COVID-19 vaccines and blood glucose control: Friend or foe?

ABSTRACT

Purpose

To overview the recent literature regarding the relationship between COVID-19 vaccines and glycemic control.

Methods

Data were extracted from text and tables of all available articles published up to September 2023 in PubMed Database describing glucose homeostasis data in subjects exposed to COVID-19 vaccines, focusing on patients with diabetes mellitus (DM).

Results

It is debated if the immune system impairment observed in diabetic patients makes them susceptible to lower efficacy of vaccines, but evidence suggests a possible improvement in immune response in those with good glycemic control. Despite their proven protective role lowering infection rates and disease severity, COVID-19 vaccines can result in diabetic ketoacidosis, new-onset diabetes, or episodes of hyper- or hypoglycemia.

Conclusions

Evidence with COVID-19 vaccines highlights the strong relationship existing between DM and immune system function. Clinicians should strive to achieve optimal glucose control before vaccination and promptly manage possible glucose homeostasis derangement following vaccine exposure.

KEYWORDS:

• Diabetes
• vaccine
• COVID-19
• immune system
• immunosenescence

Introduction

Vaccines are the most efficient and safe public health interventions, being able to decrease the incidence of certain infections and disease-related morbidity and mortality, with an excellent cost-benefit ratio.¹ Moreover, they offer “social shield” for vulnerable individuals who can’t receive vaccinations due to immunodeficiency.² The SARS-CoV-2 related disease (COVID-19) has been the largest epidemic event in the past decades and an extraordinary challenge for modern healthcare system. Although pneumonia and acute respiratory distress syndrome are the major concerns of COVID-19, a huge number of complication has been associated with this viral infection, possibly affecting multiple organs and systems, and leading to long-lasting consequences.³ The endocrine systems is majorly targeted during the acute phase of COVID-19, hence many possible derangements may occur, including new-onset symptoms or worsening of previous endocrine disorders (Table 1).⁴ From a pathophysiological perspective, a direct damage from the virus could be responsible. Indeed, the hypothalamus, the pituitary and many peripheral endocrine glands (e.g. thyroid, gonads, pancreatic islets) express the angiotensin-converting-enzyme-2 (ACE2) receptor, which is deemed to aid viral entrance through the cell surface.^4–6 To date, following COVID-19, there has been a reported increase of 30–50% in the incidence of type 2 DM (T2DM) compared with individuals without infection.^7,8 A complex mutual relationship indeed exists between immune system activity and glucose homeostasis^9,10 and it is established that DM subjects have worse infective disease outcomes,^11,12 with higher hospitalization risk and up to 7-fold higher mortality rates compared with healthy subjects.¹³ The COVID-19 health emergency raised the need of straightforward policies to protect DM individuals^14,15 and the American Diabetes Association’s (ADA’s) recommendations suggest to prioritize and offer COVID-19 vaccines to people with diabetes.¹⁶ Interestingly in this concern, beyond the possible effects directly related to the viral infection, some authors also reported endocrine-related clinical manifestations following COVID-19 vaccine administration, involving the thyroid, pituitary gland, adrenals, and also pancreatic islets and glucose homeostasis, suggesting a possible direct mechanism of disruption played by vaccine administration.¹⁷ In this narrative mini-review, we aim to provide an up-to date overview of the literature concerning the interplay between COVID-19 vaccines and glycemic control in individuals with DM. For this purpose, we reviewed all available perspective, retrospective, and review articles published up to September 2023 in PubMed Database reporting data on either the impact of DM and glycemic control on the response to COVID-19 vaccination or the effects of COVID-19 vaccines on altered glucose homeostasis. The search terms used included “diabetes,” “COVID-19 vaccination,” “blood glucose,” “immune response.” Data were extracted from the main text and from the tables of the manuscripts retrieved. Only articles written in English were considered.

Table 1. Endocrine system-related clinical disorders observed after COVID-19 infection.

Endocrine gland	Clinical manifestation
Pituitary	Panhypopituitarism Pituitary apoplexy Central diabetes insipidus SIADH (syndrome of inappropriate ADH secretion)
Thyroid	Subacute thyroiditis Thyrotoxicosis Graves’ disease Hashimoto’s thyroiditis
Parathyroid	Hypoparathyroidism Hyperphosphatemia Hypocalcemia
Adrenals	Adrenal insufficiency Addison’s disease
Gonads	Orchitis Sexual dysfunction Low serum testosterone
Pancreas	Acute pancreatitis β-cell destruction Hyperglycemia Newly-onset type 1 diabetes Insulin-resistance and newly-onset type 2 diabetes

Table adapted from Mirza et al. COVID-19 and the Endocrine System: A Review of the Current Information and Misinformation, 2022.

Impact of DM and glycemic control on the immune response to COVID-19 vaccines

Clinical evidence

There is an ongoing debate concerning the potential impact of poor glycemic control on the antibody response to COVID-19 vaccines and their effectiveness in diabetic individuals. Adequate glycemic and metabolic control is indeed considered vital for achieving an optimal immune response post-vaccination. Findings from a meta-analysis of 43 studies suggest that glucose control plays a pivotal role in determining the antibody response to all vaccines recommended to adults with DM, particularly among elderly.¹⁸ To date, few studies have explored this association within the context of COVID-19 vaccination in the diabetic population, yielding conflicting results. In a longitudinal cohort of healthcare professionals, Lustig et al. described a lower antibody response to COVID‐19 vaccination in individuals with DM compared with healthy controls; a similar effect was noted for older age, male gender and hypertension.¹⁹ In another cohort of 374 Japanese health workers, Mitsunaga and colleagues found that older age, hypertension and serum glycosylated hemoglobin (HbA1c) ≥ 6.5% at the time of vaccination were independent predictors of a lower immune response, as evidenced by lower anti-SARS-CoV-2 spike-specific antibody titer observed 7–20 days post-vaccination.²⁰ In line with these observations, in a study of 555 older residents of long-term care facilities participating in the GeroCovid Vax study, Virgilio et al. found that residents with T2DM had a weaker antibody response to the first dose of COVID-19 vaccine compared with those without diabetes. However, no differences were observed between residents with T2DM using insulin and non-diabetics, suggesting that insulin therapy might buffer this effect and restore the humoral response²¹.In a cohort of 262 adult individuals (81 with T2DM and 181 non-diabetic subjects), Ali and coauthors found that both T2DM patients and non-diabetic subjects elicited a strong immune response after the second dose of COVID-19 mRNA based-vaccine. Nonetheless, individuals with T2DM showed lower levels of anti-SARS-CoV-2 IgG and neutralizing antibodies as compared with non-diabetics, while no significant differences were observed with regard to body mass index (BMI), age, gender, and hypertension status.²² Consistently with these findings, in the Italian experience documented in the CAVEAT study, significantly reduced virus-neutralizing antibody capacity was observed in T2DM patients with serum HbA1c above 7% when compared to healthy normo-glycemic subjects and T2DM group with optimal glycemic control.²³ Interestingly, at 2 months follow-up, there was no improvement of immune response among those who continued to have poor glycemic control. However, those who achieved glycemic control after the initial assessment demonstrated a significant increase in immune response, suggesting that optimizing glucose control may enhance vaccine-induced response. Conversely, a prospective observational study by Papadokostaki and colleagues including 174 participants (14 with type 1 diabetes mellitus (T1DM), 44 with T2DM, and 116 without DM) showed that almost 17% of participants with DM did not develop adequate humoral immune response to the BNT162b2 mRNA-based vaccine after the first dose; however, the humoral immune response was high and similar between individuals with and without DM, especially after the second dose of the vaccine. Moreover, the authors found no significant correlation between anti-SARS-CoV-2 receptor-binding domain IgG titer and either age, DM duration or HbA1c levels.²⁴ In a prospective multicenter study conducted in Europe, no differences were observed in humoral responses to COVID-19 vaccination among 150 adults with DM (including T1DM and T2DM) and age-matched healthy subjects, regardless of whether they had good or poor glycemic control. Interestingly, the authors found that only age and poor renal function were associated with reduced immune responses following vaccination.²⁵ Also, in a cohort-study involving 81 adolescents with T1DM and moderate to poor glycemic control (median HbA1c: 8.6%), no differences were observed in humoral immune responses induced by vaccine administration when compared with 71 healthy control subjects. Furthermore, comparable occurrences of SARS-CoV-2 breakthrough infections were noted in both cohorts over a 6-month monitoring phase,²⁶ emphasizing the practical significance of these findings.

Pathogenetic hypotheses

As previously mentioned, impaired glycemic control is considered a crucial determinant of compromised immune system activity and function, partly explaining the higher risk of infection observed in the diabetic population.²⁷ In this context, a recent article investigated several factors that may account for this increased risk in people with DM.²⁸ According to the literature, there are three primary mechanisms through which diabetes can disrupt the functioning of the immune system:

• –Alteration of the adaptive immune system, which includes a reduction in T-regulatory cells, γδ T cells with limited secretion of IFN-2, alterations in the polarization of TH1-TH2 cells, and a decreased ability of B-cells to produce the anti-inflammatory cytokine IL-10;^28–32

• –Disruption of the innate immune system, characterized by endothelial dysfunction, reduced recruitment of neutrophils (resulting in decreased chemotaxis and phagocytosis capabilities), decreased NK lymphocytes, and increased production of pro-inflammatory cytokines;^33–37

• –Impact on glucose metabolism, leading to oxidative stress that interferes with both cellular and humoral immunity, further exacerbating cytokine release^38,39 Oxidative damage and inflammatory stress resulting from “cytokine storms” throughout one’s life can harm immune cells, contributing to the concept of “immunosenescence,” which explains the elevated risk of infection (and reduced innate response to vaccine antigens) frequently observed in older individuals.^40,41 One could speculate that similarly to the age-related vulnerability to infectious disease reported in DM patients, a reduced response to vaccine antigens could be observed in this population, especially in the elderly.

Impact of COVID-19 vaccines on glucose homeostasis

Clinical evidence

Despite previous evidence reassuring about vaccines’ neutral effect on glycemic control,^42,43 a rising number of recent reports highlights potential disruptions linked to COVID-19 vaccines. The most commonly reported adverse events after COVID-19 vaccination are local reactions (e.g. pain and the tenderness at the injection site), followed by mild to moderate systemic side effects such as headache, fatigue, and muscle pain.⁴⁴ Nevertheless, severe adverse events in both adults and children have also been described, including anaphylaxis,⁴⁵ myocarditis/pericarditis⁴⁶ and thrombosis.⁴⁷ Interestingly, some potentially severe vaccine-induced effects on glucose homeostasis have been reported in either subjects with DM, or in subjects without history of DM, suggesting a possible direct mechanism disrupting glucose homeostasis. A case-series by Edwards and colleagues⁴⁸ described 3 cases of acute and severe hyperglycemia arising shortly after the first administration of adenovirus-vectored COVID-19 (ChAdOx1) vaccine, occurred in obese subjects and in adult men with prediabetes. Cases of glycemic derangement have also been described following administration of COVID-19 mRNA vaccines. These include a case of severe diabetic ketoacidosis (DKA) in a young girl with T1DM,⁴⁹ and 3 cases (1 with new onset T2DM) of hyperglycemic hyperosmotic state (HHS) appeared within 2–10 days of vaccine exposure.⁵⁰ Moreover, Sasaki et al.⁵¹ reported the new onset of T1DM 8 weeks after the 2^nd administration of mRNA vaccine, which was associated with a marked anti-COVID-19 immunization. Similarly, Aydoğan and colleagues⁵² reported 4 cases of adult-onset T1DM occurring 2–8 weeks after mRNA vaccine in previously euglycemic subjects. DKA after the first administration of mRNA vaccine was also reported in a previously healthy 50 years old Chinese man, who was lately found to harbor genetic predisposition to fulminant diabetes (HLA: DQB1 × 02:03/03:03 and DRB1 × 09:01/09:01).⁵³ In a retrospective experience from two Italian centers, the authors found no significant difference of time in range (TIR), total daily insulin and bolus insulin requirement in 39 adolescents and young adults with T1DM treated with either advanced hybrid closed-loop (AHCL) insulin delivery system or multiple daily insulin injections (MDI) using a flash glucose monitoring (FGM) system.⁵⁴ Similar results were observed in a study carried out in Greece on 70 young adolescents with T1DM,⁵⁵ in a small Italian series of 35 subjects with T1DM using a continuous glucose monitoring (CGM) device,⁵⁶ in another Italian cohort-study involving 150 T1DM adults,⁵⁷ and in a Chinese cohort of subjects with T2DM.⁵⁸ Similarly, a retrospective study of 74 individuals with T1DM and T2DM using CGM enrolled in the multicenter COVAC-DM Study also showed no significant difference in TIR around the COVID-19 vaccination. However, a deterioration of glucose levels, represented by a decrease of TIR and an increase of time above range (TAR), was observed in T1DM patients on days on which typical vaccine-related side effects were present.⁵⁹ Conversely, in a retrospective analysis of 97 adult patients with T1DM using a FGM system, 58% of subjects experienced major perturbations of glucose control, with 30% and 10% of individuals showing a decrease of TIR of over 10% and 20%, respectively, in the 7 days after the first COVID-19 vaccination. Interestingly, this effect was more pronounced when HbA1c was lower and in patients taking oral hypoglycemic agents (metformin/dapagliflozin) in addition to basal – bolus insulin regimen. Moreover, there was no difference between mRNA-based and viral vector-based vaccines in relation to their metabolic effect.⁶⁰ Similar results were demonstrated in a smaller cohort of 20 adults with T1DM, in which the greatest fall in the % of glucose levels on target was reported in older patients, those taking metformin/dapagliflozin + basal – bolus insulin, and those with higher BMI⁶¹ In both these studies, there was no significant change in glucose variability in the 7 days post- COVID-19 vaccination compared with the previous week.^60,61 On the other hand, in the largest T1DM adult cohort so far described, the “PRO-VACS” study, conducted on 454 subjects, the authors found a higher glycemic variability without significant difference of glycemic control parameters after mRNA-1273 COVID-19 vaccine administrations.⁶² An analysis of the European reporting frequency of impaired glucose metabolism events among COVID-19 vaccines in 2021 also confirmed the finding of a larger glycemic variability, especially in subjects who received mRNA-based vaccines.⁶³ In particular, mRNA vaccines were associated with a higher reporting frequency of both T1DM and T2DM, hyperglycemia, hypoglycemia, and inadequate control of DM compared to viral vector-based vaccines.⁶³ Interestingly, while no similar result had been previously described, in a recent retrospective Chinese T2DM cohort, Lin et al. observed that the use of SGLT2i was independently associated with a reduced risk of glycemic control worsening after vaccination.⁶⁴

Pathogenetic hypotheses

Although a possible association between COVID-19 vaccination and the onset of hyperglycemia and related complications has been widely reported in both young and adult populations,^7,65 their frequency and underlying mechanisms remain largely speculative. In this context, three main pathogenic hypotheses have been proposed:

- Direct vaccine-mediated pancreatic damage. It is well established that SARS-CoV-2 virus can infect and replicate inside human pancreas.⁶⁶ Despite the heterogeneity of its expression on β-cell surface, the presence of the ACE-2 receptor is believed to facilitate viral entry.⁶⁷ Consistently, viral RNA has been found in β-cells of patients with COVID-19, possibly leading to β-cell dysregulation and consequent hyperglycemia.⁶⁸ Intriguingly, cases of pancreatic injury, acute pancreatitis, and even recurrent pancreatitis have been documented post-COVID-19 vaccination^69,70 even in individuals without concurrent SARS-Cov-2 infection, suggesting a potential direct vaccine-related mechanism of harm.

- Exaggerated vaccine-induced inflammatory response causing pancreatic injury. Beyond the hypothesis of a direct insult to the islets, the most reliable hypothesis to explain SARS-CoV-2 related pancreatic damage seems to be strictly related to the exaggerated immune response induced by the viral infection, often resulting in massive release of pro-inflammatory factors (IL-1, IL-6, TNF) known as “cytokine storm.” Some recent evidence suggests that this hyperinflammation process might be partially mediated by mast cell activation.⁷¹ Eventually, a strong glycol-metabolic disruption seems to be associated with this paradoxical immune system activation, resulting in decreased pancreatic blood flow, increased oxidative stress, reduction of insulin production rate, and a peripheral reduction in insulin-sensitivity.^72,73 Genetic susceptibility to abnormal cytokine release after vaccination has been described.⁷⁴ Although a similar release of cytokines has never been documented in vivo after vaccination, some authors speculate that, due to molecular mimicry, vaccine excipients, viral vectors (eg. Covishield vaccine) or the SARS-CoV-2 spike protein derived from mRNA vaccines could trigger an abnormal immune response, favoring pancreatic inflammation, β-cell dysfunction, and ultimately leading to acute hyperglycemia (Figure 1).⁷⁵

Figure 1. Potential mechanism of post-COVID-19 vaccination hyperglycemia and related acute complications. Created with Biorender.com.

DKA = diabetic ketoacidosis; HHS = hyperglycemic hyperosmotic state

– Autoimmune damage to the islet triggered by immunization. β-cell dysfunction could be triggered by auto-immune damage following development of islet autoimmunity, which has been found to transiently increase in individuals with high genetic risk of T1DM after COVID-19.^76,77 Growing evidence suggests that certain COVID-19 vaccines may also trigger the onset or exacerbations of autoimmune diseases by molecular mimicry, including T1DM.^78,79

Conclusions

The experience with COVID-19 vaccines highlights the intricate mutual relationship between DM and immune system function, bearing practical implications for the clinical management of diabetic patients. Vaccination can trigger the immune system and favor inflammation, mast cell activation, and exaggerated cytokine release, potentially disrupting β-cell function, increasing oxidative stress, and altering insulin sensitivity. These factors may impact short-term blood sugar control, potentially resulting in DKA, new-onset diabetes, or episodes of hyper- or hypoglycemia. Therefore, prompt management of adverse glycemic events associated with vaccination is essential. Nevertheless, given the higher risk of viral infections in the diabetic population, vaccination remains the safest, most effective, and cost-effective public health measure, therefore strongly recommended for diabetic individuals. Furthermore, optimal glycemic control appears to enhance vaccine-induced immune responses, emphasizing the importance of striving for it to maximize the protective effects of vaccination.

Author contribution statement

All authors contributed to the manuscript conception and design.

ACB, WV and NB conceptualized the article and performed literature research.

ACB, WV and NB drafted the article.

AGL, GM, MM, SP and AN critically revised the work.

All authors have read and approve the final version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.