Correlation between COVID-19 vaccination and diabetes mellitus: A systematic review

Table 1 Characteristics of the included studies

Ref.	Country	Study design	Study time span	Population	Sample size (n)	No. of patients with DM (n) T1DM T2DM		Sex (F/M)	Age, median (min-max), yr	Type and name of vaccine	Dose schedule	Related findings
Zhang et al[23]	China	Observational study	Between October 2021 and January 2022	The population is aged ≥ 60 yr with hypertension or (/and) DM	1413	620		661/752	67.6	Vero cell (19nCov-CDC-Tan-HB02)	Two doses (day 0, day 28)	After vaccination, there was no significant abnormal fluctuation in blood glucose in diabetic patients
Marfella et al[24]	Italy	Prospective observational study	December 2020	Healthcare and educator workers	478		201	212/266	18-60	mRNA-BNT162b2 (Pfizer-BioNTech) or ChAdOx1-S (Astra-Zeneca) or mRNA-1273 (Moderna)	One (day 0, day 21) or two (day 52) doses	Significant decrease in the immune response in people with poorly controlled blood glucose
Kılınç-Toker et al[25]	Turkey	Retrospective study	Between August 1, 2021 and October 31, 2021	Hospitalized patients with COVID-19	541	195		282/259	70.2 (21-98)	(CoronaVac) and/or BNT162b2 mRNA (Pfizer-BioNTech)	14 d after dose 2	For hospitalized patients after the second dose, diabetes was not associated with their ICU stay and mortality
Barocci et al[26]	Italy	Observational study	Between December 2020 and June 2021	Healthcare workers and university staff	2845	8		155/129	43-61	ChAdOx1-S and (BNT162b2/BNT162b2 and ChAdOx1-S/ChAdOx1-S)	2 mo after dose 2	DM does not affect antibody levels
Singh et al[27]1	India	Cross-sectional study	Between January 16, 2021 and May 15, 2021	Healthcare workers	5154	0	52	210/305	44.8 ± 13.19	CovishieldTM (ChAdOx1-nCOV) or CovaxinTM (BBV-152)	One (day 21) and two (day 21-28, day 83-97, and day 173-187) doses	People with T2DM had a significantly lower seropositivity rate compared to those without
Singh et al[28]1	India	Longitudinal study	Between January 16, 2021 and November 15, 2021	Healthcare workers	481	0	51	195/286	≤ 60 years, n = 411; > 60 years, n = 70	CovishieldTM (ChAdOx1-nCOV) or CovaxinTM (BBV-152)	3 wk, 3 mo, and 6 mo after dose 2	Participants with T2DM have a lower seropositivity rate at all time points
Shim et al[29]	Korea	Retrospective study	February2021	Vaccination participants	736	48		433/303	51.5 (20-80)	AZD1222, BNT162b2, mRNA-1273 and Ad26.COV2.S	2 wk before and 6 mo after dose 2	Diabetics had a lower rate of neutralizing antibodies after vaccination
Alqassieh et al[30]	Jordan	Prospective observational cohort	Between March and April 2021	Jordanian adults	288	76		189/151	20-60 years, n = 137, > 60 years, n = 151	Pfizer-BioNTech or Sinopharm	6 wk after dose 2	Although DM negatively affected IgG titer, it was not statistically significant
Wan et al[31]	China (Hong Kong)	Population-based study	Between February 23, 2021 and January 31, 2022	Patients with T2DM in Hong Kong electronic case records	350963	0	350963	167073/183890	64.7 ± 1.37/68.1 ± 0.747	BNT162b2 or CoronaVac	Complete at least one dose of vaccination	Patients with T2DM do not appear to have higher risks of AESI and acute diabetic complications after vaccination
Lee et al[32]	South Korea	Questionnaire study	Between March 8, 2021 and March 11, 2021	Healthcare workers	1603	27		1261/342	37.7 ± 10.89	ChAdOx1	7 d after dose 1	DM is associated with an increased risk of grade 3 to 4 adverse reactions after the first dose
Rangsrisaeneepitak et al[33]	Thailand	PSM observational study	Between June 8, 2021 and July 12, 2021	Healthcare workers and T2DM patients	282		94	129/153	30-83	ChAdOx1 nCoV-19 (AZD1222)	56 d after dose 1	People with T2DM had weaker antibody responses than those without diabetes after the first dose
Sourij et al[34]	Austria	Multicentre prospective cohort study	Between April and June 2021	T1DM, T2DM, and healthy participants	150	75	75	68/82	49.2 ± 14.59	BioNTech-Pfizer, Moderna, or AstraZeneca	7 to 14 d after dose 1 and 14 to 21 dafter dose 2	The antibody levels after the second vaccination were comparable in healthy controls and DM patients, irrespective of glycaemic control
Tawinprai et al[35]	Thailand	Prospective cohort study	Between March 31, 2021 and May 5, 2021	Healthcare workers	796	11		517/279	40 (30-57)3	ChAdOx1 (AZD1222)	At least 21 d after dose 1 and before dose 2	DM reduces the immune response to vaccination
Ali et al[18]	Kuwait	Case-control study	August 2021	Non-diabetics and patients with T2DM	262	0	81	126/136	49.3 ± 14.59	BNT162b2 (Pfizer-BioNTech)	At least 3 wk after dose 2	Both neutralizing antibody and IgG antibody titers were significantly lower in the T2DM group than in the non-diabetic group
Karamese et al[36]	Turkey	Descriptive study	March 2021	Participants over 65 years of age who have received two doses of vaccine	235	49		111/124	70.4 ± 4.89	CoronaVac	4 wk after dose 1 and 4 wk after dose 2	Lower rates of antibody response were detected in participants with DM
Lustig et al[37]	Israel	Single-centre, prospective, longitudinal cohort study	Between December 19, 2020 and January 30, 2021	Health-care workers	2607	139		1883/724	47.7 ± 12.59	Pfizer-BioNTech BNT162b2	1-2 wk after dose 1 and 1-2 wk after dose 2	Decreased antibody response in diabetic patients after vaccination
Islam et al[38]	Japan	Cross-sectional study	June 2021	Workers	953	21		654/299	21-75	BNT162b2 (Pfizer-BioNTech)	15 to 71 d after dose 2	Spike IgG antibody titers were lower in the presence of hyperglycemia
Parthymou et al[39]	Greece	Longitudinal observational cohort study	September 2021	Healthcare units participants	712	50		444/268	50.8 ± 11.49	BNT162b2 (BioNTech-Pfizer)	3 wk and 3 mo after Dose2	DM is not an independent factor affecting antibody titers
Priddy et al[40]	New Zealand	Prospective cohort study	Between June 10, 2021 and September 18, 2021	Participants in two centers	285	28		156/1296	52 (16-92)	BNT162b2 (BioNTech-Pfizer)	28 d after dose 2	Participants with diabetes had lower anti-S IgG antibodies compared to those without DM
Naschitz et al[41]	Israel	Retrospective study	May 2021	Residents in long-term geriatric and palliative care and assisted living facilities	304	103		208/96	≥ 60	BNT162b2 (Pfizer-BioNTech)	3-4 mo after dose 2	DM is associated with negative serological results
Güzel et al[42]	Turkey	Prospective study	May 20212	Volunteers, outpatient clinic people, and COVID-19 patients	183	80		98/85	21-60	CoronaVac-SinoVac	21 d after dose 2	IgG antibody levels were significantly lower in patients with DM than in those without DM
Virgilio et al[43]	Italy	Multicenter prospective study	Between June 2021 and December 2021	Residents of long-term care facilities	555	0	140	378/177	82.1	BNT162b2 (Cominarty) Moderna (mRNA-1273)	Before the vaccination, 2 mo, and 6 mo after dose 1	Vaccination in elderly residents with T2DM is associated with a reduced humoral immune response
Patalon et al[44]	Israel	Retrospective cohort study	Between February and May 2021	A large patient cohort from Maccabi Healthcare Services	4740	377		1914/2826	16-59 years, n = 3355; ≥ 60 years, n = 1385	BNT162b2 (BioNTech-Pfizer)	Two vaccinations at intervals of 21 to 27 d	DM is not a relevant factor affecting antibody levels
Mitsunaga et al[45]	Japan	Prospective study	Between April 15, 2021 and June 9, 2021	Hospital’s workers	374	6		264/110	36	BNT162b2 vaccine (COMIRNATY (Tozinameran)	Before vaccination, 7 to 20 d after dose 1, and 7 to 20 d after dose 2	HbA1c higher than 6.5% was a significant suppressor of antibody responses
Papadokostaki et al[46]	Greece	Prospective observational study	Between May and September 2021.	Participants attended the vaccination center	174	14	44	107/67	52.6 ± 10.6	BNT162b2 (BioNTech-Pfizer)	21 d after dose 1, 7-15 d after dose 2, and 70-75 d after dose 2 but before dose 3	It was high and similar after the second dose in both participants with and without DM
Zhao et al[47]	United States	Prospective longitudinal study	Between December 2020 and December 2021	Veterans and healthcare workers	124	39		33/91	20-95	BNT162b2 (Pfizer-BioNTech)	48 h before dose 1 and dose 2, 1 mo, 3 mo, 6 mo, 12 mo after dose 2, and 1 mo after dose 3	DM was significantly associated with a decrease in response intensity after completion of the primary vaccine series, but responses to the third dose were generally robust
Santotoribio et al[48]	Spain	Descriptive, retrospective, observational, and cross-sectional study	Between November 1, 2020 and March 31, 2021	Infected patients and vaccinated subjects	175	17		112/63	51.0 (19-89)	Pfizer-BioNTech	At least 21 d after dose 2	Serum antibody levels did not decrease significantly in patients with DM
Mehta et al[49]	India	Observational cohort study	Between March 2021 and October 2021	Vaccinated patients with AIRDs	495	63		416/79	56.5	AZD1222 (AstraZeneca)	4 wk and10-14 wk after dose 2	DM was significantly associated with lower anti-RBD antibodies
Ajlan et al[50]	Saudi Arabia	PSM prospective study	June 14, 20222	Patients from a large hospital	431	191		136/295	51.3 ± 16.29	BNT162b2 or ChAdOx1	7 d after dose 1 and dose 2, and 2 wk after dose 1 and dose 2	There was no difference in the primary outcome between the two vaccine platforms. Unresponsiveness was mainly linked to DM
Billany et al[51]	United Kingdom	Prospective observational study	March 2021	Maintenance hemodialysis patients	94	43		38/56	62.1 ± 12.29	BNT162b2 or AZD1222	28 d after dose 1	There was no difference in antibody testing with or without DM
Aberer et al[52]	Austria	Multicenter prospective study	Between April and June 2021	DM patients	74	58	16	NR	T1DM: 39.5 ± 14.1; T2DM: 60.6 ± 6.2	BioNTech-Pfizer and Moderna and AstraZeneca	First dose	No change in insulin dose before and after vaccination. Vaccination significantly reduced TIR in T1DM patients, but had no effect on TIR in T2DM patients
Piccini et al[53]	Italy	Observational cohort study	Between March and June 2021	T1DM patients	39	39	0	17/22	18.7 ± 2.19	mRNA-BNT162b1 (Pfizer-BioNTech) and Moderna (mRNA-1273)	One (day 7, day 14) and two (day 7, day 14) doses and 14 d after dose 1 and dose 2	COVID-19 vaccination was safe and not associated with significant perturbation of glycemic control in patients with T1DM
Heald et al[54]1	United Kingdom	Observational cohort study	Between January 14, and March 7, 2021	T1DM patients	20	20	0	11/9	53 (26-70)	mRNA-BNT162b2 (Pfizer-BioNTech) and Oxford /AstraZeneca	7 d before and 7 d after dose 1	COVID-19 vaccination can cause temporary relative hyperglycemia in people with T1DM. No relationship between vaccine type and blood glucose perturbation
D'Onofrio et al[55]	Italy	Observational cohort study	July 13, 20212	T1DM (AD) patients	35	35		14/21	36 (27-51)3	mRNA-BNT162b2 (Comirnaty)	14 d before and 3 d after dose 1 and dose 2	No significant differences in TIR, TAR, TBR, and CV between, after, and before the COVID-19 vaccination in T1DM patients
Heald et al[56]1	United Kingdom	Survey and evaluation study	Between January 5, 2021 and April 4, 2021	Adults (18 years of age or more) with T1DM	97	97	0	51/46	44 (18-70)	Pfizer-BioNTech or Oxford-AstraZeneca	7 d before and 7 dafter dose 1	In T1DM, vaccination can cause a temporary perturbation of interstitial glucose. There is no difference between vaccines
Gouda et al[57]	Greece	Observational study	March 2022	T1DM patients	1358	135	0	72/63	11.7 (5-18)	BNT162b2 (Pfizer-BioNTech), Moderna (mRNA-1273), or AstraZeneca	7 d before and 7 d after dose 1, dose 2, and dose 3	SARS-CoV-2 vaccination in children and adolescents with T1DM is safe and is not associated with immediate glucose imbalance
Sakurai et al[58]	Japan	Case report	December 11, 20212	Healthy woman	1			1/0	36	mRNA-BNT162b2 (Pfizer-BioNTech)	First dose	mRNA vaccine is associated with new-onset T1DM
Patrizio et al[59]	Italy	Case report	September 15, 20212	T2DM patient	1	0	1	0/1	52	mRNA-BNT162b2 (Pfizer-BioNTech)	Second dose	T1DM may be triggered after SARS-CoV-2 vaccination
Aydoğan et al[60]	Turkey	Case series	Between May 2021 and October 2021	One had Hashimoto's thyroiditis, and the other 3 were healthy	4			1/3	27-56	mRNA-BNT162b2 (Pfizer-BioNTech) or CoronaVac	Second dose	Vaccination with BNT162b2 may trigger T1DM
Sato et al[61]	Japan	Case report	April 19, 20222	Malignant melanoma patient	1			0/1	43	mRNA-based SARS-CoV-2 vaccination	Second dose	mRNA vaccine may trigger T1DM
Yakou et al[62]	Japan	Case series	December 21, 20212	T1DM patients	2	2	0	2/0	52-71	mRNA-BNT162b2 (Pfizer-BioNTech)	Second dose	A temporary decrease in insulin secretion after vaccination
Mishra et al[63]	India	Case series	Between January 18, 2021 and March 4, 2021	T2DM patients	3	0	3	1/2	58-65	Covishield™ (ChAdOx1-nCOV) (AstraZeneca)	First dose	Vaccination may result in a mild and temporary increase in blood glucose levels
Abu-Rumaileh et al[64]	Jordan	Case report	January 14, 2021	Hypertension patient	1			0/1	58	mRNA-BNT162b1 (Pfizer-BioNTech)	Second dose	COVID-19 vaccine has a risk of causing new-onset T2DM
Sasaki et al[65]	Japan	Case report	December 13, 20212	Osteoporosis, mild glucose intolerance	1	0	0	1/0	73	Moderna (Spikevax, mRNA-1273)	Second dose	The development of T1DM is attributable to the COVID-19 vaccination
Lee et al[66]	United States	Case Series	June 30, 20212	T2DM and hypertension patients	3	0	2	1/2	52-87	mRNA-BNT162b1 (Pfizer-BioNTech) and Moderna (Spikevax, mRNA-1273)	First dose	Vaccination may trigger a hyperglycemic episode and DKA
Edwards et al[67]	United Kingdom	Case Series	April 2021	Hypertension, hypothyroidism, and pre-diabetes	3			0/3	53-68	Covishield™ (ChAdOx1-nCOV)	First dose	The first administration of the COVID-19 vaccine can trigger an acute hyperglycemic crisis
Ganakumar et al[68]	India	Case series	November 2021	T1DM	2	2	0	1/1	20-25	COVISHIELD (ChAdOx1 nCoV-19) or COVAXIN (BBV152)	1 to 4 d after dose 2	COVID-19 Vaccination has the potential to induce DKA
Zilbermint et al[69]	United States	Case report	September 11, 20212	T1DM	1	1	0	1/0	24	Moderna (mRNA-1273)	15 h after dose 2	A plausible mechanism exists between COVID-19 vaccination and DKA
Yaturu et al[70]	United States	Case report	May 2021	Hypertension, primary hyperparathyroidism, and obesity patient	1	0	1	0/1	56	BNT162b2 (Pfizer-BioNTech)	Right after the second dose	COVID-19 Vaccination has the potential to induce HHS
Kshetree et al[71]	United States	Case report	NR	Hypertension and pre-diabetes	1	1	0	0/1	69	mRNA vaccine	2 mo after dose 3	COVID-19 mRNA vaccine has the potential to induce DKA
Prasad[72]	India	Case report	March 2021	Patient with T2DM	1	0	1	1/0	73	Covishield	6 d after dose 1	Vaccination may cause glycaemic disturbances
Sasaki et al[73]	Japan	Case report	January 4, 20222	Healthy person	1	1	0	1/0	45	BNT162b2 (Pfizer-BioNTech)	1 d after dose 1	COVID-19 vaccine might trigger the onset of fulminant T1DM in susceptible individuals
Yano et al[74]	Japan	Case report	November 11, 20212	Healthy person	1	1	0	1/0	51	Moderna (mRNA-1273)	28 d after dose 1	COVID-19 vaccination can induce T1DM in some individuals
Ohuchi et al[75]	Japan	Case report	November 20212	Cutaneous malignant melanoma with axillary lymph node metastasis	1	1	0	0/1	45	BNT162b2 (Pfizer-BioNTech)	3 d after dose 2	There is a highly suspicious causal relationship between fulminant T1DM and COVID-19 vaccination

¹The authors are the same, but the individual studies are different, including different phases, different samples, and different data.

²Take the date of receipt of the manuscript.

³Median (25^th-75^th percentile).

⁴Sample size for completing the second dose.

⁵Sample size for fully completed questionnaires.

⁶Contains a Non-binary participant.

⁷Age (mean ± SD) is divided according to BNT162b2 and CoronaVac groups.

⁸Sample size for T1DM, of which 70 received at least one dose of the vaccine and the other 65 were unvaccinated.

⁹mean ± SD.

NA: Not available; NR: Not reported; COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; PSM: Propensity score matching; HbA1c: Glycated hemoglobin; TIR: Time in range; DM: Diabetes mellitus; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; HHS: Hyperosmolar hyperglycemic syndrome; DKA: Diabetic ketoacidosis; AD: Autoimmune diabetes; AIRDs: Autoimmune Rheumatic Diseases; AESI: Adverse events of special interest; F: Female; M: Male; ICU: Intensive care unit; TAR: Time above range; TBR: Time below range; CV: Coefficient variation.

Table 2 Summary of the case report or case series about the effect of SARS-CoV-2 vaccination on blood glucose

Ref.	Age (yr)	Gender	Type and name of vaccine	Blood glucose (mg/dL)/HbA1c (%) pre-vaccination post-vaccination		Onset after vaccination	Pre-existing condition	Final diagnosis	C-peptide (ng/mL)	GAD65Ab (IU/mL)	Treatment	Outcomes	Conclusion
Sakurai et al[58]	36	Female	mRNA-BNT162b2 (Pfizer-BioNTech)	Normal	501/7.0	3 d after dose 1	None	Fulminant T1DM	0.13	NA	Insulin infusion	Discharged	mRNA vaccine is associated with new-onset T1DM
Patrizio et al[59]	52	Male	mRNA-BNT162b2 (Pfizer-BioNTech)	531	871	4 wk after dose 2	Vitiligo vulgaris and T2DM	Graves’ disease and T1DM	1	61.2	Insulin analogues	NR	T1DM may be triggered after SARS-CoV-2 vaccination
Aydoğan et al[60]	56	Male	mRNA-BNT162b1 (Pfizer-BioNTech)	Normal	440/8.2	15 d after dose 2	Vitiligo vulgaris and Hashimoto's thyroiditis	T1DM	1.5	> 2000	Insulin infusion	Recovery	Vaccination with BNT162b2 may trigger T1DM
	48	Male	mRNA-BNT162b2 (Pfizer-BioNTech)	Normal	352/10.1	8 wk after dose 2	None	T1DM	0.97	94	Low-carbohydrate diet	Recovery
	27	Male	mRNA-BNT162b2 (Pfizer-BioNTech)	Normal	320/12.5	3 wk after dose 2	None	T1DM	0.87	725	Basal insulin	Recovery
	36	Male	mRNA-BNT162b2 (Pfizer-BioNTech) and CoronaVac	Normal	526/12.6	3 wk after dose 2	None	T1DM	0.38	234	Insulin infusion	Recovery
Sato et al[61]	43	Male	mRNA-based SARS-CoV-2 vaccination	94/5.6	655/8.0	14 d after dose 2	Malignant melanoma	Fulminant T1DM	0.33		Insulin infusion	Discharged	mRNA vaccine may trigger T1DM
Yakou et al[62]	71	Female	mRNA-BNT162b1 (Pfizer-BioNTech)	93/8.1	944/8.0	1 d after dose 2	T1DM	Diabetic ketoacidosis	< 0.03	> 2000	Insulin infusion	Discharged	Risk of inducing ketoacidosis after vaccination in T1DM patients
	52	Female	mRNA-BNT162b1 (Pfizer-BioNTech)	106	494/11.6	1 d after dose 2	T1DM	Diabetic ketoacidosis	ND	123	Insulin infusion	Discharged
Mishra et al[63]	58	Female	Covishield™ (ChAdOx1-nCOV) (AstraZeneca)	110	183	1 d after dose 1	T2DM	T2DM	NR	NR	Increased dose of metformin.	Discharged	Vaccination may result in a mild and temporary increase in blood glucose levels
	64	Male	Covishield™ (ChAdOx1-nCOV) (AstraZeneca)	95	150	1 d after dose 1	T2DM	T2DM	NR	NR	Without additional intervention	Discharged
	65	Male	Covishield™ (ChAdOx1-nCOV) (AstraZeneca)	107	186	6 d after dose 1	T2DM	T2DM	NR	NR	Without additional intervention	Discharged
Abu-Rumaileh et al[64]	58	Male	mRNA-BNT162b1 (Pfizer-BioNTech)	80	1253/13	26 d after dose 1	Hypertension	T2DM	1.1	NR	Insulin infusion	Discharged	COVID-19 vaccine has a risk of causing new-onset T2DM
Sasaki et al[65]	73	Female	Moderna (Spikevax, mRNA-1273)	7.3	318/9.3	8 wk after dose 2	Osteoporosis, mild glucose intolerance	T1DM	0.48	> 2000	Intensive insulin therapy	NR	COVID-19 Vaccination may lead to the new-onset T1DM
Lee et al[66]	52	Female	mRNA-BNT162b2 (Pfizer-BioNTech)	5.5-6.2	1062/12.0	3 d after dose 1	Hypertension	T2DM and nonketotic HHS	NR	NR	Insulin infusion.	Discharged	Vaccination may trigger HHS
	60	Male	Moderna (mRNA-1273)	7.5	847/13.2	2 d after dose 1	T2DM	T2DM and HHS	NR	NR	Insulin infusion	Discharged	Vaccination may trigger a hyperglycemic episode
	87	Male	Moderna (mRNA-1273)	7	923	10 d after dose 1	T2DM	T2DM and HHS and DKA	NR	NR	Insulin infusion	Discharged	Vaccination may trigger HHS and DKA
Edwards et al[67]	59	Male	Covishield™ (ChAdOx1-nCOV)	5.6	594/14.1	21 d after dose 1	Obesity	Hyperglycemic ketosis	2352	NR	NA	Discharged	The first administration of the adenovirus-vectored COVID-19 vaccine can trigger an acute hyperglycemic crisis
	68	Male	Covishield™ (ChAdOx1-nCOV)	6.5	918/14.7	36 d after dose 1	Pre-diabetes	Mixed HHS/DKA	5612	NR	ICU admission	Discharged
	53	Male	Covishield™ (ChAdOx1-nCOV)	6.2	576/17.1	20 d after dose 1	Pre-diabetes	DKA	3772	NR	ICU admission	Discharged
Ganakumar et al[68]	20	Male	COVISHIELD (ChAdOx1 nCoV-19)	NR	14.1	1 d after dose 2.	None	Severe DKA	NR	NR	Insulin infusion	Discharged	COVID-19 vaccination has the potential to induce DKA
	25	Female	COVAXIN (BBV152)	NR	16.3	4 d after dose 2	None	Severe DKA	NR	NR	Insulin infusion	Discharged
Zilbermint et al[69]	24	Female	Moderna (mRNA-1273)	NR	505/12.0	15 h after dose 2	T1DM	Severe DKA	NR	NR	Insulin infusion	NR	A plausible mechanism exists between COVID-19 vaccination and DKA
Yaturu et al[70]	56	Male	BNT162b2 (Pfizer-BioNTech)	5.6	997/14	Right after the second dose.	Hypertension, primary hyperparathyroidism, and obesity	T2DM and HHS	NR	NR	Insulin infusion	Discharged	COVID-19 vaccination has the potential to induce HHS
Kshetree et al[71]	69	Male	mRNA vaccine	5.8	13.7	Two months after dose 3	Hypertension and pre-diabetes	T1DM and DKA	0.4	0.33	Insulin infusion	Discharged	COVID-19 mRNA vaccine has the potential to induce DKA
Prasad[72]	73	Male	Covishield	92/7.1	215/8	6 d after dose 1	T2DM	T2DM	NR	NR	Insulin infusion	Discharged	Vaccination may cause glycaemic disturbances
Sasaki et al[73]	45	Female	BNT162b2 (Pfizer-BioNTech)	Normal	344/7.6	1 d after dose 1	None	Fulminant T1DM and DKA	NR	NA	Insulin infusion	Discharged	COVID-19 vaccine might trigger the onset of fulminant T1DM in susceptible individuals
Yano et al[74]	51	Female	Moderna (mRNA-1273)	Normal	648/10.3	28 d after dose 1	None	Fulminant T1DM and DKA	1.72	NA	Insulin infusion	Discharged	COVID-19 vaccination can induce T1DM in some individuals
Ohuchi et al[75]	45	Male	BNT162b2 (Pfizer-BioNTech)	NR	655	3 d after dose 2	Cutaneous malignant melanoma	Fulminant T1DM	0.99	Negative	NR	NR	There is a highly suspicious causal relationship between fulminant T1DM and vaccination, especially in patients treated with ICI

¹Unit: mmol/mol and reference range is 20-38.

²Unit: pmol/L and the reference range is 370-1470.

NA: Not available; ND: Not detected; NR: Not reported; COVID-19: Coronavirus disease2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; HbA1c: Glycated hemoglobin; DM: Diabetes mellitus; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; HHS: Hyperosmolar hyperglycemic syndrome; DKA: Diabetic ketoacidosis; ICI: Immune checkpoint inhibitors.

Table 3 Outcomes of the studies based on the association between vaccination and diabetes

Ref.	Assessed variables	Findings related to variables	Conclusion	Limitations
Zhang et al[23]	Hypertension, Comorbidity, Side effects	None	After vaccination, no significant abnormal fluctuations in blood glucose values were observed in the DM patients	Lack of data on the duration of antibodies after vaccination in the study population
Marfella et al[24]	HbA1c, Time since vaccination, type of vaccine	On Day 21 after the second vaccine dose, T2DM patients with HbA1c > 7% showed significantly reduced virus-neutralizing antibody capacity than normoglycemic subjects and T2DM patients with good glycaemic control. At 21 d after the first vaccine dose, neutralizing antibody titers and CD4 cytokine responses involving type 1 helper T cells were lower in T2DM patients with HbA1c levels > 7% than in individuals with HbA1c levels ≤ 7%. The reduction of HbA1c levels 52 d after vaccination was associated with neutralizing antibody titers and CD4 cytokine increases	Hyperglycemia at the time of vaccination can worsen the immune response, and proper glycemic control can improve the immune response	The statistical significance of the relevant indicators was relatively low
Kılınç-Toker et al[25]	Age, sex, mixed vaccination, delta variant, BMI, Diabetes, hypertension, COPD, cardiovascular diseases, chronic kidney disease, cancer	Age, male gender, delta variant, and mixed vaccination (CoronaVac plus BioNTech) were associated with death. The delta variant had higher ICU admission and mortality rate	For hospitalized patients who received two doses of the vaccine, diabetes was not associated with their ICU stay and mortality	Retrospective design, short follow-up, and assessment of inpatients only
Barocci et al[26]	Homologous vaccination, heterologous vaccination, type of vaccine, vaccine schedule, sex, age, BMI, smoking, DM, cardiovascular diseases, respiratory tract diseases, previous SARS-CoV-2 infection, side effects	Heterologous vaccination induced a significantly higher humoral response than homologous vaccination. The type of vaccine influenced antibody titers	DM does not affect antibody levels	Results were influenced by anti-S IgG levels in asymptomatic subjects
Singh et al[27]1	Sex, T2DM, age, BMI, side effects, type of vaccine, dose 1, dose 2	Gender, presence of comorbidities, and vaccine type were independent predictors of antibody seropositivity and anti-spike antibody titer levels. Patients with T2DM had a significantly lower seropositivity rate compared to those without the comorbid disease. Seropositivity rates were lower in those with T2DM compared to those without T2DM. Both vaccine recipients had similar mild to moderate adverse events, and none had serious side effects	T2DM is associated with lower seropositivity rates and anti-spike antibody titers	No assessment of the cell-mediated immune response
Singh et al[28]1	Age, previous SARS-CoV-2 infection, sex, BMI, side effects, type of vaccine, dose 1, dose 2, T2DM, blood group, dyslipidemia, ischemic heart disease	The seropositivity rate was significantly higher in the ≤ 60 years age group than in the > 60 years age group at all time points. GMT was significantly higher in participants with past SARS-CoV-2 infection than in SARS-CoV-2-naiveindividuals.	Participants with T2DM had a lower rate of seropositivity at all time points	The sample was drawn from a healthy population with few comorbidities
Shim et al[29]	Age, DM, type of vaccine, side effects, vaccination interval, hypertension, BMI, sex	There were significant differences in general and neutralizing antibodies based on age, vaccine type, vaccination interval, pain score, diabetes, and hypertension	For all vaccines, subjects with diabetes showed lower rates of neutralizing antibody production after vaccination	Vaccination priority policies bring heterogeneity across age groups
Alqassieh et al[30]	Age, type of vaccine, hypertension, cardiovascular disease, DM, sex, BMI	Old people (> 60) had lower IgG titers than their younger counterparts. The use of the Pfizer-Biotech vaccine was positively associated with positive IgG titers, while cardiovascular disease had a negative effect on IgG titers. Although diabetes had a negative impact on positive IgG titers, it was not statistically significant	Although DM negatively affected IgG titer positivity, it was not statistically significant	Samples were collected only once at a specific period (6 wk) after vaccination
Wan et al[31]	Dose 1, dose 2, HbA1c, side effects	None	Patients with T2DM do not appear to have higher risks of AESI and acute diabetic complications after vaccination	Adverse events are defined using diagnosis codes and may be biased by underdiagnosis or misclassification
Lee et al[32]	Sex, age, DM, type of vaccine, BMI	Being young, female or underweight, and having diabetes were associated with an increased risk of developing grade 3 to 4 adverse reactions after the first dose of the ChAdOx1nCoV-19 vaccine	DM is associated with an increased risk of grade 3 to 4 adverse reactions after the first dose of vaccine, especially in women	Sample from relatively healthy subjects working in hospitals
Rangsrisaeneepitak et al[33]	T2DM, age, sex, BMI, side effects	After the first dose of AZD1222, the antibody response was weaker in T2DM patients than in non-diabetic patients. The seroconversion rate was higher in the control group than in the diabetic group. Older age was associated with a weaker antibody response in older diabetic patients. The GMC of SARS-CoV-2 IgG antibodies at 56 d was significantly lower in diabetic patients than in age- and sex-matched controls. In the age- and sex-matched controls, SARS-CoV-2 IgG antibody levels were significantly higher in women than in men. During the first 24 h, injection site reactions were more common in diabetic patients than in healthy controls	After the first dose of AZD1222, the antibody response was weaker in T2DM patients than in non-diabetic patients	Participants in the control group were healthcare workers, so natural immunity may have been a confounding factor
Sourij et al[34]	T2DM, eGFR, HbA1c, side effects, T1D	Age and renal function were significantly associated with the extent of antibody levels. The most common side effect was injection site reactions, with a significantly lower rate in patients with T2DM	The antibody levels after the second vaccination were comparable in healthy controls and in DM patients, irrespective of glycaemic control	Focused only on the humoral immune response after vaccination, but did not investigate the cellular immune response
Tawinprai et al[35]	DM, hematologic disease, sex, age, time since the first dose of vaccination, BMI, side effects, cardiovascular disease, hypertension, dyslipidemia, end-stage kidney disease	Participants with diabetes or hematologic comorbidities had lower concentrations of anti-RBD antibodies. Anti-RBD antibody concentrations were significantly higher in female participants than in male participants. The immune response was lower in older participants. Anti-RBD antibody concentrations were significantly higher at 2 and 3 mo post-vaccination than at 1-mo post-vaccination	Participants with diabetes or hematologic comorbidities had lower concentrations of anti-RBD antibodies	The presence of participants who did not complete two anti-RBD antibody assays withdrew from the study
Ali et al[18]	T2DM, age, sex, BMI, comorbidity, previous SARS-CoV-2 infection, hypertension	T2DM is associated with lower titers of neutralizing and IgG antibodies	Both neutralizing antibody and IgG antibody titers were significantly lower in the T2DM group than in the non-diabetic group	Participants in the study were self-selected verbally and through job advertisements
Karamese et al[36]	T2DM, age, hypertension, COPD, dose 1, dose 2	Lower antibody response rates were detected in participants with T2DM and in those aged 65 years and older	DM patients have lower antibody levels	The study population was an advanced age group with a high number of comorbidities
Lustig et al[37]	Age, sex, DM, immunosuppression, hypertension, heart disease, autoimmune disorders, BMI	Lower antibody concentrations are consistently associated with males, older age, immunosuppression, diabetes, hypertension, heart disease, and autoimmune disorders	Lower IgG concentrations and lower detectable IgA antibodies were observed in DM patients, indicating a reduced antibody response to vaccination in these patients	The sample was drawn from a healthy population with few comorbidities
Islam et al[38]	Hyperglycemia, FPG, age, sex, BMI, hypertension, smoking, alcohol consumption	Spike IgG antibody titers were lower in the presence of hyperglycemia and IFG	Vaccine recipients with diabetes and IFG had lower concentrations of SARS-CoV-2 spike IgG antibodies than the vaccine recipients with normoglycemia did	Associations observed in cross-sectional studies do not necessarily indicate causality
Parthymou et al[39]	Sex, age, smoking, BMI, DM, hypertension, statin use, vitamin D levels	Age, male gender, and tobacco use are negatively associated with antibody titers after COVID-19 vaccination	Antibody titers were numerically lower in diabetic patients, but this association was not statistically significant	Reliance on questionnaires to record anthropometric parameters and medical history affects reliability
Priddy et al[40]	Age, DM, sex, BMI, race	IgG and neutralization responses decreased with age. Lower responses were associated with age ≥ 75 and DM	Lower responses were associated with DM	Most of the IgG and neutralization tests used are not standardized
Naschitz et al[41]	Cancer, DM, congestive heart failure, sex, age, hypertension, COPD, cerebrovascular disease, chronic liver disease, cognitive disability	Cancer, DM, or congestive heart failure were all associated with having a negative serology result	DM is associated with negative serological results	There was a large age difference between the two sample groups
Güzel et al[42]	Cardiovascular diseases, DM, age, BMI, sex, smoking, vitamin use, viral load, comorbidities	Cardiovascular disease and diabetes were associated with lower IgG antibody levels. In the healthcare workers group, IgG antibody response values were negatively correlated with BMI and age	IgG antibody levels were significantly lower in patients with DM than in those without DM	ELISA test may lead to false positive results
Virgilio et al[43]	Sex, T2DM, insulin therapy	The negative impact of diabetes in determining a steeper antibody decline was greater in female residents than in male residents. T2DM is associated with a reduced humoral immune response after SARS-CoV-2 vaccination. Antibody kinetics in diabetic patients receiving insulin therapy are similar to those in patients without diabetes	Vaccination in elderly residents with type 2 diabetes is associated with a reduced humoral immune response	Data on blood glucose or glycated hemoglobin levels were not specifically collected to assess the control or severity of diabetes
Patalon et al[44]	Sex, age, BMI, COPD, DM, congestive heart failure, inflammatory bowel disease	Females were associated with higher levels of antibodies. Lower antibody levels were observed in higher age groups	DM is not a relevant factor affecting antibody levels	The study population was older and had more comorbidities
Mitsunaga et al[45]	Age, Hypertension, HbA1c, Outdoor exercises, Vaccination interval, BMI, COPD, Dyslipidemia, DM, Autoimmune diseases, Cancer, dose 1, dose 2, BG	Older than 60 years, hypertension, HbA1c higher than 6.5%, and lack of outdoor exercises were significant suppressors of antibody responses, whereas the length of days from the first to the second vaccination longer than 25 d promoted a significant antibody response	HbA1c higher than 6.5% was a significant suppressor of antibody responses	The sample was relatively healthy health workers but did not include participants with serious comorbidities
Papadokostaki et al[46]	Age, DM, dose 1, dose 2, sample testing time, HbA1c, BMI, duration of diabetes, HbA1c	In the diabetic group, Abs-RBD-IgG was significantly correlated with age and time, and dose after vaccination	The humoral immune responses after the second dose were high and similar in participants with and without DM	No comparison between type 1 and type 2 diabetes
Zhao et al[47]	DM, dose 1, dose 2, dose 3, age, end-stage kidney disease, cancer, steroid use, previous SARS-CoV-2 infection, time since vaccination	DM was significantly associated with a decrease in response intensity after completion of the primary vaccine series, but responses to the third dose were generally robust. Age and malignancy had a negative effect on the initial strength of the humoral immune response. Being over 65 years, end-stage renal disease, diabetes, and clinical comorbidities of steroid use had a negative effect on the humoral immune response. SARS-CoV-2 infection enhanced the neutralization antibody response to the third dose	DM was significantly associated with a decrease in response intensity after completion of the primary vaccine series, but responses to the third dose were generally robust	Small sample size
Santotoribio et al[48]	Age, sex, DM, hypertension, heart disease	None	Serum antibody levels were not significantly reduced in patients with common conditions such as arterial hypertension, diabetes, heart disease, or chronic respiratory disease	No assessment of the cell-mediated immune response
Mehta et al[49]	DM, immunosuppression, vaccination interval, sex, comorbidity	DM, immunosuppression, and vaccination interval were all significantly associated with anti-RBD antibodies	DM patients had significantly lower titers of anti-spiking antibodies than patients without diabetes	The sample group was patients with autoimmune rheumatic diseases with a high proportion of comorbidities
Ajlan et al[50]	DM, type of vaccine, age, triple immunosuppressive therapy, side effects, sex, time since transplantation	Diabetes and triple immunosuppressive therapy appear to significantly affect the immune response. Triple immunosuppressive therapy and age were identified as significant factors in the lack of response to the vaccine after the second dose. Response rates after the first dose of vaccine with the Pfizer vaccine were higher than those with the AstraZeneca vaccine	Diabetes mellitus and triple immunosuppressive therapy appear to significantly affect response	Lack of immunocompetence control group
Billany et al[51]	Age, immunosuppression, previous SARS-CoV-2 infection, sex, race, DM	Patients with detectable antibodies were younger than patients without detectable antibodies. Patients who were immunosuppressed were less likely to have detectable antibodies than patients who were not immunosuppressed. Patients previously infected with COVID-19 were more likely to have detectable antibodies than those with no history of SARS-CoV-2 infection	There was no difference in antibody testing with or without DM	Small sample size
Aberer et al[52]	TIR, TBR, TAR, T1DM, T2DM, carbohydrate intake, CV	None	At the time of side effects, T1DM patients had significantly less TIR and significantly more TAR, while there was no effect on T2DM patients	Short assessment time and small sample size
Piccini et al[53]	Side effects, dose 1, dose 2, TIR, time in different glucose ranges, mean glucose levels, TDD of insulin, bolus proportion, type of vaccine	Side effects after the vaccination were mild and more frequent after the second dose. No severe adverse reactions were reported	No significant differences in glycemic control and glycemic indices were observed at different times throughout the vaccination cycle and were independent of the vaccine type	Small sample size
Heald et al[54]1	Age, BMI, mode of treatment, sex, HbA1c, type of vaccine, duration of diagnosed T1DM	The fall in the percentage BG on target was also greater for those with a median BMI of 28.1 kg/m2 or more. The fall in the percentage BG on target categorized by additional Metformin/Dapagliflozin was greater than no oral hypoglycemic agents, and the median age ≥ 53 yr was greater than < 53 yr	In T1DM, COVID-19 vaccination can cause a temporary BG disturbance, and this effect is more pronounced in patients taking oral hypoglycemic drugs plus insulin and in the elderly	No analysis of changes in insulin dose in the week following the COVID-19 vaccination
D'Onofrio et al[55]	TIR, TBR, TAR, CV, dose 1, dose 2, insulin dosage, SD	None	Pre- and post-CGM data collected during the two vaccine doses did not show any significant differences between the two groups in terms of TIR, TAR, TBR, CV, and SD	Small sample size
Heald et al[56]1	Medication, HbA1c, oral hypoglycemic drugs plus insulin therapy, age, sex, type of vaccine, duration with diabetes, BMI	COVID-19 vaccination can cause a temporary perturbation of interstitial glucose, an effect that is more pronounced in patients taking oral hypoglycemic agents plus insulin. This effect was more pronounced in those with lower HbA1c	In T1DM, vaccination can cause a temporary perturbation of interstitial glucose. There is no difference between the AstraZeneca and the Pfizer vaccines	The effects of the first and second vaccination on interstitial glucose regulation could not be compared
Gouda et al[57]	TIR, TDD of insulin, dose 1, dose 2, type of vaccine, insulin dosage, average glucose level, bolus insulin, automated bolus	One week after vaccination, there was a slight decrease in TIR along with an increase in mean blood glucose levels, but both were statistically insignificant	No differences in blood glucose or glycemic perturbations were shown before and after vaccination in patients with T1DM. There was no correlation between vaccine side effects and TIR	The effects of the first and second vaccination on interstitial glucose regulation could not be compared

¹The authors are the same, but the individual studies are different, including different phases, different samples, and different data.

COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; BMI: Body mass index; HbA1c: Glycated hemoglobin; TIR: Time in range; TAR: Time above range; TBR: Time below range; CV: Coefficient variation; TDD: Total daily dose; DM: Diabetes mellitus;T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; AESI: Adverse events of special interest; CGM: Continuous glucose monitoring; GMT: Geometric mean titer; GMC: Geometric mean concentration; Abs-RBD-IgG: Anti-SARS-CoV-2 receptor-binding domain IgG; FPG: Fasting plasma glucose; IFG: Impaired fasting glucose; BG: Blood glucose; eGFR: Estimated glomerular filtration rate; COPD: Chronic Obstructive Pulmonary Disease.