Glargine blood biotransformation: in vitro appraisal with human insulin immunoassay

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“…Both products retain the glycine substitution for asparagine at A21. These are therefore closely similar to, but not identical with, human insulin [37,38], and their mitogenicity appears to be low [38]. All three forms (unchanged insulin glargine, M1 and M2) enter the circulation.…”

“…All three forms (unchanged insulin glargine, M1 and M2) enter the circulation. Further degradation of insulin glargine to M1 occurs on exposure to serum, probably mediated by carboxypeptidase enzymes [38]. These observations suggest that insulin glargine behaves to some extent as a prodrug, generating bioactive breakdown products both at the site of injection and within the circulation.…”

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“…Indeed, while exposure to supraphysiological doses of insulin is, in theory, possible, in clinical practice insulin overdose results in hypoglycemia. Furthermore, insulin glargine, in the presence of serum, is rapidly processed to its main metabolites, M1 and M2 [31] . Although insulin glargine, M1 and M2 have similar affi nities for the insulin receptor as human insulin (and hence similar metabolic eff ects), insulin glargine has a higher affi nity for IGF-1R than M1 or M2, suggesting that the metabolites have a reduced mitogenic potency [65] .…”

“…In vitro metabolism studies showed that, in the presence of serum, insulin glargine is rapidly processed to its main metabolites; M1 (GlyA21) and M2 (GlyA21desB30), with an average of 72 % (range 46 -98 % ) of insulin glargine converted to M1 within 30 min [31] .…”

“…However, data are limited and the result in these cells requires further investigation to determine the diff erential eff ects that appear in some cell lines. It has been shown that insulin glargine is rapidly transformed into its metabolites [31] . Recent in vitro data have now demonstrated a similar metabolic signaling and activity for insulin glargine and its metabolites.…”