Insulin Resistance, Obesity, and Lipotoxicity

Sep 17, 2024Advances in experimental medicine and biology

How Insulin Resistance, Obesity, and Fat Damage Are Related

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Abstract

Lipotoxicity is associated with functional impairments in metabolic pathways across various organs, including the liver, heart, pancreas, and muscle.

Ectopic lipid accumulation in organs like the kidneys and liver may lead to conditions such as diabetic nephropathy and nonalcoholic fatty liver disease.
Insulin resistance caused by lipotoxicity could contribute to reproductive system disorders, including polycystic ovary syndrome.
Increased circulating lipid levels may correlate with insulin resistance in muscle and liver due to altered fatty acid utilization and signaling.
Mechanisms involving protein kinase C pathways and the JNK-1 pathway may explain how lipotoxicity induces insulin resistance in non-adipose tissues.
Mitochondrial dysfunction and endoplasmic reticulum stress, particularly through oxidative stress, are implicated in the development of insulin resistance.

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Lipotoxicity, originally used to describe the destructive effects of excess fat accumulation on glucose metabolism, causes functional impairments in several metabolic pathways, both in adipose tissue and peripheral organs, like liver, heart, pancreas, and muscle. Ectopic lipid accumulation in the kidneys, liver, and heart has important clinical counterparts like diabetic nephropathy in type 2 diabetes mellitus, obesity-related glomerulopathy, nonalcoholic fatty liver disease, and cardiomyopathy. Insulin resistance due to lipotoxicity indirectly lead to reproductive system disorders, like polycystic ovary syndrome. Lipotoxicity has roles in insulin resistance and pancreatic beta-cell dysfunction. Increased circulating levels of lipids and the metabolic alterations in fatty acid utilization and intracellular signaling have been related to insulin resistance in muscle and liver. Different pathways, like novel protein kinase c pathways and the JNK-1 pathway, are involved as the mechanisms of how lipotoxicity leads to insulin resistance in nonadipose tissue organs, such as liver and muscle. Mitochondrial dysfunction plays a role in the pathogenesis of insulin resistance. Endoplasmic reticulum stress, through mainly increased oxidative stress, also plays an important role in the etiology of insulin resistance, especially seen in non-alcoholic fatty liver disease. Visceral adiposity and insulin resistance both increase the cardiometabolic risk, and lipotoxicity seems to play a crucial role in the pathophysiology of these associations.

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Insulin Resistance, Obesity, and Lipotoxicity

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