Changes in corneal nerve morphology and function in patients with dry eyes having type 2 diabetes

Table 1 Demographics and examination findings of the diabetes patients grouped by the duration of type 2 diabetes mellitus with or without dry eye disease

Parameters	DEwDM		P value	DMnDE		P value	DEwDM versus DMnDE P value
	Duration of diabetes ≤ 10 yr	Duration of diabetes > 10 yr		Duration of diabetes ≤ 10 yr	Duration of diabetes > 10 yr		Duration of diabetes ≤ 10 yr	Duration of diabetes > 10 yr
Number [N]	26	30		8	14
Age [yr ± SEM]	56.8 ± 9.3	57.8 ± 6.9	0.660	51.3 ± 8.9	57.1 ± 5.3	0.065	0.146	0.740
Gender			0.126			0.074a	0.257a	1b
Male [N (%)]	13 (50.0)	21 (70.0)		2 (25.0)	10 (71.4)
Female [N (%)]	13 (50.0)	9 (30.0)		6 (75.0)	4 (28.6)
Blood glucose [mmol/L ± SEM]	7.9 ± 3.7	9.6 ± 4.2	0.103	7.8 ± 1.1	9.7 ± 2.8	0.083	0.926	0.989
Duration of diabetes [years ± SEM]	5.9 ± 2.6	17.8 ± 4.8	0.000	8.3 ± 1.7	17.6 ± 5.4	0.000	0.021	0.940
HbA1c [% ± SEM]	7.8 ± 2.3	8.4 ± 1.8	0.257	7.7 ± 1.9	8.1 ± 1.4	0.652	0.921	0.484
BUT [s ± SEM]	4.1 ± 2.5	3.8 ± 2.5	0.586	11.2 ± 7.5	10.0 ± 2.9	0.601	0.000	0.000
Schirmer test [mm ± SEM]	5.9 ± 4.7	3.2 ± 3.4	0.018	18.4 ± 5.9	10.9 ± 6.2	0.012	0.000	0.000
NFL [mm/mm2 ± SEM]	17.653 ± 4.569	15.851 ± 4.881	0.162	20.445 ± 4.036	15.904 ± 5.238	0.047	0.131	0.974
NFD [num/mm2 ± SEM]	33.2 ± 12.1	30.4 ± 8.486	0.323	39.1 ± 12.4	33.9 ± 10.9	0.323	0.240	0.250
NBD [num/mm2 ± SEM]	56.7 ± 25.5	50.0 ± 25.2	0.326	61.7 ± 21.0	43.3 ± 22.4	0.072	0.619	0.401
R1 [ms]	11.8 ± 0.9	12.2 ± 0.8	0.083	10.3 ± 0.5	11.8 ± 1.0	0.001	0.000	0.183

^aP value from exact probability test.

^bP value from Chi-squared test with continuity correction.

BUT: Tear film break-up time; HbA1c: Hemoglobin A1C; OSDI: Ocular surface disease index; Schirmer: Schirmer I test; NFL: Nerve fiber length; NFD: Nerve fiber density; NBD: Nerve branch density; R1: The R1 latency in blink reflex.

Table 2 Patient characteristics

Parameters	DEwDM	DEnDM	DMnDE	nDMnDE	Statistics
Number [N]	56	33	22	20
Age [yr ± SEM]	56.9 ± 7.8	52.3 ± 11.1	55.0 ± 7.2	52.2 ± 9.4
Gender					chi-square test
Male [N (%)]	34 (60.7)	14 (42.4)	12 (54.5)	8 (40.0)
Female [N (%)]	22 (39.3)	19 (57.6)	10 (45.5)	12 (60.0)
Blood glucose [mmol/L ± SEM]	7.4 ± 4.2	NA	9.0 ± 2.5	NA
Duration of diabetes [years ± SEM]	12.3 ± 7.1	NA	14.2 ± 6.4	NA
HbA1c [% ± SEM]	8.1 ± 2.0	NA	7.9 ± 1.6	NA
OSDI scores ± SEM	5.8 ± 3.9b,c	9.7 ± 6.3a,c	3.6 ± 2.7a,b,d	10.5 ± 7.1c	Tamhane test
BUT [s ± SEM]	3.9 ± 2.5c,d	4.9 ± 3.9c,d	10.4 ± 4.9a,b	12.0 ± 6.5a,b	Tamhane test
Schirmer test [mm ± SEM]	4.5 ± 4.2c,d	3.7 ± 3.6c,d	13.6 ± 7.0a,b	11.2 ± 4.4a,b	Tamhane test

^aP < 0.05 versus diabetic dry eye syndrome (DES) group.

^bP < 0.05 versus non-diabetic DES group.

^cP < 0.05 versus diabetic without DES group.

^dP < 0.05 versus diabetic normal group.

BUT: Tear film break-up time; HbA1c: Hemoglobin A1C; OSDI: ocular surface disease index; Schirmer: Schirmer I test; NA: Not available.

Table 3 Comparisons for the nerve fiber length, nerve fiber density, nerve branch density, and R1 among four groups

Parameters	DEwDM	DEnDM	DMnDE	nDMnDE	Statistics
NFL [mm/mm2]	16.688 ± 4.782d	16.894 ± 4.855d	17.555 ± 5.236d	22.017 ± 3.369a,b,c	Tukey HSD test
NFD [num/mm2]	35.0 ± 9.4	37.5 ± 10.6	35.6 ± 11.3	41.3 ± 8.1	Tukey HSD test
NBD [num/mm2]	46.9 ± 23.1	51.3 ± 25.0	50.0 ± 23.1	60.6 ± 26.3	Tukey HSD test
R1 [ms]	12.0 ± 0.8b,c,d	11.2 ± 0.8a	11.3 ± 1.1a	10.6 ± 1.0a	Tamhane test

^aP < 0.05 versus diabetic dry eye syndrome (DES) group.

^bP < 0.05 versus non-diabetic DES group.

^cP < 0.05 versus diabetic without DES group.

^dP < 0.05 versus non-diabetic normal group.

All data are expressed as mean ± SD. NFL: Nerve fiber length; NFD: Nerve fiber density; NBD: Nerve branch density; R1, the R1 latency in blink reflex.

Table 4 Demographics and examination findings of the dry eye patients grouped by Schirmer test with or without type 2 diabetes mellitus

Parameters	DEwDM		P value	DEnDM		P value	DEwDM versus DEnDM P value
	Schirmer test ≤ 5 mm	Schirmer test > 5 mm		Schirmer test ≤ 5 mm	Schirmer test > 5 mm		Schirmer test ≤ 5 mm	Schirmer test > 5 mm
Number [N]	39	17		24	9
Age [yr ± SEM]	57.1 ± 8.5	57.9 ± 7.2	0.707	53.5 ± 11.7	49.1 ± 9.0	0.323	0.164	0.011
Gender			0.686			0.122a	0.632b	0.026a
Male [N (%)]	23 (59.0)	11 (64.7)		8 (33.3)	6 (66.7)
Female [N (%)]	16 (41.0)	6 (35.3)		16 (66.7)	3 (33.3)
Blood glucose [mmol/L ± SEM]	8.8 ± 3.6	8.9 ± 5.0	0.893	NA	NA	NA
	13.5 ± 6.8	9.5 ± 7.4	0.054	NA	NA	NA
HbA1c [% ± SEM]	8.1 ± 1.8	8.1 ± 2.5	0.995	NA	NA	NA
BUT [s ± SEM]	4.3 ± 2.9	3.1 ± 1.0	0.105	5.6 ± 4.3	3.2 ± 1.3	0.114	0.153	0.856
Schirmer test [mm ± SEM]	2.1 ± 1.7	9.9 ± 3.1	0.000	1.9 ± 1.5	8.7 ± 2.5	0.000	0.590	0.319
NFL [mm/mm2 ± SEM]	16.671 ± 4.749	16.727 ± 5.006	0.968	17.036 ± 4.691	16.514 ± 5.549	0.788	0.767	0.922
NFD [num/mm2 ± SEM]	32.4 ± 9.7	30.1 ± 11.7	0.310	35.7 ± 8.3	34.7 ± 16.3	0.429	0.072	0.039
NBD [num/mm2 ± SEM]	52.1 ± 22.9	55.5 ± 30.9	0.241	65.6 ± 23.7	49.3 ± 22.2	0.019	0.031	0.104
R1 [ms ± SEM]	12.1 ± 0.9	11.8 ± 0.6	0.406	11.1 ± 0.8	11.5 ± 0.9	0.288	0.000	0.215

^aP value from exact probability test.

^bP value from Chi-squared test with continuity correction.

BUT: Tear film break-up time; HbA1c: Hemoglobin A1C; OSDI: Ocular surface disease index; Schirmer: Schirmer I test; NA: Not available; NFL: Nerve fiber length; NFD: Nerve fiber density; NBD: Nerve branch density; R1: The R1 latency in blink reflex.

Table 5 Correlation analysis of each observation index

Group	HbA1c	P value related to R1	P value related to Schirmer	P value related to BUT	P value related to NFL	P value related to NFD	P value related to NBD
Diabetes groups	8.08 ± 1.89	0.072	0.280	0.796	0.621	0.794	0.952
Diabetic dry eye group	8.14 ± 2.01	0.933	0.508	0.141	0.589	0.823	0.851
Diabetic non-dry eye group	7.93 ± 1.57	0.419	0.376	0.140	0.910	0.421	0.832

BUT: Tear film break-up time; HbA1c: Hemoglobin A1c; R1: The R1 latency in blink reflex; Schirmer: Schirmer I test; NFL: Nerve fiber length; NFD: Nerve fiber density; NBD: Nerve branch density.