The Influence of Insulin Levels on Lipid Parameters in Atherosclerotic Cardiovascular Disease (ASCV The Influence of Insulin Levels on Lipid Parameters in Atherosclerotic Cardiovascular Disease (ASCVD)

In this AMA episode of The Drive podcast, host Peter Attia answers questions related to atherosclerotic cardiovascular disease (ASCVD) risk factors. He explains the relationship between insulin levels and other lipid parameters like APO B and LDL-C. Insulin resistance and hyperinsulinemia are associated with worse outcomes in ASCVD. Insulin affects the expression of APO C3 and lipoprotein lipase, leading to increased triglyceride levels and the production of atherogenic LDL particles. Additionally, insulin plays a role in endothelial dysfunction, which further contributes to ASCVD risk. Attia suggests that measuring insulin levels through oral glucose tolerance testing may be useful in determining one’s risk profile.

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Key Insights:

  • Hyperinsulinemia, commonly seen in type 2 diabetes, is associated with increased risk of ASCVD.
  • The impact of insulin on ASCVD risk involves two important mechanisms: increased expression of APO C3 and impairment of endothelial function.
  • APO C3 plays a role in triglyceride metabolism and its increased expression leads to higher levels of triglycerides and a specific type of LDL particle that is more atherogenic.
  • Impaired endothelial function allows APO B particles to more easily penetrate the sub-endothelial space and initiate a cascade of events that drive ASCVD.
  • The association between insulin levels and ASCVD risk can be assessed through an oral glucose tolerance test (OGTT) which evaluates insulin response to glucose challenges.


Hey everyone, welcome to The Drive Podcast. I’m your host Peter Attia. Here, we have another AMA session, so let’s get started.

Today, we are discussing questions related to atherosclerotic cardiovascular disease (ASCVD) and its various parameters, such as ApoB, LDL-C, and insulin levels. These questions have been compiled from past podcast episodes, including AMA 34, Episode 210 with Lipoprotein(a), Episode 185 with Alan Snyderman, and Episode 140 with Gerard Shulman.

The main focus is to understand how these parameters collectively influence an individual’s risk of ASCVD. For instance, some people wonder how having low ApoB but high Lipoprotein(a) or good insulin levels but high LDL or ApoB can affect their overall risk profile.

To begin, let’s clarify the relationship between ApoB and LDL-C. ApoB is the concentration of all particles that carry the ApoB lipoprotein, including LDL. In contrast, LDL-C measures the concentration of cholesterol contained within the LDL particles. Although these measures are often concordant, they can sometimes be discordant. Nevertheless, ApoB is a better predictor of ASCVD risk because it accounts for the number of atherogenic particles, rather than just the cholesterol concentration.

Now, let’s discuss the relationship between insulin levels and other ASCVD parameters. It is established that hyperinsulinemia is associated with worse outcomes in ASCVD. Type 2 diabetes, in particular, represents an extreme manifestation of hyperinsulinemia. However, hyperinsulinemia can be detected even before glucose levels are affected, such as in a postprandial state where insulin is elevated but glucose is normal. In this context, hyperinsulinemia influences ASCVD risk through two primary mechanisms.

First, insulin affects the expression of ApoC3, a lipoprotein that plays a role in blocking lipoprotein lipase (LPL) activity. LPL is an enzyme that controls the breakdown of triglycerides. When ApoC3 is upregulated, LPL activity is inhibited, leading to increased levels of triglycerides. Since triglycerides require ApoB-bearing particles to be transported in plasma, their accumulation leads to a rise in ApoB concentration, thereby increasing ASCVD risk.

Second, hyperinsulinemia promotes endothelial dysfunction, which also contributes to ASCVD. Endothelial dysfunction increases the permeability of the endothelium, allowing ApoB particles to penetrate and initiate the atherosclerotic process. Although the direct measurement of endothelial function is challenging, laboratory studies on cultured endothelial cells suggest that insulin compromises their functionality.

In summary, hyperinsulinemia is associated with increased risk in ASCVD through its impact on ApoC3 expression and endothelial dysfunction. These mechanisms lead to elevated triglyceride levels, impaired LDL metabolism, and increased ApoB concentration.

Now, if you are interested in assessing your insulin levels, there are tests available. One such test is the oral glucose tolerance test (OGTT), which can help detect insulin resistance and hyperinsulinemia. This test challenges your glucose response by measuring insulin levels after consuming glucose. It can serve as an early indicator of impaired glucose metabolism.

Remember, regardless of age or current health status, it is essential to be aware of these risk factors and their interactions. Preventive measures can be taken even before overt clinical signs of ASCVD or diabetes appear.

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