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).