Why the Same Diet Gives Different Results in Different People: The Role of Genetics and Metabolism

The keto diet works for those whose bodies derive steady energy from fat — and doesn't work for those whose bodies poorly utilize it. The Mediterranean diet lowers triglycerides in some people and has almost no effect on others. Carbohydrate-rich food produces a short energy spike followed by a sharp crash in some people, while in others it sustains stable glucose levels for hours. The difference is not about self-control or food quality.

Behind these differences lie the individual physiological mechanisms of a given person: the rate of macronutrient breakdown, the sensitivity of insulin receptors, the activity of fat metabolism enzymes, the composition of the microbiome, and — one of the foundational levels — genetic variants that influence how the body processes carbohydrates and fats.

The search for the "ideal diet" often begins with a menu. But it's more useful to start with a question: why doesn't the same eating style suit everyone equally?

Why the Same Food Can Produce Different Physiological Effects

How the Body Digests Food and Uses Its Energy

Any food undergoes several stages of transformation before the body can use it as an energy source. Carbohydrates break down into glucose, fats into fatty acids and glycerol, and proteins into amino acids. But the process doesn't end there. How efficiently the body absorbs these substances and uses them for energy depends on many factors — from digestive system function to metabolic characteristics.

Even at the stage of nutrient absorption, the body does not work the same way in everyone. The activity of transport systems, digestive enzymes, and absorption efficiency can differ, which affects how quickly and in what quantity nutrients enter the bloodstream and become available for use.

Why Calories ≠ the Same Metabolic Effect

Further differences emerge at the level of metabolic regulation. The "a calorie is a calorie" concept describes the physical energy content of food but doesn't account for biological processes. In other words, 100 kcal from carbohydrates and 100 kcal from fat are the same number, but the body's response to them differs: carbohydrates trigger a substantial insulin release, while fats trigger a mostly minimal one. So the same caloric content from foods with different macronutrient composition triggers different hormonal and metabolic processes.

Different macronutrients trigger different hormonal responses: carbohydrates activate insulin regulation, fats much less so. And even here the response is individual, since insulin sensitivity varies substantially between people.

Metabolism as an Individual System of Energy Expenditure

Basal Metabolism and Its Variation Between People

Basal metabolism is the amount of energy the body expends at rest to maintain vital functions. It depends on muscle mass, body composition, hormonal regulation, and individual characteristics.

Even in people with similar builds, basal metabolism can differ substantially. This means different daily energy expenditure even before accounting for physical activity.

Muscle tissue is more metabolically active than fat tissue, so the ratio of muscle to fat directly affects the body's energy requirements and its response to a calorie surplus or deficit.

How the Body Expends Energy: Thermogenesis, Recovery, Adaptation

The body's energy expenditure isn't limited to basal metabolism and physical activity.

Adaptive thermogenesis — the body's ability to alter heat production in response to changes in diet and environmental conditions — plays an important role. This response varies between people: with a calorie deficit, some bodies significantly reduce energy expenditure, while others adapt less aggressively.

These processes are linked to various metabolic mechanisms, including brown adipose tissue and thermoregulation systems, which shape the individual rate of adaptation to dietary changes.

Why Calorie Restriction Doesn't Produce the Same Effect

When energy intake decreases, the body activates compensatory mechanisms: a drop in basal metabolism, changes in hunger and satiety hormone levels, and adaptation of energy expenditure.

The intensity of these responses varies between people. In some, the compensatory response is more pronounced, which makes maintaining a calorie deficit and changing body weight more difficult.

This is not a question of discipline — it is a feature of physiological energy balance regulation.

Why Food Response Depends on More Than Calorie Count

Insulin Response and Carbohydrate Sensitivity

After carbohydrate intake, the pancreas releases insulin — a hormone that transports glucose into cells. Cell sensitivity to insulin — that is, how effectively cells respond to its signal — is individual. With reduced sensitivity (insulin resistance), the pancreas compensates by producing more insulin, glucose is deposited as fat, and energy levels become unstable.

Genetic variants influence how much insulin is released in response to a given amount of carbohydrate — which is why the glucose response after the same bowl of oatmeal differs between carriers of different genotypes.

Fat Metabolism and the Ability to Use Lipids as an Energy Source

The efficiency of using fats as fuel depends on the activity of lipolysis and fatty acid transport into mitochondria. The PPARG gene regulates fat cell differentiation and fat metabolism. The Pro12 variant (frequency about 25% in the population) is associated with increased fat storage and reduced lipolysis efficiency — carriers of this variant find it harder to "burn" fat as fuel on a standard diet (Madeo et al., Clin Ter, 2023).

The FTO gene (fat mass and obesity associated) is one of the most thoroughly studied in the context of weight. A 2020 study with a sample of over 1,500 people showed that carriers of different FTO variants have different responses to the percentage of fat and carbohydrates in the diet (Skolarczyk et al., Nutrients, 2020).

The Role of the Microbiome in Nutrient Absorption

The gut microbiome influences how much energy the body extracts from fiber, complex carbohydrates, and certain fats. Different microbial compositions produce different metabolites: people with a higher proportion of Firmicutes tend to extract more calories from the same food compared to people with a higher proportion of Bacteroidetes.

The microbiome is not genetically determined — it is shaped by diet, antibiotics, stress, and mode of birth. But genetic factors significantly influence its composition indirectly, through immune mechanisms and gut mucus composition.

What Shapes Individual Differences in Metabolism

Hormonal Regulation and Stress Systems

Cortisol — the main stress hormone — increases gluconeogenesis (synthesis of glucose from non-carbohydrate sources) and promotes visceral fat deposition. Under chronic stress, a person with a hyperreactive hypothalamic-pituitary-adrenal axis may accumulate abdominal fat even on moderate calorie intake.

Thyroid hormones regulate basal metabolism. Even subclinical hypothyroidism (without obvious symptoms) slows lipolysis and reduces thermogenesis. Genetic variants in the TSHR and TPO genes, which affect thyroid function, have been identified in large GWAS studies and are linked to variability in basal metabolism within the population (Teumer et al., Nat Commun, 2023).

The Impact of Lifestyle: Sleep, Activity, Chronic Load

Insufficient sleep reduces insulin sensitivity and increases appetite by disrupting the balance of leptin and ghrelin — regardless of genotype. Physical activity increases the translocation of the GLUT4 glucose transporter into muscle cells, temporarily improving carbohydrate absorption even in people with reduced insulin sensitivity.

Important: lifestyle and genetics are not competing explanations. They act together. Genetic variants set the "starting state" of metabolism; lifestyle modifies it.

Genetic Features of Enzymes and Transport Systems

The enzyme amylase (gene AMY1) breaks down starch in the mouth. The copy number of the AMY1 gene varies between people from 2 to 15 or more — one of the most pronounced examples of gene copy number variation in humans (Hamid et al., Front Nutr, 2021). Carriers of more copies begin digesting starch more effectively even before it reaches the stomach, which affects the glycemic index of carbohydrates as actually absorbed.

The fatty acid transport protein FABP2 (gene FABP2) is responsible for lipid absorption in the small intestine. Its Ala54Thr variant is associated with increased transport of saturated fatty acids and higher post-meal triglyceride levels after fatty food — a mechanism that explains why some people tolerate high-animal-fat diets less well (Ortega-Azorín et al., Nutrients, 2018).

Genetics and Nutrition: Why "Universal Diets" Don't Exist

How Genes Influence Carbohydrate and Fat Metabolism

The GCKR gene regulates the activity of glucokinase in the liver — an enzyme that "signals" cells about glucose levels. The rs1260326 variant in this gene is associated with lower fasting glucose but higher triglyceride levels — a classic trade-off between two aspects of metabolism. Carriers of this variant may tolerate carbohydrates better from a glucose standpoint but face higher lipid risk with a high intake of refined carbohydrates.

The TCF7L2 gene has the most replicated genetic risk variants for type 2 diabetes. Its product affects incretin secretion and beta-cell sensitivity to glucose. A 2021 study showed (Hosseinpour-Niazi et al., Nutr Metab, 2021) that carriers of the 

Nutrient Sensitivity and Individual Dietary Responses

Polygenic genetic risk for type 2 diabetes is expressed through different biological mechanisms — impaired insulin secretion, insulin resistance, or changes in lipid metabolism. This is why, even with a similar genetic risk, dietary responses can differ substantially.

What Genetic Predisposition Means in the Context of Diet

A genetic predisposition to a particular metabolic response is not a verdict or a mandatory program. It is a starting point. A person with an increased predisposition to visceral fat accumulation on a carbohydrate-rich diet can offset this risk by adjusting eating patterns — but only if they know about it.

It turns out that a diet that "doesn't work" often simply doesn't match a particular person's metabolic characteristics. Not abnormal carbohydrate sensitivity, not a problem with fat metabolism — but a specific genetic variant that reduces the efficiency of a particular macronutrient utilization pathway.

How to Understand Your Type of Metabolic Response

Practical Markers: Energy, Appetite, Weight, Post-Meal Reactions

The body sends signals — you just need to know what to track. Here are markers that may indicate features of your metabolic response:

• A sharp drop in energy 1–2 hours after carbohydrate-rich food — may indicate an unstable glycemic response or increased sensitivity to simple carbohydrates

• Prolonged satiety after fatty food, shorter after carbohydrate-rich food — a signal that the body uses fat more efficiently as an energy source

• Weight doesn't respond to reduced calorie intake for a long time — may be related to adaptive thermogenesis or hormonal characteristics

• Discomfort or bloating after specific foods — possible individual feature of enzymatic breakdown or the microbiome

• Persistent hunger despite adequate food intake — may indicate features of appetite regulation

These markers are observations, not diagnoses. But they help formulate a hypothesis about your own metabolic profile.

What Can Be Tracked Without Tests

Basic self-observation tools: a food diary recording wellbeing and energy levels 1–3 hours after eating, comparing responses to carbohydrate- and fat-rich meals, and monitoring sleep quality and its connection to next-day appetite. This doesn't replace tests, but it provides initial context for understanding your own metabolism.

When It Makes Sense to Pursue More In-Depth Diagnostics

If basic observations don't produce a clear picture, or if there are specific questions — for example, why triglycerides are elevated on a "healthy" diet, or why fasting glucose is at the upper limit of normal despite physical activity — it makes sense to add genetic context to standard tests.

How to Apply This Knowledge in Practice

Why One Diet Doesn't Work the Same for Everyone

Dietary recommendations are formulated for the average person. This is useful from a public health perspective, but limited from a personalization perspective. Modern nutrigenetics shows: even within "healthy eating," there is room for optimization based on a specific genetic and metabolic profile.

How to Adapt Your Diet to Your Metabolism

A few principles with scientific grounding:

• For people with reduced insulin sensitivity, it is more effective to distribute carbohydrates evenly throughout the day rather than in large portions.

• With a predisposition to elevated triglycerides, it's worth limiting refined carbohydrates and trans fats regardless of overall caloric intake.

• For carriers of variants associated with increased abdominal fat storage, regular aerobic activity provides a greater relative effect than simple calorie restriction.

• With an increased predisposition to hyperphagia, structured eating (regular meals without skipping) is more effective than intermittent fasting.

These principles become more precise when there is specific genetic context.

The Role of Genetic Testing in Personalizing Nutrition

The Apixmed Prism "Digestion, Immunity & Metabolism" test analyzes genetic variants related to carbohydrate and fat sensitivity, detoxification speed, and a range of other metabolic indicators. The analysis covers 600,000+ genetic markers and is built on polygenic risk scores (PRS) — that is, it accounts not for a single gene, but for the cumulative effect of dozens of variants.

The result is not "your diet type" and not a ready-made program. It is genetic context that helps you understand why your body responds to certain foods the way it does — and where there is room for adaptation.

If you want to understand how your body processes carbohydrates and fats at the genetic level → DNA test "Digestion, Immunity & Metabolism"

Why Personalized Nutrition Is Not a Trend, but Physiology

Different responses to the same food are not a paradox or an exception. They are the norm, supported by dozens of large GWAS studies and meta-analyses. Metabolism is a system with its own "settings": the speed of enzymatic breakdown, receptor sensitivity, transport protein activity, thermogenesis efficiency. Some of these settings are linked to inherited genetic variants.

Understanding how your metabolism works specifically means having a foundation for nutrition decisions: not "what is healthy in general," but what is beneficial for a specific body with a specific genetic and metabolic profile.

 

Disclaimer

Genetic test results are not a diagnosis and do not replace a physician's consultation. The Apixmed Prism report provides genetic context that complements examination results and supports decision-making together with a doctor.

 

References

• Schiavone S, et al. (2021). Genome-Wide Association Analysis of Pancreatic Beta-Cell Glucose Sensitivity. J Clin Endocrinol Metab, 106(1):80–90. https://doi.org/10.1210/clinem/dgaa729

• Merino J, et al. (2022). Polygenic scores, diet quality, and type 2 diabetes risk: An observational study among 35,759 adults. PLoS Med, 19(4):e1003972. https://doi.org/10.1371/journal.pmed.1003972

• Skolarczyk J, et al. (2020). The Impact of FTO Genetic Variants on Obesity and Its Metabolic Consequences is Dependent on Daily Macronutrient Intake. Nutrients, 12(11):3255. https://doi.org/10.3390/nu12113255

• Madeo G, et al. (2023). Nutrigenomics: SNPs Correlated to Lipid and Carbohydrate Metabolism. Clin Ter, 174(Suppl 2(6)):200–208. https://doi.org/10.7417/CT.2023.2488

• Valenzuela-Vallejo L, et al. (2025). Nutrigenetics and metabolic syndrome: systematic review. Genes Nutr. https://doi.org/10.1186/s12263-025-00777-6

• Yin D, et al. (2023). FTO: a critical role in obesity and obesity-related diseases. Br J Nutr, 130(10):1657–64. https://doi.org/10.1017/S0007114523000764

• Teumer A, et al. (2023). Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease. Nat Commun. https://doi.org/10.1038/s41467-023-42284-5

• Hamid AK, et al. (2021). Interaction Effect Between Copy Number Variation in Salivary Amylase Locus (AMY1) and Starch Intake on Glucose Homeostasis in the Malmö Diet and Cancer Cohort. Front Nutr, 7:598850. https://doi.org/10.3389/fnut.2020.598850

• Ortega-Azorín C, et al. (2018). Postprandial Hypertriglyceridemia Is Associated with the Variant 54 Threonine FABP2 Gene. Nutrients, 10(9):1293. https://doi.org/10.3390/nu10091293