What is insulin resistance (IR)?

Insulin resistance is a condition in which the body’s cells become less sensitive to insulin. Normally, insulin binds to receptors on the cell surface, activating a signalling cascade that moves glucose transporters (GLUT4) to the membrane, allowing glucose to enter the cell from the blood. In IR, this mechanism works less well. As a result, the body has to produce more and more insulin to keep blood sugar within the normal range. This leads to persistently elevated blood insulin and sugar. At first the pancreas may still cope with the load, but over time it can become depleted.

Insulin resistance has many causes. These include excess weight, especially abdominal fat, a sedentary lifestyle, and frequent snacking high in carbohydrates and fats. In obesity, adipose tissue releases substances that can promote inflammation and impair normal insulin action. In addition, excess weight increases fat breakdown and release of free fatty acids into the blood, which hinders cells from taking up glucose.

However, diet and obesity are not the only factors in the development of insulin resistance. Chronic stress, elevated cortisol, hormonal shifts, and genetic predisposition can also reduce cells’ sensitivity to insulin. Changes at the level of receptors and signalling pathways in muscle, liver and adipose tissue can make these tissues less responsive to insulin. For example, in muscle cells insulin signalling should move glucose transporters (GLUT4) to the membrane. In insulin resistance this process is impaired: fewer transporters reach the membrane and muscles take up less glucose from the blood.

In liver cells, insulin normally suppresses glucose production (gluconeogenesis). In IR the liver stops “hearing” the insulin signal and keeps producing extra glucose even when blood levels are already sufficient. This leads to a further rise in blood sugar.

In adipose tissue, insulin usually helps store energy: it stimulates glucose uptake and fat synthesis and suppresses fat breakdown (lipolysis). In IR these processes are disrupted—lipolysis can increase even when insulin is high. As a result, more free fatty acids enter the tissue, further reducing tissue sensitivity to insulin.

Insulin can also act differently in different tissues—“selective” insulin resistance occurs when muscle becomes less sensitive while adipose tissue still responds to insulin and actively stores fat.

More about insulin

Insulin is a hormone produced by the pancreas that not only regulates carbohydrate metabolism but also participates in fat metabolism. It acts like a key, giving cells access to glucose from the blood, helping to store it as glycogen and to slow its breakdown when needed. Without insulin, glucose cannot be transported into cells.

Insulin also affects lipid metabolism by reducing fat breakdown and stimulating fat storage in tissues. It has an anabolic effect, promoting cell growth and division. That is why excess insulin can lead to increased cell proliferation and to the development of certain tumours, such as fibroids or polyps.

Insulin levels in the body can vary under the influence of many factors. Its secretion increases with frequent meals, stress, excess body weight and chronic liver disease. During pregnancy, physiological insulin resistance develops under the influence of hormones (including progesterone), leading to a compensatory increase in insulin secretion.

Decreased insulin production can be linked to type 1 diabetes, viral damage to the pancreas, adrenal exhaustion, and deficiency of certain amino acids and B vitamins. When insulin is lacking, glucose is not taken up by cells, remains in the blood and can lead to serious consequences—hyperglycaemia and diabetes.

Insulin synthesis

Insulin is produced by the beta cells of the pancreatic islets of Langerhans. Its synthesis begins with the INS gene, which encodes a long molecule—preproinsulin. In the endoplasmic reticulum it is converted to proinsulin; then in the Golgi apparatus proinsulin is packaged into secretory granules. Inside the granules it is cleaved into two parts: insulin and C-peptide. Insulin is then stored in the granules until blood glucose rises—then it is released into the blood, giving cells access to glucose.

Cofactors required for insulin synthesis: amino acids, calcium ions, magnesium, zinc, ATP.

Main factors influencing the development of insulin resistance

• Overweight and obesity
• Low physical activity
• Diet high in sugar
• “Western diet” (abundance of trans fats, refined carbohydrates and processed foods)
• Overeating and frequent snacking
• Chronic inflammation in the body
• Insufficient sleep
• Pregnancy (a natural state with physiological insulin resistance, but with a risk of gestational diabetes)
• Exposure to toxins
• Certain medications (e.g. glucocorticoids)
• Liver disease
• Smoking
• Genetic predisposition

Insulin and carbohydrate metabolism

Although carbohydrates make up only up to 2% of dry body mass, their importance for the body is hard to overstate. The main function of carbohydrate metabolism is to supply cells with energy. Carbohydrates are the key, rapidly available fuel for most tissues, and glucose (which can also be produced by the body from protein and fat) is used by cells as the main energy source, allowing them to obtain “fuel” for work and for all vital functions. For the central nervous system it is practically the only source of energy under normal conditions, since the brain has no energy stores and cannot use protein or fat directly (except for ketone bodies during prolonged fasting).

To avoid running out of glucose between meals, the body stores it as glycogen in the liver and muscles. When it is necessary to raise blood sugar quickly or to supply energy for muscle work, glycogen is broken down to meet the body’s needs.

From a biochemical standpoint, glucose oxidation is efficient and economical: less oxygen is needed to obtain an equivalent amount of energy compared with fatty acid oxidation. Complete breakdown of one molecule of glucose to carbon dioxide and water yields a substantial amount of energy—about 30–32 molecules of ATP. For the body, carbohydrates are a kind of “quick fuel,” especially during exertion. Insulin is the main hormone of carbohydrate metabolism and an important regulator of these processes.

Link between BCAA and insulin resistance

Studies have established an interesting relationship: excess branched-chain amino acids (BCAA), found in protein-rich foods (chicken, cottage cheese, whey protein, etc.) and sports supplements, influence the development of insulin resistance. At the same time, elevated blood levels of BCAA metabolites are an early marker of risk for insulin resistance and type 2 diabetes. Their concentration can be raised long before obvious hyperglycaemia appears, making them a valuable predictor of metabolic dysfunction.

It is thought that excess BCAA may activate certain cellular mechanisms that impair insulin signalling, promote inflammation and hinder glucose uptake by muscle:

• BCAA, especially leucine, activate the mTOR pathway in cells. This pathway is important for muscle growth, but when overactivated it impairs cells’ sensitivity to insulin. Thus excessive BCAA intake can lead to cells no longer responding properly to insulin.
• BCAA supplementation stimulates the pancreas to release more insulin. For a healthy person this may not be a problem, but in people with already elevated insulin and a tendency to insulin resistance it adds load on the pancreas and worsens the situation.
• Studies have shown that a diet high in both fat and BCAA can more strongly promote insulin resistance.
• With excess fat and BCAA in the diet, acylcarnitines—intermediate metabolites formed during incomplete oxidation of fatty acids and amino acids—can accumulate in skeletal muscle. Their accumulation reflects mitochondrial overload and is associated with impaired mitochondrial function and development of insulin resistance.
• BCAA can activate a specific pathway in cells—JNK. This pathway is involved in inflammatory responses and further blocks normal insulin signalling inside the cell.
• In addition, BCAA by-products—branched-chain keto acids—also interfere with insulin action.
• High intake of BCAA and fat can impair production of the hormone that helps burn fat and maintain insulin sensitivity—FGF21.
• Genetic factors can affect BCAA metabolism. For example, mutations in the BCKD and BCAT2 enzyme genes can affect their breakdown. This may lead to accumulation of BCAA in the blood and increase the risk of insulin resistance and type 2 diabetes.

Type 2 diabetes (T2D)

Type 2 diabetes is a chronic metabolic disease in which blood glucose is persistently above normal. This condition is based on two key problems: the pancreas produces less insulin than needed, and the body’s cells respond to it less well. These disturbances lead to hyperglycaemia (elevated blood sugar).

Type 2 diabetes is not simply about “sugar” as a food, but about a systemic disorder of metabolism. In this disease, chronic inflammation develops: excess adipose tissue begins to produce inflammatory substances (cytokines) that activate immune cells in fat tissue. This inflammatory process is not acute but constant and draining. Over time it damages the pancreatic beta cells, so that even less insulin is produced and more sugar remains in the blood.

The epidemiology of type 2 diabetes is a serious concern. This disease has become a true disease of civilisation. Hundreds of millions of people have T2D and projections are worrying: prevalence is expected to keep rising into the mid-21st century. Of particular concern is the rise in type 2 diabetes among adolescents. Previously this metabolic disease was considered a risk in adulthood, but in recent decades it has been diagnosed increasingly in young people with obesity.

At the cellular and molecular level, the pathogenesis of T2D is complex. In addition to defects in insulin secretion by pancreatic beta cells and reduced tissue sensitivity to insulin, mitochondrial dysfunction and accumulation of oxidative stress also contribute to the disease.

Overall, type 2 diabetes is a disease closely linked to lifestyle but with a serious biological basis. It requires a comprehensive approach to prevention and treatment: dietary change, increased physical activity, body weight control, and in some cases medication.

Causes and risk factors for type 2 diabetes

• Genetic predisposition. Heredity is an important risk factor for type 2 diabetes. Dozens of genes affect insulin action, beta-cell development and glucose metabolism. These genetic variants can increase T2D risk. The effect of maternal origin of alleles is of particular interest: the risk of T2D may be higher if the mother, rather than the father, has the disease.
• Ethnicity. The prevalence of type 2 diabetes is higher in Asian and African ethnic groups.
• Insulin resistance
• Obesity
• Chronic systemic inflammation
• Oxidative stress. Free radicals damage cellular structures and impair pancreatic beta-cell function. Oxidative stress impairs normal insulin secretion, alters key intracellular signalling pathways and promotes disease progression.
• Chronic stress. Increased secretion of stress hormones such as cortisol raises blood glucose, promotes inflammation and disrupts carbohydrate metabolism regulation. This drives chronic inflammation. Disruption of the normal daily rhythm of cortisol secretion is also associated with increased risk of type 2 diabetes.
• Gut microbiota dysfunction. The composition and function of gut microbes affect glucose and lipid metabolism, inflammation and gut barrier integrity. Some beneficial bacteria, such as Roseburia intestinalis, Bacteroides fragilis, Akkermansia muciniphila, Lactobacillus plantarum and L. casei, can reduce inflammation and improve insulin sensitivity, and their deficiency is associated with T2D risk.
• History of gestational diabetes
• Diet and lifestyle
• Nutrient deficiencies. Insufficient vitamins and minerals can contribute to the pathogenesis of type 2 diabetes, as various micronutrients are involved in carbohydrate metabolism regulation, insulin signalling and beta-cell function. For example, the vitamin D receptor (VDR), through which vitamin D acts, is also found in tissues with high insulin sensitivity—such as the pancreas, adipose tissue and muscle. In the body, vitamin D affects gene activity and increases cell sensitivity to insulin. Vitamin D deficiency or insufficiency is associated with vascular complications in type 2 diabetes. In obesity, prediabetes and T2D, blood vitamin D is often low. Zinc plays an important role in cell signalling and processes such as cell division and apoptosis, and zinc homeostasis disturbances are also linked to diabetes and insulin resistance. Chromium effectively improves glucose tolerance. Similar relationships have been found for other micronutrients, underscoring the importance of adequate intake for metabolic health.

Diagnosis

• Fasting blood glucose
• Oral glucose tolerance test to measure glucose after a carbohydrate load (when needed, including in pregnancy)
• Insulin
• HOMA insulin resistance index
• Glycated haemoglobin (HbA1c)
• C-peptide
• Fructosamine (when needed)—reflects average glucose over the last 2–3 weeks
• Ancillary, less accurate method (for home use)—urine glucose test strips

When appropriate, consider continuous glucose monitoring systems (e.g. FreeStyle Libre). Such devices help track blood sugar changes in real time and allow a clearer view of how different foods affect glucose fluctuations throughout the day.

Metformin

Metformin holds a central place in current pharmacotherapy of type 2 diabetes. Thanks to its combination of clinical efficacy, metabolic safety and low hypoglycaemia risk, it remains the first-line drug in international guidelines. Metformin belongs to the biguanide class and has been used in T2D therapy since the mid-20th century. Its main actions are to reduce glucose production in the liver and increase tissue sensitivity to insulin, without stimulating additional insulin secretion. This lowers the risk of hypoglycaemia, which is important in diabetes treatment.

Main actions of metformin

• Reduces glucose production in the liver by suppressing gluconeogenesis.
• Activates the enzyme AMPK (a key regulator of cellular energy metabolism), leading to suppression of gluconeogenesis in the liver, increased tissue sensitivity to insulin and improved glucose uptake in muscle.
• Inhibits mitochondrial complex I, reducing ATP production in the liver, which helps lower blood sugar.
• Improves tissue sensitivity to insulin, especially in skeletal muscle, by activating glucose transporters (GLUT4).
• Affects the gut microbiota, normalising metabolic pathways linked to diabetes. However, side effects such as diarrhoea or bloating can occur.
• Lowers free fatty acid levels, reduces inflammation and suppresses excessive lipolysis.

Metformin bioavailability is about 50–60%, and up to 90% of the dose is excreted unchanged by the kidneys. Because it is not metabolised via the cytochrome P450 system, metformin has practically no drug interactions and is convenient to use.

However, metformin has a few limitations to consider.

• Gastrointestinal upset.
• Vitamin B12 deficiency with long-term use.
• In very rare cases—lactic acidosis, especially in severe kidney failure.

Genetics and metformin

Metformin enters cells via specific transporters: OCT1, OCT3, MATE1. Genetic variants can alter drug uptake and affect treatment response. For example, some polymorphisms in the SLC22A1 gene (encoding OCT1) are associated with reduced response to metformin therapy in type 2 diabetes.

Our report provides information on potential individual sensitivity to metformin.

General recommendations

Diet and lifestyle

Mediterranean and low-carbohydrate diet

These eating patterns help improve insulin sensitivity, reduce inflammation and control weight. Prefer fresh vegetables (especially leafy greens, broccoli, courgettes, etc.), whole grains (in moderation), legumes, nuts and seeds, ocean or sea fish, poultry and extra virgin olive oil.

Reducing sugar and fructose in the diet

Limiting simple sugars is a key step in controlling blood glucose. Minimise added sugar: sweetened drinks and fruit juices, sweetened yoghurts and ready-made breakfasts, sweet sauces and ketchups, syrups, pastries, etc. Also review your typical shopping basket for hidden sugar.

Supporting the gut microbiota

Probiotics and prebiotics may help improve insulin sensitivity. Support microbiota diversity with fibre, fermented foods and probiotic supplements.

Cinnamon

Include this spice in your diet, as it may help improve insulin sensitivity and support blood sugar control. You can add it to porridge, yoghurt, drinks or baked goods with minimal sugar.

Regular eating pattern

Eat on a stable schedule through the day. Finish your last meal at least 3 hours before bed to improve glucose metabolism.

Weight loss

Even modest weight loss (when overweight) significantly improves tissue sensitivity to insulin.

Physical activity

Regular aerobic and resistance exercise increases insulin sensitivity and improves glucose metabolism. Combine with strength training for best effect.

Sleep and circadian rhythms

Sleep quality is crucial for metabolism regulation. Avoid night shifts and bright light at night. Aim for at least 7–8 hours of sleep. Sleep in complete darkness—including blocking street light and any artificial sources such as night lights and device indicators (including standby screens). Even dim light at night can disrupt melatonin production and worsen blood sugar regulation. Get bright light in the morning to synchronise your body clock.

Environmental influences

Chronic exposure to chemical pollutants can impair insulin sensitivity and contribute to metabolic disorders. Pay particular attention to reducing contact with endocrine disruptors—phthalates, bisphenol A, per- and polyfluoroalkyl substances (PFAS), heavy metals and household chemicals. Avoid storing and heating food in plastic; prefer glass. When buying hygiene and cleaning products, choose formulations with minimal synthetic additives. Where possible, limit exposure to polluted air—especially when living near busy roads or industrial areas. Use HEPA air purifiers and ventilate when needed.

Phytonutrients and supplements

(In the absence of contraindications and in agreement with your healthcare provider.)

• Berberine—reduces gluconeogenesis, improves insulin sensitivity.
• Bitter melon extract—may lower blood sugar and increase insulin receptor (IRS1) expression.
• Fenugreek—helps lower glucose and improves insulin sensitivity.
• Hesperidin—a bioflavonoid with antioxidant and anti-inflammatory properties.
• TUDCA—lowers glucose and enhances hepatic insulin clearance.
• Milk thistle—supports liver function and glucose metabolism.
• Alpha-lipoic acid—an antioxidant that increases GLUT4 expression and glucose uptake by cells. Reduces oxidative stress.
• Omega-3 fatty acids—reduce systemic inflammation and support insulin sensitivity.
• Coenzyme Q10—its deficiency can impair normal glucose metabolism, slowing cellular glucose use and reducing tissue sensitivity to insulin. Coenzyme Q10 also plays an important role in mitochondrial function and energy production, and its deficiency can increase oxidative stress, which further impairs insulin sensitivity.
• Deficiencies in vitamins and minerals such as D, C, A, E, B vitamins, magnesium, zinc, selenium, boron, calcium, cobalt, chromium and iron can negatively affect insulin resistance and increase the risk of type 2 diabetes.