What Causes Insulin Resistance?

What Causes Insulin Resistance?

Insulin resistance occurs when muscle, fat, and liver cells stop responding normally to insulin, forcing the pancreas to produce more. For most people, excess refined carbohydrates and visceral fat are the primary drivers — but chronic stress, mitochondrial dysfunction, selenium deficiency, and adrenal suppression each independently impair insulin signaling and are routinely overlooked. If you've cleaned up your diet and your fasting glucose or HOMA-IR still won't budge, one of these secondary causes is likely in play.

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The Core Mechanism: What Actually Goes Wrong Inside the Cell

Insulin works by binding to its receptor on the cell surface, triggering a signaling cascade that moves glucose transporter proteins (GLUT4) to the membrane so glucose can enter. Insulin resistance describes the breakdown of that cascade — not a shortage of insulin, but a failure of the cell to act on it.

The two most studied intracellular culprits are:

• Diacylglycerol (DAG) accumulation — excess fatty acids inside muscle cells activate protein kinase C (PKC), which phosphorylates the insulin receptor substrate (IRS-1) at an inhibitory site, blocking downstream signaling (Shulman, Journal of Clinical Investigation 2000; PMID: 10974023).
• Mitochondrial reactive oxygen species (ROS) — when mitochondria are overloaded or dysfunctional, oxidative stress impairs GLUT4 translocation and IRS-1 function independently of DAG (Anderson et al., Journal of Clinical Investigation 2009; PMID: 19171537).

Both pathways converge on the same result: your cells stop absorbing glucose efficiently, blood sugar climbs, and the pancreas overcompensates with more insulin. Over time, that hyperinsulinemia drives further fat storage, inflammation, and hormonal dysregulation.

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Mitochondrial Health Root Causes

Mitochondria are the energy-producing organelles inside every cell, and their condition is inseparable from insulin sensitivity. Skeletal muscle mitochondria in people with type 2 diabetes are measurably smaller, less numerous, and produce more ROS per unit of oxygen consumed than in metabolically healthy controls (Befroy et al., Diabetes 2007; PMID: 17327455).

This matters because:

1. Impaired fatty acid oxidation in dysfunctional mitochondria leads to intramyocellular lipid accumulation — a direct trigger of DAG-mediated insulin receptor blockade.
2. Excess ROS oxidize phospholipids in the insulin receptor membrane, reducing receptor flexibility and binding affinity.
3. Low mitochondrial output reduces ATP availability for the energy-dependent steps of GLUT4 vesicle trafficking.

Key lifestyle factors that degrade mitochondrial health and worsen insulin resistance include:

• Sedentary behavior (reduces mitochondrial biogenesis via PGC-1α)
• Chronic sleep restriction (disrupts mitochondrial fission/fusion balance)
• Excess dietary refined fructose (preferentially drives hepatic lipid synthesis)
• Aging (mitochondrial copy number and efficiency naturally decline)

If your wearable is showing poor sleep quality or low HRV alongside elevated fasting glucose, mitochondrial inefficiency is a plausible bridge between those two findings — not an accident. Improving metabolic health through targeted blood sugar and insulin resistance protocols typically requires addressing mitochondrial function alongside diet.

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Stress Management Root Causes

Cortisol is insulin's metabolic antagonist. In the short term, that's adaptive — cortisol raises blood glucose during acute stress so the brain and muscles have fuel. But when the HPA axis runs hot chronically, that glucocorticoid signal never turns off.

Chronic cortisol elevation drives insulin resistance through at least three mechanisms:

1. Direct gluconeogenesis — cortisol stimulates the liver to produce glucose from amino acids, raising fasting glucose independent of diet.
2. GLUT4 downregulation — glucocorticoids reduce GLUT4 expression in adipose and skeletal muscle (Weinstein et al., Diabetes 1998; PMID: 9519729).
3. Visceral fat deposition — cortisol preferentially drives fat storage around the organs, and visceral adipocytes are more insulin-resistant than subcutaneous fat cells and release more inflammatory cytokines (IL-6, TNF-α) that directly antagonize insulin signaling.

This creates a vicious cycle: insulin resistance increases cortisol reactivity, and elevated cortisol worsens insulin resistance. Perceived psychological stress is enough to drive this loop. A 2020 meta-analysis confirmed that higher perceived stress scores are significantly associated with higher HOMA-IR values in non-diabetic adults (Hackett & Steptoe, Psychoneuroendocrinology 2017; PMID: 28187400).

If you're carrying high stress load, poor sleep, or showing signs of HPA axis dysfunction, addressing adrenal regulation is a prerequisite — not an afterthought — to improving insulin sensitivity. You can read more about cortisol dysregulation and HPA axis dysfunction and how it intersects with metabolic markers.

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Selenium Deficiency Causes and Insulin Signaling

Selenium is required for the synthesis of selenoproteins, several of which are directly involved in insulin signal transduction and oxidative defense in pancreatic beta cells. The relationship between selenium status and insulin resistance is dose-dependent and bidirectional: deficiency impairs insulin sensitivity, while extremely high intake paradoxically worsens it.

At normal-to-optimal selenium levels (serum selenium ~120–150 µg/L), the selenoprotein glutathione peroxidase (GPx) and thioredoxin reductase (TrxR) neutralize ROS that would otherwise damage the insulin receptor and impair IRS-1 phosphorylation. In selenium-deficient states, that antioxidant cover is removed and oxidative stress in pancreatic tissue rises substantially.

A large cross-sectional study using NHANES data found that individuals in the lowest quintile of serum selenium had significantly higher HOMA-IR values compared to those in the middle range (Bleys et al., Diabetes Care 2007; PMID: 17259484). This association held after adjusting for BMI, physical activity, and total caloric intake.

Low selenium also impairs thyroid hormone conversion (T4 → T3), and thyroid insufficiency is an independent cause of insulin resistance — making selenium deficiency a two-vector problem for metabolic health. If you haven't had your selenium checked, it belongs in the same panel as fasting insulin, glucose, and HbA1c. You can learn more about the lab markers associated with selenium deficiency and when to test.

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HPA Axis Suppression and Secondary Insulin Resistance

Tertiary adrenal insufficiency — where the hypothalamus fails to secrete adequate CRH, suppressing the entire HPA axis — is less discussed than primary Addison's disease but more common than most clinicians acknowledge, particularly in people with a history of long-term corticosteroid use (including topical steroids used extensively for conditions like eczema).

When the HPA axis is suppressed, cortisol output drops chronically low. This might sound like the opposite of the stress-driven insulin resistance described above — and in acute terms it is. But the metabolic consequences of low cortisol are also damaging:

• Impaired glucagon counter-regulation — without adequate cortisol, the stress response to hypoglycemia is blunted, leading to energy dysregulation.
• Increased inflammatory cytokine activity — cortisol has anti-inflammatory effects; when it's deficient, TNF-α and IL-6 rise, directly impairing IRS-1 phosphorylation and worsening insulin resistance.
• Fatigue and muscle loss — low cortisol reduces motivation and exercise tolerance, which indirectly degrades mitochondrial density and insulin sensitivity in skeletal muscle.

People who have gone through topical steroid withdrawal (TSW) after prolonged corticosteroid use often experience prolonged HPA axis recovery — a period during which cortisol rhythms are dysregulated and metabolic symptoms including fatigue, blood sugar instability, and poor stress tolerance are common. This is a distinct clinical picture that requires gradual HPA axis support rather than stimulation. You can read more about the supplements and root causes relevant to adrenal fatigue and cortisol suppression.

If your history includes extended corticosteroid use of any kind and you now have unexplained metabolic abnormalities, a morning serum cortisol and ACTH stimulation test are the appropriate starting point — not another elimination diet.

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Key Biomarkers to Assess When You Suspect Insulin Resistance

High fasting insulin with normal fasting glucose is the classic early-stage picture — the pancreas is still compensating. By the time fasting glucose is elevated, significant beta cell stress has already occurred. Testing fasting insulin proactively is more informative than waiting for a glucose or HbA1c flag. Articles on high fasting insulin patterns in women and low fasting insulin presentations explore these biomarker distinctions in more depth.

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What This Means for Your Formula

Insulin resistance rarely has a single cause, which is why a one-size supplement stack rarely works. A personalized approach that starts from your lab values, stress markers, and health history changes the targeting entirely. Here is how Ones addresses the root causes outlined in this article:

CoQ10/Ubiquinol (200mg): Mitochondrial electron transport depends on CoQ10 as a carrier. Supplementation at 200mg/day has been shown to improve insulin sensitivity in adults with metabolic syndrome by reducing mitochondrial oxidative stress and improving ATP production efficiency. Ones includes Ubiquinol — the reduced, bioavailable form — at the clinically studied 200mg dose.

Selenium (as selenomethionine, 200mcg): Selenomethionine is the most bioavailable selenium form and the one used in intervention trials examining insulin sensitivity and thyroid function. At 200mcg, it replenishes GPx and TrxR activity without approaching the upper-limit range where selenium paradoxically begins to impair insulin signaling (above ~300 µg/day). Ones includes selenium only when your lab data indicates suboptimal serum levels — not as a default addition.

Adrenal Support (proprietary blend): For users whose data indicates HPA axis dysregulation — elevated cortisol patterns, low morning cortisol, or a history of extended corticosteroid use — Ones may include its Adrenal Support System Blend. This blend is designed to modulate CRH-cortisol signaling rather than simply stimulate or suppress it, which matters in both hyperactivation and suppression contexts.

All formula decisions at Ones are driven by your specific biomarker profile. The 6- or 9-capsule daily plan is assigned by the AI based on your findings — not by you selecting from a menu — which means ingredients are prioritized by relevance, not convenience.

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Key Takeaways

• Insulin resistance is mechanistically diverse. Diet and visceral fat are the most common drivers, but mitochondrial dysfunction, chronic stress, selenium deficiency, and HPA axis suppression each independently impair insulin signaling.
• Cortisol dysregulation works both ways. Chronically high cortisol drives gluconeogenesis and visceral fat deposition; chronically low cortisol (as seen after prolonged steroid use) removes anti-inflammatory protection and worsens cytokine-driven IRS-1 inhibition.
• Fasting insulin should be tested early. HOMA-IR below 1.5 and fasting insulin below 6 µIU/mL are the targets. Waiting for fasting glucose to flag means missing years of early intervention opportunity.
• Selenium is a frequently overlooked variable. Its role in selenoprotein antioxidant defense and thyroid conversion links selenium status to insulin sensitivity through two separate pathways.
• Mitochondrial health is not a wellness buzzword. Measured mitochondrial defects in skeletal muscle precede type 2 diabetes diagnosis and are modifiable through exercise, sleep, and targeted nutrients like CoQ10.
• HPA axis history matters. If you have a history of long-term corticosteroid use, your adrenal axis may still be recovering — and that suppression pattern has real metabolic consequences that a standard metabolic panel will miss unless cortisol is included.

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This article is for informational purposes only. Consult a qualified healthcare provider before making changes to your supplement protocol, particularly if you have a diagnosed metabolic or adrenal condition.