This article was updated with Mandarin audio on November 20, 2025.
About the Author
As a physician with decades of experience in internal medicine and emergency medicine, I often manage patients with diabetes, metabolic syndrome, and cardiovascular disease. This article summarizes peer-reviewed research on insulin resistance, atherosclerosis, and nattokinase, aiming to help readers understand the biological mechanisms and limitations of current evidence.
Press play for the English audio below
🎧 Introducción en audio — Español (Latinoamérica)
En este audio hablaremos de cómo la resistencia a la insulina contribuye al desarrollo de la aterosclerosis y por qué este proceso puede comenzar muchos años antes de que aparezcan síntomas. También comentaremos estudios que exploran el papel de la nattokinasa como un posible apoyo para la salud vascular. Esta información es educativa y no reemplaza el consejo médico profesional.
This article discusses the relationship between insulin resistance and atherosclerosis formation and how nattokinase improves both.
Why Insulin Resistance Matters for Atherosclerosis
Insulin resistance is one of the most powerful and under-recognized drivers of cardiovascular disease. Even without diabetes, elevated insulin can trigger inflammation, smooth muscle proliferation, endothelial dysfunction, and progressive plaque buildup.
Understanding how these mechanisms work helps explain why interventions beyond lipid-lowering—such as improving insulin sensitivity—may influence plaque progression.
In a study previously referenced by Ren et al., they compared nattokinase (NK) 6,000 units with simvastatin 20 mg in 72 patients.
After 26 weeks, it showed that nattokinase (NK) and simvastatin could decrease total cholesterol (TC), low-density lipoprotein (LDL), and triglyceride (TG) levels.[1]
What is puzzling to them is that while simvastatin could lower TC, LDL, and TG more than nattokinase (P<0.01), the decrease in the thickness of the carotid atherosclerotic plaque was greater in the nattokinase group.
The reduction in the NK group was significantly profound (P<0.01, 36.6% reduction in plaque size in NK group versus 11.5% change in ST group).
How can NK decrease atherosclerosis more without causing the same decrease in lipid levels?
The answer lies in how atherosclerosis forms. The current dogma is the lipid hypothesis, which says that it is the cholesterol and LDL that cause atherosclerosis and cardiovascular disease.
Interpreting the Research Responsibly
The studies discussed here include human clinical trials, population studies, mechanistic reviews, and early-stage research. While the findings are promising, particularly the carotid plaque reduction seen with nattokinase, they should not be viewed as definitive medical treatment.
Large-scale, long-term randomized trials are still needed to determine the full clinical effects of nattokinase on cardiovascular outcomes.
Insulin Resistance and Atherosclerosis
In 2000, the Insulin Resistance Atherosclerosis Study (IRAS)was published in Circulation.After reviewing the studies, the authors proposed that insulin resistance leads to chronic inflammation and atherosclerosis formation.[2]
The Accepted Role of Inflammation
Modern cardiology recognizes atherosclerosis as an inflammatory disease, not merely a problem of cholesterol accumulation. Elevated insulin amplifies inflammatory pathways, increases oxidative stress, and promotes lipid uptake into arterial walls.
This aligns with the IRAS findings and supports the idea that targeting insulin resistance is essential for long-term vascular health.
Insulin resistance occurs when the skeletal muscles and liver do not respond to the physiologic or “normal dose” of insulin. The result is hyperinsulinemia, where there are higher levels of insulin.
Insulin stimulates other tissues other than the liver and skeletal muscles. Too much insulin causes disease.
A 1988 review explained how hyperinsulinemia accelerates atherosclerotic formation.[3]. Insulin promotes diet-induced atherosclerosis development and overrides healing and estrogen protection against atherosclerosis.[3]
Insulin has been shown to stimulate the smooth muscles and fibroblast cells in the arteries and increase the uptake of lipids by these cells and macrophages. Insulin also induces inhibition of fibrinolysis to allow clot progression.[3]
Diabetes does not have to be present for atherosclerosis to happen. It takes decades for atherosclerosis to present as a stroke or a heart attack. But like in everything else, atherosclerosis starts small and innocent-looking.
Post-prandial hyperglycemia, or the rise in blood sugar (glucose spike) levels after a meal, can induce damage to the inner lining of the arteries.
The body can repair the damage, but repeated insults from the glucose spikes can thicken atherosclerosis.
Stages of Atherosclerosis by By YitzhakNat – CC BY-SA 4.0,
Intermittent fasting can reverse insulin resistance. Fasting allows the body to use the circulating glucose and improve insulin sensitivity. Fasting can reverse insulin resistance to the point where the body uses its insulin again and can be weaned off prescription insulin.
But not all are inclined to miss a meal. Glucose spikes can be controlled with dietary changes without fasting. Eating vegetables first, then meat and fat, and carbohydrates last, can eliminate glucose spikes. A little walking after helps too.
The type of vegetables in the diet can also prevent high blood sugar after a meal. A Japanese study examined how eating viscose vegetables affects after-meal glucose levels in subjects who tend to spike blood sugar after a meal (glucose intolerance).[4]
The test meal included (50 gms natto, 60 gms Japanese yams, or 40 gms okras) with 200 g white rice. The control meal had white rice with non-viscous boiled soybeans, potatoes, and broccoli. Both meals contained comparable carbohydrates, fat, protein, and fiber.[4]
Natto is a traditional Japanese food made with fermented soybeans.
Results showed that eating viscose vegetables improves insulin sensitivity and total and LDL cholesterol. The authors explained that viscous fibers decrease insulin response by delaying gastric emptying and slowing absorption. [4]
Another possible explanation is the presence of nattokinase in natto. 50 gm of natto contains 2,000 Fibrin Units (FU) of nattokinase.
What Nattokinase Can and Cannot Do
Nattokinase has demonstrated biochemical effects—including fibrinolysis, improved blood flow, and favorable changes in some metabolic markers—but it is not a substitute for established treatments for diabetes, prediabetes, or cardiovascular disease.
The studies referenced here, although encouraging, are small and exploratory. They provide insight into possible mechanisms but cannot replace medical therapy prescribed by a clinician.
Nattokinase Improves Insulin Sensitivity
A double-blinded, randomized, controlled clinical trial over three months was conducted on 17 obese female subjects with diabetes. Nine received Natto 2,000 FU daily, and eight received an identical placebo capsule daily.[5]
After three months, both groups had no difference in weight loss. More subjects lost water weight in the Natto group (63%) compared to the Placebo group (33%).[5]
High insulin levels in insulin resistance promote water retention and add weight. They are stored in the fat and sometimes in the legs. When someone becomes more insulin sensitive, the insulin levels, water retention, and total weight decrease.
More subjects in the Natto group exemplify this. They had lower fasting insulin levels (75% vs. 22%), lower fasting glucose levels (50% vs. 22%), and lower HOMA index (63% vs. 22%).[5]
Additionally, more subjects in the Natto group had a decrease in HbA1c (43%) compared to Placebo (22%), with an average reduction in the Natto group of 0.9%.
Hemoglobin A1c,or glycated hemoglobin, is a blood test that measures the average blood sugar over the past two to three months. It is an indicator of blood sugar control in people with diabetes and is used to guide treatment.
The authors hypothesize that if treatment time was beyond three months, further metabolic improvement would be noted, indicating that natto could have potential as an adjunct to Diabetes Mellitus care.[5]
Understanding Population Data
The Takayama cohort study is valuable because it examines tens of thousands of participants over time, showing a correlation between natto intake and lower cardiovascular mortality.
However, dietary studies cannot prove causation. People who regularly consume natto may also engage in healthier lifestyles overall. Still, the consistency of CVD-protective signals across multiple natto-consuming populations makes these findings worth exploring further.
Natto and Nattokinase Intake Lower CVD Death Risk
The Takayama study demonstrated that natto could lower cardiovascular disease mortality. The research involved 13,355 male and 15,724 female participants aged ≥35 years.[6]
They showed that those with the highest natto intake have the lowest risk of death from total cardiovascular disease.
This article is for educational purposes only. The research discussed includes early-stage human trials, mechanistic studies, and population data. Nattokinase should not replace prescribed medications for diabetes, insulin resistance, or cardiovascular disease.
People taking blood thinners—such as warfarin, apixaban, rivaroxaban, or aspirin—should avoid nattokinase unless supervised by their healthcare provider.
Always consult your physician before starting or adjusting supplements.
Natto is uncommon in the US, but Nattokinase is readily available and inexpensive.
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