Abstract
Background: The prevalence rates for both sarcopenia and erectile dysfunction (ED) gradually increase in middle-aged and elderly diabetic male population and they impair physical functioning, sexual functioning, and quality of life. The aim of the present study was to evaluate the sarcopenia in patients with diabetic ED.
Methods: The study included 98 male patients with type II diabetes mellitus (DM) aged 18–80 years. Blood chemistry and hormone levels were obtained. The International Index of Erectile Function (IIEF-5) questionnaire was administered to the patients. The patients were divided into three groups according to the IIEF-5 score; a score of 5–10 points indicated severe ED, a score of 11–20 indicated moderate ED, and a score of 21–25 points indicated no ED. The muscle mass, handgrip strength, timed up and go test, upper mid-arm circumference, calf circumference, and body mass index were obtained. The statistical analysis was performed using MedCalc Statistical Software version 12.7.7. All parameters were compared between the three groups.
Results: Of 98 patients included in the study, 84 patients had severe sarcopenia, 13 had moderate sarcopenia, while only one patient had normal muscle mass. The mean age was 56.59 ± 11.46 years. When patients were divided into three groups according to IIEF-5 score, 38 had severe ED, 39 had moderate ED, and 21 had no ED. There was a significant difference between the three groups in terms of handgrip strength, timed up and go test scores, upper mid-arm circumference, and calf circumference (p < .05 for all).
Conclusions: Although muscle mass remains unchanged, muscle strength and physical performance decrease in diabetic ED patients. Diabetic patients with severe and moderate ED have lower muscle strength and physical performance.
Introduction
Diabetes mellitus (DM) is a global public health problem [Citation1]. The prevalence of DM is considered to be associated with the aging process and the prevalence of impaired glucose tolerance with the age increase. Type II DM is a progressive disorder caused mainly by two polygenic defects [Citation2]. These include insulin resistance and insulin secretion defect in the beta cell [Citation3]. Insulin resistance not only plays a role in the physiopathology of hypertension, hyperlipidemia, and obesity, but is also thought to be associated with sarcopenia [Citation4]. Sarcopenia is defined as the loss of muscle strength or function associated with a decrease in the muscle mass. Sarcopenia may be age-related and it may also be caused by vascular, neural, and hormonal causes; insufficient calorie intake, and cytokines [Citation5]. Androgenic hormones regulating sexual functions have been also demonstrated to be involved in obesity, diabetes, metabolic syndrome, and sarcopenia [Citation6,Citation7]. Erectile dysfunction (ED) is defined as the inability to obtain and/or maintain erection firm enough to achieve a successful sexual intercourse on a regular basis is a more common condition in males with type II DM [Citation8]. The prevalence of diabetic ED varies from 30 to 90% depending on the age, type, and duration of diabetes [Citation9]. Although many factors have been implicated in the physiopathology of ED in diabetic males, hypogonadism, diabetic neuropathy, and endothelial dysfunction are the main factors [Citation10,Citation11]. Multiple mechanisms are involved in the pathogenesis of sarcopenia and ED and they have an increasing prevalence particularly among middle-aged and advanced-age diabetic male population, impairing physical functioning, sex life, and the quality of life. Sarcopenia and ED have become a global public health problem due to treatment process, incurred treatment costs, complications, and increasing prevalence in recent years.
The present study evaluated the association between ED and sarcopenia in diabetic patients.
Materials and methods
The study was designed as a cross-sectional research and was approved by the local ethics committee. All patients gave informed consent according to the Institutional Review Board guidelines and the Declaration of Helsinki. The optimal sample size determined by power analysis was 98 patients. The study included 98 male consecutive patients, who were admitted to the diabetes outpatient clinics of the hospital. Patients aged 18–80 years diagnosed with type II DM, who have normal kidney (glomerular filtration rate >90 ml/dk/1.73m2), liver functions (alanine aminotransferase <45 U/L and aspartate transferase <34 U/L), and who perform regular physical activities and adopt normal lifestyle were included in the study. While patients with type I DM, hyperprolactinemia, prostate cancer, and patients who underwent major pelvic surgery, patients with abnormal rectal examination findings (suspected induration, nodule, fixation, etc.), patients with a past history of total or transurethral prostatectomy, severe cardiovascular and neurologic disease, acute cerebrovascular accident, acute or chronic infection, uncontrolled diabetes, patients with a history of major psychiatric disorder, patients with a pacemaker or any other type of implants, patients with severe edema ( ≥ 3+), severe electrolyte disturbances, patients with metabolic dysfunction, patients with a health condition affecting the mobility (cerebrovascular event, end-stage dementia, hip fracture, extremity injury after traffic accident, etc.), patients with diabetic neuropathy or polyneuropathy, those who have received or are currently receiving testosterone replacement therapy, and those with a comorbid condition that would result in sarcopenia were excluded from the study. A detailed medical history was obtained from all patients and all underwent physical examination (including weight, height, body mass index (BMI), upper mid arm circumference, calf circumference, and blood pressure). Blood chemistry (fasting plasma glucose, glycosylated hemoglobin (HbA1c), total cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides (TG), and creatinine) and hormone levels (luteinizing hormone (LH), total testosterone, 25 (OH) D (calcifediol), prolactin, calcium, phosphate, and prostate-specific antigen (PSA)) were obtained. Blood samples were withdrawn in the fasting state between 08:00 and 10:00 am. Blood samples were collected into Serum-separating II, LH PST II, and EDTA tubes and were analyzed simultaneously. The muscle strength was measured using a hand dynamometry (handgrip). Total body weight, BMI, basal metabolic rate (BMR in kJ and kcal), body fat percentage (%), body fat amount (kg), lean body weight (LBW, kg), and total body water were calculated with the TANITA devices (Tanita Corp., Tokyo, Japan) using bioelectrical impedance analysis method. All patients were administered International Index of Erectile Function (IIEF-5) questionnaire to detect ED.
Definition of ED according to IIEF-5
All patients were administered International Index of Erectile Function (IIEF-5) questionnaire to detect ED [Citation12]. The patients were divided into three groups according to symptom severity. Patients with an IIEF-5 score of 21–25 points were included in the no ED group, patients with an IIEF-5 score of 11–20 points were included in the moderate ED group, and patients with an IIEF-5 score of 5–10 points were included in the severe ED groups. All parameters were compared between these three groups.
Laboratory analysis
Plasma glucose was measured using an enzymatic method, glycosylated hemoglobin was measured using high-performance liquid chromatography (HPLC) method, total cholesterol, HDL cholesterol, calcium, phosphate, and TG levels were measured using enzymatic colorimetric method, creatinine was measured using the Jaffe’s reaction, and PSA was measured using chemiluminescence immunoassay. Serum LH, total testosterone, and prolactin levels were measured using chemiluminescence immunoassay.
Definition of sarcopenia
Weight, muscle mass (%), body fat percentage (%), metabolism/body fat, and lean body weight were measured using bioelectrical impedance analysis (BIA). BIA was performed using a bioelectrical impedance analyzer which is a single frequency BIA system (50 kHz) with eight-point contact electrodes and two stainless-steel rectangular foot pad electrodes, which are fastened to a metal platform set on force transducers for measurement of weight (BC-418MA, Tanita Corp.). Four separate foot-pad electrodes are mounted onto the base and two electrodes are mounted in each of the hand grips. This BIA system can estimate body composition in either “standard” or “athlete” mode. In the present study, body composition assessment was conducted in “standard mode”. Full body skeletal muscle mass (SMM) and SMM index (SMMI) were used as indicators of sarcopenia.
The skeletal muscle mass index was calculated using the following formula: SMI (kg) = [(height2/BIA resistance component × 0.401) + (gender × 3.825) + (age × −0.071)] + 5.102 (height in cm, resistance in ohm, gender: male =1, female =0, and age in years). The cutoff values for SMI in males were as follows: ≥10.76 kg/m2: normal; 8.51–10.75 kg/m2: moderate sarcopenia; and ≤8.50 kg/m2: severe sarcopenia [Citation13].
Anthropometric measurements
Upper arm circumference and calf circumference were measured. An upper arm circumference <22 cm was considered low and a value of 22 cm or higher was considered normal. A calf circumference <31 cm was considered low and a value of 31 cm or higher was considered normal [Citation14].
Muscle strength
Right and left handgrip strength was measured using a hydraulic dynamometer (baseline hydraulic hand dynamometer 300 LB). Grip strength of both hands was measured three times while the subject was in seated position with the arm by the side of the trunk and elbow in the 90 degrees flexion and an average of the three measurements was recorded [Citation15]. Muscle strength accepted included; > 30: normal and <30: decreased.
Physical performance
The physical performance was evaluated using the timed up and go test. The patients were instructed to stand from a sitting position, walk 3 m, turn without taking a hold, walk back to the chair, and sit down again. Performance was rated according to the following scale: 1 = normal, 2 = slightly abnormal, 3 = mildly abnormal, 4 = moderately abnormal and 5 = significantly abnormal. The score was considered to be normal in patients without evidence of falls while walking and the score was considered to be significantly abnormal in the presence of falls risk during the test performance [Citation16].
Statistical analysis
Descriptive statistics (mean, standard deviation, minimum, median, and maximum) were used to express continuous variables. The Student’s t-test was used to compare two independent variables with normal distribution, and Mann-Whitney U-test was used to compare two independent variables without normal distribution. Pearson’s correlation coefficient was used to analyze the relationship between normally distributed two continuous variables and Spearman’s rho correlation coefficient was calculated to analyze the relationship between two continuous variables that are normally distributed. Chi-square test (or Fisher’s exact test, where appropriate) was used to evaluate the relationship between categorical variables. The level of statistical significance was set at p < .05. The statistical analysis was performed using MedCalc Statistical Software version 12.7.7 (MedCalc Software bvba, Ostend, Belgium; http://www.medcalc.org; 2013) software package.
Results
The mean age of the study patients was 56.59 ± 11.46 years. Of the study patients, 77 (78.5%) met the criteria for ED and 21 (21.4%) patients had no ED. Demographic data, anthropometric measurements, and clinical and biochemical parameters of the patients according to IIEF-5 scores are summarized in . Of the study patients, 35.7% were using only oral antidiabetic agents and 27.6% were using only insulin therapy, while 34.7% of the patients were using both insulin and oral antidiabetic agents. 17.3% of our patients were nonsmokers, 44.9% were ex-smokers, and 37.8% were active smokers. This distribution was not significant in all three groups. The patients were divided into three groups according to IIEF-5 score (patients with IIEF-5 score of 21–25 (no ED) points, patients with IIEF-5 score of 11–20 points (moderate ED), and patients with IIEF-5 score of 5–10 points (severe ED)). All parameters were compared between these three groups (). There were significant differences between the three groups with respect to age (p < .01), hemoglobin (p < .01), upper mid arm circumference (p < .01), duration of diabetes (p < .01), zinc level (p = .049), calf circumference (p < .01), and muscle strength (p < .01), whereas there was no significant difference between IIEF-5 score and skeletal muscle mass index, skeletal muscle mass, lean body mass, prolactin, testosterone, TSH, follicle-stimulating hormone (FSH), LH, HbA1c, BMI weight, albumin, and lymphocyte. There were significant differences between patients with low muscle strength and those with normal muscle mass with respect to age (p < .01), lean body mass (p = .006), TG (p = .014), upper arm circumference (p < .01), duration of diabetes (p = .022), duration of ED (p < .01), potassium (p = .018), blood urea nitrogen (p = .013), LH level (p = .015), calf circumference (p < .01), timed up and go test score (p < .01), and IIEF-5 score (p < .01) that are summarized in . According to the classification of the European Working Group on Sarcopenia in Older People (EWGSOP), 84 patients had severe sarcopenia and 13 patients had moderate sarcopenia, while only one patient had normal muscle mass. The comparison between patients with severe and moderate sarcopenia showed significant differences with respect to height (p < .05), serum iron (p = .042), BMI (p = .012), and free thyroxine (T4; p = .042) levels, whereas skeletal muscle mass index and IIEF-5 score, testosterone, TSH, FSH, prolactin and LH levels, iron, albumin, zinc and HbA1c did not differ significantly.
Table 1. Comparison of demographic, anthropometric and clinical data according to IIEF-5 scores.
Table 2. Comparison of all biochemical parameters according to IIEF-5 scores.
Table 3. Comparison of clinical data according to muscle strength.
Discussion
The present study found a decrease in muscle strength and upper arm-calf circumference in parallel to the increase in the severity of ED in males with type II DM. The term sarcopenia is derived from the Greek words “sarx” (muscle) and “penia” (loss) and refers to progressive and generalized loss of muscle mass and muscle strength [Citation5]. Sarcopenia is often accompanied by physical inactivity, decreased mobility, slow walking, and low physical endurance and these are also common characteristics of the frailty syndrome [Citation5,Citation17]. T is primarily the disease of the elderly, but it may also occur in young patients secondary to immobility, malnutrition, hormonal, neuronal, and inflammatory conditions and cachexia [Citation18].
The maintenance of muscle functions is crucial to the maintenance of functional independence. Skeletal muscle accounts for 45–55% of the total body mass and most are localized in the lower extremities. Muscle mass and muscle strength peak between the second and fourth decades of life and then gradually decrease. Changes occurring in body composition with aging and significant decrease in the muscle mass and functions result in a decrease in physical performance, weakness, mobility disorders, falls, and disability and they constitute a significant economic burden in the health care services [Citation19].
Various definitions have been suggested to describe sarcopenia. According to one definition, sarcopenia was defined as two standard deviations below the mean height-adjusted (meter) muscle mass of a young reference group [Citation20]. In one study that used this definition as the basis, the prevalence of sarcopenia was reported to be 14% in males aged <70 years, 20% in males aged 70–74 years, 27% in males aged 75–80 years, and 53% in males over 80 years of age. In a recent similar study, frailty was evaluated in 250 women aged 76–86 years. The prevalence of sarcopenia was reported to be 52.9% in the frail group, 42% in the pre-frail group, and 41.2% in the normal group [Citation21]. The definition of sarcopenia suggested by Janssen et al. is based on BIA and sarcopenia is described as the percentage of skeletal muscle mass to body mass. Skeletal muscle mass that is 1–2 standard deviation below reference values for young adults indicates class 1 sarcopenia, two standard deviations below the reference range indicates class 2 sarcopenia. The prevalence of sarcopenia based on this definition was reported to be 7% in males and 10% in females [Citation22]. Despite common occurrence of age-related sarcopenia that is associated with physical disability, impaired quality of life, death, and significant individual and financial burden, lack of widely accepted clinical definition for sarcopenia has prompted the European Union Geriatric Medicine Society (EUGMS) to establish the European Working Group on Sarcopenia in Older People (EWGSOP) in 2009, in order to develop consensus diagnostic criteria for age-related sarcopenia [Citation19]. The consensus report relevant to the definition and diagnosis of sarcopenia by this working group was published in 2010. In this report, sarcopenia is defined as a syndrome characterized by generalized and progressive loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability, poor quality of life, and death [Citation19]. Accordingly, the diagnosis of sarcopenia requires both the presence of a decrease in the muscle mass and muscle functions. A decrease in muscle functions may be in the form of decreased strength or decreased performance.
Sarcopenia can be described as a geriatric syndrome, as the prevalence of sarcopenia is considerably higher in geriatric population. It is a common clinical picture caused by multiple factors. In most cases, sarcopenia is associated with decreased endurance, physical inactivity, decreased walking speed, decreased mobility, and increased dependence and mortality. Modifying or treating the causes of or risk factors for sarcopenia do not alter clinical phenotype or the consequences of sarcopenia [Citation23].
Multiple factors are involved in the development of sarcopenia. The decrease in the muscle strength is thought to be primarily related to the decrease in the muscle mass. The decrease in muscle mass is caused by the decrease in muscle fibers combined with muscle fiber atrophy. The process of denervation followed by reinnervation by slow motor units results in muscle weakness [Citation24,Citation25]. Although biological mechanism has not been fully understood, it was suggested that the number of satellite cells playing a role in muscle regeneration decreases with aging and this may contribute to the development of sarcopenia [Citation26].
Insulin-like growth factor-1 (IGF-1) that is involved in the regulation of growth and skeletal muscle development and androgen levels decrease with aging. Renin angiotensin system is also considered to be involved in the regulation of muscle functions. It was suggested that circulating angiotensin 2 could be associated with muscle weakness, decreased IGF-1 levels, and increased insulin resistance and that it could contribute to the development of sarcopenia [Citation27].
The aging process itself modifies muscle cycle through increased catabolic and decreased anabolic stimuli [Citation28]. Subclinical inflammation could play a role in these changes. Hormonal changes associated with aging (particularly in testosterone, growth hormone, IGF-1, and increased insulin resistance) combined with the changes in neural input are thought to be associated with a decrease in muscle mass. Decreased food and particularly protein intake, nonuse or life-long low level of physical activity, smoking, and alcohol consumption are known to increase the risk of developing sarcopenia [Citation5].
The mid-upper arm circumference and skin fold thickness are used to estimate muscle mass. The calf circumference has been reported to correlate positively with the skeletal muscle mass. A calf circumference of <31 cm was found to correlate with disability [Citation29].
However, age-related accumulation of fat deposits and loss of skin elasticity may complicate accurate estimation. Anthropometric measurements are also operator-dependent and measurement errors are possible. Thus, these measurements are not recommended routinely in the diagnosis of sarcopenia. The present study found a significant association between the severity of ED and upper arm as well as calf circumference (p < .01), whereas there was no significant association between these two anthropometric measurements and the muscle mass index.
Isometric handgrip well correlates with the calf circumference [Citation19]. Low handgrip strength has been shown to better correlate with decreased mobility and adverse clinical outcomes than the decreased muscle mass [Citation30]. In the practice, a linear relationship was found between baseline handgrip strength and dependence in daily life activities [Citation31]. One of the most important findings of the present study is that severity of ED is significantly associated with dynapenia that is defined as the loss of muscle strength, although muscle mass remains unchanged with increasing severity of ED.
Dynapenia is defined as the age-related loss of muscle strength that is not caused by a neurologic or muscular disease. Dynapenia is associated with restricted functional capacity and increased risk of mortality in the elderly. Muscle size has been suggested to play a primary role in the development of dynapenia in previous studies; however, recent studies suggest that this effect is minimal. Subclinical studies have implicated intrinsic factors affecting the structure or functions of the nervous system or the functions of skeletal muscle [Citation32]. Based on the findings reported in the present study, the authors consider that common pathways might have been involved in the pathophysiology of dynapenia and ED.
Epidemiological studies have shown an increased risk of developing ED in ∼40–50% of males with type II DM [Citation33]. Massachusetts male aging study showed three times higher risk of developing ED in diabetic males when compared with nondiabetic males [Citation34]. The level of free testosterone decreases between the ages of 45 and 74 years [Citation35]. There are different treatment options in the treatment of diabetic ED [Citation36]. Decreasing serum testosterone levels with aging have been shown to be associated with decrease in muscle mass, muscle strength, functional status, and decrease in bone density. However, studies that used testosterone replacement have reported controversial results. Most of these studies have reported an increase in the muscle mass, but no change has been reported in the muscle strength [Citation37]. On the other hand, circulating testosterone levels were found to correlate with muscle strength and myosin light chain synthesis rate in healthy older people [Citation38]. However, the present study found no relationship between muscle strength ,muscle mass index, and androgenic hormones as testosterone. This finding suggests that factors other than testosterone levels possibly play a role in the pathogenesis of reduced muscle mass and strength.
Sarcopenia was once defined as age-related decrease in muscle mass; however, it was soon realized that the muscle strength is lost (dynapenia) rather than muscle mass in sarcopenia. The same also applies for the present findings. Muscle strength was significantly lower in patients with more severe ED, although muscle mass was not lower. Almost all patients in the present study had sarcopenia, but the main difference was in the muscle strength and not in the muscle mass.
Volpato et al. [Citation39] compared three groups (sarcopenia, low muscle mass, and normal muscle mass) and reported significantly lower hemoglobin, albumin, testosterone, IGF-1, and creatinine clearance, and significantly higher Interleukin-6 and Tumor necrosis factor-α levels in sarcopenic patients, whereas vitamin D and C-reactive protein (CRP) levels did not differ significantly between the groups [Citation39]. However, the present study found no significant relationship between muscle mass index and hemoglobin, albumin, testosterone, vitamin D and CRP levels.
In the study by Ryu et al. [Citation40] sarcopenic male patients had significantly higher fasting glucose levels than those without sarcopenia, total cholesterol, low density lipoproteins (LDL), and HDL levels did not differ significantly and sarcopenic female patients had significantly higher TG levels than females without sarcopenia [Citation40]. The present study also found no significant relationship between skeletal muscle mass and HbA1c, HDL, TG, LDL, and total cholesterol levels.
Conclusions
The present study explored possible relationship between sarcopenia and ED in males with type II DM. The study found a clear relationship between ED and two of three criteria of sarcopenia, namely loss of performance and loss of muscle strength. Although ED is known to be more common in obese males with uncontrolled diabetes, this is the first study to report that ED is more common in males with reduced muscle strength. There is an association in negative direction between ED, muscle strength, and physical performance in males with type II DM. The present study showed that the relationship between ED and dynapenia was independent from the hormone levels and the muscle mass. The authors of the present manuscript consider that ED and dynapenia may share common pathways, as multiple factors are involved in the pathophysiology of these two problems. In conclusion, muscle strength and muscle function decrease as the severity of ED increases in male patients with type II DM.
Study limitations
The limitation of our study is; this was a cross-sectional study and did not obtain direct evidence of causal relationship.
Disclosure statement
The authors report no conflicts of interest in this work.
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