DIABETICMedicine
deteriorated glycemic control in type 1 diabetes. Diabetes Care 2013; 36: 2902–2908. 7 Koren D. Levitt Katz LE, Brar PC, Gallagher PR, Berkowitz RI, Brooks LJ. Sleep architecture and glucose and insulin homeostasis in obese adolescents. Diabetes Care 2011; 34: 2442–2447. 8 Sadeh A. The role and validity of actigraphy in sleep medicine: an update. Sleep Med Rev 2011; 15: 259–267. 9 Johnson B, Eiser C, Young V, Brierley S, Heller S. Prevalence of depression among young people with Type 1 diabetes: a systematic review. Diabet Med 2013; 30: 199–208.
DOI: 10.1111/dme.12421
Response to Kawada. Depressive symptoms and HbA1c in patients with Type 1 and Type 2 diabetes Diabet. Med. 31, 760–761 (2014) We thank Kawada for raising several concerns [1] about our paper ‘Differential associations between depressive symptoms and glycaemic control in outpatients with diabetes’ [2]. First, Kawada discusses the use of the Patient Health Questionnaire (PHQ-9) instrument in our study. In addition to the individual symptoms of depression, Kawada points out that the association of depression and HbA1c should be studied using the diagnostic algorithm of the PHQ-9 to classify major depressive disorder. The relationship between major depressive disorder and HbA1c in diabetes has been the topic of many papers, including a meta-analysis that showed a positive association between depression and HbA1c [3]. Depression is, however, a very heterogeneous construct, and persons with depression can differ substantially in the symptoms they express. Therefore, instead of looking at the overall depression construct, the specific purpose of the study was to study the relationship between the individual symptoms of depression and HbA1c in patients with diabetes. We did not report nor intend to propose that the individual symptoms of the PHQ-9 can be used as a substitute for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) major depressive disorder. Although the approach suggested by Kawada would provide further evidence for the potential relationship between depression and HbA1c, this would not result in differentiation of depression at the symptom level. Second, Kawada regrets that we did not discuss the potential U-shaped relationship between sleep duration and HbA1c, which has been observed in obese adolescents [4]. We believe that this specific study supports many observations that both short and long sleep duration appear to be related to poorer health in general [5,6]. Although we could only devote a limited amount of words to this important topic in the discussion section of our paper, it would be interesting to investigate the direction of the relationship between sleep duration and HbA1c. We completely agree with Kawada’s
760
Letters
suggestion to include more valid measurement of sleep quality in studies that investigate the relationship between sleep and glycaemic control, which has been carried out in the very recent study of Borel et al. [7]. Finally, Kawada incorrectly pointed out that lack of interest and depressed mood were not related to HbA1c. As shown in table 2 [2], depressed mood was a significant predictor for HbA1c in the overall sample and in individuals with Type 1 diabetes. We hope that our analysis and Kawada’s comments spur future longitudinal research that will further expand our understanding of the potential bidirectional relationship of depressive symptoms and glycaemic control in people with diabetes. We believe that the heterogenic nature of depression should not be overlooked here and may help to guide research and interventions for improving both mental health and glycaemic control in individuals with diabetes.
Funding sources
None.
Competing interests
None declared. M. Bot1, F. Pouwer2, P. de Jonge3 and F. Snoek4 Department of Psychiatry and the EMGO Institute for Health and Care Research, VU University Medical Centre, and GGZ inGeest, Amsterdam, 2Department of Medical and Clinical Psychology, Center of Research on Psychology in Somatic Diseases CoRPS, Tilburg University, Tilburg, 3Interdisciplinary Centre for Psychiatric Epidemiology, University Medical Centre Groningen, Groningen and 4Diabetes Psychology Research Group, Department of Medical Psychology, EMGO-Institute, VU University Medical Centre, Amsterdam, the Netherlands 1
References 1 Kawada T. Depressive symptoms and HbA1c in patients with Type 1 and Type 2 diabetes. Diabet Med 2014; 31: 759–760. 2 Bot M, Pouwer F, de Jonge P, Tack CJ, Geelhoed-Duijvestijn PHLM, Snoek FJ. Differential associations between depressive symptoms and glycaemic control in outpatients with diabetes. Diabet Med 2013; 30: e115–e122. 3 Lustman PJ, Anderson RJ, Freedland KE, de Groot M, Carney RM, Clouse RE. Depression and poor glycemic control: a meta-analytic review of the literature. Diabetes Care 2000; 23: 934–942. 4 Koren D. Levitt Katz LE, Brar PC, Gallagher PR, Berkowitz RI, Brooks LJ. Sleep architecture and glucose and insulin homeostasis in obese adolescents. Diabetes Care 2011; 34: 2442–2447. 5 Ayas NT, White DP, Manson JE, Stampfer MJ, Speizer FE, Malhotra A et al. A prospective study of sleep duration and
ª 2014 The Authors. Diabetic Medicine ª 2014 Diabetes UK
Letters coronary heart disease in women. Arch Intern Med 2003; 163: 205–209. 6 van Mill JG, Hoogendijk WJ, Vogelzangs N, Van Dyck R, Penninx BW. Insomnia and sleep duration in a large cohort of patients with major depressive disorder and anxiety disorders. J Clin Psychiatry 2010; 71: 239–246. 7 Borel AL, Pepin JL, Nasse L, Baguet JP, Netter S, Benhamou PY. Short sleep duration measured by wrist actimetry is associated with deteriorated glycemic control in type 1 diabetes. Diabetes Care 2013; 36: 2902–2908.
DOI: 10.1111/dme.12423
Effect of peripheral cholinergic stimulation on autonomic modulation in Type 2 diabetes with autonomic neuropathy: a randomized controlled trial Diabet. Med. 31, 761–762 (2014) Cardiovascular autonomic neuropathy is a reversible, serious and frequent complication in diabetes mellitus [1], presenting with reduced vagal modulation to the sinus node and beat-to-beat heart rate variability [2]. Alterations in the adrenergic and/or muscarinic receptor functions with a reduction in acetylcholine release [3] may be involved in this pathogenic process. Pyridostigmine bromide, an acetyl cholinesterase inhibitor, produces cholinergic stimulation by preventing the hydrolysis of acetylcholine and increasing its availability in the synaptic cleft [4]. It increases vagal modulation in healthy subjects [5] and heart failure patients [6], but the effect on cardiovascular autonomic neuropathy is unknown. In this study, we tested the hypothesis that increasing acetylcholine availability in the synaptic cleft improves vagal modulation. Thirty-four outpatients with Type 2 diabetes with cardiovascular autonomic neuropathy, attending the Endocrine Division at Hospital de Clınicas de Porto Alegre, were randomized to pyridostigmine and placebo, according to the intervention randomly drawn from a concealed envelope (Table 1). Presence of cardiovascular autonomic neuropathy was confirmed by the autonomic tests standardized by Ewing et al. [7] and a baseline 24-h Holter monitoring to calculate the following heart rate variability indices: mean of normal R–R intervals; standard deviation of normal R–R intervals; and root– mean–square successive differences [8]. The protocol was approved by the ethical committee of the institution and informed consent was obtained from each individual. Heart rate variability was re-evaluated while patients were receiving pyridostigmine bromide 30 mg orally three times daily for 24 h, or placebo. Patients and researchers were blinded to the interventions. The analysed data are described as mean SD. Differences in clinical characteristics between groups were compared using Student’s t-test for continuous variables and Pearson’s v2-test. Repeated-measures ANOVA was used to evaluate the effect
ª 2014 The Authors. Diabetic Medicine ª 2014 Diabetes UK
DIABETICMedicine
of the interventions on heart rate variability and minimum significance level was set at 5%. Both groups had similar clinical characteristics regarding age, gender, BMI, diabetes duration, blood pressure, cardiovascular autonomic neuropathy severity and use of drugs. Our results showed that pyridostigmine had no acute effect on autonomic modulation evaluated by heart rate variability, with an effect size d < 0.2 (Table 1). Differently, in our previous study in patients with heart failure with severely depressed heart rate variability, the short administration of pyridostigmine during only 24 h promoted a clear increase in time domain indices [6]. As in cardiovascular autonomic neuropathy peripheral nerves are anatomically compromised, it was not expected that a short intervention could restore its integrity, but an increase in acetylcholine availability should improve vagal modulation. The release of acetylcholine at the neuroeffector junction of the heart is regulated by the central nervous system and peripherally influenced by muscarinic receptors and pre-synaptic autoreceptors found at the postganglionic parasympathetic fibres [9]. These autoreceptors are muscarinic receptors subtypes that, when activated by endogenous acetylcholine, inhibit the release of acetylcholine in the synaptic cleft, causing a negative feedback [3,9,10]. Although acetyl cholinesterase inhibition with pyridostigmine increases the amount of acetylcholine in the synaptic cleft, in patients with diabetes, as the autoreceptors are up-regulated, this increase in acetylcholine may be followed by a negative feedback that reduces further acetylcholine release, preventing an improvement in cardiac autonomic modulation. The development of drugs that could modulate these up-regulated autoreceptors possibly would help in cardiovascular autonomic neuropathy control. There are some potential limitations to our study that could explain the lack of pyridostigmine effect. The drug was administered for a short period of time and longer exposure could bring different results. In this study, we did not assess cholinesterase activity to assure that the pyridostigmine dose used could properly block serum cholinesterase activity. In a previous study of our group, we have demonstrated that the same dose used in this study promoted a 14% reduction in cholinesterase activity [5] and increased autonomic modulation. In this present study, 58% of the patients were classified as having severe cardiovascular autonomic neuropathy. It is possible that, in a less compromised sample, pyridostigmine could increase heart rate variability. Although this study enrolled a small number of patients, the sample size was based on previous studies of our group with healthy individuals [5] and patients with heart failure [6] in whom the same dose of pyridostigmine significantly increased heart rate variability. In conclusion, peripheral acetyl cholinesterase blockage with oral administration of pyridostigmine bromide does not improve autonomic modulation of patients with Type 2 diabetes with cardiovascular autonomic neuropathy.
761
deteriorated glycemic control in type 1 diabetes. Diabetes Care 2013; 36: 2902–2908. 7 Koren D. Levitt Katz LE, Brar PC, Gallagher PR, Berkowitz RI, Brooks LJ. Sleep architecture and glucose and insulin homeostasis in obese adolescents. Diabetes Care 2011; 34: 2442–2447. 8 Sadeh A. The role and validity of actigraphy in sleep medicine: an update. Sleep Med Rev 2011; 15: 259–267. 9 Johnson B, Eiser C, Young V, Brierley S, Heller S. Prevalence of depression among young people with Type 1 diabetes: a systematic review. Diabet Med 2013; 30: 199–208.
DOI: 10.1111/dme.12421
Response to Kawada. Depressive symptoms and HbA1c in patients with Type 1 and Type 2 diabetes Diabet. Med. 31, 760–761 (2014) We thank Kawada for raising several concerns [1] about our paper ‘Differential associations between depressive symptoms and glycaemic control in outpatients with diabetes’ [2]. First, Kawada discusses the use of the Patient Health Questionnaire (PHQ-9) instrument in our study. In addition to the individual symptoms of depression, Kawada points out that the association of depression and HbA1c should be studied using the diagnostic algorithm of the PHQ-9 to classify major depressive disorder. The relationship between major depressive disorder and HbA1c in diabetes has been the topic of many papers, including a meta-analysis that showed a positive association between depression and HbA1c [3]. Depression is, however, a very heterogeneous construct, and persons with depression can differ substantially in the symptoms they express. Therefore, instead of looking at the overall depression construct, the specific purpose of the study was to study the relationship between the individual symptoms of depression and HbA1c in patients with diabetes. We did not report nor intend to propose that the individual symptoms of the PHQ-9 can be used as a substitute for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) major depressive disorder. Although the approach suggested by Kawada would provide further evidence for the potential relationship between depression and HbA1c, this would not result in differentiation of depression at the symptom level. Second, Kawada regrets that we did not discuss the potential U-shaped relationship between sleep duration and HbA1c, which has been observed in obese adolescents [4]. We believe that this specific study supports many observations that both short and long sleep duration appear to be related to poorer health in general [5,6]. Although we could only devote a limited amount of words to this important topic in the discussion section of our paper, it would be interesting to investigate the direction of the relationship between sleep duration and HbA1c. We completely agree with Kawada’s
760
Letters
suggestion to include more valid measurement of sleep quality in studies that investigate the relationship between sleep and glycaemic control, which has been carried out in the very recent study of Borel et al. [7]. Finally, Kawada incorrectly pointed out that lack of interest and depressed mood were not related to HbA1c. As shown in table 2 [2], depressed mood was a significant predictor for HbA1c in the overall sample and in individuals with Type 1 diabetes. We hope that our analysis and Kawada’s comments spur future longitudinal research that will further expand our understanding of the potential bidirectional relationship of depressive symptoms and glycaemic control in people with diabetes. We believe that the heterogenic nature of depression should not be overlooked here and may help to guide research and interventions for improving both mental health and glycaemic control in individuals with diabetes.
Funding sources
None.
Competing interests
None declared. M. Bot1, F. Pouwer2, P. de Jonge3 and F. Snoek4 Department of Psychiatry and the EMGO Institute for Health and Care Research, VU University Medical Centre, and GGZ inGeest, Amsterdam, 2Department of Medical and Clinical Psychology, Center of Research on Psychology in Somatic Diseases CoRPS, Tilburg University, Tilburg, 3Interdisciplinary Centre for Psychiatric Epidemiology, University Medical Centre Groningen, Groningen and 4Diabetes Psychology Research Group, Department of Medical Psychology, EMGO-Institute, VU University Medical Centre, Amsterdam, the Netherlands 1
References 1 Kawada T. Depressive symptoms and HbA1c in patients with Type 1 and Type 2 diabetes. Diabet Med 2014; 31: 759–760. 2 Bot M, Pouwer F, de Jonge P, Tack CJ, Geelhoed-Duijvestijn PHLM, Snoek FJ. Differential associations between depressive symptoms and glycaemic control in outpatients with diabetes. Diabet Med 2013; 30: e115–e122. 3 Lustman PJ, Anderson RJ, Freedland KE, de Groot M, Carney RM, Clouse RE. Depression and poor glycemic control: a meta-analytic review of the literature. Diabetes Care 2000; 23: 934–942. 4 Koren D. Levitt Katz LE, Brar PC, Gallagher PR, Berkowitz RI, Brooks LJ. Sleep architecture and glucose and insulin homeostasis in obese adolescents. Diabetes Care 2011; 34: 2442–2447. 5 Ayas NT, White DP, Manson JE, Stampfer MJ, Speizer FE, Malhotra A et al. A prospective study of sleep duration and
ª 2014 The Authors. Diabetic Medicine ª 2014 Diabetes UK
Letters coronary heart disease in women. Arch Intern Med 2003; 163: 205–209. 6 van Mill JG, Hoogendijk WJ, Vogelzangs N, Van Dyck R, Penninx BW. Insomnia and sleep duration in a large cohort of patients with major depressive disorder and anxiety disorders. J Clin Psychiatry 2010; 71: 239–246. 7 Borel AL, Pepin JL, Nasse L, Baguet JP, Netter S, Benhamou PY. Short sleep duration measured by wrist actimetry is associated with deteriorated glycemic control in type 1 diabetes. Diabetes Care 2013; 36: 2902–2908.
DOI: 10.1111/dme.12423
Effect of peripheral cholinergic stimulation on autonomic modulation in Type 2 diabetes with autonomic neuropathy: a randomized controlled trial Diabet. Med. 31, 761–762 (2014) Cardiovascular autonomic neuropathy is a reversible, serious and frequent complication in diabetes mellitus [1], presenting with reduced vagal modulation to the sinus node and beat-to-beat heart rate variability [2]. Alterations in the adrenergic and/or muscarinic receptor functions with a reduction in acetylcholine release [3] may be involved in this pathogenic process. Pyridostigmine bromide, an acetyl cholinesterase inhibitor, produces cholinergic stimulation by preventing the hydrolysis of acetylcholine and increasing its availability in the synaptic cleft [4]. It increases vagal modulation in healthy subjects [5] and heart failure patients [6], but the effect on cardiovascular autonomic neuropathy is unknown. In this study, we tested the hypothesis that increasing acetylcholine availability in the synaptic cleft improves vagal modulation. Thirty-four outpatients with Type 2 diabetes with cardiovascular autonomic neuropathy, attending the Endocrine Division at Hospital de Clınicas de Porto Alegre, were randomized to pyridostigmine and placebo, according to the intervention randomly drawn from a concealed envelope (Table 1). Presence of cardiovascular autonomic neuropathy was confirmed by the autonomic tests standardized by Ewing et al. [7] and a baseline 24-h Holter monitoring to calculate the following heart rate variability indices: mean of normal R–R intervals; standard deviation of normal R–R intervals; and root– mean–square successive differences [8]. The protocol was approved by the ethical committee of the institution and informed consent was obtained from each individual. Heart rate variability was re-evaluated while patients were receiving pyridostigmine bromide 30 mg orally three times daily for 24 h, or placebo. Patients and researchers were blinded to the interventions. The analysed data are described as mean SD. Differences in clinical characteristics between groups were compared using Student’s t-test for continuous variables and Pearson’s v2-test. Repeated-measures ANOVA was used to evaluate the effect
ª 2014 The Authors. Diabetic Medicine ª 2014 Diabetes UK
DIABETICMedicine
of the interventions on heart rate variability and minimum significance level was set at 5%. Both groups had similar clinical characteristics regarding age, gender, BMI, diabetes duration, blood pressure, cardiovascular autonomic neuropathy severity and use of drugs. Our results showed that pyridostigmine had no acute effect on autonomic modulation evaluated by heart rate variability, with an effect size d < 0.2 (Table 1). Differently, in our previous study in patients with heart failure with severely depressed heart rate variability, the short administration of pyridostigmine during only 24 h promoted a clear increase in time domain indices [6]. As in cardiovascular autonomic neuropathy peripheral nerves are anatomically compromised, it was not expected that a short intervention could restore its integrity, but an increase in acetylcholine availability should improve vagal modulation. The release of acetylcholine at the neuroeffector junction of the heart is regulated by the central nervous system and peripherally influenced by muscarinic receptors and pre-synaptic autoreceptors found at the postganglionic parasympathetic fibres [9]. These autoreceptors are muscarinic receptors subtypes that, when activated by endogenous acetylcholine, inhibit the release of acetylcholine in the synaptic cleft, causing a negative feedback [3,9,10]. Although acetyl cholinesterase inhibition with pyridostigmine increases the amount of acetylcholine in the synaptic cleft, in patients with diabetes, as the autoreceptors are up-regulated, this increase in acetylcholine may be followed by a negative feedback that reduces further acetylcholine release, preventing an improvement in cardiac autonomic modulation. The development of drugs that could modulate these up-regulated autoreceptors possibly would help in cardiovascular autonomic neuropathy control. There are some potential limitations to our study that could explain the lack of pyridostigmine effect. The drug was administered for a short period of time and longer exposure could bring different results. In this study, we did not assess cholinesterase activity to assure that the pyridostigmine dose used could properly block serum cholinesterase activity. In a previous study of our group, we have demonstrated that the same dose used in this study promoted a 14% reduction in cholinesterase activity [5] and increased autonomic modulation. In this present study, 58% of the patients were classified as having severe cardiovascular autonomic neuropathy. It is possible that, in a less compromised sample, pyridostigmine could increase heart rate variability. Although this study enrolled a small number of patients, the sample size was based on previous studies of our group with healthy individuals [5] and patients with heart failure [6] in whom the same dose of pyridostigmine significantly increased heart rate variability. In conclusion, peripheral acetyl cholinesterase blockage with oral administration of pyridostigmine bromide does not improve autonomic modulation of patients with Type 2 diabetes with cardiovascular autonomic neuropathy.
761
