The effect of phenformin and other adenosine triphosphate (ATP)‐lowering agents on insulin binding to IM‐9 human cultured lymphocytes

Abstract

In the present study, we investigated the mechanism by which the antidiabetic drug phenformin increases insulin binding to its receptors in IM-9 human cultured lymphocytes. After a 24-hr preincubation, phenformin induced a twofold increase in specific 125I-insulin binding, and removal of phenformin was followed 6 hr later by a return in binding to control levels. This effect of phenformin on insulin binding was not a consequence of either inhibition of cell growth, changes in cellular cyclic adenosine monophosphate (AMP) levels, or changes in guanosine triphosphate (GTP) content. Since phenformin is known to inhibit various aspects of cellular energy metabolism, the relationship between 125I-insulin binding and energy metabolism in IM-9 cells was investigated. The phenformin-induced increase in insulin binding to IM-9 cells was related to a time- and dose-dependent decrease in ATP levels. Other agents that lowered ATP levels, including antimycin, dinitrophenol, and 2-deoxyglucose, also raised insulin binding. These studies indicated, therefore, that phenformin enhances insulin binding to receptors on IM-9 cells and that this effect on insulin receptors may be related to alterations in metabolic functions that are reflected by a lowering of ATP levels.

Improvement With Metformin in Insulin Internalizaron and Processing in Monocytes From NIDDM Patients

“…In contrast, note that in untreated hyperglycemic insulin-dependent diabetic patients, the intracellular processing of insulin is normal (unpublished data; Table 3). Moreover, the biguanide phenformin per se inhibits various aspects of cellular metabolism, lowering cellular ATP levels (27).…”