High Cortisol/DHEA-S Ratio Is a Risk Factor for Sarcopenia

Abstract and Introduction

Abstract

Context: Elderly patients with type 2 diabetes mellitus (T2DM) have a high prevalence of frailty and/or sarcopenia. Sarcopenia is thought to be related to discordant secretions of the adrenal hormones cortisol and dehydroepiandrosterone (DHEA), as well as the sulfate ester of DHEA (DHEA-S). The current study sought to evaluate the risk factors for sarcopenia in elderly patients with T2DM.

Design and Patients: We enrolled 108 consecutive elderly patients aged ≥65 years with T2DM (mean age, 76.2 ± 7.3 years; 43.5% males). Sarcopenia was assessed and diagnosed based on the Asian version of the diagnostic criteria regarding muscular strength, physical function, and muscle mass. We assessed various physical parameters, blood tests, and atherosclerosis markers and statistically determined the risk factors for sarcopenia.

Results: Multiple regression analysis showed that the independent risk factors for sarcopenia were a serum cortisol/DHEA-S ratio ≥0.2, diastolic blood pressure <70 mm Hg, Hb concentration <13 g/dL, and an ankle brachial index <1.0. The strongest risk factor for sarcopenia was a serum cortisol/DHEA-S ratio ≥0.2. An increase in the serum cortisol/DHEA-S ratio reflected higher cortisol values and lower DHEA-S values in patients with sarcopenia compared with those in nonsarcopenic patients. The concentrations of cortisol and DHEA-S, as well as the cortisol/DHEA-S ratio, changed in accordance with the severity of sarcopenia.

Conclusions: A relative increase in cortisol may reflect the presence of stress and stimulate muscle catabolism, whereas a relative decrease in DHEA-S may cause a decrease in the anabolic action of DHEA on muscle; the combination of these factors may lead to sarcopenia.

Introduction

The number of patients with diabetes mellitus in Japan has reached 10 million, and 50% of these patients are elderly. The incidence of elderly patients with diabetes mellitus is likely to further increase due to the rapid expansion of an aging society. Furthermore, elderly subjects are often in a state of frailty, which comprises poor resolution of homeostasis after stress. Frailty is a consequence of a cumulative decline in multiple physiological systems, leading to falls, disability, hospitalization, and mortality.^[1–3] Frailty is narrowly defined based on physical conditions,^[1] or broadly defined to include physical and psychosocial conditions.^[2] Previous studies using the narrow definition of frailty show that the risk factors for frailty in patients with type 2 diabetes mellitus (T2DM) are high glycated Hb (HbA1c) concentrations,^[4,5] or both appropriate and high (U-shaped curve) HbA1c concentrations.^[6] However, it has recently been shown that only low HbA1c concentrations are associated with the broad definition of frailty.^[7] Early detection and/or prevention of frailty in elderly patients with T2DM are essential for the prevention of associated complications.

Sarcopenia is defined as age-associated loss of muscle mass and is related to deterioration in physical disability, metabolic impairment, and increased mortality. Therefore, sarcopenia is well established as an important risk factor for frailty.^[3,8–10] The European Working Group on Sarcopenia in Older People (EWGSOP) introduced a diagnostic algorithm for sarcopenia based on walking speed, grip strength, and skeletal muscle mass in 2010.^[9] In 2014, the Asian Working Group for Sarcopenia introduced a new diagnostic algorithm for sarcopenia that considered the differences between European and Asian populations in ethnicity, physical characteristics, and culture.^[10] Sarcopenia is affected by many factors, such as age-related alterations in various hormones, malnutrition, various chronic diseases, and inflammation.^[3,8–11]

The hormone dehydroepiandrosterone (DHEA) might be related to frailty or a decrease in physical activity.^[12–17] DHEA and its sulfate ester, DHEA-S, are prominent adrenal steroid hormones in humans.^[18–21] Serum DHEA concentrations in humans are similar to those of DHEA-S and are usually evaluated as DHEA-S.^[22] DHEA affects peripheral tissues either indirectly via conversion to androgens, estrogens, or both, or directly as a steroid.^[19] DHEA shows a characteristic secretion pattern, with serum concentrations declining with increasing age. Serum DHEA and DHEA-S concentrations peak in young adulthood and then gradually decline over time. Consequently, individuals aged 70 to 80 years have circulating DHEA concentrations that are 10% to 20% of their original young adult concentrations.^[18] In contrast, there are no clear age-related changes in the concentrations of cortisol, which is also an adrenocortical hormone.^[18,19] Although little is known about the physiological role of DHEA, human epidemiological studies have suggested that its concentrations may represent a biomarker of longevity^{[19–21,23–25]} and successful aging.^[20] Various in vivo and in vitro experiments have suggested that DHEA might be beneficial for cognitive function,^[22] obesity,^[26,27] diabetes mellitus,^[28] atherosclerosis,^[29] and osteoporosis.^[30–32] A relatively higher serum DHEA-S concentration was significantly correlated with an extended lifespan in calorie-restricted male rhesus monkeys and in a clinical study of males living in Baltimore.^[23] A 27-year study in a community-based cohort in Japan also indicated that DHEA-S concentration may be a predictor of longevity in males, independent of age, blood pressure, and plasma glucose.^[24]

Cortisol is involved in various physiological systems, including metabolism, the immune response, and the body's response to stress. Production of cortisol is usually triggered by stress-induced activation of a hormonal system known as the hypothalamic–pituitary–adrenal axis. Cortisol also provides negative feedback to this axis to maintain a physiological concentration. However, the hypothalamic–pituitary–adrenal axis is dysregulated in pathological situations, such as the autonomous cortisol overproduction seen in Cushing syndrome or chronic physical or psychiatric stress. Continuous oversecretion of cortisol mediates muscle breakdown, thus possibly leading to sarcopenia. This extreme phenotype of muscle atrophy is typified in patients with Cushing syndrome.

These findings on sarcopenia prompted us to investigate the association between sarcopenia and various risk factors in elderly patients with T2DM, especially regarding the concentrations of adrenal hormones. Secretion of cortisol and DHEA-S in an appropriate balance is essential for the maintenance of biological function and homeostasis. A high cortisol/DHEA-S ratio is reportedly associated with mortality,^[33] dementia,^[34] metabolic syndrome,^[35] and reduced immunity following physical stress.^[36] Furthermore, discordant secretion of these two adrenal hormones is related to aging.^[18,19] Therefore, the current study sought to investigate the balance between cortisol and DHEA-S in elderly patients with T2DM and sarcopenia.

Table 1. Characteristics of the Elderly Patients With Diabetes Stratified by Sarcopenia
	All Cases	Nonsarcopenia	Sarcopenia	P Values
(N = 108)	(N = 70)	(N = 38)
Age, y	76.2 ± 7.3	74.2 ± 7.0	79.8 ± 6.7	<0.001^a
Male, n (%)	47 (43.5)	34 (48.6)	13 (34.2)	0.162^b
Duration of T2DM, y	14.3 ± 12.1	12.5 ± 10.6	17.7 ± 14.1	0.054^a
Body weight, kg	57.4 ± 11.1	61.8 ± 9.6	49.1 ± 8.5	<0.001^a
BMI, kg/m²	23.7 ± 3.6	24.9 ± 3.2	21.4 ± 3.0	<0.001^a
SBP, mm Hg	135.8 ± 18.9	137.4 ± 18.3	133.0 ± 19.8	0.248^a
DBP, mm Hg	72.9 ± 11.0	75.5 ± 10.5	68.3 ± 10.3	<0.001^a
RBCs, ×10⁴/μL	422 ± 53	434 ± 52	400 ± 46	<0.001^a
Hb, g/dL	12.9 ± 1.6	13.4 ± 1.6	12.1 ± 1.4	<0.001^a
Albumin, g/dL	4.08 ± 0.36	4.11 ± 0.32	4.02 ± 0.41	0.197^a
AST, IU/L	24.9 ± 9.9	25.7 ± 10.2	23.4 ± 9.3	0.253^a
ALT, IU/L	17.0 [12.8–26.3]	18.0 [13.0–30.8]	14.0 [10.3–21.0]	0.016^c
HbA1c, %	7.01 ± 0.83	7.06 ± 0.86	6.93 ± 0.78	0.432^a
Serum creatinine, mg/dL	0.70 [0.60–0.91]	0.70 [0.60–0.90]	0.72 [0.53–0.91]	0.413^c
eGFR, mL/min/1.73 m²	61.4 ± 18.9	61.2 ± 17.2	61.7 ± 16.4	0.885^a
Uric acid, mg/dL	5.19 ± 1.33	5.18 ± 1.24	5.19 ± 1.48	0.980^a
Triglycerides, mg/dL	137 ± 67	144 ± 71	124 ± 57	0.140^a
LDL-C, mg/dL	102 ± 31	106 ± 31	95 ± 32	0.093^a
HDL-C, mg/dL	54.0 ± 13.8	52.7 ± 12.6	56.6 ± 15.6	0.162^a
Calcium, mg/dL	9.28 ± 0.34	9.25 ± 0.33	9.33 ± 0.36	0.206^a
DHEA-S, μg/dL	59.5 [40.5–90.8]	71.5 [48.3–106.0]	45.0 [32.0–60.8]	<0.001^c
Cortisol, μg/dL	9.32 ± 2.78	8.76 ± 2.67	10.33 ± 2.74	0.005^a
Ratio cortisol/DHEA-S	0.15 [0.09–0.24]	0.11 [0.09–0.18]	0.22 [0.16–0.30]	0.004^c
MMSE	25.0 ± 5.2	25.7 ± 5.76	23.8 ± 4.5	0.072^a
STFC, s	12.1 ± 5.3	11.3 ± 4.7	13.8 ± 6.1	0.024^a
Ratio two steps/height	1.07 ± 0.25	1.17 ± 0.23	0.91 ± 0.20	<0.001^a
ABI	1.08 ± 0.15	1.10 ± 0.12	1.04 ± 0.18	0.027^a
baPWV, cm/s	2101 ± 431	2056 ± 405	2182 ± 468	0.149^a
Vertebral YAM, %	83.9 ± 17.3	85.2 ± 18.2	81.6 ± 15.5	0.326^a
Walking speed, m/s	0.94 ± 0.41	1.05 ± 0.42	0.72 ± 0.31	<0.001^a
Grip, kg	21.4 ± 9.8	24.4 ± 10.1	15.8 ± 6.4	<0.001^a
SMI, kg/m²	6.27 ± 1.06	6.74 ± 0.88	5.39 ± 0.77	<0.001^a
Frailty, n (%)	32 (29.6)	16 (22.9)	16 (42.1)	0.048^b
Anti-HT drug use, n (%)	68 (63.0)	44 (62.9)	24 (63.2)	0.999^b
Anti-DL drug use, n (%)	58 (53.7)	37 (52.9)	21 (55.3)	0.842^b
Medications for T2DM
Insulin, n (%)	24 (22.2)	13 (18.6)	11 (28.9)	0.234^b
SU or glinide, n (%)	37 (34.4)	22 (31.4)	15 (39.5)	0.406^b
Others, n (%)	47 (43.5)	35 (50.0)	12 (31.6)	0.072^b

Table 1. Characteristics of the Elderly Patients With Diabetes Stratified by Sarcopenia

All Cases

Nonsarcopenia

Sarcopenia

P Values

(N = 108)

(N = 70)

(N = 38)

Age, y

76.2 ± 7.3

74.2 ± 7.0

79.8 ± 6.7

<0.001^a

Male, n (%)

47 (43.5)

34 (48.6)

13 (34.2)

0.162^b

Duration of T2DM, y

14.3 ± 12.1

12.5 ± 10.6

17.7 ± 14.1

0.054^a

Body weight, kg

57.4 ± 11.1

61.8 ± 9.6

49.1 ± 8.5

<0.001^a

BMI, kg/m²

23.7 ± 3.6

24.9 ± 3.2

21.4 ± 3.0

<0.001^a

SBP, mm Hg

135.8 ± 18.9

137.4 ± 18.3

133.0 ± 19.8

0.248^a

DBP, mm Hg

72.9 ± 11.0

75.5 ± 10.5

68.3 ± 10.3

<0.001^a

RBCs, ×10⁴/μL

422 ± 53

434 ± 52

400 ± 46

<0.001^a

Hb, g/dL

12.9 ± 1.6

13.4 ± 1.6

12.1 ± 1.4

<0.001^a

Albumin, g/dL

4.08 ± 0.36

4.11 ± 0.32

4.02 ± 0.41

0.197^a

AST, IU/L

24.9 ± 9.9

25.7 ± 10.2

23.4 ± 9.3

0.253^a

ALT, IU/L

17.0 [12.8–26.3]

18.0 [13.0–30.8]

14.0 [10.3–21.0]

0.016^c

HbA1c, %

7.01 ± 0.83

7.06 ± 0.86

6.93 ± 0.78

0.432^a

Serum creatinine, mg/dL

0.70 [0.60–0.91]

0.70 [0.60–0.90]

0.72 [0.53–0.91]

0.413^c

eGFR, mL/min/1.73 m²

61.4 ± 18.9

61.2 ± 17.2

61.7 ± 16.4

0.885^a

Uric acid, mg/dL

5.19 ± 1.33

5.18 ± 1.24

5.19 ± 1.48

0.980^a

Triglycerides, mg/dL

137 ± 67

144 ± 71

124 ± 57

0.140^a

LDL-C, mg/dL

102 ± 31

106 ± 31

95 ± 32

0.093^a

HDL-C, mg/dL

54.0 ± 13.8

52.7 ± 12.6

56.6 ± 15.6

0.162^a

Calcium, mg/dL

9.28 ± 0.34

9.25 ± 0.33

9.33 ± 0.36

0.206^a

DHEA-S, μg/dL

59.5 [40.5–90.8]

71.5 [48.3–106.0]

45.0 [32.0–60.8]

<0.001^c

Cortisol, μg/dL

9.32 ± 2.78

8.76 ± 2.67

10.33 ± 2.74

0.005^a

Ratio cortisol/DHEA-S

0.15 [0.09–0.24]

0.11 [0.09–0.18]

0.22 [0.16–0.30]

0.004^c

MMSE

25.0 ± 5.2

25.7 ± 5.76

23.8 ± 4.5

0.072^a

STFC, s

12.1 ± 5.3

11.3 ± 4.7

13.8 ± 6.1

0.024^a

Ratio two steps/height

1.07 ± 0.25

1.17 ± 0.23

0.91 ± 0.20

<0.001^a

ABI

1.08 ± 0.15

1.10 ± 0.12

1.04 ± 0.18

0.027^a

baPWV, cm/s

2101 ± 431

2056 ± 405

2182 ± 468

0.149^a

Vertebral YAM, %

83.9 ± 17.3

85.2 ± 18.2

81.6 ± 15.5

0.326^a

Walking speed, m/s

0.94 ± 0.41

1.05 ± 0.42

0.72 ± 0.31

<0.001^a

Grip, kg

21.4 ± 9.8

24.4 ± 10.1

15.8 ± 6.4

<0.001^a

SMI, kg/m²

6.27 ± 1.06

6.74 ± 0.88

5.39 ± 0.77

<0.001^a

Frailty, n (%)

32 (29.6)

16 (22.9)

16 (42.1)

0.048^b

Anti-HT drug use, n (%)

68 (63.0)

44 (62.9)

24 (63.2)

0.999^b

Anti-DL drug use, n (%)

58 (53.7)

37 (52.9)

21 (55.3)

0.842^b

Medications for T2DM

Insulin, n (%)

24 (22.2)

13 (18.6)

11 (28.9)

0.234^b

SU or glinide, n (%)

37 (34.4)

22 (31.4)

15 (39.5)

0.406^b

Others, n (%)

47 (43.5)

35 (50.0)

12 (31.6)

0.072^b

Variables	Before Adjustment		After Adjustment
Variables	OR (95% CI)	P Values	OR (95% CI)	P Values
Age ≥75, y	7.05 (2.73–18.25)	<0.001	2.56 (0.74–8.84)	0.137
BMI ≥25, kg/m²	0.10 (0.03–0.34)	<0.001	0.25 (0.05–1.17)	0.079
DBP <70, mm Hg	4.12 (1.78–9.51)	<0.001	5.18 (1.26–21.34)	0.023
Red blood cells <420, ×10⁴/μL^a	4.74 (1.99–11.31)	<0.001	0.67 (0.09–5.09)	0.701
Hb <13, g/dL^a	7.97 (3.07–20.71)	<0.001	10.07 (1.11–91.48)	0.040
ALT <22, IU/L^a	2.50 (1.00–6.24)	0.050	1.49 (0.38–5.84)	0.569
DHEA-S <73, μg/dL^a	4.18 (1.63–10.76)	0.003	Not applicable
Cortisol ≥9.3, μg/dL^a	2.73 (1.21–6.17)	0.016	Not applicable
Cortisol/DHEA-S ≥0.2	4.17 (1.78–9.74)	<0.001	7.85 (1.86–6.13)	0.005
ABI <1.0	4.02 (1.42–11.37)	0.009	6.51 (1.44–29.36)	0.015
Frailty	2.45 (1.05–5.75)	0.039	1.14 (0.33–3.95)	0.833

Risk Factors	Cutoff Values	AUC (95% CI)	P Values
DBP, mm Hg	68	0.711 (0.610–0.813)	<0.001
Hb, g/dL	12.8	0.734 (0.634–0.833)	<0.001
ABI	1.09	0.612 (0.491–0.733)	0.058
DHEA-S, μg/dL	50	0.709 (0.611–0.808)	<0.001
Cortisol/DHEA-S	0.14	0.769 (0.682–0.857)	<0.001

A High Serum Cortisol/DHEA-S Ratio Is a Risk Factor for Sarcopenia in Elderly Diabetic Patients

Abstract and Introduction

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