The possible causes of DFS may be classified as non-endocrine and endocrine factors, respectively.
Non-Endocrine DFS
Lifestyle-Related Causes
Non-endocrine factors that may contribute to DFS include an unhealthy lifestyle, inappropriate diet, and suboptimal mental health. Lack of physical conditioning, poor sleep hygiene, substance abuse (including excessive alcohol, caffeine), and drug withdrawal may lead to DFS. These factors are usually identified though history taking. Validated questionnaires may be used to screen for some of these conditions [15, 16]. The treating physician should also be aware of locally prevalent substances of abuse (such as betel quid, khat, opium) and culture-linked syndromes (e.g., Dhat syndrome) that may contribute to DFS.
Nutritional Causes
Unhealthy diets, which may lead to macronutrient or micronutrient malnutrition or starvation ketosis, can also precipitate DFS. Again, a history taking, with a detailed dietary recall, helps establish the diagnosis.
Medical Causes
Common medical conditions, such as anemia, dyselectrolytemia, and multiple vitamin deficiencies, are also characterized by fatigue. Such morbidities are as plausible in persons with diabetes as in those without. Specific symptoms and signs may point towards these comorbid causative factors of DFS. Many of these conditions coexist with dietary inadequacy. A history of breathlessness on exertion, excessive blood loss, worm infestation, and pallor on examination suggest anemia. Dyselectrolytemia usually leads to neurological symptoms and signs. Proximal muscle weakness, together with musculoskeletal aches, pains, and easy fatigability, implies vitamin D deficiency.
Psychological Causes
At times, DFS may be worsened by psychological impairment. Diabetes distress is defined as an emotional response, characterized by extreme apprehension, discomfort, or dejection due to a prescribed inability to cope with the challenges and demands of living with diabetes. This adjustment disorder is characterized by a discomfort disorder that in turn is characterized by discomfort, and it may be reported as fatigue, possibly contributing to, overlapping with, or mimicking DFS. Yet another differential diagnosis of fatigue may be major depressive disorder. The differences between fatigue and depression are highlighted in Table 2 [17, 18].
Endocrine DFS
If lifestyle, nutritional, and medical causes are ruled out, a targeted gluco-endocrine evaluation must be done to pinpoint the cause of DFS.
Diabetes-Related Causes
Diabetes-related causes include poor glycemic control, diabetic complications, and concomitant endocrinopathies. A suboptimal gluco-phenotype, involving any or all of the glycemic hexad (hyperglycemia, hypoglycemia, excessive glycemic variability), can lead to DFS. Similarly, fatigue may be the presenting symptom, or it may herald an insidious onset of vascular complications, such as heart failure and nephropathy. Lesser known comorbidities of diabetes, including chronic venous disease and Alzheimer’s disease, may also present with fatigue.
Endocrine Causes
Persons with diabetes, especially type 1 diabetes, are more prone to endocrinopathy. Diseases such as hypothyroidism, Addison’s disease, Cushing‘s syndrome, and hypothyroidism, if left unrecognized and/or untreated, may worsen DFS. The symptoms, sign, and laboratory anomalies specific to these diseases, coupled with a high index of clinical suspicion, help in their identification.
Iatrogenic Causes
At times, DFS may be iatrogenic. Drugs such as corticosteroids, beta blockers, diuretics, and statins are known to cause fatigue. Their use must be looked into during the evaluation of DFS.