Diabetes Fatigue Syndrome

Fatigue is a condition which interests researchers, clinicians, and public health specialists alike [1]. Most of the published discussion on fatigue has revolved around its description and measurement, its psychological pathogenesis and impact, and its influence on occupational and industrial health [2, 3]. Yet, a consensus on its definition has not yet been reached, and its quantification is still not standardized [1]. Fatigue is a common symptom of diabetes that is not limited to uncontrolled diabetes. Persons may complain of fatigue along with a variety of symptoms, which may together herald comorbid psychological, medical, metabolic or endocrine, 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 fatigue, diagnose the cause(s) of the fatigue, manage the condition, and prevent worsening of the morbidity.

In this editorial we seek to achieve a working definition of ‘diabetes fatigue syndrome’ (DFS), provide a clinical rubric with which to evaluate this condition, and focus attention on this relatively neglected aspect of diabetes care. Much of the discussion in this article should be relevant to general clinical care as well.

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Modern diabetes care is characterized by a strong focus on evidence-based, number-driven targets and outcomes. While this approach does have its benefits, it has shortcomings and limitations as well, one of which is that little attention is paid to the symptomatic well-being of the persons with diabetes. At times, in fact, complaints may be neglected, and symptoms sacrificed, to justify the use of particular therapeutic strategies or tools. A casual reading of modern guidelines suggests that the end-target (e.g., a specific glycated hemoglobin value, or cardiovascular outcome) is more important than the means (a drug which causes gastrointestinal or genitourinary discomfort). Understandably, such clinical judgment is bound to be met with patient dissatisfaction. One symptom which may be ignored in the quest for optimal numerical end-targets, is fatigue.

Fatigue is defined as physical and/or mental exhaustion [4] that can be triggered by stress, medication, overwork, or mental and physical illness or disease. Fatigability is a term used to assess how fast someone gets exhausted. Easy fatigability implies the occurrence of physical and/or mental exhaustion at a level of work or stress that should ordinarily not cause such exhaustion. Fatigue impairs physical as well as mental functioning, and it reduces the quality of life. Thus, a person presenting with complaints of fatigue deserves a focused endocrine and medical checkup.

Fatigue is a frequently encountered symptom in the general practice management of diabetes. Fatigue may be the presenting symptom of diabetes, or it may present as one of a constellation of complaints. It may even persist after glycemic control is achieved. All of these clinical situations, irrespective of causality or association, may be grouped together as DFS. Fatigue has been reported to be prevalent in patients with type 1 diabetes or type 2 diabetes [5, 6]. Its association with inflammation, body mass index, insulin treatment, and depression has also been studied [7, 8, 9]. The lack of correlation between fatigue on the one hand and hyperglycemia and glycemic variability on the other is also known [10]. The unique features of fatigue in persons with diabetes have also been recognized, prompting the development of disease-specific diagnostic tools [11], as opposed to generic ones [12, 13].

Diabetes and fatigue seem to have a bidirectional relationship, both feeding and worsening each other, thereby creating a vicious cycle of DFS (Fig. 1). This relationship is strengthened by biochemical, psychological, and lifestyle factors.

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The pathophysiology of fatigue centers around biochemical and ionic changes which occur in muscle and subsequently impact the electrical and contractile properties of this organ. Substrate depletion, high levels of hydrogen ions, and the presence of inorganic phosphate and potassium have been implicated in the pathogenesis of fatigue. Evidence suggests, however, that calcium ion availability at the sarcoplasmic reticulum of the mitochondria, which is linked to a decrease in ATP synthesis, may lead to fatigue [14].

In persons with diabetes, lack of insulin (relative to the body’s needs) may shift the energy substrate from carbohydrate to fat. When this occurs (once glycogen stores are exhausted), the ADP phosphorylation rate falls and ATP resynthesis slows down. This process may explain the occurrence of fatigue in diabetes.

Fatigue also has a strong psychological component [1]. The inability to self-manage diabetes may lead to a sense of fatiguability, which in turn may hamper efforts to manage the condition. Thus, there is a bidirectional relationship between easy fatiguability and diabetes distress, with each feeding on the other, creating a vicious cycle which ultimately leads to DFS.

We define DFS as a multifactorial syndrome of fatigue or easy fatigability that occurs in persons with diabetes. It may be caused by a variety of lifestyle, nutritional, medical, psychological, glycemic/diabetes-related, endocrine, and iatrogenic factors.

The possible causes of DFS may be classified as non-endocrine and endocrine factors, respectively.

Diabetes fatigue syndrome is a multifactorial multifaceted condition which should not be evaluated from a purely gluco-centered or endocrine-oriented prism. The appropriate strategy to addressing DFS should follow a simple hierarchy (Table 2; Fig. 2) which evaluates the biomedical and psychosocial causative factors in parallel. Lifestyle- and diet-related factors are evaluated prior to factors related to medical and endocrine dysfunction. Deficiencies of macronutrients, micronutrients, electrolytes, sleep, and exercise, solely or in combination, must be ruled out before further evaluation. While glycemic control is assessed along with screening for diabetic complications, a detailed drug history must be taken to rule out iatrogenic causes of fatigue, such as statins, beta blockers, centrally acting antihypertensives, and diuretics. Fatigue corrected by eating food indicates hypoglycemia, and early morning headache or fatigue may indicate nocturnal hypoglycemia.

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A careful history and physical examination may reveal clues which can help in choosing focused investigations to confirm common medical and endocrine diagnoses. Sudden onset fatigue in persons with well-controlled diabetes, accompanied by pallor, and reduction in anti-diabetic drug requirements should prompt investigation for nephropathy and hypothyroidism. Fatigue with breathlessness and inability to exercise in diabetes should prompt investigation for heart failure. Proximal muscular symptoms should prompt assessment for vitamin D deficiency, osteomalacia and Cushing’s syndrome, while predominant neuropathic symptoms suggest a diagnosis of diabetic neuropathy, hypothyroidism or hypoparathyroidism. Fatigue with predominant skeletal symptoms suggests a diagnosis of hyperparathyroidism, osteomalacia or osteoporosis.

Fatigue with periodicity suggests a diagnosis of dyselectrolytemia or premenstrual syndrome. Fatigue with loss of libido or other sexual dysfunction may suggest a diagnosis of hypogonadism, including menopause or andropause. Psychological morbidity, such as diabetes distress, should be ruled out prior to diagnosing psychiatric conditions.

The astute physician should be able to correlate the patient’s symptoms and sign and apply ‘good clinical sense’ to order relevant investigations. At the same time, DFS is multi-etiologic, and the treating physician must take the opportunity to optimize lifestyle, nutritional intake psychological status, and medication usage in persons with fatigue. Table 3 lists some pragmatic suggestions which reinforce this clinical approach.

The psychological aspect of DFS can be minimized by effective management of diabetes distress. Diabetes distress occurs due to the person’s inability to cope with the demands of life with diabetes. Therefore, its management is best done by following a four pronged strategy: enhancing self-perception, enhancing coping skills, minimizing the discomfort of change, and utilizing external support. An effective coping adjustment with diabetes may help mitigate not only psychological distress, but also psychosomatic symptoms such as fatigue as well.

Lifestyle optimization, including a healthy diet, physical activity regimen, stress control, and a good sleep pattern, will help mitigate fatigue precipitated by unhealthy living habits.

Effective and safe glycemic control, along with maintenance of optimal endocrine, medical, and metabolic function, is necessary to tackle the physical component of DFS. A focus on euglycemia, with minimal hypoglycemia and glycemic variability, is required to ensure efficient mitochondrial function and achieve maximal musculoskeletal efficiency.

Diabetes fatigue syndrome is defined as a multifactorial syndrome of fatigue or easy fatigability, occurring in persons with diabetes, which may be caused by a variety of lifestyle, nutritional, medical, psychological, glycemia/diabetes-related, endocrine, and iatrogenic factors. Though this communication, we share a pragmatic approach to the identification and management of DFS. We highlight clinically relevant issues which will help improve the quality of care provided to persons with diabetes.