Insulin resistance. What do you need to know?.

What is insulin resistance?

Insulin resistance is defined as a disorder of glucose metabolism involving reduced sensitivity of muscle, adipose tissue, liver and other tissues to insulin despite normal or elevated blood levels of insulin.

Insulin is secreted by the beta cells of the pancreas and, acting via specific receptors present on the surface of most cells in the body, is responsible for maintaining normal blood glucose levels. In a state of insulin resistance, higher levels of insulin are required to ensure normal carbohydrate metabolism, both under basal conditions and in response to a physiological increase in post-meal glycaemia.

What could be the causes of insulin resistance?

Insulin resistance can be primary (genetically determined) or secondary (acquired). The most common cause of insulin resistance is obesity and excessive abdominal fat accumulation.

A state of reduced insulin sensitivity also develops in a number of endocrine disorders associated with the presence in the blood of a substance or hormone with antagonistic effects to insulin. Insulin resistance accompanies many diseases associated with impaired endocrine function such as:

• acromegaly or growth hormone deficiency,
• Hypercortisolemia in Cushing's syndrome,
• thyroid dysfunction,
• hyperprolactinaemia,
• congenital adrenal hyperplasia,
• gonadal disorders (mainly polycystic ovary syndrome)
• syndromes associated with ovarian and testicular insufficiency.

Significantly lower insulin sensitivity is also presented by women with eating disorders in the form of anorexia or bulimia. This condition persists even many years after weight normalisation.

What are the symptoms of insulin resistance?

Virtually the majority of people with abdominal-type obesity have reduced tissue sensitivity to insulin. Thus, pathological fat accumulation is a symptom of reduced insulin sensitivity. A visible exponent of insulin resistance is a symptom in the form of dark discolouration on the skin of the neck (acanthosis nigricans). In women, menstrual disorders and excessive hair in areas typical of men (hirsutism) may occur.

How to detect insulin resistance? Research

Methods for diagnosing insulin resistance in people without diabetes are based on simultaneous determination of serum glucose and insulin levels Glucose and insulin levels are measured either under basal conditions or after intravenous administration of a specific amount of glucose or insulin.

Tests to assess insulin sensitivity can be divided into direct and indirect. Currently, measurement of tissue glucose consumption by the 'euglycaemic metabolic clamp' method is considered the 'gold standard' for assessing insulin sensitivity. This method involves the simultaneous intravenous infusion of insulin and glucose with calculation of the glucose distribution ratio (GDR). However, this method is time-consuming, technically quite complex and rather feasible only in a hospital setting.

In patients with normal glucose tolerance and without yet impaired insulin secretion, calculated indirect indices can be introduced to estimate insulin sensitivity. The most commonly used in clinical practice is the HOMA-IR (Homeostasis Model Assesment) mathematical model, which is calculated from basal insulin levels and fasting glycaemia [IR=fasting insulinaemia (mU/ml) x fasting glycaemia (mmol/l)/22.5]. Similarly, the logarithmic Qantative Insulin Sensitivity Check Index QUICKI is calculated.

In the group of people with impaired glucose tolerance, the Mastuda index has a higher value. In its calculation, the mean value of glycaemia and insulinaemia during an oral glucose load test is used. However, it should be emphasised that the above tests can only be performed in people without diabetes. In people with diabetes, in addition to the rarely performed 'metabolic buckle', indirect estimated indices of tissue glucose distribution are calculated. Metabolic compensation of diabetes (glycated haemoglobin value), Waist/Hip ratio-WHR or the presence of hypertension are taken into account. Serum lipid levels, particularly elevated triglycerides, are also thought to correlate with the level of insulin resistance.

Is insulin resistance treatable?

Insulin resistance in itself is not a disease - it is a symptom that accompanies obesity or a range of reversible and irreversible diseases. There is some genetic susceptibility to impaired function of the receptors for insulin. In this case, effective diet and weight normalisation, as well as drug treatment, only promotes improved insulin sensitivity.

In the case of acquired insulin resistance caused by fat accumulation, an effective diet and weight reduction can almost completely eliminate the problem.

In the course of an endocrine imbalance, the best therapeutic results in terms of improving the insulin sensitivity of tissues come from effective treatment. However, full recovery from a particular endocrine disease is not always possible. Normalisation of carbohydrate imbalance depends on many factors such as:

• age,
• duration and severity of endocrine or metabolic disorders,
• genetic predisposition.

Therefore, behavioural and pharmacological management should be implemented to reduce insulin resistance. When impaired insulin sensitivity is a consequence of obesity, measures aimed at weight reduction through diet and exercise lead to a reduction in insulin resistance. In pharmacological management, a drug called metformin is used. Metformin is the first-line treatment for type 2 diabetes, but also for pre-diabetic conditions and impaired insulin sensitivity. Metformin reduces insulin resistance mainly in the liver and peripheral tissues (skeletal muscle and adipose tissue). In addition, virtually the same drugs used in type 2 diabetes (incretins, glitazones) are used in the treatment of insulin resistance.

Insulin resistance - effects

A long-term state of reduced insulin sensitivity can consequently lead to the development of hyperglycaemia, impaired glucose tolerance and overt type 2 diabetes. The development of type 2 diabetes is mainly triggered by obesity with associated insulin resistance. As a consequence of the pancreas working "at high speed" for many years to break down insulin-resistant tissues, insulin secretion declines and metabolic disorders become apparent. In a state of insulin resistance, hyperlipidaemia (mainly hypertriglyceridaemia), hypertension are also more frequently found, which, along with abdominal obesity, are components of the so-called 'metabolic syndrome'. The metabolic syndrome, on the other hand, is a strong risk factor for cardiovascular disease and premature atherosclerosis. In women, it has furthermore been observed that insulin resistance and elevated insulin levels may be an important element in the pathogenesis of polycystic ovary syndrome (PCOS).

Insulin resistance and fertility

Insulin resistance and elevated insulin levels may be an important element in the pathogenesis of polycystic ovary syndrome - PCOS. Hyperinsulinaemia increases the activity of the pituitary-hypothalamic-adrenal axis, resulting in increased androgen production. Adverse effects of hyperinsulinaemia on the ovaries have also been observed. Through an increase in the number of receptors for luteinising hormone (LH) and insulin-like growth factor (IGF-1), there is an increased production of testosterone. Increased levels of hormones such as testosterone, insulin and IGF-1 block the maturation of the ovarian follicles towards the dominant follicle and inhibit the onset of ovulation.

Increased insulin levels further inhibit the synthesis of sex hormone-binding protein (SHBG), resulting in increased concentrations of the biologically active fraction of free testosterone. Many authors emphasise the occurrence of PCOS in genetically predisposed women following an initiating factor such as obesity or hyperinsulinaemia. It should also be mentioned that obese men with metabolic syndrome and insulin resistance also have lower testosterone levels and poorer sperm quality. Higher levels of body fat favour excessive conversion of testosterone to oestradiol. In older men, insulin resistance and associated chronic inflammation is a cause of premature atherosclerosis responsible for erectile dysfunction.

Insulin resistance and pregnancy. Important information

Women with insulin resistance and polycystic ovary syndrome have reduced fertility and are often diagnosed or treated for infertility. However, this does not exclude the possibility of spontaneous pregnancy. A significant percentage of women with PCOS have ovulatory cycles. When considering the relationship between insulin resistance and pregnancy, the situation of the individual patient must therefore be taken into account. Only after appropriate investigations and history can the doctor say more about fertility in insulin resistance.

Is pregnancy higher risk with insulin resistance?

Obese women with insulin resistance are at high risk of developing gestational diabetes, pregnancy-induced hypertension or pre-eclampsia. It also happens, especially in women over 35that disorders of carbohydrate metabolism, hyperlipidaemia or hypertension are diagnosed even before pregnancy. Effective treatment of these conditions then reduces the risk of foetal loss.

Before pregnancy, insulin resistance-reducing drugs such as metformin are used. However, current guidelines do not recommend the use of this drug during pregnancy - it should be discontinued when pregnancy is confirmed. However, there is scientific evidence for the safety of this drug also during pregnancy. It is important to note that only some antihypertensive drugs can be used during pregnancy, so they should be switched to those that are safe already in the pre-conceptional period. Some blood pressure lowering drugs have a teratogenic effect and should preferably not be used in women of childbearing potential who are not using effective contraception. In the pregnancy of an obese woman with insulin resistance, weight gain should also be carefully monitored and excessive weight gain during pregnancy should be avoided. Women with a BMI >30 kg/m2 should not gain more than 8 kg. Moderate exercise is also beneficial, provided there are no obstetric contraindications.

How to improve fertility with insulin resistance?

Many women wonder how to improve fertility when diagnosed with insulin resistance. Reducing weight by lowering insulinemia causes a decrease in androgen production and can lead to a return of ovulation. On the other hand, support with metformin, an insulin sensitising drug, appears to be effective in inducing ovulation and return of impaired fertility in PCOS. It is increasingly being shown to be superior to clomiphene, a first-line anti-estrogen drug. Patients with PCOS become pregnant more frequently with dual therapy with metformin and clomiphene. Metformin is also used to treat insulin resistance-related hyperandrogenism manifested by hirsutism or acne. Similarly, in obese men with sub-fertility - reducing body weight improves sperm quality. Improving fertility with insulin resistance is therefore possible and worth the effort.

An important risk factor for the development of PCOS syndrome is obesity in childhood and adolescence. Excessive levels of body fat are responsible for the increase in insulin resistance and so characteristic of puberty. Excessively elevated insulin levels during this period lead to premature puberty and the development of PCOS in genetically predisposed individuals. In view of the above facts, appropriate healthy eating habits and physical exercise that will prevent excessive weight gain can significantly reduce the risk of insulin resistance in the future. And, consequently, reduce the negative impact of insulin resistance on fertility.

It is worth remembering that insulin resistance in itself is not a disease entity. By leading a healthy, balanced lifestyle, we can effectively protect ourselves against it, preventing future health problems. The general condition of the body in both women and men has a significant impact on fertility. When planning for a larger family, let us take care of ourselves regularly by ensuring a good diet, exercise, relaxation and nourishing sleep every night.