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Beware Of Insulin Resistance

Updated: Jul 5, 2022

With rising statistics over the years, obesity has become an area of concern because of its complexity. The classical definition of obesity includes an excess accumulation of body fat build up over time. It is a medical condition that enhances the risk of other metabolic disorders, such as diabetes, cardiac disease, hypertension, and some specific cancers.


Obesity is considered an epidemic because of its frequency in recent times. The effects of obesity on multiple organ systems and their diseases have mandated the study of the role of inflammation in the health complications of obesity, broadening different spectrums of its study and research. The most important spectrums that are evolving at a fast pace include immunology and nutrient physiology. [1]


The endocrine system is a very important system of our body. It is responsible for producing hormones that participate in various reactions of our body. Insulin is a hormone that is made by the pancreas and helps in glucose catabolism. It is one of the most important hormones in our body because any imbalance in its level leads to serious consequences. Insulin resistance, one of the imbalances of the endocrine system, occurs when tissues of the liver, heart, bones, and muscle stop responding to the available insulin, thereby failing to absorb glucose. This results in the production of more insulin and further failure to absorb glucose. Individuals who are obese, or have a history of PCOS, hypertension, gestational diabetes, or HIV, are at a higher risk of insulin resistance.


Obesity leads to insulin resistance. The major tissues that are affected by obesity are adipose, skeletal, and muscle tissues, thereby affecting organs such as the liver, gut, pancreas (islets of Langerhans), and brain. This creates a disorder in insulin functioning, scientifically known as obesity-linked inflammation, causing cardiovascular diseases and type 2 diabetes mellitus. [2]


A high-fat diet (HFD) containing dietary saturated fatty acids leads to obesity by causing hypoxic stress in the adipose tissues. This causes metabolic endotoxemia with an increase in lipopolysaccharide levels in plasma, which promotes inflammation in adipose tissues by the activation and polarisation of immunologically important cells.


This can also be explained from a broader perspective. Not only does it have a physiological relation but also that at a molecular or cellular level. It has immunological reactions, where particles of small size and higher molecular weight act as chemical messengers to carry out various functions of the cell.


The link between obesity and any disease is inflammation. Inflammation is the instant coordinated response of our body to a stimulus. The response triggered by obesity involves a complementary action of the classical and systemic inflammatory responses. The role of this inflammatory response is, thus, to respond to pathogens, to circulate inflammatory cytokines and acute C-reactive proteins, to regulate the migration and activation of leukocytes to inflamed tissues, and to generate the required responses.


Inflammation is an immune response that majorly includes cells such as B cells, macrophages, natural killer cells, T cells, neutrophils, eosinophils, mast cells, along with cytokines such as tumour necrosis factors (TNFs) and interferons.


Obesity-linked inflammation is guided by both adaptive and innate immunities. This first incidence of inflammation linked to obesity that was reported was an elevation in TNF-α level in the adipose tissue. Following this, repeated incidences of inflammation were reported in adipose tissues in animals and humans suffering from obesity.


For experimentation, TNF-α was induced on messenger RNA and the expression was observed in the adipose tissue from four different rodent models of obesity and diabetes. An elevation in the protein was observed locally and systemically. Neutralisation of the protein expressed resulted in the peripheral uptake of glucose in response to insulin significantly. This experiment highlighted the contribution of obesity to insulin resistance and diabetes.

Illustration Credit: Ben Smith


Obesity leads to the accumulation of fat, especially in the abdomen and the visceral organs. Waist size of more than 40 inches in men and more than 35 inches in women leads to obesity-linked inflammation. Research shows that belly fat contributes majorly to the secretion of hormones that contribute to chronic or long-lasting inflammation, which then leads to insulin resistance, type 2 diabetes, and cardiovascular disease.


In terms of immunological and molecular interactions, adipose tissues are rich in type 2 immune cells such as M2-like macrophages (M2), innate lymphoid type 2 cells (ILC2), regulatory T cells (Treg), T helper type 2 cells (Th2), and eosinophils which, upon interaction with each other, produce type 2 cytokines such as IL (interleukin)-4, IL-5, and IL-13.


Inflammation plays a major role in obesity and thus, contributes majorly to systemic and local insulin resistance. It exerts autocrine effects on cells of inflammation responsible for insulin signalling and metabolism, particularly in adipocytes. Apart from this, the endocrine effects of inflammatory molecules secreted by cells have a deep impact on insulin sensitivity in other tissues, particularly skeletal, muscle, and liver. In adverse conditions, it can lead to fat spillover from adipocytes to other tissues, such as skeletal, muscle, and liver, leading to ectopic fat deposition and insulin resistance. [3]


The cytokines secreted by immune cells, adipose tissue, and adipocytes help them interact with each other. Alternatively, they communicate by direct cell-cell contact. This leads to activation, polarization, and inflammation of immune cells and adipocytes.


This mechanism of understanding has helped develop novel drugs and targets. A new therapy for the same is targeting inflammation for diseases where insulin resistance is a major characteristic. This mechanism has been used in the development of multiple anti-diabetic and anti-inflammatory drugs, although the challenge remains in the fact that this approach is quite difficult in treating most metabolic disorders. [4]



References


[1] Lumeng, C.N. and Saltiel, A.R., 2011. Inflammatory links between obesity and metabolic disease. The Journal of clinical investigation, 121(6), pp.2111-2117.


[2] Wu, H. and Ballantyne, C.M., 2020. Metabolic inflammation and insulin resistance in obesity. Circulation research, 126 (11), pp.1549-1564.


[3] Hotamisligil, G.S., 2017. Inflammation, metaflammation and immunometabolic disorders. Nature, 542 (7640), pp.177-185.


[4] McLaughlin, T., Ackerman, S.E., Shen, L. and Engleman, E., 2017. Role of innate and adaptive immunity in obesity-associated metabolic disease. The Journal of clinical investigation, 127 (1), pp.5-13.

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