REGULATION OF HUMAN INSULIN GENE-TRANSCRIPTION BY GLUCOSE, EPINEPHRINE, AND SOMATOSTATIN

We observed in the HIT cell, a clonal insulin-secreting cell line, tha t epinephrine and somatostatin lower insulin mRNA levels and intracell ular insulin content in addition to the well-recognized effect of thes e hormones to inhibit insulin secretion. To determine whether these in hibitory hormones might regulate insulin synthesis at the level of ins ulin gene transcription, we studied HIT cell expression of a human ins ulin-chloramphenicol acetyl transferase (CAT) reporter gene in the pre sence of glucose, epinephrine, and somatostatin. HIT cell expression o f this human insulin-CAT reporter gene was responsive to glucose in a concentration-dependent manner, increasing threefold as the glucose co ncentration increased from 0.4 to 11 mM. Epinephrine significantly inh ibited insulin-CAT reporter gene expression (61 +/- 5% of control), an effect mediated specifically by the human insulin gene promoter/enhan cer sequence. Somatostatin significantly inhibited expression of the h uman insulin-CAT reporter gene (65 +/- 4% of control) and, to a lesser extent, expression of a control reporter gene, pRSVCAT (78 +/- 4% of control). Thus, somatostatin may inhibit insulin gene transcription by insulin gene-specific effects as well as more general effects on gene expression. Both epinephrine and somatostatin inhibited expression of the human insulin-CAT reporter gene in a concentration-dependent mann er that paralleled inhibition of insulin secretion. These studies indi cate that epinephrine and somatostatin lower HIT cell insulin mRNA lev els in part by inhibiting insulin gene transcription. Thus, hormonal i nhibition of insulin secretion may be coupled with inhibition of insul in synthesis, thereby allowing the beta-cell to match insulin supply t o secretory demand.