METABOLIC SYNDROME IN PATIENTS WITH MYOTONIC DYSTROPHY TYPE 1 MILORAD VUJNIC, MD, MSc,1 STOJAN PERIC, MD, PhD,2 SRDJAN POPOVIC, MD, PhD,3 NELA RASETA, MD, PhD,1 VESNA RALIC, MS,2 VALERIJA DOBRICIC, PhD,2 IVANA NOVAKOVIC, MD, PhD,2 and VIDOSAVA RAKOCEVIC-STOJANOVIC, MD, PhD2 1
Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotica 6, 11 000 Belgrade, Serbia 3 Endocrinology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia 2
Accepted 4 December 2014 ABSTRACT: Introduction: The aim of this study was to assess the frequency and features of metabolic syndrome (MetS) in myotonic dystrophy type 1 (DM1). Methods: We studied 66 DM1 patients (50% men, aged 41.9 6 10.5 years, disease duration of 19.3 6 8.6 years). New worldwide consensus criteria for MetS from 2009 were used. Results: Components of MetS were present at the following frequencies: hypertriglyceridemia 67%; low HDL cholesterol 35%; hypertension 18%; central obesity 14%; and hyperglycemia 9%. MetS was present in 11 (17%) patients. The presence of MetS was not associated with patients’ gender, age, disease severity, disease duration, or CTG repeat length (P > 0.05). Patients with MetS had significantly lower total SF-36 scores as a measure of quality of life in comparison to patients without MetS (P < 0.05). Conclusion: Although certain components of MetS were very frequent in patients with DM1, only 17% met the criteria for MetS. Muscle Nerve 52: 273–277, 2015
Myotonic
dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults.1 DM1 is an autosomal dominant disease caused by an expansion of CTG repeats in noncoding sequences of the DMPK gene. It is a multisystem disorder that affects many different organs and systems besides muscle.1 Metabolic syndrome (MetS) is a cluster of metabolic and hemodynamic disturbances that appear together and can multiply the risk of atherosclerotic cardiovascular diseases and diabetes mellitus type 2.2 In patients with muscle disorders the frequency of MetS is significantly higher than in the general population.3 A sedentary lifestyle related to muscle weakness is considered to be the main risk factor for developing MetS in these patients.
Abbreviations: BMI, body mass index; BP, bodily pain; DM1, myotonic dystrophy type 1; ECG, electrocardiography; GH, general health; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MCS, mental composite score; MetS, metabolic syndrome; MH, mental health; MIRS, Muscular Impairment Rating Scale; PCS, physical composite score; PF, physical functioning; QoL, quality of life; RE, role emotional; RP, role physical; SF, social functioning; SF-36, 36-item Short Form; VT, vitality Key words: dyslipidemia; hypertension; metabolic syndrome; myotonic dystrophy type 1; obesity This study was supported by a grant (No. 175083) from the Ministry of Education, Science and Technological Development of the Republic of Serbia. Correspondence to: S. Peric; e-mail: [email protected] C 2014 Wiley Periodicals, Inc. V
Published online 8 December 2014 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24540
Metabolic Syndrome in DM1
No study has specifically investigated the frequency of MetS in DM1, but data on individual components of MetS are available. Patients with DM1 have an increased percentage of body fat.4 Insulin resistance due to impaired alternative splicing of the insulin receptor5–7 and dyslipidemia with high levels of serum triglycerides and lowdensity lipoprotein (LDL) cholesterol5,8–10 are common features of DM1. On the other hand, glucose intolerance and diabetes mellitus type 2 seem to be as frequent as in the general population,5,6 and increased blood pressure is rare in DM1.5,10 Furthermore, atherosclerosis, the most significant complication of MetS, is atypical in DM1.1,5 The aim of this study was to determine the frequency and assess the features of MetS in patients with DM1. METHODS
Sixty-six DM1 patients were recruited consecutively from the outpatient and inpatient units of the Neurology Clinic, Clinical Centre of Serbia, University of Belgrade, from November 1, 2011 to May 31, 2012. Patients 0.05). None of our patients had a history of myocardial infarction or symptoms of coronary disease. On ECG, abnormalities potentially related to ischemia were observed in 7 (10.6%) patients as follows: negative T wave in 3 (4.5%); ST elevation in 2 (3.0%); and pathological Q wave in 2 patients (3.0%). These abnormalities were present in 27.3% of patients with MetS and only 7.3% without MetS (P < 0.05). None of our patients had a previous history of stroke, territorial stroke on magnetic resonance imaging, or significant stenosis of cervical blood vessels. Only 1 patient had nonsignificant stenosis of approximately 40% of both internal carotid arteries, but she did not have MetS. Regarding QoL, only the vitality subscore was significantly lower in DM1 patients with MetS compared to those without MetS (29.5 6 24.6 vs. 55.1 6 25.7, P < 0.05) (Table 3). However, both physical and mental composite scores as well as total SF-36 scores were lower in DM1 patients with MetS (P < 0.01 for PCS, P < 0.05 for MCS, P < 0.05 for total SF-36 score). DISCUSSION
Metabolic disturbances were very common in our cohort of DM1 patients, but only 17% met the criteria for MetS. The most frequent component of MetS was dyslipidemia; 67% of all DM1 patients had increased serum triglycerides, and 35% had decreased serum HDL. The majority of studies have shown increased serum triglyceride and LDL cholesterol levels in DM1 patients.3,5,8–10 However, some investigators have reported normal lipid studMetabolic Syndrome in DM1
ies in DM1, noting that fat accumulated in adipose deposits of these patients, thus protecting blood vessels from the harmful effect of lipids.4,8 According to the strict criteria we applied,13 increased blood pressure was present in 18% of DM1 patients, although mean blood pressure was only 114/74 mm Hg. Arterial hypertension has been reported to be rare in DM1.5,10 Some investigators15 even stated that hypotension is the most frequent cardiovascular impairment in DM1. Decreased tone of smooth muscles has been shown in Tg26-h DMPK mice due to persistent overexpression of the DMPK gene showing a direct association between the genetic defect and the phenotype.15 Central obesity was reported in 14% of our patients. An increased percentage of body fat has been found in DM1 patients, even those with normal BMI and normal quantity of visceral fat, primarily due to the fatty degeneration of muscle tissue.4 Obesity in DM1 is generally considered a consequence of physical inactivity due to muscle weakness, but even patients with a mild form of the disease may be obese.16 Thus, other factors should be considered, including socioeconomic aspects, because DM1 patients usually have a lower socioeconomic status and are known to eat food high in carbohydrates and fat.16 The rarest component of MetS in our cohort was hyperglycemia; it was observed in only 9% of patients. Insulin resistance is common in DM1,6 mostly due to the impaired alternative splicing of the insulin receptor that leads to expression of the fetal A form of the receptor that has less sensitivity for insulin than the adult B form.7 Other potential causes of insulin resistance should also be noted, namely pathological secretion of insulin from MUSCLE & NERVE
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Table 3. Quality of life in DM1 patients with vs. without MetS. Features PF RP BP GH VT† SF RE MH PCS** MCS* Total SF-36 score*
DM1 patients with MetS (n 5 11)
DM1 patients without MetS (n 5 55)
30.9 6 30.7 18.2 6 35.5 57.1 6 31.7 30.8 6 15.0 29.5 6 24.6 57.4 6 28.6 21.2 6 40.2 55.6 6 21.6 29.7 6 20.8 38.1 6 23.0 34.8 6 21.6
52.2 6 32.6 38.2 6 36.0 67.5 6 28.7 42.7 6 22.0 55.1 6 25.7 71.1 6 27.5 37.0 6 40.9 67.6 6 22.0 50.9 6 23.5 54.7 6 22.1 53.8 6 23.2
DM1, myotonic dystrophy type 1; MetS, metabolic syndrome; PF, physical functioning; RP, role physical; BP, bodily pain; GH, general health; VT, vitality; SF, social functioning; RE, role emotional; MH, mental health; PCS, physical composite score; MCS, mental composite score; SF-36, 36-item Short Form questionnaire. *P < 0.05, **P < 0.01.
pancreas islet cells, decreased muscle mass due to the dystrophic process, and physical inactivity.4,17,18 Although insulin resistance is common, glucose intolerance and manifested diabetes mellitus type 2 seem to be no more frequent than in the general population.5,10 Investigation of certain factors that protect DM patients from developing diabetes despite insulin resistance should be investigated further, because this may open new opportunities for therapeutic interventions in the general population. The frequency of only 17% of patients having MetS is far lower than in other neuromuscular disorders,3 and even lower than in the general population.19 Aitkens et al. reported that 55% of neuromuscular patients satisfied the criteria for MetS.3 In the general population older than age 20–25 years, the prevalence of MetS varies in urban areas from 8% in India to 24% in USA in men and from 7% in France to 43% in Iran in women. The prevalence of MetS in the general population is age-dependent.19 In a French population, its prevalence ranges from 50% of DM1 patients have insulin resistance,6 and
Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotica 6, 11 000 Belgrade, Serbia 3 Endocrinology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia 2
Accepted 4 December 2014 ABSTRACT: Introduction: The aim of this study was to assess the frequency and features of metabolic syndrome (MetS) in myotonic dystrophy type 1 (DM1). Methods: We studied 66 DM1 patients (50% men, aged 41.9 6 10.5 years, disease duration of 19.3 6 8.6 years). New worldwide consensus criteria for MetS from 2009 were used. Results: Components of MetS were present at the following frequencies: hypertriglyceridemia 67%; low HDL cholesterol 35%; hypertension 18%; central obesity 14%; and hyperglycemia 9%. MetS was present in 11 (17%) patients. The presence of MetS was not associated with patients’ gender, age, disease severity, disease duration, or CTG repeat length (P > 0.05). Patients with MetS had significantly lower total SF-36 scores as a measure of quality of life in comparison to patients without MetS (P < 0.05). Conclusion: Although certain components of MetS were very frequent in patients with DM1, only 17% met the criteria for MetS. Muscle Nerve 52: 273–277, 2015
Myotonic
dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults.1 DM1 is an autosomal dominant disease caused by an expansion of CTG repeats in noncoding sequences of the DMPK gene. It is a multisystem disorder that affects many different organs and systems besides muscle.1 Metabolic syndrome (MetS) is a cluster of metabolic and hemodynamic disturbances that appear together and can multiply the risk of atherosclerotic cardiovascular diseases and diabetes mellitus type 2.2 In patients with muscle disorders the frequency of MetS is significantly higher than in the general population.3 A sedentary lifestyle related to muscle weakness is considered to be the main risk factor for developing MetS in these patients.
Abbreviations: BMI, body mass index; BP, bodily pain; DM1, myotonic dystrophy type 1; ECG, electrocardiography; GH, general health; HDL, high-density lipoprotein; LDL, low-density lipoprotein; MCS, mental composite score; MetS, metabolic syndrome; MH, mental health; MIRS, Muscular Impairment Rating Scale; PCS, physical composite score; PF, physical functioning; QoL, quality of life; RE, role emotional; RP, role physical; SF, social functioning; SF-36, 36-item Short Form; VT, vitality Key words: dyslipidemia; hypertension; metabolic syndrome; myotonic dystrophy type 1; obesity This study was supported by a grant (No. 175083) from the Ministry of Education, Science and Technological Development of the Republic of Serbia. Correspondence to: S. Peric; e-mail: [email protected] C 2014 Wiley Periodicals, Inc. V
Published online 8 December 2014 in Wiley Online Library (wileyonlinelibrary. com). DOI 10.1002/mus.24540
Metabolic Syndrome in DM1
No study has specifically investigated the frequency of MetS in DM1, but data on individual components of MetS are available. Patients with DM1 have an increased percentage of body fat.4 Insulin resistance due to impaired alternative splicing of the insulin receptor5–7 and dyslipidemia with high levels of serum triglycerides and lowdensity lipoprotein (LDL) cholesterol5,8–10 are common features of DM1. On the other hand, glucose intolerance and diabetes mellitus type 2 seem to be as frequent as in the general population,5,6 and increased blood pressure is rare in DM1.5,10 Furthermore, atherosclerosis, the most significant complication of MetS, is atypical in DM1.1,5 The aim of this study was to determine the frequency and assess the features of MetS in patients with DM1. METHODS
Sixty-six DM1 patients were recruited consecutively from the outpatient and inpatient units of the Neurology Clinic, Clinical Centre of Serbia, University of Belgrade, from November 1, 2011 to May 31, 2012. Patients 0.05). None of our patients had a history of myocardial infarction or symptoms of coronary disease. On ECG, abnormalities potentially related to ischemia were observed in 7 (10.6%) patients as follows: negative T wave in 3 (4.5%); ST elevation in 2 (3.0%); and pathological Q wave in 2 patients (3.0%). These abnormalities were present in 27.3% of patients with MetS and only 7.3% without MetS (P < 0.05). None of our patients had a previous history of stroke, territorial stroke on magnetic resonance imaging, or significant stenosis of cervical blood vessels. Only 1 patient had nonsignificant stenosis of approximately 40% of both internal carotid arteries, but she did not have MetS. Regarding QoL, only the vitality subscore was significantly lower in DM1 patients with MetS compared to those without MetS (29.5 6 24.6 vs. 55.1 6 25.7, P < 0.05) (Table 3). However, both physical and mental composite scores as well as total SF-36 scores were lower in DM1 patients with MetS (P < 0.01 for PCS, P < 0.05 for MCS, P < 0.05 for total SF-36 score). DISCUSSION
Metabolic disturbances were very common in our cohort of DM1 patients, but only 17% met the criteria for MetS. The most frequent component of MetS was dyslipidemia; 67% of all DM1 patients had increased serum triglycerides, and 35% had decreased serum HDL. The majority of studies have shown increased serum triglyceride and LDL cholesterol levels in DM1 patients.3,5,8–10 However, some investigators have reported normal lipid studMetabolic Syndrome in DM1
ies in DM1, noting that fat accumulated in adipose deposits of these patients, thus protecting blood vessels from the harmful effect of lipids.4,8 According to the strict criteria we applied,13 increased blood pressure was present in 18% of DM1 patients, although mean blood pressure was only 114/74 mm Hg. Arterial hypertension has been reported to be rare in DM1.5,10 Some investigators15 even stated that hypotension is the most frequent cardiovascular impairment in DM1. Decreased tone of smooth muscles has been shown in Tg26-h DMPK mice due to persistent overexpression of the DMPK gene showing a direct association between the genetic defect and the phenotype.15 Central obesity was reported in 14% of our patients. An increased percentage of body fat has been found in DM1 patients, even those with normal BMI and normal quantity of visceral fat, primarily due to the fatty degeneration of muscle tissue.4 Obesity in DM1 is generally considered a consequence of physical inactivity due to muscle weakness, but even patients with a mild form of the disease may be obese.16 Thus, other factors should be considered, including socioeconomic aspects, because DM1 patients usually have a lower socioeconomic status and are known to eat food high in carbohydrates and fat.16 The rarest component of MetS in our cohort was hyperglycemia; it was observed in only 9% of patients. Insulin resistance is common in DM1,6 mostly due to the impaired alternative splicing of the insulin receptor that leads to expression of the fetal A form of the receptor that has less sensitivity for insulin than the adult B form.7 Other potential causes of insulin resistance should also be noted, namely pathological secretion of insulin from MUSCLE & NERVE
August 2015
275
Table 3. Quality of life in DM1 patients with vs. without MetS. Features PF RP BP GH VT† SF RE MH PCS** MCS* Total SF-36 score*
DM1 patients with MetS (n 5 11)
DM1 patients without MetS (n 5 55)
30.9 6 30.7 18.2 6 35.5 57.1 6 31.7 30.8 6 15.0 29.5 6 24.6 57.4 6 28.6 21.2 6 40.2 55.6 6 21.6 29.7 6 20.8 38.1 6 23.0 34.8 6 21.6
52.2 6 32.6 38.2 6 36.0 67.5 6 28.7 42.7 6 22.0 55.1 6 25.7 71.1 6 27.5 37.0 6 40.9 67.6 6 22.0 50.9 6 23.5 54.7 6 22.1 53.8 6 23.2
DM1, myotonic dystrophy type 1; MetS, metabolic syndrome; PF, physical functioning; RP, role physical; BP, bodily pain; GH, general health; VT, vitality; SF, social functioning; RE, role emotional; MH, mental health; PCS, physical composite score; MCS, mental composite score; SF-36, 36-item Short Form questionnaire. *P < 0.05, **P < 0.01.
pancreas islet cells, decreased muscle mass due to the dystrophic process, and physical inactivity.4,17,18 Although insulin resistance is common, glucose intolerance and manifested diabetes mellitus type 2 seem to be no more frequent than in the general population.5,10 Investigation of certain factors that protect DM patients from developing diabetes despite insulin resistance should be investigated further, because this may open new opportunities for therapeutic interventions in the general population. The frequency of only 17% of patients having MetS is far lower than in other neuromuscular disorders,3 and even lower than in the general population.19 Aitkens et al. reported that 55% of neuromuscular patients satisfied the criteria for MetS.3 In the general population older than age 20–25 years, the prevalence of MetS varies in urban areas from 8% in India to 24% in USA in men and from 7% in France to 43% in Iran in women. The prevalence of MetS in the general population is age-dependent.19 In a French population, its prevalence ranges from 50% of DM1 patients have insulin resistance,6 and
