Energy Toxicity and Insulin Resistance

In this episode of The Metabolic Classroom, Dr. Bikman, a biomedical scientist and professor of cell biology, delves into the concept of energy toxicity.

He begins by explaining that energy toxicity attempts to explain why certain cells, particularly those capable of storing energy like muscle and liver cells, become insulin resistant. The primary idea is that when these cells accumulate excess energy, particularly in the form of triglycerides, they become resistant to further energy storage by becoming insulin resistant. He clarifies that this is closely related to lipotoxicity, where the stored fat itself, rather than glycogen, is seen as the main culprit for this condition.

Ben notes that while the notion of energy toxicity encompasses both glucose and fats, triglycerides, a type of fat stored in muscle and liver cells, play a significant role. However, studies, such as one on endurance athletes, have shown that muscle triglycerides alone do not cause insulin resistance, leading to the concept of the “athlete’s paradox.”

Dr. Bikman further explores the biochemical pathways involved in insulin resistance, emphasizing that specific lipid intermediates, particularly diacylglycerols (DAGs) and ceramides, are more relevant than triglycerides in causing insulin resistance. DAGs disrupt the insulin signaling pathway by activating protein kinase C, while ceramides inhibit insulin signaling and affect mitochondrial function, increasing reactive oxygen species and contributing to insulin resistance.

Ben challenges the notion of energy toxicity as a primary cause of insulin resistance, advocating instead for a focus on lipotoxicity and its mediators. He concludes that chronically elevated insulin levels, rather than the stored energy itself, are the main drivers of insulin resistance, suggesting that the term “insulin toxicity” might be more appropriate. This understanding is crucial for addressing what he identifies as the most common health issue worldwide—insulin resistance.

01:16: Defining Energy Toxicity

02:58: Lipotoxicity vs. Energy Toxicity

06:20: Ectopic Fat Storage

08:20: Triglycerides in Muscle Cells

13:57: The Athlete's Paradox

17:11: DAGs and Insulin Resistance

19:26: Ceramides and Mitochondrial Function

29:21: Insulin and Lipolysis

33:59: High Insulin and Insulin Resistance

Studies Referenced:

A phenomenon known as the “athlete’s paradox”:

https://academic.oup.com/jcem/article/86/12/5755/2849249

https://www.sciencedirect.com/science/article/abs/pii/S0165614717300962?via=ihub

https://www.sciencedirect.com/science/article/pii/S0021925820859080?via=ihub

https://www.jci.org/articles/view/43378

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