A new study from Hong Kong Baptist University examined how mRNA COVID-19 vaccines might influence insulin signaling.
The finding?
The spike protein can interfere with metabolic pathways - but mainly in people with type 2 diabetes (T2D)🧵
The finding?
The spike protein can interfere with metabolic pathways - but mainly in people with type 2 diabetes (T2D)🧵
In mice given 4 doses of the mRNA vaccine, researchers observed impaired glucose tolerance, reduced insulin sensitivity, and higher triglycerides.
At the molecular level, phosphorylation of IRβ and Akt - key insulin signaling steps - was reduced.
Liver transcriptomics showed activation of NF-κB, MAPK, and AMPK-related pathways.
Liver transcriptomics showed activation of NF-κB, MAPK, and AMPK-related pathways.
Mechanistically, the spike protein interacts not only with ACE2, but also with TLR4 and the estrogen receptor (ER).
These interactions disrupt insulin signaling.
Blocking TLR4 or stimulating ER largely prevented the metabolic effects.
These interactions disrupt insulin signaling.
Blocking TLR4 or stimulating ER largely prevented the metabolic effects.
In the human arm (n 180)
Healthy - no significant change
Prediabetes - mild, non-significant fluctuations
T2D - measurable worsening of insulin sensitivity (↑HOMA-IR, ↑TG, ↑HbA1c)
The magnitude of this effect correlated with anti-spike antibody levels.
Healthy - no significant change
Prediabetes - mild, non-significant fluctuations
T2D - measurable worsening of insulin sensitivity (↑HOMA-IR, ↑TG, ↑HbA1c)
The magnitude of this effect correlated with anti-spike antibody levels.
Metformin showed a protective effect improving insulin sensitivity and restoring IR/Akt phosphorylation, without weakening the immune response to the vaccine.
Mechanistically, this worked through AMPK activation and dampening of TLR4-driven inflammation.
Mechanistically, this worked through AMPK activation and dampening of TLR4-driven inflammation.
The spike behaves as a metabolically active ligand, capable of triggering inflammatory and insulin-resistant signaling - especially in already dysregulated metabolic states (T2D, obesity).
Healthy individuals appear able to compensate.
Healthy individuals appear able to compensate.
The study did not show whether these effects are transient.
In mice, they persisted for ≥4 weeks after the last dose.
In humans, follow-up lasted only 14 days - too short to know if glucose metabolism normalizes.
In mice, they persisted for ≥4 weeks after the last dose.
In humans, follow-up lasted only 14 days - too short to know if glucose metabolism normalizes.
Limits.
Only 14-day human follow-up
Small sample (66 T2D)
No unvacc control group
High cumulative mRNA dose in mice
Observational design (cannot prove causality)
Only 14-day human follow-up
Small sample (66 T2D)
No unvacc control group
High cumulative mRNA dose in mice
Observational design (cannot prove causality)
It shows that the spike protein itself can have systemic, non-immune effects, particularly in metabolically vulnerable groups.
Authors’ takeaway - monitor glycemia after boosters - and metformin may offer protection.
Authors’ takeaway - monitor glycemia after boosters - and metformin may offer protection.
Zhai et al., MedComm 2025. SARS-CoV-2 Spike Protein as a Target of the COVID-19 Vaccine Disrupts Insulin Signaling in Type 2 Diabetes. onlinelibrary.wiley.com/doi/10.1002/mc…
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