Pathogenesis of DIDM during ALL therapy
Occurrence of DIDM during ALL therapy has been mainly attributed to chemotherapeutic agents like L-asparaginase and corticosteroids(8)(9)(10). However, diabetogenic effect of leukemic process affecting glucose homeostasis has also been hypothesised to cause DIDM in ALL patients. Corticosteroids such as dexamethasone and prednisolone induce DIDM by damaging pancreatic beta cells, reducing insulin production, increasing insulin resistance, stimulating gluconeogenesis and lipolysis, and increasing counter regulatory hormones such as glucagon and adrenaline(3). Corticosteroids reduce the expression of glucose transporter 2 and glucokinase while increasing the activity of glucose-6-phosphate dehydrogenase(11)(12)(13). Also, corticosteroids stimulate the apoptosis of pancreatic beta cells by repressing the anti-apoptotic protein B-cell lymphoma 2, and by activating calcineurin(3). Type of corticosteroids (dexamethasone Vs prednisolone) doesn’t seem to influence the occurrence of DIDM during ALL therapy(14)(15), however the dose and duration of corticosteroids administration may impact DIDM (supplementary file, Table-1). L-asparaginase acts by depleting L-asparagine which may lead to decreased insulin synthesis and secretion. It has also been shown to increase the insulin resistance possibly by inducing conformational change and depletion of insulin receptors(16). Direct toxic effect of L-asparaginase resulting in pancreatitis may in turn cause DIDM. Native L-asparaginase is associated with higher risk of DIDM in ALL patients compared to PEG-L-asparaginase(17). Dose and schedule of L-asparaginase administration may also affect the incidence of DIDM during ALL therapy. Treatment with corticosteroids and L-asparaginase in combination synergistically increases glucose intolerance and DIDM(18). Impaired glucose tolerance can lead to immune dysfunction predisposing ALL patients to severe infections. Poor outcomes in ALL patients with DIDM associated altered metabolism that supports the proliferative state of leukemic cells, is an area of active research(19).