What Is Insulin Resistance and How Does It Develop?

Insulin is not just a blood sugar hormone. It’s a comprehensive metabolic signal that affects fat storage, protein synthesis, inflammation, and cell growth. When that signal gets disrupted, a wide range of downstream problems follow. Insulin resistance sits at the center of most of those problems.

Understanding how resistance develops requires looking at the molecular machinery of insulin signaling, not just the blood tests.

Normal Insulin Signaling: How It’s Supposed to Work

When blood glucose rises after a meal, the pancreas secretes insulin. Insulin travels through the bloodstream to target tissues, primarily skeletal muscle, liver, and fat cells. At each target cell, it binds to the insulin receptor, a protein embedded in the cell membrane.

This binding triggers a phosphorylation cascade inside the cell. The insulin receptor activates itself (autophosphorylation), then activates insulin receptor substrates (IRS-1 and IRS-2), which activate PI3K (phosphoinositide 3-kinase), which activates Akt, which ultimately causes GLUT4 transporters to move from their storage vesicles inside the cell to the cell membrane (Petersen and Shulman, 2018, Physiological Reviews).

GLUT4 is the glucose transporter in muscle and fat cells. It only works when it’s at the cell surface. Insulin causes it to move there. With GLUT4 at the surface, glucose enters cells rapidly, blood glucose falls, and the system resets.

In a healthy cell, this entire sequence is fast and responsive. Small amounts of insulin produce large glucose uptake. The signaling is amplified at every step.

What Goes Wrong in Insulin Resistance

Insulin resistance is when this signaling chain breaks down. The insulin binds to its receptor normally, but the downstream signal gets blocked somewhere in the cascade. Cells don’t hear the message as loudly. GLUT4 doesn’t mobilize as effectively. Less glucose enters cells per unit of insulin.

The pancreas compensates by secreting more insulin. For years, this compensation can keep blood glucose in a normal range while insulin levels run chronically high. This is the hidden phase of insulin resistance.

DeFronzo and Tripathy (2009, Diabetes Care) established that skeletal muscle insulin resistance is the primary defect driving type 2 diabetes development. Muscle is the largest glucose disposal site in the body, accounting for roughly 70-80% of glucose uptake after a meal. When muscle cells become resistant, the system is severely compromised.

The Role of Ectopic Fat

The most mechanistically supported cause of skeletal muscle insulin resistance is ectopic fat. Not subcutaneous fat under the skin. But fat deposited inside muscle cells (intramyocellular lipid) and in the liver.

When excess fatty acids accumulate inside muscle cells, they generate lipid intermediates called diacylglycerol (DAG) and ceramides. These molecules directly inhibit IRS-1 phosphorylation, essentially jamming the insulin signaling cascade at an early step (Samuel and Shulman, 2012, Cell).

Think of it this way: the cell’s normal insulin signal is like a car key turning a lock smoothly. DAG and ceramides are grit in the lock. The key still goes in, but the lock doesn’t turn as easily.

Ectopic fat accumulation in muscle and liver correlates more strongly with insulin resistance than total body fat or BMI. This is why visceral obesity (where fat surrounds organs and has higher spillover into ectopic depots) is more metabolically harmful than subcutaneous obesity.

Chronic Inflammation as a Contributing Factor

Excess adipose tissue, particularly visceral fat, secretes pro-inflammatory cytokines including TNF-alpha and IL-6. These inflammatory signals also interfere with insulin receptor signaling. TNF-alpha can phosphorylate IRS-1 at an inhibitory site, blunting the insulin response in muscle cells.

This creates a feedback loop. Excess fat causes inflammation. Inflammation worsens insulin resistance. Insulin resistance raises blood glucose and insulin, promoting more fat storage. The cycle builds on itself.

Dietary patterns consistently linked to higher inflammatory markers (like ultra-processed food intake) may worsen insulin sensitivity partly through this inflammatory pathway, though the direct mechanistic evidence is stronger for ectopic fat than for dietary inflammation per se.

The Chronic Exposure Hypothesis

A separate but related hypothesis proposes that chronically elevated insulin levels themselves downregulate insulin receptor sensitivity, similar to how chronic drug exposure can desensitize receptors. This hypothesis has some support in cell culture studies, but the evidence in humans is less clear.

What is clear is that chronically elevated postprandial blood glucose and insulin in people with metabolic syndrome correlates with progressive insulin resistance. Whether this is a cause or consequence of ectopic fat accumulation is debated. Most current evidence points to ectopic fat as the more causally important factor.

Exercise: The Most Reliable Intervention

Exercise improves insulin sensitivity through two pathways. During exercise, muscles contract and take up glucose via a completely separate pathway, the AMP-kinase pathway, that doesn’t require insulin at all. This is why exercise lowers blood glucose even in the absence of functional insulin signaling.

More importantly for the long term, exercise training increases GLUT4 protein expression in muscle cells. More GLUT4 means more glucose uptake capacity in response to insulin. This adaptation is durable and is one of the primary reasons exercise training is such a powerful intervention for insulin resistance (Richter and Hargreaves, 2013, Physiological Reviews).

Both resistance training and aerobic exercise improve insulin sensitivity, though through somewhat different mechanisms. Resistance training increases muscle mass, creating more glucose storage capacity. Aerobic training increases mitochondrial density and fat oxidation capacity in muscle, which reduces intramyocellular lipid accumulation. Combining both appears more effective than either alone.

The effect of exercise on insulin sensitivity appears within 24-72 hours of a single session and builds with consistent training over weeks.

This article is for educational purposes only. It’s not medical advice. Talk to your doctor or a registered dietitian before making significant changes to your diet.