3 - The translational control of proinsulin synthesis by glucose

Summary

Introduction

Insulin has long been known to be synthesized in the pancreatic B-cells of islets of Langerhans. However, an additional protein, similar to but larger than insulin, was discovered by Steiner & Oyer (1967). These workers used human islet-cell tumors, but it was not until a method for isolating actual islets from the pancreas was established that further progress could be made in the study of insulin biosynthesis. Using islets thus isolated from rat pancreases, Steiner and others were able to show the larger protein to be a precursor of insulin and proposed for it the name proinsulin (Steiner et al., 1972; Steiner & Tager, 1979; Permutt, 1981).

Both proinsulin synthesis and insulin secretion in the islets of Langerhans are shown to be highly stimulated by glucose, in marked contrast to non-proinsulin proteins, the synthesis of which is only slightly stimulated. Thus, there must be in the islets a highly selective mechanism for proinsulin synthesis (Steiner et al., 1972; Steiner & Tager, 1979; Permutt, 1981), either at the transcription level of the proinsulin gene or at the translation level of the proinsulin mRNA or both. Permutt & Kipnis (1972) demonstrated that actinomycin D had little effect on the stimulation of proinsulin synthesis by glucose in the early phase (within 45 min). This result suggested that the stimulation of proinsulin synthesis was regulated at the post-transcription level. In order to clarify the mechanism by which glucose stimulates proinsulin synthesis, a direct determination of the proinsulin mRNA level and the transcriptional activity of the proinsulin gene in the islets during the induction of proinsulin synthesis by glucose seemed desirable.