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

Ikumi Yanagita; Yuya Fujihara; Yuichi Kitajima; Misuzu Tajima; Masanao Honda; Tomoko Kawajiri; Terumi Eda; Kazue Yonemura; Noriko Yamaguchi; Hideko Asakawa; Yukiko Nei; Yumi Kayashima; Mihoko Yoshimoto; Mayumi Harada; Yuhei Araki; Shoji Yoshimoto; Eiji Aida; Toshihiko Yanase; Hajime Nawata; Kazuo Muta


J Endo Soc. 2019;3(4):801-813. 

In This Article

Materials and Methods


In the current study, we retrospectively reviewed the data from 108 consecutive elderly patients aged ≥65 years with T2DM who were being treated as outpatients or were hospitalized in Muta Hospital from October 2016 to September 2017; all 108 patients (47 males, 61 females) were enrolled in the current study. Patients taking glucocorticoids by oral or inhalation administration were excluded, as glucocorticoid administration affects the serum concentrations of cortisol and DHEA-S. None of the included patients was taking psychiatric drugs because of mental illness, and none was affected by alcoholism. T2DM was diagnosed based on the criteria proposed by the Japan Diabetes Society[37] or was diagnosed when the patient had a history of taking medication comprising insulin or oral hypoglycemic agents (OHAs). Data regarding age, blood test results, general physical assessments, and administered drugs were obtained from the medical records. The duration of T2DM was estimated from the time of the initial detection of hyperglycemia.

Hematological Tests and Hormonal Measurements

Blood samples were obtained in the morning between 0900 and 1200 hours. We collected information on the concentrations of HbA1c, red blood cells, Hb, serum albumin, aspartate aminotransferase, alanine aminotransferase (ALT), creatinine, uric acid, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, and corrected calcium. The estimated glomerular filtration rate was calculated from the serum creatinine concentration. We collected information on height, body weight, and body mass index (BMI). BMI was calculated as the weight in kilograms divided by the squared height in meters. Systolic blood pressure and diastolic blood pressure (DBP) were measured using a mercury sphygmomanometer with the patient at rest in the sitting position.

Serum cortisol concentrations were measured using the chemiluminescence enzyme immunoassay method using an Abbott cortisol kit[38] (Abbott Japan, Tokyo, Japan). Serum DHEA-S concentrations were measured via chemiluminescence enzyme immunoassay using an Access DHEA-S kit[39] (Beckman Coulter, Tokyo, Japan). The detection limits for cortisol and DHEA-S were 0.8 μg/dL and 2.0 μg/dL, respectively. The respective intra-assay coefficient of variance values of cortisol and DHEA-S were both <10%. The cortisol (μg/dL)/DHEA-S (μg/dL) ratio was finally determined.

Evaluations of Frailty, Sarcopenia, Dementia, Arthrosclerosis, and Osteoporosis

A broad-definition frailty scale, the Clinical Frailty Scale (CFS),[2] was determined as previously described.[7] The CFS contains nine stages (1, very fit; 2, well; 3, managing well; 4, vulnerable; 5, mildly frail; 6, moderately frail; 7, severely frail; 8, very severely frail; and 9, terminally ill). Patients classified as CFS stages 1 to 4 were defined as having no frailty, as these patients could live independently; patients with CFS stages 5 to 9 were defined as having frailty, as these patients required assistance with the activities of daily life. The CFS stages of the 108 included patients ranged from 1 to 7.

Sarcopenia was assessed by handgrip strength as an indicator of muscular strength, walking speed as an indicator of physical function, and bioelectrical impedance analysis as an indicator of muscle mass. Handgrip strength was measured using a handgrip dynamometer (Takei Scientific Instruments, Tokyo, Japan).[40] Bioelectrical impedance analysis has been accepted as a method for detecting sarcopenia by the EWGSOP[9] and the Asian Working Group for Sarcopenia.[10] The actual diagnosis of sarcopenia was made in accordance with the Asian version of the diagnostic criteria for sarcopenia,[10] based on the presence of low muscle mass plus low muscle strength and/or low physical performance. The cutoff values for sarcopenia regarding muscle mass were <7.0 kg/m2 for males and <5.7 kg/m2 for females; those regarding grip strength were <26 kg for males and <18 kg for females; those regarding walking speed were ≤0.8 m/s for both males and females.[10]

The severity of sarcopenia was determined using the criteria of the EWGSOP.[10] Among the components of muscle mass, muscle strength, and physical activity, a decrease in muscle mass only was diagnosed as presarcopenia, a decrease in muscle mass plus a decrease in muscular strength or physical ability was diagnosed as sarcopenia, and a decrease in all three components was diagnosed as severe sarcopenia. Dementia was diagnosed using the Mini-Mental State Examination (MMSE).[41] The maximum MMSE score is 30; a score of ≤23 indicates dementia, and a score of 24 to 27 indicates mild cognitive impairment. Brachial-ankle pulse wave velocity was used to evaluate arteriosclerosis, and the ankle-brachial index (ABI)[42] was measured as a screening marker for arteriosclerosis obliterans. Osteoporosis was diagnosed based on the bone mineral density evaluated by dual-energy X-ray absorptiometry.[43]

Treatments for T2DM

At the time of sarcopenia evaluation, patients were divided into three groups in accordance with the T2DM treatment being received: (i) insulin therapy group, (ii) OHA using sulfonylurea (SU) or glinide group, and (iii) "others" group. The others group was treated with diet only and/or OHAs other than SU or glinide. Thus, the insulin therapy and the SU or glinide groups were considered to have a relatively higher risk of hypoglycemia than did the others group. Additionally, we investigated the administration of antihypertensive drugs and drugs for dyslipidemia, such as statins and fibrates.

Informed Consent

The Research Ethics Committee of Muta Hospital approved the current study (date of approval, 15 May 2017; approval no. 29–001), and the study conformed to the Helsinki Declaration, as revised in 2013. The current study was also registered in the UMIN Clinical Trials Registry (ID no. UMIN000031357). We obtained informed consent by publishing an opt-out option on the homepage of Muta Hospital.

Statistical Analysis

Data are expressed as mean ± SD, medians with quartile values (25% to 75%), or numbers with percentages. Differences in continuous variables between the two groups were compared using the unpaired t test for normally distributed data, or the Mann–Whitney U test for nonnormally distributed data. Differences in categorical variables between the two groups were examined using Fisher's exact test. Differences in continuous variables among four groups (nonsarcopenia, presarcopenia, sarcopenia, and severe sarcopenia) were compared by the multiple comparison method (Fisher's least significant difference method) after analysis of variance. An increased or decreased tendency of continuous variables (age, BMI, DBP, Hb concentration, cortisol concentration, DHEA-S concentration, MMSE score, ABI, frailty, and cortisol/DHEA-S ratio) in accordance with the severity of sarcopenia was tested by the Jonckheere–Terpstra test. Differences in categorical variables among the four groups were tested using the χ 2 test with a Bonferroni adjustment. Binary regression analysis was performed to identify the risk factors for sarcopenia in elderly patients with T2DM, and to calculate the ORs and 95% CIs. Univariate and multivariate binary regression analyses were performed with and without adjustment for other variables. As there were comparisons made between groups with and without medical endpoints, variables with P < 0.05 were selected and used in the multiple binary regression model. When there were collinear characteristics between two variables, either of the two variables was excluded from the multiple regression model. Receiver operating characteristics (ROC) curve analysis was used to determine the cutoff values of continuous parameters as risk factors for sarcopenia, and their areas under the curve (AUCs) and 95% CIs were calculated. All statistical analyses were performed using SPSS version 18.0 (IBM). P < 0.05 was considered statistically significant.