Insulin resistance in the lean in athletes: causes and the link with exercise load and pharmacology

Insulin resistance is usually associated with obesity, but it is also found in people of normal weight — including among those who train. The phenomenon of “metabolically unhealthy normal weight” was described as far back as the 1990s. The editorial team examines the mechanisms behind it, how exertion, diets and pharmacology affect insulin sensitivity, and why the scales alone are not enough to assess metabolism.

What insulin resistance is and how it is measured

Insulin resistance is a state in which tissues (muscles, liver, adipose tissue) respond more weakly to insulin. To maintain normal glucose, the pancreas is forced to release more of the hormone. For a long time the sugar level remains normal, and the disorder is revealed only by the insulin level or by special tests.

The “gold standard” of measurement is the hyperinsulinaemic euglycaemic clamp, described by DeFronzo and co-authors in 1979. It is accurate but labour-intensive and is used mainly in research. In clinical practice indirect indices are used.

The best known of them is HOMA-IR (Matthews et al., 1985), calculated from fasting glucose and insulin. There is also the QUICKI index and indicators derived from the oral glucose tolerance test. None of the indirect indices is perfect, and the thresholds of “normal” differ between populations and laboratories.

Importantly, in athletes the fasting indices may be distorted: after a hard workout, against the background of a low-carbohydrate diet or an energy deficit, insulin sensitivity temporarily changes. So a single indicator without context is easy to misinterpret.

Metabolically unhealthy normal weight: mechanisms

The concept of a “metabolically obese person of normal weight” was formulated by Ruderman and co-authors in 1998. They described people with a normal body mass index but with hyperinsulinaemia, insulin resistance and raised triglycerides. The key role here is played not by the amount of fat overall but by its distribution.

Visceral fat (around internal organs) and ectopic fat (in the liver, muscles, pancreas) are metabolically more active and more strongly linked to insulin resistance than subcutaneous fat on the thighs. The review by Stefan (2020) emphasises that it is precisely a disorder of fat distribution that determines metabolic health regardless of weight.

The “personal fat threshold” hypothesis (Taylor, Holman, 2015) explains why type 2 diabetes can develop in people of normal weight: each person has an individual capacity to safely store fat in subcutaneous depots. When it is exhausted, fat accumulates in the liver and pancreas.

Genetics also matters: in some populations, for example people of South Asian origin, insulin resistance develops at a lower BMI. A small muscle mass (“thin but without muscle”) also lowers the body’s overall capacity to utilise glucose, since it is precisely skeletal muscle that is the main consumer of glucose after eating.

Training: protection and paradoxes

Physical exercise is one of the most powerful ways to increase insulin sensitivity. Muscle contraction stimulates the movement of GLUT4 glucose transporters to the membrane independently of insulin, and after a workout sensitivity remains raised for hours and even a day. Strength training increases muscle mass, that is, the “capacity” for glucose.

Nevertheless, athletes sometimes have situations where the indices indicate insulin resistance. There is a known “athlete’s paradox”: in endurance-trained people the lipid content in the muscles is high, but insulin sensitivity is good because the fat is oxidised quickly. So intramuscular fat in itself is not always a sign of a problem.

A sharp cessation of training (injury, off-season) quickly lowers insulin sensitivity — within just a few days of inactivity. Chronic sleep deprivation and stress, through cortisol and sympathetic activation, also worsen carbohydrate metabolism.

An energy deficit and low-carbohydrate diets create so-called “physiological insulin resistance”: the body conserves glucose for the brain, and a glucose tolerance test after prolonged carbohydrate restriction may look worse. In relative energy deficiency in sport (RED-S) the hormonal background also changes, which affects metabolism.

• Increase sensitivity:regular aerobic and strength training, increased muscle mass, adequate sleep.
• Decrease sensitivity:inactivity, sleep deprivation, chronic stress, excess visceral fat.
• Distort tests:a hard workout the day before, a keto diet, fasting, acute illness.

Pharmacology that affects insulin sensitivity

Growth hormone is one of the classic counter-insular hormones. It enhances lipolysis and reduces glucose utilisation by muscles. Acromegaly (an excess of the body’s own growth hormone) is often accompanied by impaired glucose tolerance and diabetes. The Endocrine Society scientific statement mentions insulin resistance among the risks of non-medical growth hormone use.

Glucocorticoids (prednisolone, dexamethasone and others) suppress the action of insulin and stimulate the production of glucose in the liver. In athletes they are used for medical reasons (injuries, asthma, allergies), and their systemic use in the competition period is regulated by WADA.

The effect of anabolic steroids is ambiguous: physiological testosterone in men with hypogonadism generally improves insulin sensitivity, but supraphysiological doses and certain drugs are linked to a worsening of carbohydrate metabolism. High-quality data are scarce. Beta-2 agonists such as clenbuterol, and thyroid hormones, also change glucose metabolism.

Insulin used in a non-medical way for “anabolism” does not “treat” insulin resistance but masks it and creates a risk of severe hypoglycaemia, which can lead to death. Among drugs, insulin resistance can be worsened by some antipsychotics, thiazide diuretics and isotretinoin. Any of these drugs should be discussed with a doctor.

Why this matters for the athlete

Insulin resistance in a person of normal weight is not a “cosmetic” indicator. It is associated with an increased risk of type 2 diabetes, non-alcoholic (metabolically associated) fatty liver disease, dyslipidaemia and cardiovascular disease. For former athletes the risk rises after the end of their career, when the load drops sharply while eating habits remain.

For female athletes insulin resistance may be linked to polycystic ovary syndrome, which also occurs in lean women. It manifests as menstrual cycle disorders and signs of hyperandrogenism and requires examination by a gynaecologist-endocrinologist.

The condition also affects performance: impaired glucose use can manifest as rapid fatigue, energy fluctuations after eating and poorer glycogen recovery. However, these symptoms are non-specific and do not allow a diagnosis to be made without tests.

How to get examined and what to do for prevention, we describe in the material on the diagnosis of insulin resistance in the lean. We also recommend our articles on glycaemic control in athletes and on the risks of non-medical use of growth hormone and insulin.

Editorial conclusions

Normal weight and a low body-fat percentage do not guarantee healthy carbohydrate metabolism. The decisive factors are fat distribution, muscle mass, genetics and lifestyle.

Training is the most effective “natural sensitiser” to insulin, but inactivity, sleep deprivation, energy deficit and diets can temporarily change the indicators and distort tests.

Growth hormone, glucocorticoids and non-medical pharmacology can worsen insulin sensitivity, and using insulin without indication is deadly dangerous.

The condition is best assessed by a combination of tests under stable conditions and together with a doctor.

References

1. Ruderman N, Chisholm D, Pi-Sunyer X, Schneider S. The metabolically obese, normal-weight individual revisited. Diabetes. 1998;47(5):699–713.
2. Stefan N. Causes, consequences, and treatment of metabolically unhealthy fat distribution. Lancet Diabetes Endocrinol. 2020;8(7):616–627.
3. Taylor R, Holman RR. Normal weight individuals who develop type 2 diabetes: the personal fat threshold. Clin Sci (Lond). 2015;128(7):405–410.
4. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237(3):E214–E223.
5. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412–419.
6. Pope HG Jr, Wood RI, Rogol A, et al. Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement. Endocr Rev. 2014;35(3):341–375.
7. Mountjoy M, Sundgot-Borgen J, Burke L, et al. International Olympic Committee (IOC) Consensus Statement on Relative Energy Deficiency in Sport (RED-S): 2018 update. Br J Sports Med. 2018;52(11):687–697.