Part 2
Insulin resistance is often viewed as a localized issue, affecting specific organs such as the liver or muscles. However, the reality is far more complex. It’s a system-wide metabolic dysfunction that unfolds in a predictable sequence, much like a chain reaction.
At the root of this problem lies ultra-processed foods, excess sugar, and fructose consumption, which disrupts brain signalling, drives overeating, and ultimately overloads the body's energy systems. As insulin resistance develops, it doesn’t stay confined to a single organ—it spreads, impacting multiple tissues, leading to conditions like type 2 diabetes, fatty liver disease, kidney damage, and even cognitive decline.
Picking up from earlier blog, where we looked at some of the root causes of Insulin Resistance; in this blog, we’ll break down how insulin resistance progresses step by step, from the brain to the muscles, liver, kidneys, pancreas, and even back to the brain, completing a vicious cycle.
Step 1: The Brain—The Root of the Problem
Before insulin resistance manifests in the body, it starts in the brain. Our modern diet, rich in ultra-processed foods, hijacks gut-brain signaling, causing us to eat far beyond our energy needs.
Leptin resistance develops, suppressing satiety signals, making us feel constantly hungry.
The brain becomes addicted to quick energy hits from sugar and refined carbs, reinforcing cravings.
Chronic overconsumption leads to repeated insulin spikes, followed by hypoglycemia, triggering even more hunger.
This creates a self-reinforcing loop of overeating, energy surpluses, and metabolic stress—setting the stage for insulin resistance.
Step 2: Excess Glucose and Fructose Overload
With a diet high in sugar and refined carbs, blood glucose levels remain chronically elevated, forcing the pancreas to pump out insulin to maintain balance. However, fructose follows a different pathway—it is rapidly converted into fat (FFAs and triglycerides) in the liver via de novo lipogenesis (DNL).
The result? Excess circulating free fatty acids (FFAs) and high insulin levels, which start interfering with normal energy metabolism.
Step 3: Muscle Insulin Resistance—The First Domino Falls
The first organ to become insulin resistant is skeletal muscle, the primary site for glucose uptake.
Excess FFAs accumulate inside muscle cells, blocking insulin signaling via the DAG-PKC pathway.
As muscles become resistant to insulin, they stop absorbing glucose efficiently.
Blood glucose levels stay elevated, prompting the pancreas to release even more insulin in an attempt to compensate.
Since muscle can no longer store glucose properly, more glucose gets shuttled to the liver and fat cells, accelerating the progression of insulin resistance.
Step 4: Adipose Tissue Insulin Resistance—The Overflow Problem
Fat cells (adipocytes) are designed to store excess energy safely. However, when they become overwhelmed with FFAs from both diet and liver conversion, they start resisting insulin too.
Normally, insulin suppresses fat breakdown (lipolysis), keeping FFAs in check.
But in insulin-resistant adipose tissue, fat cells "leak" FFAs into the bloodstream.
This leads to chronically elevated FFAs, worsening insulin resistance in muscle and liver.
Now, there’s a constant supply of FFAs flooding the system, fuelling further metabolic dysfunction.
Step 5: Liver Insulin Resistance and Fatty Liver Disease
With both muscle and fat failing to properly regulate glucose and FFAs, the liver takes a massive hit.
Excess FFAs from adipose tissue and de novo lipogenesis accumulate in the liver, leading to metabolic-associated steatotic liver disease (MASLD, formerly NAFLD).
Normally, insulin tells the liver to stop producing glucose. But in insulin-resistant individuals, the liver keeps dumping glucose into the blood, despite already high levels.
The liver also churns out more triglycerides and VLDL, raising plasma triglycerides and lowering protective HDL cholesterol.
This stage is critical because fatty liver is a major driver of worsening metabolic disease, increasing the risk of cardiovascular issues.
Step 6: Kidney Damage and Hypertension
As insulin resistance worsens, the kidneys start to suffer:
Hyperinsulinemia promotes sodium retention, increasing blood pressure.
Excess glucose damages the kidney filtration system, leading to early signs of diabetic kidney disease.
Increased albumin leakage in the urine is an early marker of kidney stress.
By this stage, insulin resistance is now impacting glucose, lipid, and blood pressure regulation, further compounding disease risk.
Step 7: Pancreatic Beta-Cell Burnout
Up until now, the pancreas has been overcompensating, pumping out higher levels of insulin to keep blood glucose in check. However, this can’t last forever.
Over time, beta cells become exhausted and start failing.
Insulin production drops, leading to uncontrolled hyperglycemia and full-blown type 2 diabetes.
This marks the transition from insulin resistance to insulin deficiency, requiring medical intervention.
Once pancreatic function declines, reversing metabolic disease becomes significantly harder.
Step 8: Brain Insulin Resistance and Cognitive Decline
Ironically, after initiating this cascade, the brain also becomes insulin resistant.
The brain depends on insulin for glucose metabolism, and when it becomes resistant, cognitive function declines.
Studies link brain insulin resistance to Alzheimer’s disease (sometimes called “type 3 diabetes”).
This completes a vicious cycle—brain dysfunction further drives appetite dysregulation, worsening metabolic disease.
Stage | Event | Source of Excess Energy | Key Consequences |
1. Brain Dysfunction & Gut-Brain Signalling Breakdown | Overconsumption of ultra-processed foods due to impaired gut-brain signalling (leptin resistance, dopamine-driven cravings). | Glucose, fructose, refined carbs from processed foods. | Increased appetite, loss of satiety signals, continuous overeating. |
2. Frequent Insulin Spikes & Hypoglycemia | High glycemic foods trigger excessive insulin release, causing rapid glucose drops, leading to more hunger and overeating. | Repeated spikes in blood glucose from high-carb meals. | Metabolic rollercoaster → hypoglycemia-induced cravings, reinforcing overeating. |
3. Elevated Free Fatty Acids (FFAs) in Circulation | Excess calories (especially fructose) converted to FFAs by the liver via de novo lipogenesis (DNL); high carb intake also raises insulin, reducing fat oxidation. | Excess glucose/fructose converted into triglycerides (TG) in the liver, released as FFAs and VLDL. | Increased circulating FFAs, metabolic stress on tissues. |
4. Muscle Insulin Resistance | Excess FFAs accumulate in muscle cells, interfering with insulin signalling (via DAG-PKC pathway). | Initially, muscle glucose uptake declines due to lipid overload, forcing reliance on FFAs for energy. | Reduced glucose uptake by muscle, increased circulating glucose and insulin resistance. |
5. Adipose Tissue Insulin Resistance | Overflow of FFAs from the liver and dietary sources saturates adipose tissue, impairing its ability to store fat. | Fat cells become "full" and insulin-resistant, leading to uncontrolled lipolysis and more FFAs in circulation. | More FFAs released into the bloodstream, worsening muscle & liver insulin resistance. |
6. Liver Insulin Resistance & Fatty Liver (MASLD) | Liver becomes overwhelmed with FFAs, driving further de novo lipogenesis (DNL) and fat accumulation. Insulin fails to suppress hepatic glucose production. | Glucose/fructose is converted into triglycerides (TG) and FFAs in the liver. | Increased blood glucose, hyperinsulinemia, elevated triglycerides, low HDL, fatty liver. |
7. Kidney Damage & Dysfunction | Chronic hyperglycemia and hyperinsulinemia lead to sodium retention, hypertension, and glomerular damage. | Glucose overload damages kidney filtration system. | Increased blood pressure, kidney stress, and diabetic kidney disease risk. |
8. Pancreatic Beta Cell Burnout | The pancreas overproduces insulin to compensate for insulin resistance, leading to beta-cell dysfunction and eventual failure. | Chronic glucose/FFA overload exhausts beta cells. | Hyperinsulinemia initially, then pancreatic failure → type 2 diabetes. |
9. Brain Insulin Resistance & Cognitive Decline | Chronic insulin resistance impairs neuronal energy metabolism, increasing risk for Alzheimer’s disease and cognitive dysfunction. | Glucose metabolism in neurons declines, leading to energy deficits. | Memory issues, neurodegeneration, further appetite dysregulation. |
Key Takeaways:
The root cause is brain dysfunction from processed food overconsumption, leading to a cascade of insulin resistance across multiple organs.
Excess glucose and fructose are converted to FFAs in the liver via de novo lipogenesis, driving metabolic dysfunction.
The sequence follows a metabolic overload model: first muscle becomes insulin resistant (unable to take up glucose), then adipose tissue, followed by liver, kidneys, pancreas, and finally the brain.
Image Credit: Nature Reviews
Insulin Resistance, eNOS Dysfunction, and Cardiovascular Complications
One of the lesser-known but critical consequences of insulin resistance is its impact on endothelial nitric oxide synthase (eNOS)—the enzyme responsible for producing nitric oxide (NO), a key molecule for vascular health and blood flow regulation.
Insulin resistance impairs eNOS activation, reducing NO production.
Lower NO levels lead to endothelial dysfunction, increasing blood vessel stiffness and reducing their ability to dilate properly.
Poor blood flow contributes to hypertension, as vessels can no longer relax efficiently.
This dysfunction has systemic effects:
NASH and Liver Fibrosis – Reduced NO impairs hepatic blood flow, exacerbating liver hypoxia and promoting inflammation, fibrosis, and progression from fatty liver to NASH (non-alcoholic steatohepatitis).
Hypertension – With less NO available to relax blood vessels, blood pressure rises, further straining the heart and kidneys.
Cardiac Events – Endothelial dysfunction increases the risk of atherosclerosis, setting the stage for heart attacks and strokes.
Thus, insulin resistance isn’t just a metabolic issue—it’s a vascular disease as well, with far-reaching consequences beyond glucose control.
Breaking the Cycle: Diet & Lifestyle Interventions
The good news? This process is reversible if caught early. The key is reducing energy overload and restoring insulin sensitivity through:
✔️ Whole Foods, Low-Processed Diet: Eliminate ultra-processed foods, refined carbs, and fructose-laden drinks.
✔️ Intermittent Fasting: Allows insulin levels to drop and improves metabolic flexibility.
✔️ Strength Training & Exercise: Increases muscle glucose uptake and reduces insulin resistance.
✔️ Healthy Fats & Fiber: Support gut health, slow glucose absorption, and improve satiety.
✔️ Sleep & Stress Management: Reduces cortisol spikes, which contribute to insulin resistance.
By addressing the root cause—our modern diet and lifestyle—we can stop insulin resistance before it spirals into full-blown disease.
In the upcoming blogs, we will dive deeper into how each of these organs are impacted by insulin resistance and understand how to reverse insulin resistance at each stage. Stay tuned for our next blog!
*Disclaimer:
The information provided in this blog is for educational and informational purposes only and should not be construed as medical advice. While every effort is made to ensure accuracy, the content is not intended to replace professional medical consultation, diagnosis, or treatment. Always seek the guidance of a qualified healthcare provider with any questions regarding your health, medical conditions, or treatment options.
The author is not responsible for any health consequences that may result from following the information provided. Any lifestyle, dietary, or medical decisions should be made in consultation with a licensed medical professional.
If you have a medical emergency, please contact a healthcare provider or call emergency services immediately.
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