Risks of Developing Diabetes and Hyperglycemic Crisis Following Carbon Monoxide Poisoning: A Study Incorporating Epidemiologic Analysis and Animal Experiment

Figures & data

Table 1 Comparison of Age, Sex, and Underlying Comorbidities Between Patients with and without Carbon Monoxide (CO) Poisoning

Variable	With CO Poisoning N = 29,141	Without CO Poisoning N = 87,423	p value
Age (year)			>0.999
18−34	13,054 (44.8)	39,153 (44.8)
35−49	10,681 (36.7)	32,039 (36.7)
50−64	3997 (13.7)	12,003 (13.7)
≥65	1409 (4.8)	4228 (4.8)
Sex
Female	15,078 (51.7)	45,234 (51.7)	>0.999
Male	14,063 (48.3)	42,189 (48.3)
Underlying comorbidity
Hypertension	2070 (7.1)	5500 (6.3)	<0.001
Obesity	31 (0.1)	67 (0.1)	0.129
Smoking	126 (0.4)	130 (0.2)	<0.001
Pre-diabetes	20 (0.1)	51 (0.1)	0.537
Gestational diabetes	3 (0.01)	12 (0.01)	0.775
Polycystic ovary syndrome	25 (0.1)	89 (0.1)	0.449
Hyperlipidemia	739 (2.5)	2086 (2.4)	0.145
Hyperuricemia	490 (1.7)	1364 (1.6)	0.152
Chronic obstructive pulmonary disease	913 (3.1)	1623 (1.9)	<0.001
Coronary artery disease	652 (2.2)	1181 (1.4)	<0.001
Congestive heart failure	172 (0.6)	233 (0.3)	<0.001

Note: Data are expressed as n (%).

Table 2 Independent Predictors for Diabetes Identified by Cox Proportional Hazards Regressions

Variable	Crude HR (95% CI)	AHR (95% CI)^a
Cohort
Without CO poisoning	1 (reference)	1 (reference)
With CO poisoning	1.20 (1.15−1.25)	1.23 (1.18−1.28)
Age (year)
18−34	1 (reference)	1 (reference)
35−49	2.63 (2.50−2.76)	2.53 (2.41−2.66)
50−64	5.18 (4.91−5.47)	4.41 (4.17−4.67)
≥65	6.84 (6.37−7.35)	4.75 (4.39−5.14)
Sex
Female	1 (reference)	1 (reference)
Male	1.22 (1.18−1.27)	1.13 (1.09−1.17)
Underlying comorbidity
Hypertension	3.79 (3.60−3.99)	1.71 (1.61−1.82)
Obesity	3.75 (2.57−5.47)	2.32 (1.59−3.39)
Smoking	1.40 (0.96−2.06)	1.22 (0.83−1.79)
Pre-diabetes	4.35 (2.62−7.22)	1.80 (1.08−3.00)
Polycystic ovary syndrome	1.21 (0.67−2.19)	2.17 (1.20−3.91)
Hyperlipidemia	3.50 (3.23−3.79)	1.35 (1.24−1.48)
Hyperuricemia	3.19 (2.91−3.50)	1.61 (1.47−1.78)
Chronic obstructive pulmonary disease	2.07 (1.87−2.28)	1.19 (1.08−1.32)
Coronary artery disease	3.24 (2.93−3.57)	1.03 (0.93−1.15)
Congestive heart failure	4.41 (3.62−5.36)	1.58 (1.29−1.93)

Notes: ^aAdjusted for hypertension, obesity, smoking, pre-diabetes, polycystic ovary syndrome, hyperlipidemia, hyperuricemia, chronic obstructive pulmonary disease, coronary artery disease, and congestive heart failure.

Abbreviations: HR, hazard ratio; AHR, adjusted hazard ratio; CI, confidence interval; CO, carbon monoxide.

Table 3 Comparison of the Risk for Developing Diabetes Between Patients with and without Carbon Monoxide (CO) Poisoning Using Cox Proportional Hazards Regressions

Variables	Patients with CO Poisoning n = 29,141			Patients without CO Poisoning (Reference) n = 87,423			Crude HR (95% CI)	AHR (95% CI)^a
	Case (%)	PY	Rate^b	Case (%)	PY	Rate
Overall analysis	3019 (10.4)	207,832.6	14.5	8248 (9.4)	681,255.8	12.1	1.20 (1.15−1.25)	1.23 (1.18−1.28)
Stratified analysis
Age (year)
18−34	653 (5.0)	103,039.5	6.3	1778 (4.5)	326,552.6	5.4	1.17 (1.07−1.28)	1.17 (1.07−1.28)
35–49	1347 (12.6)	75,750.9	17.8	3491 (10.9)	252,115.4	13.9	1.29 (1.21−1.38)	1.28 (1.21−1.37)
50–64	738 (18.5)	22,703.0	32.5	2145 (17.9)	78,855.2	27.2	1.02 (1.10−1.30)	1.18 (1.09−1.29)
≥65	281 (19.9)	6339.2	44.3	834 (19.7)	23,732.7	35.1	1.25 (1.09−1.43)	1.21 (1.05−1.38)
Sex
Female	1512 (10.0)	110,587.7	13.7	3833 (8.5)	355,559.5	10.8	1.27 (1.20−1.35)	1.28 (1.20−1.35)
Male	1507 (10.7)	97,244.9	15.5	4415 (10.5)	325,696.4	13.6	1.15 (1.08−1.22)	1.18 (1.12−1.25)
Underlying comorbidity
Hypertension	492 (23.8)	10,316.2	47.7	1283 (23.3)	32,665.8	39.3	1.21 (1.09−1.35)	1.21 (1.09−1.34)
Obesity	7 (22.6)	179.6	39.0	20 (29.9)	402.6	49.7	0.80 (0.34−1.90)	0.84 (0.31−2.25)
Smoking	14 (11.1)	673.5	20.8	12 (9.2)	828.5	14.5	1.46 (0.68−3.18)	1.81 (0.73−4.47)
Pre-diabetes	5 (25.0)	71.6	69.9	10 (19.6)	214.4	46.6	1.47 (0.50−4.31)	1.30 (0.35−4.77)
Polycystic ovarian syndrome^c	<3	–	–	<3	–	–	0.87 (0.19−4.01)	1.10 (0.23−5.21)
Hyperlipidemia	186 (25.2)	3941.4	47.2	470 (22.5)	11,921.9	39.4	1.20 (1.01−1.42)	1.23 (1.03−1.46)
Hyperuricemia	128 (26.1)	2910.2	44.0	347 (25.4)	9316.9	37.2	1.19 (0.97−1.46)	1.24 (1.01−1.52)
Chronic obstructive pulmonary disease	138 (15.1)	5008.0	27.6	268 (16.5)	10,948.0	24.5	1.12 (0.91−1.38)	1.17 (0.95−1.44)
Coronary artery disease	133 (20.4)	3414.2	39.0	272 (23.0)	6926.7	39.3	1.00 (0.81−1.23)	1.08 (0.88−1.34)
Congestive heart failure	44 (25.58)	708.7	62.1	56 (24.0)	1143.5	49.0	1.27 (0.85−1.88)	1.31 (0.87−1.96)
Follow-up period
<1 year	470 (1.6)	27,861.7	16.9	920 (1.1)	86,735.5	10.6	1.59 (1.42−1.77)	1.58 (1.42−1.77)
<2 years	817 (2.8)	54,008.1	15.1	1792 (2.1)	169,707.5	10.6	1.43 (1.32−1.55)	1.44 (1.32−1.56)
<3 years	1126 (3.9)	77,496.4	14.5	2579 (3.0)	245,457.6	10.5	1.38 (1.29−1.48)	1.39 (1.30−1.49)
<4 years	1403 (4.8)	98,962.3	14.2	3404 (3.9)	315,383.8	10.8	1.31 (1.23−1.40)	1.33 (1.25−1.41)
<5 years	1630 (5.6)	118,347.4	13.8	4204 (4.8)	379,162.5	11.1	1.24 (1.17−1.32)	1.26 (1.19−1.33)
<6 years	1897 (6.5)	135,810.5	14.0	4846 (5.5)	437,011.0	11.1	1.26 (1.19−1.33)	1.28 (1.21−1.35)
≥6 years	1122 (3.9)	72,022.1	15.6	3402 (3.9)	244,244.8	13.9	1.12 (1.05−1.20)	1.15 (1.08−1.23)

Notes: ^aAdjusted for hypertension, obesity, smoking, pre-diabetes, polycystic ovary syndrome, hyperlipidemia, hyperuricemia, chronic obstructive pulmonary disease, coronary artery disease, and congestive heart failure. ^bPer 1000 PY. ^cThe database management does not provide count data when the number is smaller than 3 because of confidentiality concerns.

Abbreviations: HR, hazard ratio; AHR, adjusted hazard ratio; CI, confidence interval; PY, person-year.

Figure 1 Comparison of the risk for diabetes between patients with and without CO poisoning using Kaplan-Meier’s method and Log rank test.

Abbreviation: CO, carbon monoxide.

Table 4 Comparison of the Risk for Hyperglycemic Crises Between Diabetic Patients with and without Carbon Monoxide (CO) Poisoning Using Cox Proportional Hazards Regressions

Variables	Patients with CO Poisoning n = 2302			Patients without CO Poisoning (Reference) n = 6906			Crude HR (95% CI)	AHR (95% CI)^a
	Case (%)	PY	Rate^b	Case (%)	PY	Rate
Overall analysis	55 (2.4)	12,151.4	4.5	94 (1.4)	43,455.5	2.2	2.07 (1.49−2.89)	2.12 (1.52−2.96)
Stratified analysis
Age (year)
18−34	0 (0.0)	117.1	0.0	0 (0.0)	315.9	0.0	–	–
35–49	16 (3.6)	2682.8	6.0	13 (1.0)	9415.8	1.4	4.29 (2.06−8.92)	4.33 (2.08−9.03)
50–64	22 (2.0)	6227.0	3.5	39 (1.2)	22,106.1	1.8	1.97 (1.17−3.32)	2.01 (1.19−3.39)
≥65	17 (2.3)	3124.5	5.4	42 (1.9)	11,617.7	3.6	1.50 (0.85−2.64)	1.52 (0.86−2.67)
Sex
Female	17 (2.3)	3124.5	5.4	42 (1.9)	11,617.7	3.6	1.85 (1.11−3.07)	1.84 (1.11−3.07)
Male	32 (2.6)	6055.0	5.3	52 (1.4)	22,954.0	2.3	2.28 (1.47−3.54)	2.33 (1.50−3.63)
Underlying comorbidity
Hypertension	25 (2.1)	5797.4	4.3	45 (1.3)	19,660.7	2.3	1.87 (1.15−3.05)	1.98 (1.21−3.24)
Hyperlipidemia	13 (1.8)	3727.4	3.5	26 (1.1)	13,589.6	1.9	1.84 (0.95−3.58)	1.92 (0.98−3.78)
Hyperuricemia	3 (1.9)	828.6	3.6	7 (1.7)	2460.9	2.8	1.24 (0.32−4.81)	1.29 (0.31−5.39)
Chronic obstructive pulmonary disease	3 (1.4)	1021.8	2.9	6 (1.3)	2531.9	2.4	11.20 (0.30−4.81)	1.03 (0.24−4.47)
Coronary artery disease	7 (1.9)	1715.9	4.1	12 (1.4)	4835.4	2.5	1.64 (0.65−4.18)	1.78 (0.69−4.57)
Follow-up period
<1 year	16 (0.7)	2113.3	7.6	18 (0.3)	6758.5	2.7	2.82 (1.44−5.54)	2.85 (1.45−5.60)
<2 years	27 (1.2)	3969.5	6.8	29 (0.4)	12,996.7	2.2	3.03 (1.79−5.11)	3.10 (1.84−5.25)
<3 years	33 (1.4)	5528.8	6.0	39 (0.6)	18,423.9	2.1	2.79 (1.76−4.44)	2.88 (1.81−4.58)
<4 years	38 (1.7)	6882.0	5.5	48 (0.7)	23,240.1	2.1	2.64 (1.73−4.05)	2.70 (1.76−4.14)
<5 years	42 (1.8)	8037.9	5.2	61 (0.9)	27,443.9	2.2	2.33 (1.57−3.45)	2.38 (1.61−3.53)
<6 years	43 (1.9)	9021.2	4.8	71 (1.0)	31,087.8	2.3	2.07 (1.42−3.02)	2.12 (1.45−3.09)
≥6 years	12 (0.5)	3130.2	3.8	23 (0.3)	12,367.6	1.9	2.09 (1.04−4.19)	2.15 (1.07−4.33)

Notes: ^aAdjusted for age, sex, hypertension, hyperlipidemia, hyperuricemia, chronic obstructive pulmonary disease, and coronary artery disease. ^bPer 1000 PY. The median duration of diabetes was 5.61 years in patients with CO poisoning and 5.73 years in patients without CO poisoning cohort patients (p = 0.086).

Abbreviations: HR, hazard ratio; AHR, adjusted hazard ratio; CI, confidence interval; PY, person-year.

Figure 2 Comparison of the risk for hyperglycemic crises between diabetic patients with and without CO poisoning using Kaplan-Meier’s method and Log rank test.

Abbreviation: CO, carbon monoxide.

Figure 3 Pathological change in the pancreas with different magnification using hematoxylin-eosin stain and relevance of biochemical parameters manifestation. Upper row represents the sham group and the bottom row represents the CO poisoning group on CO poisoning-Day 28 (A) and statistical quantification of damage scores between two groups (B), n = 10 per group, ****p < 0.0001. Biochemical indicator like glucose (C) and relative hormone like insulin (D) and glucagon (E) were detected from the serum by ELISA assay at the indicated day, n = 10–12 per group, **p < 0.01, ***p < 0.001, ****p < 0.0001.

Abbreviation: CO, carbon monoxide.

Figure 4 Insulin expression by immunofluorescence staining. Pancreatic islet was labeled by insulin antibody co-staining with nucleus staining (DAPI) shown in different magnification (200×–400×) in the sham (A) and CO poisoning group (B). Comparison of the number of insulin-positive cells per field was showed in the (C) ***p < 0.001.

Abbreviation: CO, carbon monoxide.

Figure 5 Histopathological change of the brain region by hematoxylin-eosin stain. Significant damages such as pyknosis, karyorrhexis, vacuolation, and immune cell infiltration were found in the hypothalamus of CO poisoning rats (A). The damage score of the hypothalamus was significantly higher in the CO poisoning-Day 28 group than that of the sham group (B). ***p < 0.001.

Abbreviation: CO, carbon monoxide.