Metabolic Inflammation As A Cause Of Insulin Resistance

Metabolic inflammation causes insulin resistance by jamming insulin’s signal. Over-nutrition packs fat into fat cells. That fat drives inflammatory cytokines (immune signal proteins). Then muscle, fat and liver cells start ignoring insulin. The pancreas overworks until its beta cells wear out, and prediabetes or type 2 diabetes follows.

In past articles, I have talked about the role of metabolic inflammation in obesity and diabetes. Today we zoom in on insulin resistance. What is it? What does it do? And how does metabolic inflammation raise the chances that one gets it?

1. What is Insulin resistance?

About 30% of Americans, and up to 50% of those 60 and over, have a silent blood sugar problem called insulin resistance. Insulin resistance raises the risk for prediabetes, Type 2 diabetes and a host of other serious health problems. These include heart attacks, strokes, and cancer.

So what is Insulin Resistance? It is when cells in your muscles, body fat and liver start pushing back on or ignoring insulin’s signal. That signal tells cells to take glucose from the blood to burn or store. Glucose, often called blood sugar, is the body’s main fuel.

2. How does Insulin Resistance Develop?

Some factors that shape insulin resistance are aging and ethnicity. But the driving forces seem to be excess body weight, too much belly fat, a lack of exercise, smoking, and even lack of sleep.

Over time, as insulin resistance builds, your body makes more insulin to fight back. After a long stretch, even several years, the beta cells in your pancreas get worn out from all the extra work. They can no longer keep up with the higher demand for insulin. Then, years after insulin resistance quietly started, your blood sugar may spike. You may show prediabetes or type 2 diabetes. You are also at risk of non-alcoholic fatty liver disease (NAFLD). That condition raises your risk for liver damage and heart disease.

3. What are the Signs and Symptoms of Insulin Resistance?

You can’t always see insulin resistance, but here are some signs to watch for:

• A large waist. Experts say the best way to tell if you’re at risk for insulin resistance takes a tape measure and a moment of truth in front of the bathroom mirror. Some waist sizes raise the odds of insulin resistance and metabolic syndrome, which is also linked to insulin resistance. For women, that is 35 inches or more. For men, it is 40 or more. If you’re of Southeast Asian, Chinese or Japanese descent, it is 31.5 inches for women and 35.5 inches for men.
• You have other signs of metabolic syndrome. The National Institutes of Health says to look beyond a large waist. If you also have three or more of the following, you likely have metabolic syndrome, which creates insulin resistance.
• High triglycerides. Levels of 150 or higher or taking medication to treat high levels of these blood fats.
• Low HDLs. HDL (good cholesterol) levels below 50 for women and 40 for men – or taking medication to raise low high-density lipoprotein (HDL) levels.
• High blood pressure. Readings of 130/85 mmHg or higher, or taking medication to control high blood pressure
• High blood sugar. Levels of 100-125 mg/dl (the prediabetes range) or over 125 (diabetes).
• High fasting blood sugar (or you’re on medicine to treat high blood sugar). Mildly high blood sugar may be an early sign of diabetes.
• You get dark skin patches. If insulin resistance is severe, you may see skin changes. These include patches of darker skin on the back of your neck or on your elbows, knees, knuckles or armpits. This darkening is called acanthosis nigricans.

4. Does inflammation cause insulin resistance?

As early as the 1950s, there was epidemiological evidence suggesting a correlation between inflammation and insulin-resistant states such as obesity. But no one knew how they were linked. In the last decade, however, it has become more and more clear that obesity, and the inflammation that comes with it, are major parts of insulin resistance. Studies of human obesity and insulin resistance have shown a clear association between two things. One is pro-inflammatory signaling pathways that stay switched on. The other is lower insulin sensitivity. For example, high levels of tumor necrosis factor-α (TNF), interleukin-6 (IL-6) and interleukin-8 (IL-8) have all been reported in various diabetic and insulin-resistant states. Also, the inflammatory marker C-reactive protein (CRP), a general marker of acute inflammation, is commonly high in human insulin-resistant states. Experiments have used rodents that are naturally obese, as well as knockout and transgenic mice. Detailed studies of insulin signaling at the molecular level have also been done. Together, they have begun to show how obesity-driven inflammation links to insulin-resistant states.

5. What Health Conditions are Related to Insulin Resistance?

An estimated 87 million American adults have prediabetes; 30-50% will go on to develop full-blown type 2 diabetes. Also, up to 80% of people with type 2 diabetes have NAFLD. But those aren’t the only threats posed by insulin resistance.

Years of high insulin are followed by a flood of cell-damaging high blood sugar. Because of that, people with insulin resistance, prediabetes, and type 2 diabetes are at high risk for cardiovascular (heart and blood vessel) disease. The International Diabetes Federation says insulin resistance doubles your risk for heart attack and stroke. It also triples the odds that your heart attack or ‘brain attack’ will be deadly.

Insulin resistance and metabolic syndrome are also linked with higher risk for cancers of the bladder, breast, colon, cervix, pancreas, prostate and uterus. The connection: high insulin levels early in insulin resistance seem to fuel tumor growth. They also seem to hold back the body’s ability to protect itself by killing cancer cells.

Research has also found a strong association between insulin resistance and a decline in memory. That raises the risk of Alzheimer’s disease.

6. Can understanding the causes of Insulin Resistance aid in future preventive approaches?

Chronic low-grade inflammation associated with obesity is responsible for the drop in insulin sensitivity. That is why obesity is a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. This low-grade inflammation is caused by over-nutrition, which leads to fat building up in adipocytes (fat cells).

Obesity might raise the expression of some inflammatory cytokines and turn on several signaling pathways. Both play a part in causing insulin resistance, because they get in the way of insulin’s signal and action. It has been suggested that specific factors and signaling pathways are often correlated with each other. So studies of inflammation-related insulin resistance should look at both the shifts in cytokines and the state of the related signaling pathways.

Frequently asked questions

What causes insulin resistance?

The driving forces are excess body weight, too much belly fat, a lack of exercise, smoking and sleep deprivation. Aging and ethnicity add risk. Underneath them sits metabolic inflammation. Over-nutrition packs fat into fat cells. That fat raises inflammatory cytokines such as TNF and IL-6. Those signals jam insulin’s message to muscle, fat and liver cells.

Why am I insulin resistant but not diabetic?

Because your pancreas is still keeping up. As your cells ignore insulin, your body makes more of it to force the message through. For years, that extra insulin holds blood sugar in range. After years of overwork, the beta cells in the pancreas wear out. Only then does blood sugar climb into prediabetes or type 2 diabetes.

What are the warning signs of insulin resistance?

Often there is nothing you can see. The clearest clues are a waist of 35 inches or more for women or 40 inches or more for men, high triglycerides, low HDL, blood pressure of 130/85 or higher, and fasting blood sugar of 100 or above. When it is severe, dark patches of skin appear on the neck, elbows, knees, knuckles or armpits.

Related reading

• Diabesity and Inflammation
• Metabolic Inflammation and Type 2 Diabetes
• Does Overeating Cause Diabetes?
• Does Overnutrition Cause Metabolic Inflammation?
• What Causes Type 2 Diabetes

References

1. NCBI (2007): Inflammation and Insulin Resistance. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246086/
2. Scientific American (2009): Does Inflammation Trigger Insulin Resistance and Diabetes? Retrieved from https://www.scientificamerican.com/article/inflammatory-clues/

3. NCBI (2006): Inflammation and Insulin Resistance. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1483173/
4. Physiology.org (2008): Skeletal muscle insulin resistance: role of inflammatory cytokines and reactive oxygen species. Retrieved from https://www.physiology.org/doi/full/10.1152/ajpregu.00561.2007
5. Hindawi (2015): Mechanisms Linking Inflammation to Insulin Resistance. Retrieved from https://www.hindawi.com/journals/ije/2015/508409/

6. Endocrineweb (2019): Insulin Resistance Causes and Symptoms. Retrieved from https://www.endocrineweb.com/conditions/type-2-diabetes/insulin-resistance-causes-symptoms

Medically reviewed by Dr. Gurpreet Singh Padda, MD, MBA, MHP
Interventional pain physician, addiction medicine specialist and obesity medicine diplomate.
Licensed in Missouri and Illinois.
Last reviewed June 18, 2026