The in vitro effects of two
biguanides (
phenformin and
metformin) and four sulfonylureas (
tolbutamide,
glyburide,
gliclazide, and
glisolamide) on
insulin binding to its receptors were studied in four cultured cell lines: human skin fibroblasts, IM-9 lymphoblasts, MCF-7
human mammary carcinoma, and H35 rat
hepatoma. After a 24-h preincubation with maximal stimulatory concentrations of
phenformin, specific [125I]
insulin binding to its receptors in the four different cell lines were increased over control by 67.2 +/ 17.0%, 101.3 +/- 11.5%, 65.1 +/- 8.0%, and 44.0 +/- 12.1%, respectively (mean +/- SE).
Phenformin was effective in IM-9 cells that were down-regulated by unlabeled
insulin, and the effect of
phenformin on
insulin binding was not affected by inhibition of
protein synthesis with
cycloheximide. In concert with this observation. Scatchard plots indicated that
phenformin increased the
insulin receptor's affinity rather than the number of
insulin-binding sites on IM-9 cells.
Metformin was also effective in significantly enhancing
insulin binding in both IM-9 and MCF-7 cells. In contrast to the effects of
biguanides, none of the four sulfonylureas tested had any significant influence on
insulin binding to any of the four cell lines. These agents were also ineffective in IM-9 cells that were down-regulated by
insulin. Therefore, these studies suggest that: 1) in vitro,
biguanides enhance
insulin binding to its receptors in a variety of cell types; 2) this effect of
biguanides doesn't depend on new receptor synthesis; it is a result of changes in the affinity of the
insulin receptor; and 3) in contrast to the
biguanides, the sulfonylureas do not have a major direct effect on
insulin binding to its receptors in most cell types.