Abstract
Diabetes is associated with an increased risk of coronavirus disease 2019 (COVID-19)-associated morbidity and mortality. COVID-19 vaccines substantially reduce the risk of serious COVID-19 outcomes, making them important for individuals with diabetes. However, the effects of the COVID-19 vaccines on glucose control in patients with diabetes remain unclear. Here, we demonstrate that COVID-19 vaccine boosters impair insulin sensitivity in both mice and patients with type 2 diabetes (T2D). In mice, the administration of four vaccine doses elevated the levels of SARS-CoV-2 spike protein and impaired glucose tolerance and insulin sensitivity. Mechanistically, we showed that the SARS-CoV-2 spike protein, guided by the mRNA COVID-19 vaccine, interferes with insulin signaling by binding to angiotensin-converting enzyme 2, TLR4, and ER. We found that 66% of T2D patients exhibited aggravated insulin resistance to booster shots of the mRNA COVID-19 vaccine. Furthermore, treatment with metformin improved insulin signaling variations induced by COVID-19 vaccine boosters in mice. These findings indicate that COVID-19 vaccine boosters impair insulin sensitivity in T2D and that metformin may mitigate these effects. These results maintain the risk-benefit ratio in favor of COVID-19 vaccination for the prevention of severe clinical outcomes, yet highlight the need for close glycemic monitoring of patients with diabetes after receiving mRNA COVID-19.