized as a systemic vascular condition. It quietly alters the structure and behavior of blood vessels long before symptoms appear, creating the physiologic groundwork for thrombosis and cardiovascular disease even in patients who have never been diagnosed with diabetes.

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Diagnosis

How is insulin resistance diagnosed?

Insulin resistance is challenging to identify early because routine screening is not yet standardized. Many individuals maintain normal blood glucose levels for years due to compensatory hyperinsulinemia—their pancreas simply produces more insulin to overcome cellular resistance. Diagnosis, therefore, relies on a combination of clinical assessment, biochemical markers, and risk stratification rather than a single definitive test.

A healthcare provider will evaluate your medical and family history, perform a physical examination for clinical indicators such as central adiposity, acanthosis nigricans, and elevated blood pressure, and assess symptoms consistent with metabolic dysfunction. Family history of Type 2 diabetes, polycystic ovary syndrome (PCOS), metabolic syndrome, or cardiovascular disease strengthens clinical suspicion.

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Testing

What tests are used to evaluate insulin resistance?

Western medicine and functional medicine approach insulin resistance from complementary perspectives. Conventional testing focuses on glycemic control and lipid metabolism, while functional medicine adds dynamic insulin markers and inflammatory profiling to detect earlier metabolic dysfunction.

Standard diagnostic and screening tests typically include:

Fasting Plasma Glucose (FPG)

Measures blood sugar after an overnight fast. A level between 100–125 mg/dL suggests prediabetes, while ≥126 mg/dL confirms diabetes.

Hemoglobin A1c (HbA1c)

Reflects average blood glucose levels over approximately three months. Values between 5.7–6.4% indicate prediabetes; ≥6.5% confirms diabetes. Though widely used, A1c can underestimate risk in early insulin resistance when glucose remains normal but insulin is elevated.

Oral Glucose Tolerance Test (OGTT)

Measures how the body processes a glucose load over two hours. A 2-hour glucose of 140–199 mg/dL indicates impaired glucose tolerance; ≥200 mg/dL confirms diabetes. OGTT is especially useful for identifying early insulin resistance in patients with normal fasting glucose.

Lipid Panel

Evaluates cholesterol and triglyceride levels, which often reveal a thermogenic dyslipidemic pattern typical of insulin resistance—elevated triglycerides (>150 mg/dL), low HDL cholesterol (<40 mg/dL in men, <50 mg/dL in women), and increased small dense LDL particles.

Blood Pressure and Waist Circumference

Both serve as indirect clinical markers. A waist circumference >35 inches in women or >40 inches in men indicates central adiposity, while blood pressure above 130/85 mmHg supports metabolic syndrome criteria.

Functional medicine aims to identify insulin resistance before overt hyperglycemia develops by measuring insulin levels, inflammatory cytokines, and endothelial function. These markers provide a more complete picture of metabolic and vascular stress.

Fasting Insulin

Elevated fasting insulin (>10 µIU/mL) is often the earliest measurable sign of insulin resistance, even when glucose remains normal.

HOMA-IR (Homeostatic Model Assessment of Insulin Resistance)

Calculated using fasting glucose and insulin: HOMA-IR = (fasting insulin µIU/mL × fasting glucose mg/dL) / 405. A score above 2.5–3.0 suggests insulin resistance; values above 4.0 indicate significant metabolic impairment.

C-Peptide

Assesses pancreatic beta cell activity. Elevated levels indicate compensatory hyperinsulinemia, while declining levels signal beta cell exhaustion.

hs-CRP (High-Sensitivity C-Reactive Protein)

A marker of systemic inflammation. Levels above 1.0 mg/L correlate with endothelial dysfunction and increased vascular risk.

Adiponectin and leptin

Low adiponectin and high leptin levels reflect adipose tissue inflammation and impaired insulin signaling.

Fibrinogen and Plasminogen Activator Inhibitor-1 (PAI-1)

Elevated levels indicate a prothrombotic state linked to endothelial stress and metabolic dysfunction.

Oxidative Stress and Liver Markers

Tests such as ALT, AST, and GGT help identify metabolic dysfunction–associated steatohepatitis (MAS), a common comorbidity in insulin-resistant patients.

A diagnosis of insulin resistance is typically made when multiple findings overlap: elevated fasting insulin or HOMA-IR, dyslipidemia, increased waist circumference, and early signs of endothelial or inflammatory activation. From a functional perspective, identifying and treating insulin resistance at this stage—before glucose dysregulation occurs—can prevent or reverse the trajectory toward diabetes, cardiovascular disease, and thrombosis.

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Treatment

How is insulin resistance treated?

Because insulin resistance results from a combination of genetic, hormonal, and lifestyle factors, treatment focuses on controlling modifiable contributors while mitigating long-term cardiovascular and metabolic risks. While age and genetics cannot be altered, targeted changes in nutrition, physical activity, body composition, and inflammation management can significantly improve insulin sensitivity—even in advanced stages.

Lifestyle-based interventions (first-line therapy) typically include:

Nutritional Therapy

Dietary intervention remains the foundation of treatment. Your provider may recommend reducing intake of refined carbohydrates, added sugars, and saturated fats while emphasizing low-glycemic, nutrient-dense foods that minimize postprandial glucose spikes.

• Prioritize vegetables, fruits lower on the glycemic index (berries, apples, citrus), whole grains, legumes, nuts, and lean proteins such as fish and poultry.

  
  

• Limit red and processed meats, sweetened beverages, and ultra-processed starches that rapidly elevate insulin demand.

  
  

• Functional medicine approaches often include anti-inflammatory dietary patterns and Mediterranean-style diets, with omega-3 fatty acids and polyphenols shown to improve endothelial function and reduce systemic inflammation.

  
  

Physical Activity

Regular movement is one of the most effective tools for restoring insulin sensitivity. Moderate-intensity aerobic exercise (150 minutes per week) and resistance training (2–3 times weekly) enhance muscle glucose uptake and mitochondrial efficiency. Exercise also reduces visceral fat—the most metabolically active and inflammatory fat depot—thereby improving vascular health and lowering the risk of thrombosis.

Weight Optimization

Even modest weight loss of 5–10% of total body weight can markedly improve fasting insulin levels and lipid profiles. Structured lifestyle programs combining caloric control, exercise, and behavioral support show measurable reversal of insulin resistance within three to six months.

Over time, these interventions can reduce circulating insulin and improve glucose utilization, lower blood pressure and systemic inflammation, decrease triglyceride and LDL (“bad”) cholesterol while increasing HDL (“good”) cholesterol, and enhance endothelial function by reducing prothrombotic markers such as plasminogen activator inhibitor-1 (PAI-1) and fibrinogen. Patients with persistent insulin resistance benefit most from a coordinated, multidisciplinary approach involving an endocrinologist, registered dietitian, and exercise physiologist, ensuring that nutritional, metabolic, and vascular interventions are precisely aligned with individual risk profiles.

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Medications and Supplements

What medications are used to manage insulin resistance?

While there are currently no FDA-approved medications that directly reverse insulin resistance, several pharmacologic therapies help improve insulin sensitivity, glucose metabolism, and vascular health by addressing the underlying pathways that drive metabolic dysfunction. Treatment plans are often individualized and may combine conventional medications with evidence-based nutritional and functional medicine interventions to optimize results.

Medications commonly used in insulin resistance management include:

Metformin

Considered first-line therapy for prediabetes, Type 2 diabetes, and polycystic ovary syndrome (PCOS), metformin decreases hepatic glucose output and enhances peripheral insulin uptake by activating AMP-activated protein kinase (AMPK). It also reduces levels of inflammatory cytokines and may improve endothelial function.

Thiazolidinediones (Pioglitazone)

Improve insulin sensitivity at the cellular level by activating peroxisome proliferator-activated receptor gamma (PPAR-γ). These medications increase adiponectin, a hormone that enhances glucose uptake, but caution is warranted in patients with heart failure due to the potential for fluid retention.

GLP-1 Receptor Agonists (Semaglutide, Liraglutide)

Mimic natural glucagon-like peptide-1, improving insulin secretion, reducing appetite, and supporting weight loss. These agents lower postprandial glucose and have demonstrated cardiovascular and renal protective effects independent of glycemic control.

SGLT2 Inhibitors (Empagliflozin, Dapagliflozin)

Promote urinary glucose excretion, reduce blood pressure, and improve metabolic flexibility. Increasingly used in patients with metabolic syndrome or heart failure to reduce hospitalization risk.

Statins and Antihypertensives

Used to control dyslipidemia and blood pressure—key contributors to metabolic and vascular stress. Some statins, however, may slightly raise blood sugar; this risk is generally outweighed by their cardiovascular benefits.

From a functional standpoint, your healthcare provider will also address comorbidities such as hypertension, dyslipidemia, and hypercoagulability to reduce long-term vascular and thrombotic risk. In parallel, a functional medicine approach emphasizes nutrient repletion, mitochondrial support, and reduction of oxidative and inflammatory stress to enhance insulin sensitivity and vascular resilience. While these therapies do not replace medical treatment, they can meaningfully improve outcomes when used under professional supervision, helping restore metabolic balance and protect endothelial function.

Magnesium

Essential for insulin receptor function and glucose transport. Low magnesium levels are found in up to 50% of individuals with insulin resistance. Supplementation (200–400 mg/day, as glycinate or citrate) has been shown to improve fasting glucose and HOMA-IR scores.

Alpha-Lipoic Acid (ALA)

A potent antioxidant that improves insulin-stimulated glucose uptake in skeletal muscle and reduces oxidative endothelial stress. Typical doses range from 300 to 600 mg twice daily.

Berberine

A plant alkaloid with mechanisms similar to metformin—it activates AMPK, reduces hepatic gluconeogenesis, and improves lipid metabolism. Studies show berberine can reduce fasting glucose and HbA1c comparably to metformin when taken at 500 mg two to three times daily.

Chromium Picolinate

Enhances insulin binding and signaling. Supplementation (200–1,000 mcg/day) may lower fasting glucose and improve body composition when combined with exercise and dietary control.

Inositol (myo- and D-chiro-inositol)

Especially beneficial in women with PCOS, inositol improves insulin signaling in ovarian tissue and normalizes menstrual cycles. Clinical trials show reductions in fasting insulin and androgen levels within 8–12 weeks.

Omega-3 Fatty Acids (EPA/DHA)

Reduce systemic inflammation, improve triglyceride levels, and enhance endothelial function. Dosages of 1,000–2,000 mg/day have been linked to improved insulin sensitivity and lower cardiovascular risk.

Vitamin D

Deficiency is common in individuals with metabolic syndrome and contributes to impaired insulin receptor signaling. Supplementation to maintain serum 25(OH)D above 40 ng/mL supports glucose regulation and immune balance.

Coenzyme Q10 (CoQ10)

Supports mitochondrial energy production and offsets oxidative stress from both insulin resistance and statin use. A dose of 100–200 mg/day is commonly recommended.

Cinnamon Extract and Curcumin

Both have shown mild but clinically meaningful effects on fasting glucose, HbA1c, and inflammatory markers when used in combination with dietary therapy.

Combining conventional pharmacology with functional and nutritional support allows for a more comprehensive approach to metabolic restoration. Under supervision, these strategies can improve fasting insulin, lipid balance, and vascular integrity—addressing insulin resistance as both a metabolic and endothelial condition rather than a glucose disorder alone.

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Reversing Disease

Can insulin resistance be reversed?

While genetic predisposition and aging cannot be changed, metabolic flexibility can be restored. Lifestyle interventions can significantly reverse insulin resistance when implemented early. Functional medicine often integrates continuous glucose monitoring (CGM), nutrient status evaluation, and stress-reduction techniques to fine-tune interventions and track progress in real time.

In some patients, insulin sensitivity improves to near-normal levels within three to six months of sustained lifestyle change. Long-term reversal depends on maintaining reduced visceral fat, steady physical activity, and a balanced diet.

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Diet and Nutrition

How does diet specifically affect insulin resistance?

Diet directly influences postprandial glucose and insulin response. The glycemic index (GI) ranks foods by how quickly they raise blood sugar levels, guiding patients toward foods that promote stable glucose control.

High-GI foods (rapidly absorbed carbohydrates) cause sharp glucose spikes and high insulin demand. Frequent consumption of:

• White bread and refined grains

  
  

• Potatoes and starchy sides

  
  

• Sweetened cereals, cakes, and pastries

  
  

• Sugary beverages and fruit juices

  
  

• High-sugar fruits such as watermelon or dates

  
  

These foods accelerate the progression of insulin resistance and endothelial injury. Low-GI foods promote gradual glucose absorption, reducing pancreatic stress and improving energy stability. Examples include:

• Legumes and beans (lentils, chickpeas, black beans)

  
  

• Low-sugar fruits (berries, apples, pears)

  
  

• Non-starchy vegetables (broccoli, leafy greens, cauliflower, asparagus)

  
  

• Nuts, seeds, dairy, fish, and lean meats

  
  

Adopting a low-GI, anti-inflammatory diet can lower fasting insulin, improve lipid balance, and reduce vascular inflammation within weeks. Before making major dietary changes, consult a qualified healthcare provider or dietitian experienced in metabolic and functional nutrition to ensure a safe, individualized plan.

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