INSULIN, BUT NOT GLUCOSE LOWERING CORRECTS THE HYPERGLUCAGONEMIA AND INCREASED PROGLUCAGON MESSENGER-RIBONUCLEIC-ACID LEVELS OBSERVED IN INSULINOPENIC DIABETES

The factors that;regulate glucagon biosynthesis and proglucagon gene e xpression are poorly defined. We previously reported that insulin inhi bits proglucagon gene expression in vitro. In vivo, however, the effec ts of insulin on the regulation of the proglucagon gene have been cont roversial. Furthermore, whether glucose plays any role alone or in con junction with insulin on proglucagon gene expression is unknown. We in vestigated the consequences of insulinopenic diabetes on glucagon gene expression in the endocrine pancreas and intestine and whether insuli n and/or glucose could correct the observed abnormalities. We show her e that in the first days after induction of hyperglycemia by streptozo tocin, rats have levels of plasma glucagon and proglucagon messenger R NA comparable to those of normoglycemic controls despite hyperglycemia . With more prolonged diabetes, plasma glucagon and proglucagon messen ger RNA levels increase; this increase is corrected by insulin treatme nt, but not by phloridzin despite normalization of the glycemia by bot h treatments. Proglucagon gene expression exhibits the same regulatory response to glucose and insulin in both pancreas and ileum. We conclu de that insulin tonically inhibits proglucagon gene expression in the pancreas and ileum and that glucose plays a minor, if any, role in thi s regulation.