Diabetes Ther (2018) 9:1421–1429 https://doi.org/10.1007/s13300-018-0453-x EDITORIAL Sanjay Kalra Rakesh Sahay Received: April 11, 2018 / Published online: June 4, 2018 The Author(s) 2018 ABSTRACT INTRODUCTION In this editorial we propose a condition that we Fatigue is a condition which interests research- refer to as ‘diabetes fatigue syndrome’ (DFS), ers, clinicians, and public health specialists alike which is commonly encountered in clinical . Most of the published discussion on fatigue practice. We deﬁne DFS as a multifactorial has revolved around its description and mea- syndrome of fatigue or easy fatigability that surement, its psychological pathogenesis and occurs in persons with diabetes. It may be impact, and its inﬂuence on occupational and industrial health [2, 3]. Yet, a consensus on its caused by a variety of lifestyle, nutritional, medical, psychological, glycemia/diabetes-re- deﬁnition has not yet been reached, and its quantiﬁcation is still not standardized . Fati- lated, and endocrine and iatrogenic factors. The authors share clinical pearls which can help the gue is a common symptom of diabetes that is diabetes healthcare provider diagnose DFS, not limited to uncontrolled diabetes. Persons identify its etiologic factors and manage the may complain of fatigue along with a variety of syndrome. The editorial highlights the need to symptoms, which may together herald comor- focus on symptomatic well-being in diabetes, bid psychological, medical, metabolic or endo- along with efforts to achieve numerical targets. crine, and acute or chronic complications. For the diabetes healthcare professional, the debates on fatigue are a distraction from the ultimate clinical challenge, namely, to identify Keywords: Adrenal; Anemia; Fatigue syndrome; fatigue, diagnose the cause(s) of the fatigue, Lifestyle modiﬁcation; Pituitary; Thyroid; manage the condition, and prevent worsening Vascular complications; Vitamin D deﬁciency of the morbidity. Enhanced digital features To view enhanced digital In this editorial we seek to achieve a working features for this article go to https://doi.org/10.6084/ deﬁnition of ‘diabetes fatigue syndrome’ (DFS), m9.ﬁgshare.6304445. provide a clinical rubric with which to evaluate this condition, and focus attention on this rel- S. Kalra (&) atively neglected aspect of diabetes care. Much Department of Endocrinology, Bharti Hospital, Karnal, India of the discussion in this article should be rele- e-mail: email@example.com vant to general clinical care as well. All named authors meet the International R. Sahay Committee of Medical Journal Editors (ICMJE) Department of Endocrinology, Osmania Medical College, Hyderabad, India 1422 Diabetes Ther (2018) 9:1421–1429 criteria for authorship for this manuscript, take FATIGUE IN DIABETES: A VICIOUS responsibility for the integrity of the work as a CYCLE whole, and have given ﬁnal approval for the version to be published. This article is based on Fatigue is a frequently encountered symptom in previously conducted studies and does not the general practice management of diabetes. involve any new studies of human or animal Fatigue may be the presenting symptom of subjects performed by any of the authors. diabetes, or it may present as one of a constel- lation of complaints. It may even persist after glycemic control is achieved. All of these clini- THE IMPORTANCE OF SYMPTOMS cal situations, irrespective of causality or asso- ciation, may be grouped together as DFS. Modern diabetes care is characterized by a Fatigue has been reported to be prevalent in strong focus on evidence-based, number-driven patients with type 1 diabetes or type 2 diabetes targets and outcomes. While this approach [5, 6]. Its association with inﬂammation, body does have its beneﬁts, it has shortcomings and mass index, insulin treatment, and depression limitations as well, one of which is that little has also been studied [7–9]. The lack of corre- attention is paid to the symptomatic well-be- lation between fatigue on the one hand and ing of the persons with diabetes. At times, in hyperglycemia and glycemic variability on the fact, complaints may be neglected, and symp- other is also known . The unique features of toms sacriﬁced, to justify the use of particular fatigue in persons with diabetes have also been therapeutic strategies or tools. A casual reading recognized, prompting the development of of modern guidelines suggests that the end- disease-speciﬁc diagnostic tools , as opposed target (e.g., a speciﬁc glycated hemoglobin to generic ones [12, 13]. value, or cardiovascular outcome) is more Diabetes and fatigue seem to have a bidirec- important than the means (a drug which cau- tional relationship, both feeding and worsening ses gastrointestinal or genitourinary discom- each other, thereby creating a vicious cycle of fort). Understandably, such clinical judgment DFS (Fig. 1). This relationship is strengthened by is bound to be met with patient dissatisfaction. biochemical, psychological, and lifestyle factors. One symptom which may be ignored in the quest for optimal numerical end-targets, is fatigue. THE BIOCHEMISTRY OF DIABETES FATIGUE FATIGUE The pathophysiology of fatigue centers around biochemical and ionic changes which occur in Fatigue is deﬁned as physical and/or mental muscle and subsequently impact the electrical exhaustion  that can be triggered by stress, and contractile properties of this organ. Substrate medication, overwork, or mental and physical depletion, high levels of hydrogen ions, and the illness or disease. Fatigability is a term used to presence of inorganic phosphate and potassium assess how fast someone gets exhausted. Easy have been implicated in the pathogenesis of fati- fatigability implies the occurrence of physical gue. Evidence suggests, however, that calcium ion and/or mental exhaustion at a level of work or availability at the sarcoplasmic reticulum of the stress that should ordinarily not cause such mitochondria, which is linked to a decrease in exhaustion. Fatigue impairs physical as well as ATP synthesis, may lead to fatigue . mental functioning, and it reduces the quality In persons with diabetes, lack of insulin (rel- of life. Thus, a person presenting with com- ative to the body’s needs) may shift the energy plaints of fatigue deserves a focused endocrine substrate from carbohydrate to fat. When this and medical checkup. occurs (once glycogen stores are exhausted), the ADP phosphorylation rate falls and ATP Diabetes Ther (2018) 9:1421–1429 1423 Fig. 1 The vicious cycle of diabetes fatigue syndrome resynthesis slows down. This process may glycemic/diabetes-related, endocrine, and explain the occurrence of fatigue in diabetes. iatrogenic factors. In this section we discuss the common forms of DFS that are encountered in clinical practice THE PSYCHOLOGY OF FATIGUE and describe the neuropsychiatric, muscu- loskeletal, and general symptoms and signs that Fatigue also has a strong psychological compo- facilitate the diabetes healthcare provider in nent . The inability to self-manage diabetes making the differential diagnosis of DFS may lead to a sense of fatiguability, which in (Tables 1, 2). We also list ‘clinical pearls’ which turn may hamper efforts to manage the condi- help the healthcare provider to diagnose and tion. Thus, there is a bidirectional relationship manage DFS (Tables 2, 3). Chronic fatigue syn- between easy fatiguability and diabetes distress, drome is extreme fatigue which persists unabated with each feeding on the other, creating a for at least 6 months and which is not the result vicious cycle which ultimately leads to DFS. of a diagnosed disease or illness. It is just one cause (out of many) of fatigue and does not fall within the range of the subject discussed here. We deﬁne DFS as a multifactorial syndrome of ETIOLOGY AND PRESENTATION fatigue or easy fatigability that occurs in persons with diabetes. It may be caused by a variety of The possible causes of DFS may be classiﬁed as non- lifestyle, nutritional, medical, psychological, endocrine and endocrine factors, respectively. 1424 Diabetes Ther (2018) 9:1421–1429 Table 1 Causes of fatigue in persons with diabetes Non-endocrine causes Endocrine causes Lifestyle related Glycemic related Lack of physical conditioning/exercise High HbA1c in spite of normal glucose levels Poor sleep hygiene Postprandial hyperglycemia with normal fasting glucose Excessive caffeine, alcohol intake Recurrent hypoglycemia Substance abuse High glycemic variability Drug withdrawal Complications of diabetes Diet related Nephropathy Excessive caloric intake Heart failure Excessive caloric restriction Myopathy Protein malnutrition Neuropathy Starvation ketosis Concomitant endocrinopathy Medical Hypothyroidism Anemia Cushing’s syndrome Dyselectrolytemia Hypogonadism Vitamin deﬁciency Addison’s disease Diabetes distress Iatrogenic Chronic corticosteroid use Statins Diuretics Beta blockers HbA1c Glycated hemoglobin Non-Endocrine DFS (such as betel quid, khat, opium) and culture- linked syndromes (e.g., Dhat syndrome) that may contribute to DFS. Lifestyle-Related Causes Non-endocrine factors that may contribute to DFS include an unhealthy lifestyle, inappropri- Nutritional Causes ate diet, and suboptimal mental health. Lack of Unhealthy diets, which may lead to macronu- physical conditioning, poor sleep hygiene, trient or micronutrient malnutrition or starva- substance abuse (including excessive alcohol, tion ketosis, can also precipitate DFS. Again, a caffeine), and drug withdrawal may lead to DFS. history taking, with a detailed dietary recall, These factors are usually identiﬁed though his- helps establish the diagnosis. tory taking. Validated questionnaires may be used to screen for some of these conditions Medical Causes [15, 16]. The treating physician should also be Common medical conditions, such as anemia, aware of locally prevalent substances of abuse dyselectrolytemia, and multiple vitamin Diabetes Ther (2018) 9:1421–1429 1425 Table 2 Fatigue and depression: differential diagnosis Parameter Fatigue Depressive disorder Deﬁnition Used to refer to loss of energy with complaints of increased fatigue after A mood disorder characterized by depressed mood, loss of mental effort, often associated with some decrease in occupational interest and enjoyment, and reduced energy leading to performance or coping efﬁciency in daily tasks. Mental fatiguability is increased fatiguability and diminished activity typically described as an unpleasant intrusion of distracting associations or recollections, difﬁculty in concentrating, and generally inefﬁcient thinking Symptoms Physical symptoms: reduced activity, low energy, tiredness, decreased Depressed mood, loss of interest and enjoyment, and physical endurance, increased effort to do physical tasks, general weakness, reduced energy leading to increased fatiguability and heaviness, slowness or sluggishness, nonrestorative sleep, and sleepiness. diminished activity Cognitive symptoms: decreased concentration, decreased attention, decreased mental endurance, and slowed thinking. Emotional symptoms: decreased motivation or initiative (apathy), decreased interest, feeling overwhelmed, feeling bored, aversion to effort, and feeling low Deﬁnite Deﬁnite diagnosis requires the following: Deﬁnitive diagnosis requires that the individual usually diagnosis suffers from (1) depressed mood, (2) loss of interest and (1) Either persistent and distressing complaints of increased fatigue after enjoyment, and (3) reduced energy leading to increased mental effort, or persistent and distressing complaints of bodily weakness fatiguability and diminished activity. Marked tiredness and exhaustion after minimal effort; after only slight effort is common. (2) At least two of the following: Other common symptoms are: - Feelings of muscular aches and pains - Reduced concentration and attention - Dizziness - Reduced self-esteem and self-conﬁdence - Tension headaches - Ideas of guilt and unworthiness (even in a mild type of - Sleep disturbance episode) - Inability to relax - Bleak and pessimistic views of the future - Irritability - Ideas or acts of self-harm or suicide - Dyspepsia - Disturbed sleep (3) Any autonomic or depressive symptoms present that are not sufﬁciently - Diminished appetite persistent and severe to fulﬁl the criteria for any other disorders, including Mild: at least two of three main symptoms and at least depressive disorders two of the other common symptoms Moderate: at least two of the three main symptoms and at least three of the other common symptoms Severe: all of the three main symptoms and at least four of the other common symptoms Associated Associated with decrease in occupational performance or coping efﬁciency in Associated with signiﬁcant distress and/or dysfunction morbidity daily tasks Instruments Fatigue Questionnaire and the Fatigue Associated with Depression scales Beck’s Depression inventory, Hamilton Depression for severity (FasD) Rating Scale rating deﬁciencies, are also characterized by fatigue. symptoms and signs. Proximal muscle weak- Such morbidities are as plausible in persons ness, together with musculoskeletal aches, with diabetes as in those without. Speciﬁc pains, and easy fatigability, implies vitamin D symptoms and signs may point towards these deﬁciency. comorbid causative factors of DFS. Many of these conditions coexist with dietary inade- Psychological Causes quacy. A history of breathlessness on exertion, At times, DFS may be worsened by psychologi- excessive blood loss, worm infestation, and cal impairment. Diabetes distress is deﬁned as pallor on examination suggest anemia. Dyse- an emotional response, characterized by lectrolytemia usually leads to neurological extreme apprehension, discomfort, or dejection 1426 Diabetes Ther (2018) 9:1421–1429 Table 3 Pragmatic suggestions Pragmatic suggestions Every person with diabetes must be asked about fatigue at each clinical encounter Every person with DFS should be screened clinically for lifestyle, drug intake, and medical and endocrine factors, and by history taking and physical examination Every person with a suggestive history or physical examination ﬁndings should be assessed for speciﬁc medical conditions and endocrinopathies Relevant investigations for DFS must be prescribed based upon index of clinical suspicion and economic considerations A therapeutic trial of vitamin D and calcium may be considered in South Asian persons with fatigue, taking the ubiquitous occurrence of vitamin D deﬁciency into consideration Hormone replacement or supplementation should be not initiated as a treatment for DFS without documentation of endocrine deﬁciency or insufﬁciency DFS Diabetes fatigue syndrome due to a prescribed inability to cope with the Alzheimer’s disease, may also present with challenges and demands of living with diabetes. fatigue. This adjustment disorder is characterized by a discomfort disorder that in turn is characterized Endocrine Causes by discomfort, and it may be reported as fatigue, Persons with diabetes, especially type 1 dia- possibly contributing to, overlapping with, or betes, are more prone to endocrinopathy. Dis- mimicking DFS. Yet another differential diag- eases such as hypothyroidism, Addison’s nosis of fatigue may be major depressive disor- disease, Cushing‘s syndrome, and hypothy- der. The differences between fatigue and roidism, if left unrecognized and/or untreated, depression are highlighted in Table 2 [17, 18]. may worsen DFS. The symptoms, sign, and laboratory anomalies speciﬁc to these diseases, Endocrine DFS coupled with a high index of clinical suspicion, help in their identiﬁcation. If lifestyle, nutritional, and medical causes are ruled out, a targeted gluco-endocrine evaluation Iatrogenic Causes must be done to pinpoint the cause of DFS. At times, DFS may be iatrogenic. Drugs such as corticosteroids, beta blockers, diuretics, and statins are known to cause fatigue. Their use Diabetes-Related Causes must be looked into during the evaluation of Diabetes-related causes include poor glycemic DFS. control, diabetic complications, and concomi- tant endocrinopathies. A suboptimal gluco- phenotype, involving any or all of the glycemic CLINICAL APPROACH hexad (hyperglycemia, hypoglycemia, excessive glycemic variability), can lead to DFS. Similarly, Diabetes fatigue syndrome is a multifactorial fatigue may be the presenting symptom, or it multifaceted condition which should not be may herald an insidious onset of vascular evaluated from a purely gluco-centered or complications, such as heart failure and endocrine-oriented prism. The appropriate nephropathy. Lesser known comorbidities of strategy to addressing DFS should follow a diabetes, including chronic venous disease and simple hierarchy (Table 2; Fig. 2) which Diabetes Ther (2018) 9:1421–1429 1427 Fig. 2 Approach to diagnosing diabetes fatigue syndrome evaluates the biomedical and psychosocial cau- A careful history and physical examination sative factors in parallel. Lifestyle- and diet-re- may reveal clues which can help in choosing lated factors are evaluated prior to factors focused investigations to conﬁrm common related to medical and endocrine dysfunction. medical and endocrine diagnoses. Sudden onset Deﬁciencies of macronutrients, micronutrients, fatigue in persons with well-controlled diabetes, electrolytes, sleep, and exercise, solely or in accompanied by pallor, and reduction in anti- combination, must be ruled out before further diabetic drug requirements should prompt evaluation. While glycemic control is assessed investigation for nephropathy and hypothy- along with screening for diabetic complications, roidism. Fatigue with breathlessness and a detailed drug history must be taken to rule out inability to exercise in diabetes should prompt iatrogenic causes of fatigue, such as statins, beta investigation for heart failure. Proximal mus- blockers, centrally acting antihypertensives, cular symptoms should prompt assessment for and diuretics. Fatigue corrected by eating food vitamin D deﬁciency, osteomalacia and Cush- indicates hypoglycemia, and early morning ing’s syndrome, while predominant neuro- headache or fatigue may indicate nocturnal pathic symptoms suggest a diagnosis of diabetic hypoglycemia. neuropathy, hypothyroidism or hypoparathy- roidism. Fatigue with predominant skeletal 1428 Diabetes Ther (2018) 9:1421–1429 symptoms suggests a diagnosis of hyper- SUMMARY parathyroidism, osteomalacia or osteoporosis. Fatigue with periodicity suggests a diagnosis Diabetes fatigue syndrome is deﬁned as a mul- of dyselectrolytemia or premenstrual syndrome. tifactorial syndrome of fatigue or easy fatiga- Fatigue with loss of libido or other sexual dys- bility, occurring in persons with diabetes, which function may suggest a diagnosis of hypogo- may be caused by a variety of lifestyle, nutri- nadism, including menopause or andropause. tional, medical, psychological, glycemia/dia- Psychological morbidity, such as diabetes dis- betes-related, endocrine, and iatrogenic factors. tress, should be ruled out prior to diagnosing Though this communication, we share a prag- psychiatric conditions. matic approach to the identiﬁcation and man- The astute physician should be able to cor- agement of DFS. We highlight clinically relate the patient’s symptoms and sign and relevant issues which will help improve the apply ‘good clinical sense’ to order relevant quality of care provided to persons with investigations. At the same time, DFS is multi- diabetes. etiologic, and the treating physician must take the opportunity to optimize lifestyle, nutri- tional intake psychological status, and medica- ACKNOWLEDGEMENTS tion usage in persons with fatigue. Table 3 lists some pragmatic suggestions which reinforce this clinical approach. Funding. No funding or sponsorship was received for this study or publication of this article. MANAGEMENT OF DFS Medical Writing and Editorial Assis- The psychological aspect of DFS can be mini- tance. No medical or editorial assistance was mized by effective management of diabetes sought or received for the writing of this distress. Diabetes distress occurs due to the manuscript. person’s inability to cope with the demands of life with diabetes. Therefore, its management is Authorship. All named authors meet the best done by following a four pronged strategy: International Committee of Medical Journal enhancing self-perception, enhancing coping Editors (ICMJE) criteria for authorship for this skills, minimizing the discomfort of change, manuscript, take responsibility for the integrity and utilizing external support. An effective of the work as a whole, and have given ﬁnal coping adjustment with diabetes may help approval for the version to be published. mitigate not only psychological distress, but also psychosomatic symptoms such as fatigue as Disclosures. Sanjay Kalra and Rakesh Sahay well. have nothing to disclose. Lifestyle optimization, including a healthy diet, physical activity regimen, stress control, Compliance with Ethics Guidelines. This and a good sleep pattern, will help mitigate article is based on previously conducted studies fatigue precipitated by unhealthy living habits. and does not involve any new studies of human Effective and safe glycemic control, along or animal subjects performed by any of the with maintenance of optimal endocrine, medi- authors. cal, and metabolic function, is necessary to tackle the physical component of DFS. A focus Data Availability. Data sharing is not on euglycemia, with minimal hypoglycemia applicable to this article as no datasets were and glycemic variability, is required to ensure generated or analyzed during the current study. efﬁcient mitochondrial function and achieve maximal musculoskeletal efﬁciency. Open Access. This article is distributed under the terms of the Creative Commons Diabetes Ther (2018) 9:1421–1429 1429 treatment. Psychoneuroendocrinology. Attribution-NonCommercial 4.0 International 2012;37(9):1468–78. 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