|INVITED BRIEF COMMUNICATION
|Year : 2022 | Volume
| Issue : 2 | Page : 207-209
Obesity is the alleyway to insulin resistance and Type 2 diabetes mellitus
Susmita Sinha1, Mainul Haque2
1 Department of Physiology, Khulna City Medical College and Hospital, Khulna, Bangladesh
2 The Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kuala Lumpur, Malaysia
|Date of Submission||13-Jan-2022|
|Date of Decision||27-Jan-2022|
|Date of Acceptance||31-Jan-2022|
|Date of Web Publication||04-Mar-2022|
The Unit of Pharmacology, Faculty of Medicine and Defence Health, Universiti Pertahanan Nasional Malaysia (National Defence University of Malaysia), Kem Perdana Sungai Besi, Kuala Lumpur
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Sinha S, Haque M. Obesity is the alleyway to insulin resistance and Type 2 diabetes mellitus. Adv Hum Biol 2022;12:207-9
Obesity is becoming a prevalent health problem worldwide and is a significant risk factor for developing insulin resistance, type 2 diabetes mellitus (T2DM) and coronary artery disease. Several causes lead to obesity, including genetic and environmental factors. Genetic factors account for 40%–70% of obesity cases. However, environmental factors such as unhealthy eating patterns and the absence of physical activity play a significant role in producing obesity. The precise mechanism by which adipose tissue causes insulin resistance is not discovered yet. The cause of insulin resistance in obesity and T2DM involves the complex interplay of multiple metabolic pathways. Metabolites such as lipids, amino acids and bile acids can regulate insulin sensitivity by modulating insulin signalling pathway components. Many studies showed that obesity is linked with adipocyte dysfunction, macrophage infiltration and low-grade inflammation. Moreover, these factors may have contributed to the development of insulin resistance. Health complications resulting from obesity have become one of the leading causes of mortality in developed countries. Obesity-related adipose tissue mass gain requires further detailed research to understand the influence of this tissue on the generation of insulin resistance.
Obesity is a pathological increase in adipose tissue, which enhances the risk of several diseases, such as cardiovascular disease, some types of cancer and T2DM. Body mass index (BMI) is a simple index of weight-for-height that is commonly used to classify overweight and obesity in adults. It is defined as a person's weight in kilograms divided by the square of his height in meters (kg/m2). For adults, the WHO defines obesity as BMI ≥30. Studies have shown that obesity and related metabolic disorders depend upon the number of calories consumed, type of diet, frequency and timing of meals., It has been reported that diet and physical activity are independently associated with obesity. Furthermore, duration of sleep and daytime sleepiness are linked with obesity. Insulin is an anabolic hormone secreted by β-cells of pancreatic islets, causing glycogen accumulation in the liver and skeletal muscles. This hormone decreases blood glucose levels by increasing glucose uptake by muscles and adipose tissue, stimulates glucose oxidation and glycogenesis and inhibits gluconeogenesis and glycogenolysis. It also stimulates lipogenesis and inhibits lipolysis, which leads to the storage of free fatty acids (FFAs) in triacylglycerol in adipose tissue. Moreover, it increases the uptake of amino acids by tissues and enhances protein synthesis. Insulin resistance is a decrease in tissue response to insulin stimulation. It is characterised by defects in uptake and oxidation of glucose, a decrease in glycogen synthesis and, to a lesser extent, the ability to suppress lipid oxidation, resulting in elevated blood glucose levels. Insulin has a wide variety of effects on metabolic processes in adipocytes. Thus, it plays an important role in regulating anti-lipolytic processes. In addition, declination of cell sensitivity to insulin or impairment of the insulin pathway may affect the metabolism of adipose tissue. The mechanisms that link obesity with insulin resistance are still uncertain. However, some studies suggest that obese subjects have fewer insulin receptors, especially in the skeletal muscle, liver and adipose tissue, than lean subjects. Insulin resistance is mostly caused by defects of the signalling pathways that link receptor activation with multiple cellular effects. Impaired insulin signalling may be closely related to toxic effects of lipid accumulation in tissues such as skeletal muscle and liver due to excess weight gain. Impairment of insulin action on the adipose tissue contributes to systemic insulin resistance. Adipose tissue is an endocrine organ that influences glucose and lipid metabolism by releasing adipokines, pro-inflammatory factors and FFAs, which adversely affects glucose metabolism and muscle adenosine triphosphate synthesis, promotes the generation of toxic substances through lipid metabolism and alters insulin signaling.,, Insulin acts on adipose tissue first by stimulating glucose uptake and triglyceride synthesis and second by suppressing triglyceride hydrolysis and releasing FFA and glycerol into the circulation. Adipose tissue insulin resistance index (Adipo-IR) represents an index for adipose tissue resistance to the anti-lipolytic effect of insulin, which has been linked with glucose intolerance and elevated plasma FFA levels.,, Increased plasma FFA levels cause impaired muscle insulin signalling, promote hepatic gluconeogenesis and impair glucose-stimulated insulin response., Recent studies have shown, several indices of Adipo-IR have been proposed that are based on tracer turnover (i.e., labelled palmitate or glycerol) or FFA suppression during insulin infusion (euglycaemic-hyperinsulinaemic clamp) or oral glucose tolerance test. In contrast, another study used the product of fasting plasma FFA and fasting plasma insulin concentrations as the index of Adipo-IR as the circulating plasma FFA concentration closely reflects the rate of peripheral lipolysis. Adipose tissue synthesises and secretes various bioactive molecules such as adipokines and cytokines. The tissue adipocytokines (leptin, adiponectin, tumour necrosis factor-α (TNF-α), interleukin-6 and plasminogen activator inhibitor-1) are synthesised and secreted into the bloodstream, which affects the insulin sensitivity of tissues, such as skeletal muscles and the liver. In addition, adiponectin is one of the few adipokines that have a protective effect on developing metabolic disorders, e.g., insulin resistance. In obese individuals, low plasma adiponectin levels are found in different ethnic groups. There is a significant positive correlation between serum concentration of adiponectin and insulin sensitivity., It has been observed that plasma adiponectin concentration significantly decreased in the high-fat diet (HFD) group compared to the control group. Other adipokines are leptin, which is produced by adipocytes. The concentration of leptin in plasma elevates with increased adipose tissue mass and decreases body weight during ingestion of a low-fat diet. Interleukin-6 is a cytokine produced in the immune system cells, which inhibits the expression of insulin receptors and reduces adiponectin expression., Studies have shown that obesity is accompanied by moderate inflammation, in which adipocytes and immune cells present in adipose tissue contribute to increasing the level of circulating pro-inflammatory cytokines such as TNF-α. Besides, TNF-α is involved in the inflammatory reaction that links central obesity with insulin resistance. It inhibits an insulin-stimulated tyrosine kinase activity of the insulin receptor and insulin receptor substrate-1. As a result, impairs docking of insulin-regulated glucose transporter (GLUT4) impairs docking with the plasma membrane, thereby decreasing insulin-dependent glucose transport to the cells. Studies showed that plasma TNF-α concentration is increased in the HFD group compared to the control group. Furthermore, it is known that TNF-α activates sphingomyelinase, thereby stimulating ceramide production. It has been demonstrated that ceramide accumulation in adipose tissue inhibits adiponectin secretion. Under physiological conditions, insulin inhibits hormone-sensitive lipase (HSL) activity, so the release of fatty acids is limited in the presence of high glucose concentration. In an insulin-resistant state, insulin cannot hinder HSL, which results in an increased plasma FFA concentration. Other peripheral tissues uptake plasma FFAs used in the β-oxidation as an energy source or as a substrate for de novo synthesis of other lipids. It has been established that lipid accumulation in the skeletal muscle or the liver is responsible for the induction of insulin resistance.,,,, Again, in T2DM, the insulin response is diminished, and during this state, insulin is ineffective and is initially countered by an increase in insulin production to maintain glucose homeostasis. Insulin production decreases with time, resulting in T2DM. Most of the patients with T2DM are obese and have a higher body fat percentage. The increased adipose tissue mass of obese individuals enhances the risk of metabolic syndrome, T2DM and cardiovascular diseases. This adipose tissue promotes insulin resistance through various inflammatory mechanisms, including increased FFA release and adipokine dysregulation resulting in T2DM.,,,
According to the latest data, the accumulation of biologically active lipids in adipose tissue is probably related to the development of insulin resistance. These studies specify that the collection of biologically active lipids in adipose tissue may regulate the synthesis and secretion of adipokines and pro-inflammatory cytokines.,, The role of bioactive lipid accumulation in adipose tissue is not understood clearly yet. Adipose tissue is the primary site responsible for insulin-dependent glucose metabolism besides the skeletal muscle and the liver. Therefore, metabolic disturbances in these tissues lead to the induction of insulin resistance. Recent studies have discovered that inflammation caused by excess fatty tissue and defects in lipid metabolism may be responsible for developing obesity-related insulin resistance. However, the mechanism linking obesity and adipose tissue inflammation with insulin resistance are still not fully elucidated. Therefore, understanding the relationship between obesity and adipose tissue dysfunction with insulin resistance is crucial, could provide information for further medical care, early diagnosis and treatments for metabolic disorders and minimise obesity-related other complications.
Assessment of circulating nucleosome could be a helpful marker of obesity and metabolic syndrome. In both humans and animals, nucleosomes are released in response to several factors such as obesity, a HFD and inflammation. Although the available data are encouraging, advanced research is needed to determine the exact mechanism for insulin resistance associated with obesity.
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