Insulin Resistance: Theory and Practice

Introduction

The XX century radically transformed both the lifespan and the causes of death for people. The current adult generation exhibits lower health indicators compared to previous generations. The real age of an individual needs to be calculated by adding 15 years, according to The Daily Mail [1]. The prevalence of obesity among 40-year-old men and women can confidently be equated to levels seen in 55-year-olds.

Etiology

Insulin release in the human body is managed by the pancreas, which possesses both exocrine and endocrine functions. The exocrine function of the organ is realized through the secretion of pancreatic juice containing digestive enzymes. By producing hormones, the pancreas plays a crucial role in regulating carbohydrate, fat, and protein metabolism.

Among the main glandular cells releasing pancreatic juice, there are clusters of specialized cells called the Islets of Langerhans (pancreatic islets), consisting of α-, β-, and δ-cells. α-cells secrete the hormone glucagon. Functions of glucagon include increasing blood glucose levels by breaking down glycogen in the liver and stimulating lipid breakdown. β-cells secrete the hormone insulin. Functions of insulin include increasing cell membrane permeability to glucose, facilitating its transition from the blood into tissue cells; promoting the conversion of glucose into glycogen in the liver and muscles; reducing blood glucose levels; stimulating protein synthesis, lipid metabolism, and more.

Thus, insulin and glucagon determine the consistency of blood glucose levels, regulating carbohydrate metabolism.

Several diseases are linked to a diet rich in fats and calories, low physical activity, and consequently, obesity. These conditions often coexist as they share a common complex of changes known as the metabolic syndrome. It includes insulin resistance, or elevated fasting blood glucose levels, obesity in various forms, dyslipidemia, and elevated blood pressure.

Insulin resistance is the reduced sensitivity of insulin-dependent cells to insulin action, leading to impaired glucose metabolism and its uptake into cells.

Factors that provoke decreased insulin reactivity include:

•  Genetic predisposition,
• Excess body weight,
• Arterial hypertension,
• Inadequate physical activity,
• Unhealthy diet,
• Infectious diseases,
• Harmful habits,
• Poor sleep (disrupted sleep-wake cycle),
• Frequent stressful situations.

Insulin resistance is one of the key and proven mechanisms of aging and the pathogenesis of age-associated diseases. Current data from available literature indicate an increased risk of mortality in patients with IR/type II diabetes and COVID-19 compared to patients without such disorders. On the other hand, COVID-19 infection induces insulin resistance in patients who did not have it before infection.

Cutaneous markers of insulin resistance:

• Acanthosis nigricans – darkening of the armpits, skin folds, finger joints on the hands and feet,
• Abdominal obesity,
• Increased hair growth above the upper lip,
• Cracks on the heels,
• Papilloma growth,
• Red spots on the body,
• Deterioration of skin, hair, nails,
• Slow wound healing.

Behavioral signs of insulin resistance:

• Persistent hunger (a drop in blood sugar increases hunger),
• Excessive thirst,
• Frequent urination (especially at night), increased urine volume,
• Numbness and tingling in the extremities,
• Cravings for sweets, stress eating,
• Chronic fatigue,
• Sleepiness, weakness.

Consequences of insulin resistance:

• Excess weight. Excess insulin greatly reduces blood glucose levels, which, in turn, signals to the brain that the body urgently needs nutrients. This creates a vicious cycle: the more we eat, the more often we feel hungry.
• Reduced immunity and frequent infectious diseases. Insulin stimulates the activity of T-lymphocytes, helping them to divide quickly and activate the immune system. With insulin resistance, immune cells become less effective in fighting viruses and some bacteria.
• Polycystic ovary syndrome. The most common hormonal disorder in women of reproductive age and one of the main causes of infertility, affecting 8–13% of young women. Prolonged elevated insulin levels stimulate the ovaries to produce androgens.
• Pancreatic dysfunction. Pancreatic cells are replaced by secretory tissue of the pancreas. As a result of digestion disorders, the development of diabetes occurs. This arises from impaired carbohydrate metabolism and insulin secretion.
• “Sugar face” – inflamed, aging skin. Reduced tissue sensitivity to insulin can lead to skin problems such as reduced skin resistance to bacterial, fungal infections (folliculitis, acne), increased sebum production (a consequence of hyperandrogenism), exacerbation of androgenic alopecia, chronic inflammation, and oxidative stress (increased frequency of autoimmune diseases, such as psoriasis), impaired wound healing, disturbed microcirculation in the skin, collagen structure disruption, skin aging.

• Oncology. Insulin resistance is associated with an increased risk of developing colorectal cancer, endometrial cancer, pancreatic cancer, and breast cancer.

How to Recognize Insulin Resistance?

Metabolic syndrome is traditionally considered a reversible condition and usually does not involve obvious organ damage before the development of diabetes. Although type II diabetes is the main manifestation of metabolic syndrome, in some cases, arterial hypertension (hypertension) may develop earlier or, in the presence of additional lipid metabolism pathologies, ischemic heart disease (angina) [4].

Overall, detecting one component of the metabolic syndrome indicates the need to check other components. Early concern about the development of diabetes, hypertension, and other metabolic disorders is highly beneficial. Lifestyle and diet are easier to modify when there are no clinical manifestations of diseases yet, and the effect can be complete normalization of metabolism without medication [5].

However, it sometimes happens that the development of insulin resistance and diabetes goes unnoticed in a person with normal or slightly increased BMI. The term “Skinny Fat” refers to individuals with asthenic, less frequently normosthenic body build, who have poorly developed muscles and an increased percentage of subcutaneous fat (from 20-22%). At the same time, their weight is within the normal range relative to their height, age, and constitution. Excess fat with a thin muscle corset makes their figure saggy, disproportionate, and flabby. An increased percentage of subcutaneous fat with average body weight can be observed in both women and men.

How to Recognize Insulin Resistance?

Metabolic syndrome is traditionally considered a reversible condition and usually does not involve obvious organ damage before the development of diabetes. Although type II diabetes is the main manifestation of metabolic syndrome, in some cases, arterial hypertension (hypertension) may develop earlier or, in the presence of additional lipid metabolism pathologies, ischemic heart disease (angina) [4].

Overall, detecting one component of the metabolic syndrome indicates the need to check other components. Early concern about the development of diabetes, hypertension, and other metabolic disorders is highly beneficial. Lifestyle and diet are easier to modify when there are no clinical manifestations of diseases yet, and the effect can be complete normalization of metabolism without medication [5].

However, it sometimes happens that the development of insulin resistance and diabetes goes unnoticed in a person with normal or slightly increased BMI. The term “Skinny Fat” refers to individuals with asthenic, less frequently normosthenic body build, who have poorly developed muscles and an increased percentage of subcutaneous fat (from 20-22%). At the same time, their weight is within the normal range relative to their height, age, and constitution. Excess fat with a thin muscle corset makes their figure saggy, disproportionate, and flabby. An increased percentage of subcutaneous fat with average body weight can be observed in both women and men.

Signs of Skinny Fat:

• Low-hanging buttocks,
• Soft folds when the gluteal muscles are tensed,
• Cellulite visible without grasping the fold,
• Absence of waist, protruding or sagging abdomen, presence of palpable fat fold when the abdomen is tensed,
• Sagging of the lateral surface of the thigh when lifting the leg in a lying position,
• Fat deposits in the area of “love handles” and saddlebags on the thighs,
• Flabby thin arms, inability to push up, pull up, or carry weight over 3-4 kg,
• Formation of side rolls above jeans and underwear.

In addition to the listed signs, Skinny Fat individuals may have slender legs, thin wrists, neck, and ankles.

The localization of fat deposits depends on the type of figure (thyroid, gynoid, and others).

In the view of most doctors, obesity and metabolic syndrome are synonymous, but the key feature of metabolic syndrome is insulin resistance, not obesity.

Conversely, sometimes a person suffering from obesity does not exhibit other signs of metabolic syndrome. In most populations, subgroups of people with excess body weight who do not have health problems can be identified. This category is highly debatable because health criteria can be interpreted differently. According to the softest criteria, in Europe and North America, up to 50% of people with obesity fall into this group, while according to the strictest criteria, about 7% [6] [7]. Approximately 25-30% of overweight individuals have no metabolic problems and can be considered quite healthy: they have normal blood pressure, good cholesterol and lipid profiles, stable blood sugar levels, and most importantly, they do not suffer from insulin resistance.

Dr. Frank Hu, a professor of nutrition and epidemiology at the Harvard School of Public Health, believes that healthy plumpness can be determined by the following criteria: waist circumference not exceeding 101 cm for men and 89 cm for women, blood pressure, cholesterol, and blood sugar levels within normal limits, normal insulin sensitivity, good physical fitness.

A study published in 2011 showed that overweight but metabolically healthy individuals are at lower risk of heart disease than individuals with normal weight but increased insulin resistance.

What determines the development of metabolic syndrome in slim individuals or those of healthy plumpness?

Human adipose tissues are heterogeneous. In all patients with metabolic syndrome, visceral adipose tissue thickens, but in patients without an increase in BMI, its growth relative to subcutaneous adipose tissue is significantly higher [8]. It is important to note that the absolute level of lipid disorders still matters. Researchers from Oxford compared the absolute expression of ectopic and visceral obesity in patients with type II diabetes with obesity and normal body mass but the same duration of illness. In the latter group, not only were all deposits of adipose tissue smaller, but complications related to them from the liver and heart were also less pronounced [9]. Adipose tissue cells (adipocytes) can respond to an excess of lipids in two ways: by increasing the size of cells (hypertrophy) and by increasing the number of cells (hyperplasia) [10]. The healthy response of adipose tissue to the need for calorie storage is hyperplasia with a moderate increase in cell size. In this variant, the influence of adipocytes on the body is minimal. If adipose tissue has a low capacity for hyperplasia or if the lipid load is very high, the sizes of adipocytes increase multiple times. In response to such cellular stress, local inflammation develops in adipose tissue, leading to systemic inflammation; insulin resistance develops; lipids transition to visceral fat depots [11] [Fig. 2]. Possible reasons for the low ability of adipose tissue to hyperplasia include a smaller number of stem cells, altered growth factor balance, and low receptor sensitivity. In patients with type II diabetes without obesity, hypertrophy of adipocytes significantly prevails over hyperplasia, and the size of cells correlates with the severity of metabolic disorders [11].

Insulin resistance is the basis of the pathogenesis of many metabolic disorders and conditions. Additionally, it worsens the course of chronic diseases and accelerates the development of their complications. Therefore, insulin resistance can be a potential target for therapeutic interventions.

In this context, a new extract-peptide complex with active components 1-DNJ and IPH LGAT pancreatic peptides becomes of interest. This complex can influence the insulin receptor and increase tissue sensitivity to insulin, which is accompanied by the activation of insulin-dependent glucose metabolism.

1-Deoxynojirimycin (DNJ) is a natural analogue of D-glucose. It can inhibit α-glucosidase in the small intestine and liver, enhance adiponectin mRNA expression in white adipose tissue, slow down aging of blood vessels, and affect reverse cholesterol metabolism. Studies on 1-DNJ have shown that it improves lipid homeostasis and attenuates liver steatosis in mice. Human studies have demonstrated that 1-DNJ significantly suppresses postprandial blood glucose elevation and insulin secretion.

The second active component of the preparation is short peptides IPH derived from sea urchins and shrimp. The IPH LGAT peptide complex has tissue-specific effects on pancreatic cells, contributing to the normalization of carbohydrate metabolism, improvement of digestive enzyme synthesis by pancreatic cells, and normalization of digestion processes.

Although short insulin-potentiating peptides have been described in a patent (EP No. 1268518 Insulin potentiating peptides, IPC C 07 K 5/10; A 61 K 38/07; A 61 K 38/08, 2001), it should be noted that the claimed peptide compound – LGAT tetrapeptide – has no structural analogs. Its action is aimed at obtaining a new biologically active compound of peptide nature regulating glucose levels in both types of diabetes.

The tetrapeptide is obtained by the classical method of peptide synthesis in solution. This invention relates to a new tetrapeptide lysine-glutamate-aspartyl-tryptophan amide with the general formula: Lys-Glu-Asp-Trp-NH2, sequence 1 [SEQ ID NO:1], possessing biological activity manifested in regulating glucose levels. Such action has been demonstrated in experiments on alloxan diabetes. Alloxan diabetes is characterized by damage to pancreatic cells and pronounced hyperglycemia due to insulin deficiency and activation of gluconeogenesis.

Additionally, the preparation contains plant extracts that lower LDL cholesterol levels, decrease glucose levels, restore liver glycogen stores, improve digestion, alleviate constipation, and stimulate fat metabolism.

Conclusion

In conclusion, unbalanced and excessive nutrition is never beneficial for the body and can lead to serious diseases, sometimes despite having a normal body mass or leading a long comfortable life with obesity. Lifestyle changes, control over a balanced diet and sleep, stress resilience, and adding nutraceutical support from outside sources form the basis for preventing insulin-dependent diseases.