Insulin Sensitivity and the Risk of Type 2 Diabetes: The Genetic Dimension

Fasting glucose is the most widely used measure of metabolic health. Millions of people take this test every year and receive one of two answers: normal or not normal. But there is a third category that this test cannot see: people whose glucose is still within range, while the pancreas is already working twice as hard to keep it there.

Insulin sensitivity is the ability of cells to respond to insulin and absorb glucose from the bloodstream. It can decline gradually, over years, with no outward signs. The pancreas compensates by secreting more insulin. Glucose stays within reference values. Meanwhile, the beta-cell reserve quietly shrinks.

This is the hidden stage in the formation of type 2 diabetes (T2D) risk. And this is exactly where a question arises that standard tests cannot answer: why does this process unfold faster in some people? Why, given similar diets, similar weight, and similar lifestyles, do metabolic consequences appear at different times and with different severity? The answer lies in genetics.

How Cells Stop Responding to Insulin

Insulin resistance is not a sudden failure — it is a gradual process. It unfolds as follows:

Chronic energy surplus → lipid accumulation in muscle and liver → desensitisation of insulin receptors → compensatory hyperinsulinaemia → pancreatic beta-cell exhaustion

When the body consistently takes in more energy than it can use, excess lipids accumulate not only in adipose tissue but also in muscle and liver cells. This disrupts the normal function of insulin receptors on the surface of those cells. The signalling cascade from insulin binding to glucose uptake weakens. The pancreas responds by increasing insulin secretion, attempting to overcome the cells' diminishing responsiveness.

Over time, beta-cells exhaust under sustained overload. Insulin secretion falls. Fasting glucose begins to exceed the normal range. Prediabetes appears, followed eventually by T2D (Sørensen et al., Diabetologia, 2022).

An important nuance: this process can begin before clinical obesity develops. If the compensatory mechanisms in a given individual are less efficient — due to functional characteristics of beta-cells, tissue sensitivity, or lipid metabolism — insulin resistance can develop with only modest excess body weight, or even without it. This explains why T2D occurs in people without pronounced obesity.

But there is another question: why, with an identical lifestyle and similar body composition, does insulin resistance develop in some people earlier while in others it appears later or not at all? The answer lies partly in genetics.

On individual differences in the response to nutrition — Why the Same Diet Produces Different Results in Different People: The Role of Genetics and Metabolism.

Polygenic Risk: Not One Gene but Hundreds of Variants

Type 2 diabetes is not a monogenic disease. There is no single "diabetes gene" that determines everything. The largest multi-population genome-wide analysis to date, covering more than 2.5 million participants, identified 1,289 independent genetic signals across 611 loci associated with T2D risk (Suzuki et al., Nat. Med., 2024). Each variant has a small individual effect, but their combined action forms a polygenic predisposition to the disease.

It is the aggregate of these variants that constitutes the individual genetic risk profile for T2D — the Polygenic Risk Score (PRS). This is a measure of where a person stands relative to the population distribution of predisposition. People with a higher PRS will not necessarily develop the disease — but for them, the threshold at which unfavourable conditions lead to metabolic consequences may be lower.

Genes Affecting Insulin Secretion

The most consistently replicated T2D risk locus across different populations is the gene TCF7L2 (transcription factor 7-like 2). It encodes a transcription factor that regulates gene expression in pancreatic beta-cells through the Wnt signalling pathway. Variants of TCF7L2 are associated with reduced glucose-stimulated insulin secretion, a diminished incretin effect, and lower beta-cell mass (del Bosque-Plata et al., Diabetes, 2021).

In practice, this means that at the same blood glucose level, beta-cells in carriers of risk variants of TCF7L2 may secrete less insulin in response to a meal. The compensatory reserve is smaller. The transition to prediabetes under unfavourable conditions occurs faster.

Genes Affecting Tissue Response and Glucose Transport

The gene PPARG (peroxisome proliferator-activated receptor gamma) is a key regulator of adipocyte differentiation (adipogenesis) and peripheral insulin sensitivity. This nuclear receptor controls the expression of genes involved in the insulin signalling cascade in adipocytes and ensures the proper distribution of lipids between adipose tissue and non-adipose organs (Maciejewska-Skrendo et al., Nutrients, 2022). Certain variants of PPARG reduce the efficiency of this process — adipocytes become less able to absorb lipids, and excess fatty acids are directed to muscle and liver, promoting insulin resistance.

The gene SLC2A2/GLUT2 (solute carrier family 2 member 2) encodes a glucose transporter protein that carries glucose into pancreatic beta-cells. It is through this transporter that the beta-cell "reads" blood glucose levels and adjusts insulin secretion accordingly. Variants of SLC2A2 can affect the precision of this sensing mechanism — and therefore the timeliness of the insulin response.

All three genes — TCF7L2, PPARG, and SLC2A2/GLUT2 — operate at different levels of the same process: from the signal "how much glucose is in the blood" to "how much insulin to secrete" and "how effectively will peripheral tissues respond to it." Their variants do not cause T2D, but they shape predisposition — shifting the threshold at which an unfavourable lifestyle begins to produce metabolic consequences.

What Knowledge of Your Genetic Profile Offers — and Who Needs It Most

The Digestion, Immunity & Metabolism test from Apixmed Prism includes an assessment of predisposition to reduced insulin sensitivity. Like all indicators in the Prism Test, it is presented as a Polygenic Risk Score (PRS) — a percentile relative to the reference population. This means not "you have diabetes" and not "you will get it," but rather "your genetic predisposition to reduced insulin sensitivity is at the Nth percentile in the population" (Slunecka et al., Hum. Genom., 2021).

But the most important question is not "what is the number" — it is "what do I do with it." Knowledge of the genetic profile provides a concrete practical foundation and shapes a strategy:

• Begin monitoring fasting insulin and HbA1c earlier than standard age-based recommendations, without waiting for deviations to appear in routine tests.

• Pay close attention to body weight dynamics — not only the absolute value but the trend — and work toward reaching and maintaining a target weight.

• Factor in a family history of T2D as an additional reason for regular preventive check-ups.

• Discuss check-up results with your doctor, drawing on not only current indicators but also the genetic profile of metabolic predispositions.

Who benefits most from this information:

• people with a family history of T2D;

• those who have excess body weight or are seeing it gradually increase;

• those who have already been told about "borderline glucose values";

• those who want to understand their metabolic profile before clinical signs appear — in order to act preventively.

A genetic profile does not replace laboratory tests. It complements them with a depth of context that a standard fasting glucose test cannot provide.

Genetic Predisposition to T2D Is a Signal, Not a Diagnosis

Elevated genetic risk is a starting point. Research consistently shows that the effect of lifestyle modification is preserved even in carriers of risk variants. In the Diabetes Prevention Program randomised trial, people with impaired glucose tolerance who lost 7% of their body weight and added 150 minutes of physical activity per week were half as likely to progress to T2D — the incidence fell by 58% compared with the control group (Knowler et al., N. Engl. J. Med., 2002).

What is critical: an analysis of this trial's data incorporating genetic risk showed that carriers of higher polygenic risk for T2D benefited from successful lifestyle modification to the same degree as people with lower genetic risk. Genetic risk did not nullify the effect of behavioural change (Raghavan et al., Diabetes Obes. Metab., 2021).

A systematic review of gene–environment interactions in T2D confirms that variants of TCF7L2 in particular are linked to a pattern in which carriers of risk alleles can reduce their elevated risk specifically through weight loss and dietary adjustment (Dietrich et al., Obes. Rev., 2021).

That is the practical meaning of knowing your genetic profile. Not anxiety, but early awareness. If you have an elevated genetic predisposition to insulin resistance or type 2 diabetes, that is an argument to act now — while the compensatory reserves are still sufficient.

T2D Risk Is Measurable and Modifiable

Insulin sensitivity is not a fixed characteristic, set once and for all. It is shaped by both lifestyle and genetic factors — which influence how quickly and under what conditions insulin resistance may develop. The polygenic nature of T2D risk means that no single variant is decisive and none of them acts in isolation.

Knowing your genetic profile is an opportunity to understand your metabolic state at a level that standard tests do not reflect. It does not eliminate the need to work with a doctor, maintain a healthy lifestyle, or pay attention to how you feel. Nor does it offer guarantees. It makes it possible to act with awareness and at the right time.

How your body responds to carbohydrate loading — DNA test "Digestion, Immunity & Metabolism".

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

Sources

1. Suzuki, K., Hatzikotoulas, K., Southam, L. et al. (2024). Genetic drivers of heterogeneity in type 2 diabetes pathophysiology. Nature, 627, 347–357.https://doi.org/10.1038/s41586-024-07019-6

2. del Bosque-Plata, L., Martínez-Martínez, E., Espinoza-Camacho, M. Á., & Gragnoli, C. (2021). The role of TCF7L2 in type 2 diabetes. Diabetes, 70(6), 1220–1228.https://doi.org/10.2337/db20-0573

3. Maciejewska-Skrendo, A., Massidda, M., Tocco, F., & Leźnicka, K. (2022). The influence of the differentiation of genes encoding peroxisome proliferator-activated receptors and their coactivators on nutrient and energy metabolism. Nutrients, 14(24), 5378.https://doi.org/10.3390/nu14245378

4. Sørensen, T. I. A., Metz, S., & Kilpeläinen, T. O. (2022). Do gene–environment interactions have implications for the precision prevention of type 2 diabetes? Diabetologia, 65(11), 1804–1813.https://doi.org/10.1007/s00125-021-05639-5

5. Dietrich, S., Jacobs, S., Zheng, J. S., Meidtner, K., Schwingshackl, L., & Schulze, M. B. (2021). Gene–lifestyle interaction on risk of type 2 diabetes: a systematic review. Obesity Reviews, 20(12), e12921.https://doi.org/10.1111/obr.12921

6. Raghavan, S., Jablonski, K., Delahanty, L. M. et al. (2021). Interaction of diabetes genetic risk and successful lifestyle modification in the Diabetes Prevention Program. Diabetes, Obesity and Metabolism, 23(4), 1030–1040.https://doi.org/10.1111/dom.14309

7. Knowler, W. C., Barrett-Connor, E., Fowler, S. E. et al.; Diabetes Prevention Program Research Group. (2002). Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New England Journal of Medicine, 346(6), 393–403.https://doi.org/10.1056/NEJMoa012512

8. Slunecka, J. L., van der Zee, M. D., Beck, J. J. et al. (2021). Implementation and implications for polygenic risk scores in healthcare. Human Genomics, 15, 46.https://doi.org/10.1186/s40246-021-00338-5