Brief Introduction of Insulin Resistance and Its Effects

 Insulin is a crucial hormone that affects metabolism at an important level. Inefficiency or lower level of insulin is related to many chronic diseases. That is why understanding the mechanism and secretion of insulin became a priority in most of the research. Insulin is an endocrine peptide hormone that regulates anabolic responses by binding receptors in target cells¹. It is secreted in the pancreatic islets by the β cells². Insulin initiates its action by activation of tyrosine-specific protein kinase. The activation occurs with the binding of the insulin to a glycoprotein receptor, resulting in a signal that affects mainly glucose, also followed by lipid and protein metabolism³.

 Glucose homeostasis is maintained by the production of glucose in the liver. With the pathway of gluconeogenesis, glucose is carried outside of the liver and transported into skeletal muscle and adipose tissue by glucose transporter GLUT2 and insulin-sensitive GLUT4⁴. The insulin signaling pathways are affecting glucose homeostasis, so basically insulin regulation is affected. Insulin binding to Tyrosine kinase initiates the phosphorylation of insulin-receptor substances (IRS). After several steps, the interaction between PDK1 and Akt protein kinases is maintained, and glucose dynamics are regulated. It is observable that the signaling of insulin hormone plays a top role in glucose metabolism and any distribution related to this has many critical effects.

Insulin resistance marks the state that a normal or increased level of insulin cannot create the desired response². An in-vivo study showed that the dysfunction of several main molecules involved in the intercellular processing of insulin signals are the main reasons for insulin resistance, such as insulin receptor substrate (IRS)-2 and the protein kinase B (PKB)-β isoform⁵. The resistance occurs when body cells have created a resistance to insulin in different scenarios. For instance, having high glucose diet will increase insulin levels that are secreted from the host. The high amount of glucose in the blood results in the hypersecretion of insulin. Normally, the pancreas can keep up with the high insulin needed from the body. Unfortunately, after some time, either when the pancreas becomes tired in years (this can be explained with type 2 diabetes, the disease can be asymptomatic for years until the pancreas cannot produce the required insulin⁶) or cells increase their insulin resistance to a way higher levels due to other dysfunctions, the secreted insulin starts to not affect the metabolism as it should be. Whoever occurs first, hypersecretion or resistance is not fully clear. One study suggested that hypersecretion occurs first, and develops resistance after a couple of years in the individuals in the study⁷. Due to this fact, glucose intake from blood to cells is incredibly decreased, and the door for many chronic diseases opens. These diseases can be opened as obesity, hypertension, and dyslipidemia⁸. Disruption of insulin signaling in skeletal muscle, liver, and adipose tissue, cause hyperinsulinemia, a condition of excess level of insulin existence, and lead to diabetes in mices⁴. From the human perspective, studies showed that mutations in insulin signaling, for developing insulin resistance, showed a high level of circulating insulin, and showed the first start of diabetes⁴.

In the figure, the glucose dynamic and its feedback is designated. Meanwhile, some organs are only related to transporting or taking glucose, such as the stomach and brain, and some organs use it as a regulatory factor, like the liver or pancreas with insulin secretion. Insulin must travel into muscle and fat to regulate the glucose uptake in the cells, so any dysfunction in insulin signaling will directly affect these two parts.

 Several other studies create important relations between insulin resistance and the overall metabolism of lipids, protein, and glucose. For example, adiponectin, a 247-amino acid adipocytokine with a role in energy homeostasis and insulin sensitivity, has a relationship with insulin resistance. It is observed that adiponectin mRNA is reduced in adipose tissue in diabetic obese humans. Levels of adiponectin are negatively affected by obesity, cardiovascular disease, and insulin resistance⁸. Another research has shown that TNF-α, a proinflammatory cytokine can induce insulin resistance. The discovery drew attention in the 1990s, with the fact that a substance derived from fat directly affected the metabolism⁹. Their suggested research showed that neutralization of TNF-α in obese rats caused an increase in glucose uptake in the response to insulin¹⁰. Lipolysis is also discussed in the mechanisms of insulin resistance¹¹. Series of studies applied to individuals with acipimox, an inhibitor of lipolysis. When lipolysis is inhibited, the glucose infusion rate was greatly increased.

 Insulin is one of the star players in the metabolism and its impact cannot fit in several pages. For such a powerful hormone, its dysfunction’s effects are also powerful as the hormone itself and insulin resistance is the best example in that case. One developed unwanted resistance to a hormone that affects many different specific molecules in different areas of metabolism and organs. The diversity of this effect points out different diseases and each one of them is worth studying as a high priority. Understanding the mechanism of insulin, its effects, and its relationships with other systems are key factors to deal with insulin resistance and creating alternatives to decrease this effect in the system.

References:

1. Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev. 2018;98(4):2133-2223. doi:10.1152/physrev.00063.2017
2. Wilcox G. Insulin and Insulin Resistance. Clin Biochem Rev. 2005;26(2):19. Accessed May 17, 2022. /pmc/articles/PMC1204764/
3. Kahn C. The Molecular Mechanism of Insulin Action. Annu Rev Med. 1985;36(1):429-451. doi:10.1146/annurev.med.36.1.429
4. Czech MP. Insulin action and resistance in obesity and type 2 diabetes. Nat Med. 2017;23(7):804-814. doi:10.1038/nm.4350
5. Schinner S, Scherbaum W, Bornstein S, Barthel A. Molecular Mechanisms of Insulin Resistance in Glucagon-Producing. Diabet Med. 2005;22:674-682.
6. Wang G. Raison d’être of insulin resistance: The adjustable threshold hypothesis. J R Soc Interface. 2014;11(101). doi:10.1098/rsif.2014.0892
7. Isganaitis E, Lustig RH. Fast food, central nervous system insulin resistance, and obesity. Arterioscler Thromb Vasc Biol. 2005;25(12):2451-2462. doi:10.1161/01.ATV.0000186208.06964.91
8. Pittas AG, Joseph NA, Greenberg AS. Adipocytokines and Insulin Resistance. J Clin Endocrinol Metab. 2004;89(2):447-452. doi:10.1210/jc.2003-031005
9. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116(7):1793-1801. doi:10.1172/JCI29069
10. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose Expression of Tumor Necrosis Factor-α: Direct Role in Obesity-Linked Insulin Resistance. Science (80- ). 1993;259(5091):87-91. doi:10.1126/SCIENCE.7678183
11. Lucidi P, Rossetti P, Porcellati F, et al. Mechanisms of insulin resistance after insulin-induced hypoglycemia in humans: The role of lipolysis. Diabetes. 2010;59(6):1349-1357. doi:10.2337/db09-0745

Figure References:

1. Kahn C. The Molecular Mechanism of Insulin Action. Annu Rev Med. 1985;36(1):429-451. doi:10.1146/annurev.med.36.1.429
2. Wang G. Raison d’être of insulin resistance: The adjustable threshold hypothesis. J R Soc Interface. 2014;11(101). doi:10.1098/rsif.2014.0892

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