Insulin is produced by the beta cells of the endocrine pancreas. “Insulin resistance” is a condition in which the actions of insulin on peripheral tissues — including skeletal muscle, liver, and adipose — are impaired. When this impairment occurs, your body can’t move enough sugar (glucose) into your cells, so your blood glucose levels stay chronically high. Insulin resistance is the condition that typically precedes type 2 diabetes (T2D) and a constellation of conditions known as metabolic syndrome, which in turn increases your risk for heart disease. This report sums up what causes insulin resistance in the first place, and what you can do to prevent it.

Acute insulin action: “Sensitivity” 

When your insulin activity is normal, from a medical standpoint you’re deemed “insulin sensitive.” As one research paper explains, over an “acute” period (i.e., hours to days), nutrient “sensors” within skeletal muscle and the liver modulate insulin sensitivity (independently of significant weight gain or weight loss) and in turn nutrient (i.e., glucose) uptake. These processes provide a means of regulating insulin sensitivity that is cell autonomous (i.e., intrinsic to the cell) and independent of extracellular stimuli.  

Most likely these acute effects are distinct from the mechanisms, which we summarize in the next sections, that lead to chronic insulin resistance.

Chronic insulin action: “Resistance”

The exact causes of insulin resistance are varied, and the relative importance of each is a matter of ongoing scientific research. A consensus of leading scientists describe insulin resistance as a multifactorial condition brought on by a series of events and conditions, all of which may be, to varying degrees, interconnected:

• Inflammation and immune response disturbance
• Changes in lipid metabolism
• Gut microbe changes (or dysbiosis) 

But what are “the causes behind these causes”? Certain predispositions toward insulin resistance are genetic. However, as one research team opines, “it is likely that any genetic component must interact with environmental factors in order for insulin resistance to develop into a pathophysiologically meaningful abnormality.” 

The most common (and no doubt interrelated) environmental, or “acquired,” causative factors, especially in Western cultures, are:

• Obesity and low-fiber diets
• Sedentary lifestyle
• Aging

Immune cells, inflammation and insulin resistance

It has become widely accepted that chronic, low-grade tissue inflammation is a major cause of obesity-induced insulin resistance. The science is complex, but essentially what researchers see in the adipose tissue of obese individuals is a striking accumulation of highly activated macrophages (immune cells associated with inflammation) that express a large array of proinflammatory genes, including a set of cytokines — particularly tumor necrosis factor (TNF-α), which directly cause insulin resistance. Visceral adipose tissue has a much greater negative metabolic effect than subcutaneous adipose tissue. Similar inflammatory events can also occur in the liver and skeletal muscle, although the exact mechanisms (particularly in skeletal muscle) remain under study.

Interestingly, some research points to the possibility that obesity may first cause insulin resistance that then causes macrophage infiltration — instead of the macrophage infiltration preceding the insulin resistance. That’s how complicated the interconnections may be, each  amplifying the other on the road toward chronic metabolic disorders such as diabetes.

Macrophages are by no means the only immune cell types that participate in the process of inflammation-induced insulin resistance. Neutrophils, lymphocytes, eosinophils, and natural killer T (NKT) cells all appear to play a role in what one scientific team aptly called “an ongoing interactive immune cell conversation.”

Lipid metabolism and insulin resistance

There are a variety of lipid metabolism abnormalities that either cause or result from insulin resistance. Lipotoxicity happens when circulating fatty acids activate cell-signaling pathways that interfere with insulin action. Also, fat metabolism can lead to the accumulation of intracellular lipid products that cause insulin resistance. In a seemingly cyclic relationship, hyperglycemia (or high blood glucose, a hallmark of type 2 diabetes) can worsen lipotoxicity, which can then worsen glucotoxicity (the set of negative outcomes associated with high blood glucose). 

Your gut microbiome and insulin resistance

It has become widely accepted that chronic disruption of the gut barrier can produce systemic (i.e., throughout the body) low-grade inflammation, which in turn contributes to a greater risk for intestinal diseases. But only recently has it become more evident that when a gut barrier becomes unhealthy (known as “microbiota dysbiosis”), this can contribute to the development of metabolic, autoimmune, and aging-related disorders. A 2022 review paper summarizes the factors that can affect gut barrier integrity, such as enteric infection, antibiotics, low-fiber diets, circadian rhythm disruption, and psychological stress.

Initial research into how the gut microbiome influences chronic metabolic processes centered around the hypothesis that bacteria physically translocate to tissues, where they may invoke an inflammatory response; but this theory later generated mixed results in the literature. A more recent line of reasoning relates gut microbiota to inflammation and cardiometabolic disease. Researchers now conclude that to sustain a symbiotic relationship with the gut microbiota, a controlled and appropriate immune response is essential to benefit from the gut microbiota's numerous functions. That controlled immune response appears to be boosted when the production of certain metabolites, particularly short-chain fatty acids (SCFAs) — acetate, butyrate and propionate — are promoted, which also improves hosts energy homeostasis and glucose tolerance.

We can promote the production of SFCAs by ingesting a diet rich in fiber. High fiber intake has been associated with:

• Protection from several metabolic diseases, such as T2D
• Improved glucose tolerance in people with T2D
  

In other words, both obesity and a low-fiber diet — made worse when the two are combined (as they so often are) — disturb the gut’s immune intestinal response and ability to ward off insulin resistance and the ensuing glucose intolerance that is the hallmark of chronic metabolic disorders like T2D.

Preventing insulin resistance and metabolic disease:
Managing weight, eating well and other smart lifestyle choices

The constellation of factors behind insulin resistance — inflammation and immune response disturbances, negative changes in lipid metabolism, and gut microbiome damage — are complex and interconnected. While those processes are certainly affected by family history and your age, and there’s not much you can do about that, three lifestyle factors play very big roles in your metabolic health: body weight, fitness and diet. 

Managing your weight: Caloric restriction and exercise are keys

Nearly 90% of adults with diabetes — a staggering 34 million of whom have T2D — are overweight or obese with a body mass index (BMI) over 25, according the Centers for Disease Control (CDC). 

As we detailed in our report, The Top 7 Risk Factors for Prediabetes and Type 2 Diabetes, if you focus on bringing your weight down, even a little bit, the payoff can be huge for your blood sugar and total metabolic health. Even an extra 15 or 20 pounds can throw off your system as your fat cells send out compounds that ramp up inflammation. The closer you can get to your healthy weight (even if you don’t reach your summer-bathing-suit goal), the calmer your inflammatory response will be. 

The Diabetes Prevention Program (DPP) developed an intervention program that required participants to lose just 7% of their body weight and maintain about 150 minutes of exercise per week over the course of six months. The results were astounding: Researchers saw a 58% reduction in the incidence of diabetes among those who followed the plan. To put it in real terms, someone who starts at a weight of 200 pounds could lose just 14 pounds and exercise a little more than 20 minutes a day to cut their risk by more than half. No drugs, no extreme dieting or exercise — just life-changing health benefits.

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Exercise, independent of weight loss, has benefits

Scientists have known for several decades that exercise/muscle contraction activates glucose transport, independent of insulin; and that after exercise, insulin sensitivity increases. This means that if you exercise, you don’t need as much insulin to achieve the same positive effect on glucose control. More recently, studies have shown that regular physical activity reduces the risk of insulin resistance, metabolic syndrome and type 2 diabetes. It has also been shown that anti-inflammatory compounds are released during exercise. 

While the debate goes on about whether aerobic exercise induces better improvement in glycemic regulation than does resistance exercise, or whether both are better together than one alone, what’s clear is that fitness in general is a powerful weapon against diabetes, heart disease and a host of other disorders. Even when weight management isn’t the goal, clinical studies suggest that consistent exercise can reduce the risk of type 2 diabetes by up to a staggering 50%. For those that already have prediabetes or diabetes, consistent physical activity has been shown to improve insulin sensitivity and glycemic control, while reducing the risk of mortality. (Exercise is also a natural stress buster — see why that’s important, below.) 

The American Diabetes Association recommends 150 minutes a week, or just a little more than 20 minutes a day. Just getting up out of your chair and moving around a bit every hour counts, too.

Learn more:
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Eating well

It’s not just what you weigh, but what you eat. Preventing insulin resistance and the development of a chronic, metabolic disorder such as T2D involves better eating:

1. Increase your consumption of prebiotics (high-fiber carbs)

Prebiotics are fibrous, non-digestible carbohydrates that can assist in maintaining the higher microbial gene richness that scientists associate with lower inflammation. Good sources include:

• Vegetables (such as kale, collards, broccoli, Brussels sprouts)
• Fruits (such as bananas, pears, apples, oranges, grapefruits, berries)
• Beans, lentils and legumes
• Whole grains
• Seeds (such as chia, pumpkin or sunflower)

2. Avoid processed foods

Wean off as many foods as you can that contain “added sugars,” known as processed foods, including white bread, pasta and rice; baked goods; refined crackers and crunchy snacks; fast foods; and processed meats (including hot dogs and bacon). A 2020 study examined more than 100,000 diabetes-free participants and found that those who had a diet high in heavily processed foods — in which these foods accounted for more than 22% of their overall intake — were more likely to develop diabetes compared to those who ate the least amount of processed foods (roughly 11% of their diet). What’s more, they found a 5% increase in T2D for every 100 grams of ultra-processed food consumed.

Learn more:

Why The Gut Microbiome Is Key To Your Health
How Consuming More Fiber Can Benefit Diabetes Management
What Is Fiber?
Choosing the best immunity-boosting foods

3. Add in healthy sources of protein and fats

Studies show that in healthy individuals, protein doesn’t have a significant effect on insulin sensitivity. However, protein is essential to creating insulin, while insulin helps a protein’s building blocks (amino acids) enter the cells that need it. Furthermore, eating meals that balance high-quality proteins, fiber-rich carbohydrates and healthy fats can help you be less controlled by hunger and stay fuller for longer — helping you better manage your weight. The best protein sources are both nutrient-dense and low in saturated fat, sodium and processed carbohydrates (i.e., sugars). Optimal sources include: poultry, eggs, seafood, unprocessed red meat on a limited basis, legumes (such as lentils, peanuts, black beans, chickpeas), nuts and seeds, and whole grains.

Healthy fats, particularly Omega-3s, are also important in your diet, as they are associated with reduced inflammation and a related reduction in the risk of atherosclerosis, obesity and diabetes. Fatty fish (think salmon or mackerel), nuts, seeds, oils, and some vegetables and herbs (Brussel’s sprouts, basil) are examples of healthy fats.

Other smart lifestyle choices

Insulin resistance and the debilitating progression toward chronic metabolic disorders may be most impacted by weight control and diet, but other factors that you should attend to include: 

• Sleep hygiene, or getting the recommended 7 hours/night, is advisable because researchers are finding a compelling connection between lack of sleep and both insulin resistance and inflammation, which put subjects at greater risk for glucose intolerance and diabetes. 

• Hydration (especially drinking more water) is associated with better insulin sensitivity.  

• Moderate alcohol consumption is better than over-consumption because alcohol disrupts your body’s process of using glucose for energy and it can negatively impact your blood glucose levels.

• Managing your stress level is beneficial in that certain stress hormones may cause body tissues (muscle and fat) to be less sensitive to insulin. As a result, blood sugar levels can rise due to chronic, untreated stress. 

Key Takeaways

Insulin resistance is an impairment that prevents your body from moving enough sugar (glucose) into your cells, a problem associated with the onset of type 2 diabetes (T2D) and a constellation of conditions known as metabolic syndrome. The multitude of factors behind insulin resistance — inflammation and immune response disturbances, negative changes in lipid metabolism, and gut microbiome damage — are complex and interconnected. While those processes are certainly affected by family history and your age, three lifestyle factors play very big roles in your insulin sensitivity and overall metabolic health: body weight, fitness and diet. Managing those lifestyle choices, by following some simple strategies, pays huge health dividends and will, in fact, lengthen your lifespan materially.