Table of contents
In recent decades, the incidence of metabolic disorders—particularly insulin resistance (IR) and type 2 diabetes mellitus (T2D)—has risen dramatically worldwide. This is largely due to urbanisation, sedentary lifestyles, and the proliferation of high-calorie, Western-style diets. Insulin resistance is one of the most common yet often overlooked metabolic disorders; it can remain latent for years while silently damaging the body’s metabolic functions. It is not only a precursor to type 2 diabetes, but also contributes to several other conditions, including non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and cardiovascular disease. In addition to traditional risk factors such as genetic predisposition, excessive caloric intake, and lack of physical activity, growing research highlights the importance of gut microbiome balance. The composition of gut flora influences glucose metabolism, chronic low-grade inflammation, and insulin sensitivity. Obesity—particularly visceral fat—significantly increases the risk of T2D. Epidemiological data indicate that approximately 86% of people with type 2 diabetes are overweight or obese. However, it is crucial to emphasise that obesity is neither the sole nor a sufficient condition for developing diabetes. Whether being overweight actually leads to diabetes depends largely on individual insulin sensitivity, fat distribution, hormonal regulation, and, crucially, the functioning of the gut microbiome. Therefore, diabetes is not merely a matter of body weight but the result of complex, multi-level metabolic and immunological interactions. [1]
What is insulin resistance?
Glucose is a vital energy source for the human body. The brain and many tissues rely on it for energy, and red blood cells—responsible for oxygen transport—can only use glucose. Due to its chemical structure, glucose is highly reactive and easily binds to proteins, including those in blood vessels, nerve cells, and red blood cells. This glycation can damage affected cells and cause red blood cells to clump together, which hinders their passage through narrow capillaries, impairing microcirculation—especially in sensitive organs like the retina and kidneys.
The HbA1c value, measured in laboratory tests, indicates the proportion of glycated haemoglobin—reflecting how much sugar is bound to haemoglobin in red blood cells.
Blood sugar levels are tightly regulated, and insulin plays a central role.
It allows glucose to enter cells from the bloodstream, where it is converted into energy.
About insulin
Insulin is produced by beta cells in the islets of Langerhans in the pancreas. In response to dietary sugar, insulin is released into the bloodstream. It acts on specific cells (e.g., liver, muscle, and fat cells) via insulin receptors, opening small pores in the cell membrane through which glucose enters. These cells use glucose for energy, and some (such as the liver and muscles) can store it in the form of carbohydrates (glycogen).
This mechanism helps maintain blood sugar levels within a narrow range—even during fasting—because the liver continuously produces glucose (via gluconeogenesis).
Gluconeogenesis is controlled by two hormones: insulin (which inhibits it) and glucagon (which stimulates it). Under normal conditions, the liver produces about 250 g of glucose daily.
Insulin’s effects fall into two categories:
- Membrane effects: Promotes uptake of glucose, amino acids, and potassium into muscle and fat cells.
- Metabolic effects: Stimulates anabolic processes (e.g., glycogen, fatty acid, and protein synthesis), making it a “building” hormone, while inhibiting catabolic (breakdown) pathways. In insulin’s absence, patients tend to lose weight. [2]
Positive effects of insulin [3]:
- Improves cognitive and memory function (especially when administered intranasally to patients with Alzheimer’s or cognitive decline); protects nerve cells
- Relaxes arterial walls, improving blood circulation and the heart’s pumping capacity
- Reduces platelet aggregation [4]
- Increases muscle mass and improves muscle circulation
- Enhances protein digestion by increasing pepsin production in the stomach [5–6]
The precursor to insulin is proinsulin, which is cleaved to form insulin and C-peptide in a 1:1 ratio. Measuring C-peptide levels can help assess insulin production. C-peptide itself also has important physiological effects: it improves kidney function, reduces albumin excretion, enhances kidney barrier function, and helps restore normal heart rate variability (HRV), thereby reducing autonomic neuropathy. Additionally, it stimulates sodium-potassium ATPase activity in the renal tubules. [7]
Cell surface receptors, including insulin receptors, function optimally under fluctuating hormone levels—meaning they work best when insulin is present intermittently. Persistently high insulin levels can lead to a gradual decline in receptor sensitivity and responsiveness, a phenomenon known as insulin resistance. This can occur due to two main mechanisms: internalisation of receptors from the cell surface and inhibition of intracellular signalling pathways. Any tissue with insulin receptors can become insulin resistant, but the degree of reduced insulin sensitivity is most influenced by the liver, skeletal muscles, and adipose tissue. [8]
To counteract the rising blood sugar levels caused by impaired glucose uptake, pancreatic β-cells increase insulin production, leading to hyperinsulinemia.
As long as the pancreas produces enough insulin to regulate blood sugar, levels remain within the healthy range. However, if receptor sensitivity continues to decline, glucose can no longer enter cells effectively, resulting in hyperglycaemia (high blood sugar). Interestingly, hyperinsulinemia can itself contribute to the development of insulin resistance, making it unclear which comes first. This is clinically important because hyperinsulinemia, especially when driven by excess calorie intake, may be a trigger for insulin resistance-related metabolic disorders. [9]
Insulin resistance sets off a cascade of harmful metabolic processes. Immediate consequences include hyperglycemia (high blood sugar) and hypertension (high blood pressure), as insulin’s vasodilatory effect is lost. This loss makes blood vessels stiffer and narrower, leading to elevated blood pressure. Another direct consequence is dyslipidaemia: elevated triglycerides, cholesterol, and LDL levels; while the ‘good’ blood fat, HDL, is reduced. Consequently, hyperuricemia is often observed: high insulin levels inhibit uric acid excretion via the kidneys. In addition, insulin resistance is associated with chronic, low-grade inflammation, marked by elevated inflammatory markers such as CRP. Insulin resistance also impairs the function of the endothelial cells lining the inner surface of blood vessels (endothelial dysfunction) and increases the risk of thrombosis. If left untreated, insulin resistance can lead to complex conditions like non-alcoholic fatty liver disease (NAFLD), type 2 diabetes, and metabolic syndrome. [10–11]
Metabolic syndrome—a cluster of conditions including elevated blood sugar, abdominal obesity, high blood pressure, and dyslipidaemia—is now widespread in developed countries, affecting 20–25% of the population according to European studies. [12]
Figure 1. Consequences of insulin resistance
What are the symptoms of insulin resistance?
The symptoms of insulin resistance typically develop slowly and gradually, meaning that noticeable complaints are rare in the early stages. Over time, however, various often non-specific symptoms may appear, such as fatigue, daytime drowsiness, and difficulty concentrating. Many people also experience irritability, mood swings, and increased appetite—especially for sweet foods.
In women, elevated insulin levels can affect the ovaries by stimulating the production of androgen hormones (e.g., testosterone) within ovarian cells. This can lead to menstrual irregularities and polycystic ovary syndrome (PCOS). Visible skin changes may also occur due to insulin’s similarity to insulin-like growth factor 1 (IGF-1), which stimulates cell proliferation. Skin cells may divide more rapidly, become thicker, and produce more pigment—leading to acanthosis nigricans, a condition marked by dark, velvety patches in skin folds (e.g., on the neck or underarms). Abdominal (visceral) obesity is also common, along with difficulty losing weight even when following a healthy diet and exercising regularly. This accumulation of fat in the abdominal cavity—around internal organs—poses multiple health risks. The liver plays a key role here: it converts excess blood sugar into fat in an effort to moderate elevated glucose levels. While this process helps protect the body from short-term harm caused by hyperglycaemia, it also serves as an evolutionary mechanism for energy storage during potential periods of starvation. The fat stored in the abdominal cavity becomes an easily accessible energy reserve. Over time, however, this visceral fat contributes to metabolic disturbances, chronic inflammation, and insulin resistance. People affected by IR often experience increased hunger, particularly after consuming carbohydrate-rich foods. This is due to fluctuating blood sugar levels: reduced insulin efficiency leads to rapid spikes and crashes, which in turn trigger stronger cravings—especially for fast-absorbing carbohydrates. [13]
Figure 2. Symptoms of insulin resistance
How can insulin resistance be diagnosed?
Insulin resistance can remain asymptomatic for a long time, which makes early detection particularly important. Several laboratory tests can assist in diagnosis, including the aforementioned HbA1c, C-peptide (a by-product of insulin synthesis), blood glucose levels, and various indices calculated from these values. The diagnostic process usually begins with a fasting blood sample to determine fasting glucose and insulin levels. An oral glucose tolerance test (OGTT) may also be performed. In this test, the patient drinks a sugar solution, and their blood sugar and insulin levels are monitored over the following hours. From this data, various indices—such as HOMA-IR, QUICKI, or the Matsuda index—can be calculated to assess insulin sensitivity. These tests play a key role in early identification of the condition, which allows for timely lifestyle changes or, if necessary, medical intervention to prevent more serious complications.
Figure 3. Methods for measuring insulin resistance
Additional considerations in diagnosis:
- Body weight and body mass index (BMI)
- Hormone tests (e.g., androgens, SHBG, LH/FSH ratio)
- Gynaecological indicators (e.g., irregular menstrual cycles, suspected PCOS)
- Family history (e.g., type 2 diabetes, metabolic syndrome) [10]
What are the causes of insulin resistance?
Insulin resistance can result from a combination of genetic predisposition, environmental influences, and lifestyle factors such as lack of exercise or poor diet. These elements often interact, collectively contributing to the development of the condition. While genetics can play a significant role in some individuals, scientific evidence shows that in most cases, acquired factors—such as a sedentary lifestyle, unhealthy eating habits, excess weight or obesity, and chronic stress—are the primary drivers.
Sedentary lifestyle
During physical activity—whether walking, running, or engaging in other types of exercise—muscles increase their energy demand and primarily use glucose from the bloodstream. Remarkably, during this state, muscles can absorb glucose without insulin, naturally lowering blood sugar levels. Regular exercise not only reduces blood glucose in the short term but also increases insulin sensitivity over time. During physical activity, muscles release biologically active proteins called myokines (e.g., irisin), which help break down fat tissue, reduce inflammation, and regulate metabolism. [14]
Muscle tissue, therefore, serves not only for movement but also as a central regulator of energy balance and blood glucose control. During intense exercise, muscles may not receive enough oxygen, prompting anaerobic metabolism—converting glucose into lactic acid. Although this process yields less energy (ATP), it is rapid and provides an immediate energy supply. Later, the lactic acid can be broken down in the presence of oxygen or converted back into glucose by the liver via the Cori cycle. This prevents the accumulation of lactic acid in the muscles and allows its energy to be reused. However, this glucose reconversion requires additional energy, which the body generates from fat breakdown (beta-oxidation)—effectively switching into a fat-burning state. Interestingly, when the liver produces glucose, the body temporarily inhibits its use to avoid simultaneous “opposing” processes. After exercise, depleted muscles again absorb glucose and store it, thereby smoothing out blood sugar spikes and dips. Without regular physical activity, this metabolic synergy breaks down: the liver continues to overproduce glucose, while muscles do not participate in sugar utilisation. This “metabolic debt” can worsen over time. Exercise supports energy utilisation, improves insulin sensitivity, balances blood sugar, and reduces liver burden. In addition, muscle mass helps maintain metabolism even at rest. [15]
The role of obesity in the development of insulin resistance
Obesity, particularly the accumulation of abdominal (visceral) fat, plays a central role in the development of insulin resistance. Adipose tissue is not merely an energy reserve; it also functions as an endocrine organ, secreting adipokines, inflammatory cytokines (e.g., TNF-α, IL-6), and free fatty acids (FFAs). [16] These substances interfere with insulin signalling pathways inside cells, reducing glucose uptake—especially in muscle and fat tissues. The chronic, low-grade inflammation associated with obesity exacerbates this effect and contributes directly to the persistence of insulin resistance. Visceral fat, in particular, produces higher levels of inflammatory mediators that disrupt insulin action more aggressively than other fat types. It is important to note that not all adipose tissue is the same. Visceral fat (fat around internal organs) has much more active hormone production and a stronger impact on insulin resistance, while subcutaneous fat (just under the skin) has a more moderate effect. This difference explains why apple-shaped obesity (central or abdominal fat distribution) is more closely associated with insulin resistance and metabolic syndrome than pear-shaped obesity (fat around the hips), which is predominantly subcutaneous. [17–18]
Consumption of foods with a high glycaemic index
Obesity is often seen as a result of excessive calorie intake, but it’s important to understand that overeating alone can have serious physiological consequences. Even short-term consumption of a high-energy diet can reduce the brain’s sensitivity to insulin, independently of any drop in insulin sensitivity in peripheral tissues. Excess calorie intake impairs insulin signalling in brain cells, alters the gut microbiome, activates inflammatory pathways, and ultimately disrupts brain function. This creates a vicious cycle, where molecular changes in the brain trigger neuroinflammation and, over time, contribute to conditions such as depression, cognitive decline, Alzheimer’s disease, and other neurological disorders.
Additional risk factors include gut dysbiosis (imbalanced microbiota), the release of endotoxins from bacteria, and increased intestinal permeability. Inflammation that begins in adipose tissue can spread to the brain and further reduce insulin sensitivity in the central nervous system. [19]
Fat metabolism becomes increasingly important in the context of obesity. When blood contains excess fatty acids, cells switch to burning fat for energy, which suppresses carbohydrate metabolism—a process essential for stable blood sugar, low insulin levels, and efficient energy use. This competitive, mutually inhibitory relationship between fat and carbohydrate metabolism is described by the Randle cycle. In overweight individuals, elevated FFAs create an energy surplus at the cellular level, reducing glucose uptake and contributing directly to insulin resistance and type 2 diabetes. Interestingly, calorie restriction alone—regardless of carbohydrate intake—can reduce blood glucose and insulin levels. [20]
Chronic inflammation
Obesity leads to persistent, low-grade systemic inflammation, which plays a key role in the development of long-term complications associated with type 2 diabetes—such as non-alcoholic fatty liver disease, retinopathy, cardiovascular disease, and kidney damage (nephropathy). This inflammation also helps explain the links between diabetes and other conditions like Alzheimer’s disease, polycystic ovary syndrome (PCOS), gout, and rheumatoid arthritis. Chronic inflammation particularly affects insulin-sensitive tissues such as adipose tissue, the liver, muscles, and the pancreas. This phenomenon, known as immunometabolism, refers to the close, reciprocal relationship between the immune and metabolic systems. Metabolic dysfunction triggers inflammatory responses, which in turn further disrupt metabolism. As fat mass increases and insulin sensitivity declines, the production of pro-inflammatory cytokines rises, while levels of adiponectin—a hormone beneficial for metabolism—decrease. This imbalance also alters the immune cell composition of adipose tissue, increasing pro-inflammatory M1 macrophages and reducing anti-inflammatory M2 macrophages [21]. The accumulation and activation of macrophages are the primary drivers of chronic inflammation in metabolic tissues, but other immune cells—such as T and B lymphocytes—also contribute to this inflammatory environment. [22]
Stress, sleep deprivation
Stress has been shown to contribute significantly to the development of type 2 diabetes. It arises when the body encounters a stimulus it must resist or adapt to, triggering the mobilisation of energy. These stimuli can be physical (e.g., temperature, radiation), chemical or biological (e.g., infections), or psychological in nature. While short-term stress is a necessary and beneficial response that promotes survival, problems arise when stress is intense, prolonged, or chronic, as this can exhaust the body’s adaptive resources. During the classic “fight or flight”response, the body shifts to catabolic metabolism to rapidly mobilise energy, while suppressing less immediate processes such as digestion, growth, reproduction, and immune function. This evolutionary response, originally designed to help humans escape predators, is driven by rapid mobilisation of immediately available energy reserves (e.g. glucose). [23]
In such cases, the body produces stress hormones, primarily glucocorticoids (e.g., cortisol) and catecholamines (e.g., adrenaline). These hormones stimulate the liver to increase gluconeogenesis, raising blood sugar levels to provide a quick energy source. However, if this surge in glucose is not followed by physical activity, as is often the case in modern life, blood sugar remains elevated—eventually contributing to chronic hyperglycaemia. Over time, this promotes insulin resistance. Cortisol also inhibits glucose uptake by muscle cells, reducing their contribution to blood sugar regulation. In today’s world, chronic stress is frequently accompanied by a lack of exercise, irregular eating patterns, or an unhealthy diet—factors that further disturb metabolism and contribute to the development of visceral (abdominal) obesity. [23]
Not just stress, but also the quantity and quality of sleep have a significant impact on insulin sensitivity. Modern lifestyles—marked by long working hours, study pressures, and excessive screen time—often result in sleep deprivation [24]. Although the exact causal mechanisms are not yet fully understood, insufficient sleep increases inflammation and can contribute to insulin resistance and type 2 diabetes, even in the absence of weight gain. [25]
Experts recommend that adults get at least seven hours of sleep per night to maintain metabolic health. [26]
The role of the gut microbiome
Individuals with insulin resistance often have an imbalance in their gut flora, known as dysbiosis, which plays a causal role in impaired glucose metabolism and the persistence of chronic low-grade inflammation. Abnormal activity in the gut microbiome increases intestinal permeability, allowing bacteria and lipopolysaccharides (LPS)—inflammatory components of bacterial cell walls—to enter the bloodstream. This condition, known as metabolic endotoxemia, contributes to systemic inflammation, a key factor in the development of insulin resistance, metabolic syndrome, and even certain types of cancer.
Dysbiosis can involve either a decrease in beneficial bacteria (e.g., Akkermansia muciniphila, Faecalibacterium prausnitzii) and/or an overgrowth of pro-inflammatory strains (e.g., certain Proteobacteria or Firmicutes species). Reduced production of short-chain fatty acids (SCFAs)—especially butyrate—by these beneficial microbes weakens the intestinal barrier and exacerbates systemic inflammation.
Beyond inflammation, the gut microbiome can also directly affect insulin action. Some bacterial strains enhance insulin sensitivity and improve glucose metabolism. In experimental models, introducing these strains into the gut lowered blood sugar levels, reduced simple sugars in the stool, improved lipid profiles, and alleviated symptoms of insulin resistance. Conversely, when excess sugar remains unprocessed in the intestines, it promotes fat storage and inflammation, increasing the risk of obesity. [27]
The gut flora of insulin-resistant individuals differs significantly from that of insulin-sensitive individuals. In the former, bacteria from the genera Blautia and Dorea (family Lachnospiraceae) dominate, while in the latter, Alistipesand Bacteroides species are more common. These latter species metabolise carbohydrates more efficiently, leaving less sugar in the intestine. Oral administration of Alistipes indistinctus has even been shown to protect against obesity and insulin resistance, even when subjects consume a high-fat diet [8]. Several studies have demonstrated correlations between gut microbiome composition, plasma metabolites (e.g., branched-chain amino acids (BCAAs), SCFAs, and LPS), various forms of obesity, and distinct types of diabetes (e.g., insulin-resistant vs. insulin-deficient), alongside environmental influences. In cases of obesity, populations of Faecalibacterium prausnitzii, Akkermansia, Oscillibacter, and Intestinimonas tend to decrease, while in type 2 diabetes, Escherichia/Shigella strains often increase. [1]
Short-chain fatty acids (SCFAs)—especially acetate, propionate, and butyrate—produced by gut bacteria play critical roles in regulating metabolism, appetite, and insulin sensitivity. Their concentrations and ratios in stool or plasmacan serve as useful biomarkers for assessing the severity of insulin resistance. Butyrate and propionate typically have anti-obesity effects: they promote leptin and other satiety hormones, reduce inflammation, and improve insulin sensitivity. Propionate, as a gluconeogenesis substrate, helps stabilise blood sugar, though in excess, it may promote insulin resistance by stimulating insulin and glucagon secretion and activating the sympathetic nervous system [28]. Acetate stimulates ghrelin (the hunger hormone), promoting appetite, fat storage, and potential weight gain [29]. A decline in butyrate-producing bacteria—such as Faecalibacterium prausnitzii and Roseburia intestinalis—is a hallmark of insulin resistance. Their absence contributes to increased inflammation and reduced intestinal metabolic function. [30]
Higher levels of Akkermansia muciniphila and Parabacteroides distasonis in the gut are associated with improved insulin sensitivity under calorie restriction, highlighting the protective role of these species. [30]
Studying the composition and function of the gut microbiome may become a valuable tool in the diagnosis and treatment of insulin resistance.
Gut-brain axis
The gut-brain axis is a bidirectional communication pathway through which the gut microbiota, nervous system, endocrine system, and immune system interact. This complex network plays a particularly important role in the regulation of metabolism. The gut microbiota not only contributes to digestion but also influences brain function via neural, hormonal, and immunological mechanisms. A nutrient-rich but imbalanced diet, as well as obesity, can alter the composition of the gut microbiome. The metabolites produced by these microbes can send signals to the brain, often via the vagus nerve.
Enteroendocrine cells, located in the intestinal lining, function both as sensors and hormone producers. They detect changes in the gut environment—such as nutrients or microbial activity—and secrete various gut hormones like GLP-1, PYY, and CCK. These hormones influence not only insulin secretion and blood glucose response but also appetite, mood, and even learning and memory processes. The immune system is also a key participant in the gut-brain axis. Activated immune cells—such as Th1, Th17, Treg cells, neutrophils, and macrophages—can release inflammatory signals that affect brain function and disrupt the gut-brain balance. When the intestinal barrier becomes compromised, it allows harmful substances to enter the bloodstream—this is known as “leaky gut.” This condition increases systemic inflammation, which not only impairs brain function but also exacerbates insulin resistance. [19]
Figure 4. Possible causes of insulin resistance
Mitochondrial function
In insulin resistance, cellular energy utilisation declines due to several factors: a reduction in the number of mitochondria and it’s oxidative enzymes, impaired ATP production, and structural changes in mitochondria. ATP (adenosine triphosphate) is the body’s main energy carrier, and each day we use an amount equivalent to our entire body weight. This energy must be continually regenerated by the mitochondria. Excessive calorie intake increases the production of reactive oxygen species (ROS), which damage mitochondria, trigger inflammation, and activate immune cells in the nervous system. The accumulation of fat inside cells also reduces oxidative capacity, especially in individuals with a genetic predisposition. [31]
Mitochondria can be damaged not only by various metabolic disturbances but also by ageing, which gradually impairs their efficiency. Over time, levels of key hormones—such as growth hormone and IGF-1, both of which support these energy-producing organelles—decline, increasing the risk of metabolic diseases. [32]
Optimal mitochondrial function is essential for an adequate insulin response. Approximately 3% of people with diabetes have mitochondrial diabetes (MIDD), which may resemble either type 1 or type 2 diabetes. The condition is characterised by β-cell dysfunction and reduced insulin sensitivity in muscle tissue, both of which worsen with age. [33–34]
Within cells, mitochondria also require water to function properly—and it is beneficial if this water has low deuterium content. Deuterium is a heavy isotope of hydrogen containing a neutron in addition to the proton. It naturally occurs in drinking water at around 150 ppm, though this varies geographically (lower levels are found at higher altitudes and inland regions). [35]
The final step in cellular energy production occurs in the electron transport chain (or redox chain) within the inner mitochondrial membrane, which consists of five complexes. Complex V acts like a microscopic turbine, returning protons – pumped into the intermembrane space by the previous four complexes – into the mitochondrial matrix to drive ATP synthesis. If deuterium passes through Complex V, it can damage the mechanism, reducing the mitochondria’s capacity to produce energy. From a metabolic standpoint, fats are a better fuel than carbohydrates, as they contain more hydrogen and less deuterium. As a result, fat oxidation produces metabolic water that is naturally lower in deuterium than drinking water. Elevated deuterium levels in cells impair mitochondrial energy production, increase inflammation, and may reduce insulin sensitivity. The gut microbiota also plays a protective role here by producing hydrogen gas and short-chain fatty acids (e.g., butyric acid, butyrate, acetate), all of which support mitochondrial and metabolic health. Notably, hydrogen gas generated in the gut is low in deuterium, helping to safeguard cellular energy production. Butyric acid, in particular, serves as a key energy source for colonocytes (colon cells), regulates inflammation, and supports healthy cellular function. In this way, the gut microbiome indirectly and directly contributes to optimal energy metabolism. [36]
What are the consequences of insulin resistance?
Persistently elevated blood sugar levels resulting from insulin resistance can lead to serious long-term complications, particularly within the vascular system. The earliest damage often occurs in the smallest blood vessels—this is known as microvascular damage. These changes affect several critical organs:
- Eyes: Damage to the fine network of blood vessels in the retina can lead to diabetic retinopathy, potentially resulting in vision loss or even blindness.
- Kidneys: Damage to the small renal blood vessels can cause diabetic nephropathy, which may progress to kidney failure and require dialysis.
- Nervous system: Impaired blood supply to small nerves can result in peripheral neuropathy, leading to sensory disturbances, numbness, pain, or muscle weakness, particularly in the hands and feet.
However, these changes affect not only the peripheral parts of the body, but also the central nervous system—most notably, the brain. Damage to the brain’s small blood vessels can contribute to dementia (cognitive decline), stroke, mood disorders such as depression and anxiety, as well as balance problems and unsteady gait. Similarly, damage to the small blood vessels of the heart muscle can lead to chest pain (angina) and contribute to structural and functional deterioration of the heart (cardiomyopathy).
Damage to larger blood vessels is known as macrovascular complications, and these often include:
- Peripheral arterial disease (PAD): Narrowing or blockage of arteries in the limbs—most commonly the legs—leading to leg pain when walking, cold extremities, delayed wound healing, and, in severe cases, ulcers or amputation.
- Coronary artery disease (CAD): Blockage or narrowing of the heart’s arteries—which supply the heart muscle—can lead to angina, heart attacks, or heart failure.
- Stroke: A sudden loss of blood flow to the brain. There are two major types:
- Ischaemic stroke: Caused by a blocked artery (e.g., due to a blood clot)
- Haemorrhagic stroke: Caused by a ruptured blood vessel, leading to bleeding in the brain
Both stroke types can lead to severe consequences, including paralysis, speech impairment, memory loss, or death.
A rapidly growing disease closely associated with insulin resistance is non-alcoholic fatty liver disease (NAFLD). In this condition, fat accumulates in the liver despite the absence of alcohol consumption. Over time, this fat buildup may cause inflammation, cell damage, and fibrosis (scarring), impairing liver function and potentially progressing to cirrhosis. NAFLD is extremely common among individuals with insulin resistance and type 2 diabetes. Alarmingly, its prevalence is rising globally—including among children. As a result, all healthcare professionals who treat patients with insulin resistance—whether general practitioners, dietitians, or internists—should prioritise early detection and treatment of fatty liver, even in the absence of symptoms. [10]
What are the treatment options for insulin resistance?
Conventional medicine
Most medications currently used in clinical practice to treat carbohydrate metabolism focus primarily on regulating blood sugar levels. These drugs were not specifically developed to address the associated complications of insulin resistance, such as retinopathy, non-alcoholic fatty liver disease, or chronic inflammation. While some have secondary benefits for these conditions, only one—metformin—has demonstrated an ability to slow disease progression. [22]
Metformin is the first-line medication for treating insulin resistance, particularly in prediabetes and type 2 diabetes. It primarily reduces glucose production in the liver and also enhances insulin sensitivity in peripheral tissues. It does not cause hypoglycaemia and is especially suitable for overweight or obese patients due to its weight-reducing effect. According to the Diabetes Prevention Program (DPP) study, metformin lowered the risk of developing type 2 diabetes by around 30% in insulin-resistant individuals. The treatment is generally well tolerated, although gastrointestinal side effects such as bloating or diarrhoea may occur initially. [37]
Metformin also affects the gut microbiome. Compared to untreated type 2 diabetes patients, those taking metformin show an increased abundance of Parabacteroides distasonis, improved tight junction integrity in intestinal epithelial cells, and a microbiome composition more similar to that of healthy individuals.
Interestingly, specific gut microbiome profiles may predict a patient’s response or side effects to metformin. A higher abundance of Segatella copri (formerly Prevotella copri) is associated with reduced HbA1c-lowering efficacy. The HbA1c value reflects the average blood sugar level over the past 2–3 months. In contrast, a higher presence of Streptococcus parasanguinis may indicate a greater risk of side effects. Since these microbial patterns can also be influenced by concurrent medications (e.g., proton pump inhibitors, anticoagulants), analysing the gut microbiome may be essential for understanding how polypharmacy impacts metformin’s effectiveness. [30]
Weight loss: diet and exercise recommendations
A low-carbohydrate diet may temporarily improve insulin sensitivity, particularly when blood glucose and blood lipid levels are elevated. Reducing carbohydrate intake can support fat burning and ease metabolic overload. However, traditional low-carb or ketogenic diets—due to their high fat content—can impair carbohydrate metabolism over time, potentially leading to physiological insulin resistance. In this state, cells lose the ability to efficiently process carbohydrates. The key to a stable metabolism is metabolic flexibility—the body’s ability to switch between fat and carbohydratesas energy sources. Restoring healthy carbohydrate metabolism is therefore essential. The goal should not be permanent carbohydrate restriction, but rather to reintroduce carbohydrates gradually and intelligently so the body learns to use them effectively again. [20]
Properly selected physical activity also supports this process by increasing the insulin sensitivity of skeletal muscle and by positively influencing the gut microbiome. While very intense exercise may stress the digestive system—potentially leading to dysbiosis or exercise-induced gastrointestinal syndrome—moderate-intensity activity has beneficial effects. It increases the proportion of bacteria such as Akkermansia muciniphila and Oscillospira and enhances the production of short-chain fatty acids (SCFAs), as well as lactic acid. These compounds are important not only for intestinal health, but also for indirectly improving metabolic flexibility and insulin sensitivity. [30]
Functional medicine
Restoring gut health is a key step in improving metabolic function, and this lies at the heart of the functional medicine approach. The foundation includes a personalised diet, lifestyle adjustments, and plant-based, natural therapies, tailored to the individual’s needs.
Targeted nutritional supplementation and nutrient replacement
A variety of natural compounds and micronutrients can support the treatment of insulin resistance by reducing inflammation, decreasing oxidative stress, and enhancing insulin action.
Berberine, quercetin, and omega-3 fatty acids, which have strong anti-inflammatory properties and can help restore insulin sensitivity. Antioxidants like vitamins C and E, selenium, and resveratrol, which combat oxidative damage—a key factor in the development and progression of insulin resistance.
Vitamin D, which supports calcium and phosphorus metabolism, and also reduces pro-inflammatory cytokines. Studies have shown that vitamin D increases insulin receptor density in muscles, liver, and fat tissue, enhancing both insulin sensitivity and glucose utilisation. [38]
Inositol (especially in the forms myo-inositol and D-chiro-inositol) is a promising supplement for insulin resistance. It improves insulin signalling, lowers fasting insulin levels, and helps regulate menstrual cycles in women with PCOS, who frequently experience insulin resistance. [39]
Chromium is an essential trace element that supports insulin function and the metabolism of carbohydrates, fats, and proteins. Supplementation can improve fasting blood glucose and reduce insulin resistance. [40]
Cinnamon enhances insulin receptor function, promotes glucose uptake, and inhibits glucose production in the liver. Its antioxidant and anti-inflammatory effects contribute to normalising blood sugar, lipid levels, and blood pressure, helping to prevent type 2 diabetes. [41]
Selenium protects cells from oxidative damage that can impair insulin function, while zinc plays a crucial role in insulin synthesis, storage, and secretion, thereby indirectly improving glucose metabolism. [42–43]
Combinations of these nutrients are often more effective than individual compounds, working synergistically to reduce inflammation, lower oxidative stress, improve insulin sensitivity, and support metabolic restoration
Nutritional guidelines
A low-glycaemic diet is one of the foundational strategies for restoring metabolic health. It’s advisable to eat frequent, balanced meals that include a combination of protein, healthy fats, and complex carbohydrates, including in the afternoon and evening. Fasting should be approached with caution—particularly at the beginning of treatment—because a sudden drop in blood sugar can place stress on the body. Once energy metabolism has stabilised, meal intervals can be gradually extended. Supporting mitochondrial function may also be critical, especially in individuals with diabetes or those taking metformin. This is because metformin partly works by inhibiting complex I in the mitochondrial respiratory chain. Over the long term, this may lead to energy production issues, vitamin B12 deficiency, and, in rare cases, lactic acidosis. Therefore, supplementation with nutrients that support mitochondrial health is often recommended, such as: vitamin B12 (methylcobalamin), alpha-lipoic acid, Coenzyme Q10 (CoQ10), vitamin B1 (benfotiamine), taurine, magnesium, other mitochondrial cofactors. [44]
Other beneficial dietary approaches include the mediterranean diet, rich in vegetables, healthy fats (e.g., olive oil), and moderate amounts of fish as well as moderate, well-timed intermittent fasting, which can help restore metabolic flexibility.
The role of prebiotics and probiotics
Probiotics—especially specific strains of Lactobacillus and Bifidobacterium—have been shown to improve blood lipid profiles and reduce fasting blood glucose, insulin levels, and HbA1c. One particularly promising strain, Akkermansia muciniphila, has been found to strengthen the gut barrier, lower inflammation, and improve metabolic function.
The combined use of prebiotics and probiotics (known as synbiotics) has demonstrated additional benefits in reducing hyperglycaemia and supporting weight loss.
Individual differences in gut microbiota composition can also influence the effectiveness of dietary and supplement interventions. For example, people with a gut flora dominated by Bacteroides tend to respond well to capsaicin, a natural compound that also acts as a prebiotic. In individuals with a high Prevotella:Bacteroides ratio, arabinoxylan—a type of hemicellulose prebiotic—has shown protective effects against weight gain. [30]
Lifestyle factors
Regular exercise, effective stress management, and good sleep quality significantly influence both gut microbiota composition and overall metabolic health. These lifestyle factors can play a highly effective role in the comprehensive management of insulin resistance—not only on their own, but also in synergy with the dietary and supplementation strategies mentioned above.
Consult our experts!
Insulin resistance is a complex metabolic disorder that affects multiple organ systems. Effective treatment requires an integrated, multi-layered approach. At HealWays, we believe that symptom-focused care is not enough. To achieve real, lasting results, it is essential to identify and address the root causes of the condition. Our approach focuses on restoring microbiome balance, following an anti-inflammatory and nutrient-rich diet, managing both psychological and physical stress, and supporting and regulating the hormonal system. Together, these interventions can help improve insulin signalling at the cellular level and contribute to the long-term normalisation of metabolic function. In this context, lifestyle interventions are not secondary or optional—they are central to the healing process. When implemented thoughtfully and consistently, they empower the body’s own regenerative capacity and support true recovery.
References
[1] L. B. Thingholm et al., ‘Obese Individuals with and without Type 2 Diabetes Show Different Gut Microbial Functional Capacity and Composition’, Cell Host Microbe, vol. 26, no. 2, pp. 252-264.e10, Aug. 2019, DOI: https://doi.org/10.1016/j.chom.2019.07.004
[2] ‘Inzulin’, WikipédiaOct. 24, 2024, https://hu.wikipedia.org/w/index.php?title=Inzulin&oldid=27540767
[3] C. Tello, ‘7 Benefits of Insulin & 2 Negative Effects’, SelfHacked, Dec. 18, 2019 https://selfhacked.com/blog/insulin-101/
[4] M. Trovati, P. Massucco, L. Mattiello, E. Mularoni, F. Cavalot, and G. Anfossi, ‘Insulin increases guanosine-3’,5’-cyclic monophosphate in human platelets. A mechanism involved in the insulin anti-aggregating effect’, Diabetes.., vol. 43, no. 8, pp. 1015–1019, 1994, DOI: https://doi.org/10.2337/diab.43.8.1015
[5] O. Farooq and J. I. Isenberg, ‘Effect of continuous intravenous infusion of insulin versus rapid intravenous injection of insulin on gastric acid secretion in man’, Gastroenterology, vol. 68, no. 4 Pt 1, pp. 683–686, Apr. 1975 https://pubmed.ncbi.nlm.nih.gov/1123136/
↓ Read More ↓Table of contents
In recent decades, the incidence of metabolic disorders—particularly insulin resistance (IR) and type 2 diabetes mellitus (T2D)—has risen dramatically worldwide. This is largely due to urbanisation, sedentary lifestyles, and the proliferation of high-calorie, Western-style diets. Insulin resistance is one of the most common yet often overlooked metabolic disorders; it can remain latent for years while silently damaging the body’s metabolic functions. It is not only a precursor to type 2 diabetes, but also contributes to several other conditions, including non-alcoholic fatty liver disease (NAFLD), polycystic ovary syndrome (PCOS), and cardiovascular disease. In addition to traditional risk factors such as genetic predisposition, excessive caloric intake, and lack of physical activity, growing research highlights the importance of gut microbiome balance. The composition of gut flora influences glucose metabolism, chronic low-grade inflammation, and insulin sensitivity. Obesity—particularly visceral fat—significantly increases the risk of T2D. Epidemiological data indicate that approximately 86% of people with type 2 diabetes are overweight or obese. However, it is crucial to emphasise that obesity is neither the sole nor a sufficient condition for developing diabetes. Whether being overweight actually leads to diabetes depends largely on individual insulin sensitivity, fat distribution, hormonal regulation, and, crucially, the functioning of the gut microbiome. Therefore, diabetes is not merely a matter of body weight but the result of complex, multi-level metabolic and immunological interactions. [1]
What is insulin resistance?
Glucose is a vital energy source for the human body. The brain and many tissues rely on it for energy, and red blood cells—responsible for oxygen transport—can only use glucose. Due to its chemical structure, glucose is highly reactive and easily binds to proteins, including those in blood vessels, nerve cells, and red blood cells. This glycation can damage affected cells and cause red blood cells to clump together, which hinders their passage through narrow capillaries, impairing microcirculation—especially in sensitive organs like the retina and kidneys.
The HbA1c value, measured in laboratory tests, indicates the proportion of glycated haemoglobin—reflecting how much sugar is bound to haemoglobin in red blood cells.
Blood sugar levels are tightly regulated, and insulin plays a central role.
It allows glucose to enter cells from the bloodstream, where it is converted into energy.
About insulin
Insulin is produced by beta cells in the islets of Langerhans in the pancreas. In response to dietary sugar, insulin is released into the bloodstream. It acts on specific cells (e.g., liver, muscle, and fat cells) via insulin receptors, opening small pores in the cell membrane through which glucose enters. These cells use glucose for energy, and some (such as the liver and muscles) can store it in the form of carbohydrates (glycogen).
This mechanism helps maintain blood sugar levels within a narrow range—even during fasting—because the liver continuously produces glucose (via gluconeogenesis).
Gluconeogenesis is controlled by two hormones: insulin (which inhibits it) and glucagon (which stimulates it). Under normal conditions, the liver produces about 250 g of glucose daily.
Insulin’s effects fall into two categories:
- Membrane effects: Promotes uptake of glucose, amino acids, and potassium into muscle and fat cells.
- Metabolic effects: Stimulates anabolic processes (e.g., glycogen, fatty acid, and protein synthesis), making it a “building” hormone, while inhibiting catabolic (breakdown) pathways. In insulin’s absence, patients tend to lose weight. [2]
Positive effects of insulin [3]:
- Improves cognitive and memory function (especially when administered intranasally to patients with Alzheimer’s or cognitive decline); protects nerve cells
- Relaxes arterial walls, improving blood circulation and the heart’s pumping capacity
- Reduces platelet aggregation [4]
- Increases muscle mass and improves muscle circulation
- Enhances protein digestion by increasing pepsin production in the stomach [5–6]
The precursor to insulin is proinsulin, which is cleaved to form insulin and C-peptide in a 1:1 ratio. Measuring C-peptide levels can help assess insulin production. C-peptide itself also has important physiological effects: it improves kidney function, reduces albumin excretion, enhances kidney barrier function, and helps restore normal heart rate variability (HRV), thereby reducing autonomic neuropathy. Additionally, it stimulates sodium-potassium ATPase activity in the renal tubules. [7]
Cell surface receptors, including insulin receptors, function optimally under fluctuating hormone levels—meaning they work best when insulin is present intermittently. Persistently high insulin levels can lead to a gradual decline in receptor sensitivity and responsiveness, a phenomenon known as insulin resistance. This can occur due to two main mechanisms: internalisation of receptors from the cell surface and inhibition of intracellular signalling pathways. Any tissue with insulin receptors can become insulin resistant, but the degree of reduced insulin sensitivity is most influenced by the liver, skeletal muscles, and adipose tissue. [8]
To counteract the rising blood sugar levels caused by impaired glucose uptake, pancreatic β-cells increase insulin production, leading to hyperinsulinemia.
As long as the pancreas produces enough insulin to regulate blood sugar, levels remain within the healthy range. However, if receptor sensitivity continues to decline, glucose can no longer enter cells effectively, resulting in hyperglycaemia (high blood sugar). Interestingly, hyperinsulinemia can itself contribute to the development of insulin resistance, making it unclear which comes first. This is clinically important because hyperinsulinemia, especially when driven by excess calorie intake, may be a trigger for insulin resistance-related metabolic disorders. [9]
Insulin resistance sets off a cascade of harmful metabolic processes. Immediate consequences include hyperglycemia (high blood sugar) and hypertension (high blood pressure), as insulin’s vasodilatory effect is lost. This loss makes blood vessels stiffer and narrower, leading to elevated blood pressure. Another direct consequence is dyslipidaemia: elevated triglycerides, cholesterol, and LDL levels; while the ‘good’ blood fat, HDL, is reduced. Consequently, hyperuricemia is often observed: high insulin levels inhibit uric acid excretion via the kidneys. In addition, insulin resistance is associated with chronic, low-grade inflammation, marked by elevated inflammatory markers such as CRP. Insulin resistance also impairs the function of the endothelial cells lining the inner surface of blood vessels (endothelial dysfunction) and increases the risk of thrombosis. If left untreated, insulin resistance can lead to complex conditions like non-alcoholic fatty liver disease (NAFLD), type 2 diabetes, and metabolic syndrome. [10–11]
Metabolic syndrome—a cluster of conditions including elevated blood sugar, abdominal obesity, high blood pressure, and dyslipidaemia—is now widespread in developed countries, affecting 20–25% of the population according to European studies. [12]
Figure 1. Consequences of insulin resistance
What are the symptoms of insulin resistance?
The symptoms of insulin resistance typically develop slowly and gradually, meaning that noticeable complaints are rare in the early stages. Over time, however, various often non-specific symptoms may appear, such as fatigue, daytime drowsiness, and difficulty concentrating. Many people also experience irritability, mood swings, and increased appetite—especially for sweet foods.
In women, elevated insulin levels can affect the ovaries by stimulating the production of androgen hormones (e.g., testosterone) within ovarian cells. This can lead to menstrual irregularities and polycystic ovary syndrome (PCOS). Visible skin changes may also occur due to insulin’s similarity to insulin-like growth factor 1 (IGF-1), which stimulates cell proliferation. Skin cells may divide more rapidly, become thicker, and produce more pigment—leading to acanthosis nigricans, a condition marked by dark, velvety patches in skin folds (e.g., on the neck or underarms). Abdominal (visceral) obesity is also common, along with difficulty losing weight even when following a healthy diet and exercising regularly. This accumulation of fat in the abdominal cavity—around internal organs—poses multiple health risks. The liver plays a key role here: it converts excess blood sugar into fat in an effort to moderate elevated glucose levels. While this process helps protect the body from short-term harm caused by hyperglycaemia, it also serves as an evolutionary mechanism for energy storage during potential periods of starvation. The fat stored in the abdominal cavity becomes an easily accessible energy reserve. Over time, however, this visceral fat contributes to metabolic disturbances, chronic inflammation, and insulin resistance. People affected by IR often experience increased hunger, particularly after consuming carbohydrate-rich foods. This is due to fluctuating blood sugar levels: reduced insulin efficiency leads to rapid spikes and crashes, which in turn trigger stronger cravings—especially for fast-absorbing carbohydrates. [13]
Figure 2. Symptoms of insulin resistance
How can insulin resistance be diagnosed?
Insulin resistance can remain asymptomatic for a long time, which makes early detection particularly important. Several laboratory tests can assist in diagnosis, including the aforementioned HbA1c, C-peptide (a by-product of insulin synthesis), blood glucose levels, and various indices calculated from these values. The diagnostic process usually begins with a fasting blood sample to determine fasting glucose and insulin levels. An oral glucose tolerance test (OGTT) may also be performed. In this test, the patient drinks a sugar solution, and their blood sugar and insulin levels are monitored over the following hours. From this data, various indices—such as HOMA-IR, QUICKI, or the Matsuda index—can be calculated to assess insulin sensitivity. These tests play a key role in early identification of the condition, which allows for timely lifestyle changes or, if necessary, medical intervention to prevent more serious complications.
Figure 3. Methods for measuring insulin resistance
Additional considerations in diagnosis:
- Body weight and body mass index (BMI)
- Hormone tests (e.g., androgens, SHBG, LH/FSH ratio)
- Gynaecological indicators (e.g., irregular menstrual cycles, suspected PCOS)
- Family history (e.g., type 2 diabetes, metabolic syndrome) [10]
What are the causes of insulin resistance?
Insulin resistance can result from a combination of genetic predisposition, environmental influences, and lifestyle factors such as lack of exercise or poor diet. These elements often interact, collectively contributing to the development of the condition. While genetics can play a significant role in some individuals, scientific evidence shows that in most cases, acquired factors—such as a sedentary lifestyle, unhealthy eating habits, excess weight or obesity, and chronic stress—are the primary drivers.
Sedentary lifestyle
During physical activity—whether walking, running, or engaging in other types of exercise—muscles increase their energy demand and primarily use glucose from the bloodstream. Remarkably, during this state, muscles can absorb glucose without insulin, naturally lowering blood sugar levels. Regular exercise not only reduces blood glucose in the short term but also increases insulin sensitivity over time. During physical activity, muscles release biologically active proteins called myokines (e.g., irisin), which help break down fat tissue, reduce inflammation, and regulate metabolism. [14]
Muscle tissue, therefore, serves not only for movement but also as a central regulator of energy balance and blood glucose control. During intense exercise, muscles may not receive enough oxygen, prompting anaerobic metabolism—converting glucose into lactic acid. Although this process yields less energy (ATP), it is rapid and provides an immediate energy supply. Later, the lactic acid can be broken down in the presence of oxygen or converted back into glucose by the liver via the Cori cycle. This prevents the accumulation of lactic acid in the muscles and allows its energy to be reused. However, this glucose reconversion requires additional energy, which the body generates from fat breakdown (beta-oxidation)—effectively switching into a fat-burning state. Interestingly, when the liver produces glucose, the body temporarily inhibits its use to avoid simultaneous “opposing” processes. After exercise, depleted muscles again absorb glucose and store it, thereby smoothing out blood sugar spikes and dips. Without regular physical activity, this metabolic synergy breaks down: the liver continues to overproduce glucose, while muscles do not participate in sugar utilisation. This “metabolic debt” can worsen over time. Exercise supports energy utilisation, improves insulin sensitivity, balances blood sugar, and reduces liver burden. In addition, muscle mass helps maintain metabolism even at rest. [15]
The role of obesity in the development of insulin resistance
Obesity, particularly the accumulation of abdominal (visceral) fat, plays a central role in the development of insulin resistance. Adipose tissue is not merely an energy reserve; it also functions as an endocrine organ, secreting adipokines, inflammatory cytokines (e.g., TNF-α, IL-6), and free fatty acids (FFAs). [16] These substances interfere with insulin signalling pathways inside cells, reducing glucose uptake—especially in muscle and fat tissues. The chronic, low-grade inflammation associated with obesity exacerbates this effect and contributes directly to the persistence of insulin resistance. Visceral fat, in particular, produces higher levels of inflammatory mediators that disrupt insulin action more aggressively than other fat types. It is important to note that not all adipose tissue is the same. Visceral fat (fat around internal organs) has much more active hormone production and a stronger impact on insulin resistance, while subcutaneous fat (just under the skin) has a more moderate effect. This difference explains why apple-shaped obesity (central or abdominal fat distribution) is more closely associated with insulin resistance and metabolic syndrome than pear-shaped obesity (fat around the hips), which is predominantly subcutaneous. [17–18]
Consumption of foods with a high glycaemic index
Obesity is often seen as a result of excessive calorie intake, but it’s important to understand that overeating alone can have serious physiological consequences. Even short-term consumption of a high-energy diet can reduce the brain’s sensitivity to insulin, independently of any drop in insulin sensitivity in peripheral tissues. Excess calorie intake impairs insulin signalling in brain cells, alters the gut microbiome, activates inflammatory pathways, and ultimately disrupts brain function. This creates a vicious cycle, where molecular changes in the brain trigger neuroinflammation and, over time, contribute to conditions such as depression, cognitive decline, Alzheimer’s disease, and other neurological disorders.
Additional risk factors include gut dysbiosis (imbalanced microbiota), the release of endotoxins from bacteria, and increased intestinal permeability. Inflammation that begins in adipose tissue can spread to the brain and further reduce insulin sensitivity in the central nervous system. [19]
Fat metabolism becomes increasingly important in the context of obesity. When blood contains excess fatty acids, cells switch to burning fat for energy, which suppresses carbohydrate metabolism—a process essential for stable blood sugar, low insulin levels, and efficient energy use. This competitive, mutually inhibitory relationship between fat and carbohydrate metabolism is described by the Randle cycle. In overweight individuals, elevated FFAs create an energy surplus at the cellular level, reducing glucose uptake and contributing directly to insulin resistance and type 2 diabetes. Interestingly, calorie restriction alone—regardless of carbohydrate intake—can reduce blood glucose and insulin levels. [20]
Chronic inflammation
Obesity leads to persistent, low-grade systemic inflammation, which plays a key role in the development of long-term complications associated with type 2 diabetes—such as non-alcoholic fatty liver disease, retinopathy, cardiovascular disease, and kidney damage (nephropathy). This inflammation also helps explain the links between diabetes and other conditions like Alzheimer’s disease, polycystic ovary syndrome (PCOS), gout, and rheumatoid arthritis. Chronic inflammation particularly affects insulin-sensitive tissues such as adipose tissue, the liver, muscles, and the pancreas. This phenomenon, known as immunometabolism, refers to the close, reciprocal relationship between the immune and metabolic systems. Metabolic dysfunction triggers inflammatory responses, which in turn further disrupt metabolism. As fat mass increases and insulin sensitivity declines, the production of pro-inflammatory cytokines rises, while levels of adiponectin—a hormone beneficial for metabolism—decrease. This imbalance also alters the immune cell composition of adipose tissue, increasing pro-inflammatory M1 macrophages and reducing anti-inflammatory M2 macrophages [21]. The accumulation and activation of macrophages are the primary drivers of chronic inflammation in metabolic tissues, but other immune cells—such as T and B lymphocytes—also contribute to this inflammatory environment. [22]
Stress, sleep deprivation
Stress has been shown to contribute significantly to the development of type 2 diabetes. It arises when the body encounters a stimulus it must resist or adapt to, triggering the mobilisation of energy. These stimuli can be physical (e.g., temperature, radiation), chemical or biological (e.g., infections), or psychological in nature. While short-term stress is a necessary and beneficial response that promotes survival, problems arise when stress is intense, prolonged, or chronic, as this can exhaust the body’s adaptive resources. During the classic “fight or flight”response, the body shifts to catabolic metabolism to rapidly mobilise energy, while suppressing less immediate processes such as digestion, growth, reproduction, and immune function. This evolutionary response, originally designed to help humans escape predators, is driven by rapid mobilisation of immediately available energy reserves (e.g. glucose). [23]
In such cases, the body produces stress hormones, primarily glucocorticoids (e.g., cortisol) and catecholamines (e.g., adrenaline). These hormones stimulate the liver to increase gluconeogenesis, raising blood sugar levels to provide a quick energy source. However, if this surge in glucose is not followed by physical activity, as is often the case in modern life, blood sugar remains elevated—eventually contributing to chronic hyperglycaemia. Over time, this promotes insulin resistance. Cortisol also inhibits glucose uptake by muscle cells, reducing their contribution to blood sugar regulation. In today’s world, chronic stress is frequently accompanied by a lack of exercise, irregular eating patterns, or an unhealthy diet—factors that further disturb metabolism and contribute to the development of visceral (abdominal) obesity. [23]
Not just stress, but also the quantity and quality of sleep have a significant impact on insulin sensitivity. Modern lifestyles—marked by long working hours, study pressures, and excessive screen time—often result in sleep deprivation [24]. Although the exact causal mechanisms are not yet fully understood, insufficient sleep increases inflammation and can contribute to insulin resistance and type 2 diabetes, even in the absence of weight gain. [25]
Experts recommend that adults get at least seven hours of sleep per night to maintain metabolic health. [26]
The role of the gut microbiome
Individuals with insulin resistance often have an imbalance in their gut flora, known as dysbiosis, which plays a causal role in impaired glucose metabolism and the persistence of chronic low-grade inflammation. Abnormal activity in the gut microbiome increases intestinal permeability, allowing bacteria and lipopolysaccharides (LPS)—inflammatory components of bacterial cell walls—to enter the bloodstream. This condition, known as metabolic endotoxemia, contributes to systemic inflammation, a key factor in the development of insulin resistance, metabolic syndrome, and even certain types of cancer.
Dysbiosis can involve either a decrease in beneficial bacteria (e.g., Akkermansia muciniphila, Faecalibacterium prausnitzii) and/or an overgrowth of pro-inflammatory strains (e.g., certain Proteobacteria or Firmicutes species). Reduced production of short-chain fatty acids (SCFAs)—especially butyrate—by these beneficial microbes weakens the intestinal barrier and exacerbates systemic inflammation.
Beyond inflammation, the gut microbiome can also directly affect insulin action. Some bacterial strains enhance insulin sensitivity and improve glucose metabolism. In experimental models, introducing these strains into the gut lowered blood sugar levels, reduced simple sugars in the stool, improved lipid profiles, and alleviated symptoms of insulin resistance. Conversely, when excess sugar remains unprocessed in the intestines, it promotes fat storage and inflammation, increasing the risk of obesity. [27]
The gut flora of insulin-resistant individuals differs significantly from that of insulin-sensitive individuals. In the former, bacteria from the genera Blautia and Dorea (family Lachnospiraceae) dominate, while in the latter, Alistipesand Bacteroides species are more common. These latter species metabolise carbohydrates more efficiently, leaving less sugar in the intestine. Oral administration of Alistipes indistinctus has even been shown to protect against obesity and insulin resistance, even when subjects consume a high-fat diet [8]. Several studies have demonstrated correlations between gut microbiome composition, plasma metabolites (e.g., branched-chain amino acids (BCAAs), SCFAs, and LPS), various forms of obesity, and distinct types of diabetes (e.g., insulin-resistant vs. insulin-deficient), alongside environmental influences. In cases of obesity, populations of Faecalibacterium prausnitzii, Akkermansia, Oscillibacter, and Intestinimonas tend to decrease, while in type 2 diabetes, Escherichia/Shigella strains often increase. [1]
Short-chain fatty acids (SCFAs)—especially acetate, propionate, and butyrate—produced by gut bacteria play critical roles in regulating metabolism, appetite, and insulin sensitivity. Their concentrations and ratios in stool or plasmacan serve as useful biomarkers for assessing the severity of insulin resistance. Butyrate and propionate typically have anti-obesity effects: they promote leptin and other satiety hormones, reduce inflammation, and improve insulin sensitivity. Propionate, as a gluconeogenesis substrate, helps stabilise blood sugar, though in excess, it may promote insulin resistance by stimulating insulin and glucagon secretion and activating the sympathetic nervous system [28]. Acetate stimulates ghrelin (the hunger hormone), promoting appetite, fat storage, and potential weight gain [29]. A decline in butyrate-producing bacteria—such as Faecalibacterium prausnitzii and Roseburia intestinalis—is a hallmark of insulin resistance. Their absence contributes to increased inflammation and reduced intestinal metabolic function. [30]
Higher levels of Akkermansia muciniphila and Parabacteroides distasonis in the gut are associated with improved insulin sensitivity under calorie restriction, highlighting the protective role of these species. [30]
Studying the composition and function of the gut microbiome may become a valuable tool in the diagnosis and treatment of insulin resistance.
Gut-brain axis
The gut-brain axis is a bidirectional communication pathway through which the gut microbiota, nervous system, endocrine system, and immune system interact. This complex network plays a particularly important role in the regulation of metabolism. The gut microbiota not only contributes to digestion but also influences brain function via neural, hormonal, and immunological mechanisms. A nutrient-rich but imbalanced diet, as well as obesity, can alter the composition of the gut microbiome. The metabolites produced by these microbes can send signals to the brain, often via the vagus nerve.
Enteroendocrine cells, located in the intestinal lining, function both as sensors and hormone producers. They detect changes in the gut environment—such as nutrients or microbial activity—and secrete various gut hormones like GLP-1, PYY, and CCK. These hormones influence not only insulin secretion and blood glucose response but also appetite, mood, and even learning and memory processes. The immune system is also a key participant in the gut-brain axis. Activated immune cells—such as Th1, Th17, Treg cells, neutrophils, and macrophages—can release inflammatory signals that affect brain function and disrupt the gut-brain balance. When the intestinal barrier becomes compromised, it allows harmful substances to enter the bloodstream—this is known as “leaky gut.” This condition increases systemic inflammation, which not only impairs brain function but also exacerbates insulin resistance. [19]
Figure 4. Possible causes of insulin resistance
Mitochondrial function
In insulin resistance, cellular energy utilisation declines due to several factors: a reduction in the number of mitochondria and it’s oxidative enzymes, impaired ATP production, and structural changes in mitochondria. ATP (adenosine triphosphate) is the body’s main energy carrier, and each day we use an amount equivalent to our entire body weight. This energy must be continually regenerated by the mitochondria. Excessive calorie intake increases the production of reactive oxygen species (ROS), which damage mitochondria, trigger inflammation, and activate immune cells in the nervous system. The accumulation of fat inside cells also reduces oxidative capacity, especially in individuals with a genetic predisposition. [31]
Mitochondria can be damaged not only by various metabolic disturbances but also by ageing, which gradually impairs their efficiency. Over time, levels of key hormones—such as growth hormone and IGF-1, both of which support these energy-producing organelles—decline, increasing the risk of metabolic diseases. [32]
Optimal mitochondrial function is essential for an adequate insulin response. Approximately 3% of people with diabetes have mitochondrial diabetes (MIDD), which may resemble either type 1 or type 2 diabetes. The condition is characterised by β-cell dysfunction and reduced insulin sensitivity in muscle tissue, both of which worsen with age. [33–34]
Within cells, mitochondria also require water to function properly—and it is beneficial if this water has low deuterium content. Deuterium is a heavy isotope of hydrogen containing a neutron in addition to the proton. It naturally occurs in drinking water at around 150 ppm, though this varies geographically (lower levels are found at higher altitudes and inland regions). [35]
The final step in cellular energy production occurs in the electron transport chain (or redox chain) within the inner mitochondrial membrane, which consists of five complexes. Complex V acts like a microscopic turbine, returning protons – pumped into the intermembrane space by the previous four complexes – into the mitochondrial matrix to drive ATP synthesis. If deuterium passes through Complex V, it can damage the mechanism, reducing the mitochondria’s capacity to produce energy. From a metabolic standpoint, fats are a better fuel than carbohydrates, as they contain more hydrogen and less deuterium. As a result, fat oxidation produces metabolic water that is naturally lower in deuterium than drinking water. Elevated deuterium levels in cells impair mitochondrial energy production, increase inflammation, and may reduce insulin sensitivity. The gut microbiota also plays a protective role here by producing hydrogen gas and short-chain fatty acids (e.g., butyric acid, butyrate, acetate), all of which support mitochondrial and metabolic health. Notably, hydrogen gas generated in the gut is low in deuterium, helping to safeguard cellular energy production. Butyric acid, in particular, serves as a key energy source for colonocytes (colon cells), regulates inflammation, and supports healthy cellular function. In this way, the gut microbiome indirectly and directly contributes to optimal energy metabolism. [36]
What are the consequences of insulin resistance?
Persistently elevated blood sugar levels resulting from insulin resistance can lead to serious long-term complications, particularly within the vascular system. The earliest damage often occurs in the smallest blood vessels—this is known as microvascular damage. These changes affect several critical organs:
- Eyes: Damage to the fine network of blood vessels in the retina can lead to diabetic retinopathy, potentially resulting in vision loss or even blindness.
- Kidneys: Damage to the small renal blood vessels can cause diabetic nephropathy, which may progress to kidney failure and require dialysis.
- Nervous system: Impaired blood supply to small nerves can result in peripheral neuropathy, leading to sensory disturbances, numbness, pain, or muscle weakness, particularly in the hands and feet.
However, these changes affect not only the peripheral parts of the body, but also the central nervous system—most notably, the brain. Damage to the brain’s small blood vessels can contribute to dementia (cognitive decline), stroke, mood disorders such as depression and anxiety, as well as balance problems and unsteady gait. Similarly, damage to the small blood vessels of the heart muscle can lead to chest pain (angina) and contribute to structural and functional deterioration of the heart (cardiomyopathy).
Damage to larger blood vessels is known as macrovascular complications, and these often include:
- Peripheral arterial disease (PAD): Narrowing or blockage of arteries in the limbs—most commonly the legs—leading to leg pain when walking, cold extremities, delayed wound healing, and, in severe cases, ulcers or amputation.
- Coronary artery disease (CAD): Blockage or narrowing of the heart’s arteries—which supply the heart muscle—can lead to angina, heart attacks, or heart failure.
- Stroke: A sudden loss of blood flow to the brain. There are two major types:
- Ischaemic stroke: Caused by a blocked artery (e.g., due to a blood clot)
- Haemorrhagic stroke: Caused by a ruptured blood vessel, leading to bleeding in the brain
Both stroke types can lead to severe consequences, including paralysis, speech impairment, memory loss, or death.
A rapidly growing disease closely associated with insulin resistance is non-alcoholic fatty liver disease (NAFLD). In this condition, fat accumulates in the liver despite the absence of alcohol consumption. Over time, this fat buildup may cause inflammation, cell damage, and fibrosis (scarring), impairing liver function and potentially progressing to cirrhosis. NAFLD is extremely common among individuals with insulin resistance and type 2 diabetes. Alarmingly, its prevalence is rising globally—including among children. As a result, all healthcare professionals who treat patients with insulin resistance—whether general practitioners, dietitians, or internists—should prioritise early detection and treatment of fatty liver, even in the absence of symptoms. [10]
What are the treatment options for insulin resistance?
Conventional medicine
Most medications currently used in clinical practice to treat carbohydrate metabolism focus primarily on regulating blood sugar levels. These drugs were not specifically developed to address the associated complications of insulin resistance, such as retinopathy, non-alcoholic fatty liver disease, or chronic inflammation. While some have secondary benefits for these conditions, only one—metformin—has demonstrated an ability to slow disease progression. [22]
Metformin is the first-line medication for treating insulin resistance, particularly in prediabetes and type 2 diabetes. It primarily reduces glucose production in the liver and also enhances insulin sensitivity in peripheral tissues. It does not cause hypoglycaemia and is especially suitable for overweight or obese patients due to its weight-reducing effect. According to the Diabetes Prevention Program (DPP) study, metformin lowered the risk of developing type 2 diabetes by around 30% in insulin-resistant individuals. The treatment is generally well tolerated, although gastrointestinal side effects such as bloating or diarrhoea may occur initially. [37]
Metformin also affects the gut microbiome. Compared to untreated type 2 diabetes patients, those taking metformin show an increased abundance of Parabacteroides distasonis, improved tight junction integrity in intestinal epithelial cells, and a microbiome composition more similar to that of healthy individuals.
Interestingly, specific gut microbiome profiles may predict a patient’s response or side effects to metformin. A higher abundance of Segatella copri (formerly Prevotella copri) is associated with reduced HbA1c-lowering efficacy. The HbA1c value reflects the average blood sugar level over the past 2–3 months. In contrast, a higher presence of Streptococcus parasanguinis may indicate a greater risk of side effects. Since these microbial patterns can also be influenced by concurrent medications (e.g., proton pump inhibitors, anticoagulants), analysing the gut microbiome may be essential for understanding how polypharmacy impacts metformin’s effectiveness. [30]
Weight loss: diet and exercise recommendations
A low-carbohydrate diet may temporarily improve insulin sensitivity, particularly when blood glucose and blood lipid levels are elevated. Reducing carbohydrate intake can support fat burning and ease metabolic overload. However, traditional low-carb or ketogenic diets—due to their high fat content—can impair carbohydrate metabolism over time, potentially leading to physiological insulin resistance. In this state, cells lose the ability to efficiently process carbohydrates. The key to a stable metabolism is metabolic flexibility—the body’s ability to switch between fat and carbohydratesas energy sources. Restoring healthy carbohydrate metabolism is therefore essential. The goal should not be permanent carbohydrate restriction, but rather to reintroduce carbohydrates gradually and intelligently so the body learns to use them effectively again. [20]
Properly selected physical activity also supports this process by increasing the insulin sensitivity of skeletal muscle and by positively influencing the gut microbiome. While very intense exercise may stress the digestive system—potentially leading to dysbiosis or exercise-induced gastrointestinal syndrome—moderate-intensity activity has beneficial effects. It increases the proportion of bacteria such as Akkermansia muciniphila and Oscillospira and enhances the production of short-chain fatty acids (SCFAs), as well as lactic acid. These compounds are important not only for intestinal health, but also for indirectly improving metabolic flexibility and insulin sensitivity. [30]
Functional medicine
Restoring gut health is a key step in improving metabolic function, and this lies at the heart of the functional medicine approach. The foundation includes a personalised diet, lifestyle adjustments, and plant-based, natural therapies, tailored to the individual’s needs.
Targeted nutritional supplementation and nutrient replacement
A variety of natural compounds and micronutrients can support the treatment of insulin resistance by reducing inflammation, decreasing oxidative stress, and enhancing insulin action.
Berberine, quercetin, and omega-3 fatty acids, which have strong anti-inflammatory properties and can help restore insulin sensitivity. Antioxidants like vitamins C and E, selenium, and resveratrol, which combat oxidative damage—a key factor in the development and progression of insulin resistance.
Vitamin D, which supports calcium and phosphorus metabolism, and also reduces pro-inflammatory cytokines. Studies have shown that vitamin D increases insulin receptor density in muscles, liver, and fat tissue, enhancing both insulin sensitivity and glucose utilisation. [38]
Inositol (especially in the forms myo-inositol and D-chiro-inositol) is a promising supplement for insulin resistance. It improves insulin signalling, lowers fasting insulin levels, and helps regulate menstrual cycles in women with PCOS, who frequently experience insulin resistance. [39]
Chromium is an essential trace element that supports insulin function and the metabolism of carbohydrates, fats, and proteins. Supplementation can improve fasting blood glucose and reduce insulin resistance. [40]
Cinnamon enhances insulin receptor function, promotes glucose uptake, and inhibits glucose production in the liver. Its antioxidant and anti-inflammatory effects contribute to normalising blood sugar, lipid levels, and blood pressure, helping to prevent type 2 diabetes. [41]
Selenium protects cells from oxidative damage that can impair insulin function, while zinc plays a crucial role in insulin synthesis, storage, and secretion, thereby indirectly improving glucose metabolism. [42–43]
Combinations of these nutrients are often more effective than individual compounds, working synergistically to reduce inflammation, lower oxidative stress, improve insulin sensitivity, and support metabolic restoration
Nutritional guidelines
A low-glycaemic diet is one of the foundational strategies for restoring metabolic health. It’s advisable to eat frequent, balanced meals that include a combination of protein, healthy fats, and complex carbohydrates, including in the afternoon and evening. Fasting should be approached with caution—particularly at the beginning of treatment—because a sudden drop in blood sugar can place stress on the body. Once energy metabolism has stabilised, meal intervals can be gradually extended. Supporting mitochondrial function may also be critical, especially in individuals with diabetes or those taking metformin. This is because metformin partly works by inhibiting complex I in the mitochondrial respiratory chain. Over the long term, this may lead to energy production issues, vitamin B12 deficiency, and, in rare cases, lactic acidosis. Therefore, supplementation with nutrients that support mitochondrial health is often recommended, such as: vitamin B12 (methylcobalamin), alpha-lipoic acid, Coenzyme Q10 (CoQ10), vitamin B1 (benfotiamine), taurine, magnesium, other mitochondrial cofactors. [44]
Other beneficial dietary approaches include the mediterranean diet, rich in vegetables, healthy fats (e.g., olive oil), and moderate amounts of fish as well as moderate, well-timed intermittent fasting, which can help restore metabolic flexibility.
The role of prebiotics and probiotics
Probiotics—especially specific strains of Lactobacillus and Bifidobacterium—have been shown to improve blood lipid profiles and reduce fasting blood glucose, insulin levels, and HbA1c. One particularly promising strain, Akkermansia muciniphila, has been found to strengthen the gut barrier, lower inflammation, and improve metabolic function.
The combined use of prebiotics and probiotics (known as synbiotics) has demonstrated additional benefits in reducing hyperglycaemia and supporting weight loss.
Individual differences in gut microbiota composition can also influence the effectiveness of dietary and supplement interventions. For example, people with a gut flora dominated by Bacteroides tend to respond well to capsaicin, a natural compound that also acts as a prebiotic. In individuals with a high Prevotella:Bacteroides ratio, arabinoxylan—a type of hemicellulose prebiotic—has shown protective effects against weight gain. [30]
Lifestyle factors
Regular exercise, effective stress management, and good sleep quality significantly influence both gut microbiota composition and overall metabolic health. These lifestyle factors can play a highly effective role in the comprehensive management of insulin resistance—not only on their own, but also in synergy with the dietary and supplementation strategies mentioned above.
Consult our experts!
Insulin resistance is a complex metabolic disorder that affects multiple organ systems. Effective treatment requires an integrated, multi-layered approach. At HealWays, we believe that symptom-focused care is not enough. To achieve real, lasting results, it is essential to identify and address the root causes of the condition. Our approach focuses on restoring microbiome balance, following an anti-inflammatory and nutrient-rich diet, managing both psychological and physical stress, and supporting and regulating the hormonal system. Together, these interventions can help improve insulin signalling at the cellular level and contribute to the long-term normalisation of metabolic function. In this context, lifestyle interventions are not secondary or optional—they are central to the healing process. When implemented thoughtfully and consistently, they empower the body’s own regenerative capacity and support true recovery.
References
[1] L. B. Thingholm et al., ‘Obese Individuals with and without Type 2 Diabetes Show Different Gut Microbial Functional Capacity and Composition’, Cell Host Microbe, vol. 26, no. 2, pp. 252-264.e10, Aug. 2019, DOI: https://doi.org/10.1016/j.chom.2019.07.004
[2] ‘Inzulin’, WikipédiaOct. 24, 2024, https://hu.wikipedia.org/w/index.php?title=Inzulin&oldid=27540767
[3] C. Tello, ‘7 Benefits of Insulin & 2 Negative Effects’, SelfHacked, Dec. 18, 2019 https://selfhacked.com/blog/insulin-101/
[4] M. Trovati, P. Massucco, L. Mattiello, E. Mularoni, F. Cavalot, and G. Anfossi, ‘Insulin increases guanosine-3’,5’-cyclic monophosphate in human platelets. A mechanism involved in the insulin anti-aggregating effect’, Diabetes.., vol. 43, no. 8, pp. 1015–1019, 1994, DOI: https://doi.org/10.2337/diab.43.8.1015
[5] O. Farooq and J. I. Isenberg, ‘Effect of continuous intravenous infusion of insulin versus rapid intravenous injection of insulin on gastric acid secretion in man’, Gastroenterology, vol. 68, no. 4 Pt 1, pp. 683–686, Apr. 1975 https://pubmed.ncbi.nlm.nih.gov/1123136/
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