Does Insulin cause Atherosclerosis?

Main Points

• Insulin is not inherently atherogenic: When tested in isolation (in insulin-sensitive models), elevated insulin does not increase plaque formation.

• Context matters: In insulin resistance, cells may reroute insulin signaling through alternative pathways (e.g., via the IGF-1 receptor) that promote inflammation and plaque growth.

• Study 1: Smooth muscle cells with diminished insulin receptors showed more inflammatory activation and cell migration, likely via non-insulin receptor pathways.

• Study 2: Mice with high insulin but normal sensitivity developed no more plaque than controls, showing that insulin resistance—not insulin itself—is the likely driver of vascular harm.

• Clinical takeaway: Insulin injections at physiological doses (as used in Type 1 diabetes) are unlikely to promote atherosclerosis. The combination of hyperinsulinemia and insulin resistance, common in Type 2 diabetes and prediabetes, is more concerning.

• Intervention: Improving insulin sensitivity through exercise and dietary modification can reduce both glucose and insulin levels and potentially lower atherosclerotic risk.

More on mechanisms is covered in the full analysis, found here. 

Insulin resistance is a well-known contributor to cardiovascular disease, often leading to Type 2 diabetes. But while high blood glucose is commonly blamed for this risk, there’s a deeper question worth exploring: is insulin itself contributing to atherosclerosis—or is its effect dependent on the context in which it’s found?

This article explores that question by diving into molecular studies and animal models, examining how insulin interacts with vascular tissue, and teasing apart the complex relationship between insulin levels, insulin resistance, and artery plaque development.

The Hypothesis: Is Insulin the Poison?

Some researchers argue that elevated insulin—hyperinsulinemia—promotes atherosclerosis (plaque buildup in arteries), while others claim that insulin is only harmful when paired with insulin resistance. This is more than an academic debate: if insulin is independently atherogenic, then insulin injections, especially in type 1 diabetics, could pose a risk. On the other hand, if context is key, then insulin alone may not be harmful at all.

Study 1: Insulin’s Effects on Vascular Smooth Muscle Cells

In a molecular study [A, B], researchers applied low to very high levels of insulin directly to smooth muscle cells—those involved in blood vessel constriction and plaque development. Some cells had normal insulin receptor function, while others were genetically modified to drastically reduce their insulin receptor activity.

• Result: In normal cells, insulin activated the Akt pathway, known for its role in metabolism and cell survival.

• Surprisingly, in receptor-deficient cells, another pathway—related to inflammation and migration—was more activated, despite reduced insulin signaling in the insulin receptor deficient cells. This pathway is associated with atherosclerosis.

This unexpected finding suggests that impaired insulin signaling may reroute insulin’s actions through alternative receptors—particularly the IGF-1 receptor, which becomes more active in insulin resistance and can drive pro-atherogenic processes like cell migration and inflammation.

Study 2: Hyperinsulinemia Without Insulin Resistance

To isolate insulin’s effects from insulin resistance, researchers used a clever animal model [C]:

• Mice were genetically altered (∆ in the image below) to have only one functioning insulin receptor gene (haploinsufficiency), leading to elevated insulin levels in the blood.

• These mice were also insulin sensitive and genetically predisposed to develop plaque (APOE-deficient).

• Result: Despite higher insulin levels, the (∆) mice did not develop more plaque than control mice.

This demonstrates that hyperinsulinemia alone does not appear to promote atherosclerosis—insulin resistance must be present for insulin to have a pro-plaque effect.

Mechanistic Insight: The Role of IGF-1 Receptors

In insulin-resistant states, cells may downregulate insulin receptors but upregulate IGF-1 receptors, which can also bind insulin. Unlike the metabolic Akt pathway, the IGF-1 receptor activates the ERK pathway, linked to inflammation and smooth muscle cell migration—both key steps in plaque progression. This shift in receptor usage may be what makes insulin dangerous in the insulin-resistant state. More on mechanisms is covered in the full analysis, found here. 

Clinical Implications

This evidence challenges the idea that insulin is intrinsically harmful. Physiological doses of insulin, like those used in Type 1 diabetes, likely do not promote plaque formation. However, in insulin-resistant states—such as prediabetes and advanced Type 2 diabetes—where more insulin is needed to control blood sugar, the combination of elevated insulin and impaired insulin signaling may contribute significantly to atherosclerosis.

The good news? Insulin resistance can be reversed or improved through lifestyle interventions:

• Exercise improves insulin sensitivity and reduces both glucose and insulin levels.

• Dietary changes—whether low-carb, plant-based, or simply less processed and lower in calories—can reduce the metabolic load on the body and improve vascular outcomes.

Main Points

• Insulin is not inherently atherogenic: When tested in isolation (in insulin-sensitive models), elevated insulin does not increase plaque formation.

• Context matters: In insulin resistance, cells may reroute insulin signaling through alternative pathways (e.g., via the IGF-1 receptor) that promote inflammation and plaque growth.

• Study 1: Smooth muscle cells with diminished insulin receptors showed more inflammatory activation and cell migration, likely via non-insulin receptor pathways.

• Study 2: Mice with high insulin but normal sensitivity developed no more plaque than controls, showing that insulin resistance—not insulin itself—is the likely driver of vascular harm.

• Clinical takeaway: Insulin injections at physiological doses (as used in Type 1 diabetes) are unlikely to promote atherosclerosis. The combination of hyperinsulinemia and insulin resistance, common in Type 2 diabetes and prediabetes, is more concerning.

• Intervention: Improving insulin sensitivity through exercise and dietary modification can reduce both glucose and insulin levels and potentially lower atherosclerotic risk.

More on mechanisms is covered in the full analysis, found here. 

Dr. Nicolas Verhoeven, PhD / Physionic

References

[A] Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 2011;14(5):575-585. doi:10.1016/j.cmet.2011.07.015

[B] Lightell DJ Jr, Moss SC, Woods TC. Loss of canonical insulin signaling accelerates vascular smooth muscle cell proliferation and migration through changes in p27Kip1 regulation. Endocrinology. 2011;152(2):651-658. doi:10.1210/en.2010-0722

[C] Rask-Madsen C, Buonomo E, Li Q, et al. Hyperinsulinemia does not change atherosclerosis development in apolipoprotein E null mice. Arterioscler Thromb Vasc Biol. 2012;32(5):1124-1131. doi:10.1161/ATVBAHA.111.239558