Cyclic adenosine monophosphate prevents the glucocorticoid-mediated inhibition of insulin gene expression in rodent islet cells.

Abstract

Dexamethasone negatively regulates insulin gene expression in HIT-15 cells. In vivo, however, an excess of glucocorticoids results in an increase in insulin biosynthesis and peripheral hyperinsulinemia. To resolve this contradiction, we have studied the effects of dexamethasone in primary rat islet cells. We show here that dexamethasone decreases insulin mRNA levels in single islet cells, as in HIT-15 cells, but does not affect these levels in reaggregated islet cells and increases them in intact islets of Langerhans. Because cAMP is an important regulator of insulin gene expression and intracellular cAMP content may be decreased in single (3 cells, we investigated whether cAMP could prevent the inhibitory effect of dexamethasone on insulin mRNA levels. In the presence of cAMP analogues, the inhibitory action of dexamethasone was not only prevented, but insulin mRNA increased to levels comparable to those observed when cAMP analogues were used alone. We conclude that the insulin gene is negatively regulated by dexamethasone in single islet cells, but that other factors such as cAMP prevent this effect when the native environment of islet cells is preserved. Our results indicate that insulin gene regulation is influenced by cell to cell contacts within the islet, and that intracellular cAMP levels might be influential in this regulation. (J. Clin. Invest. 1992. 90:2228-2233

Glikokortykosteroidy a czynność komórek beta

“…Accordingly, DEX exerts a negative regulatory effect on insulin mRNA levels when assessed in dispersed primary rat islet cells [70]. However, an opposite DEX action was noticed with regard to the intact islet cell mass, which was ascribed to higher intracellular cAMP content in clustered cells enhancing their secretory responsiveness [70,71]. Similar to this latter observation, a stimulatory role of DEX on insulin gene transcription in rat pancreatic islets was also reported in the past [72].…”

“…Indeed, a negative glucocorticoid response element was identified on insulin promoter [69]. Accordingly, DEX exerts a negative regulatory effect on insulin mRNA levels when assessed in dispersed primary rat islet cells [70]. However, an opposite DEX action was noticed with regard to the intact islet cell mass, which was ascribed to higher intracellular cAMP content in clustered cells enhancing their secretory responsiveness [70,71].…”

“…Rzeczywiście, w promotorze genu insuliny zidentyfikowano PRACE POGLĄDOWE negatywny element odpowiedzi na GKS (GRE, glucocorticoid response element) [69]. Zgodnie z tym DEX wywiera negatywny efekt regulatorowy na poziom mRNA oceniany w izolowanych rozproszonych wyspach trzustkowych pochodzących od szczurów [70]. Natomiast odwrotne działanie DEX odnotowano w odniesieniu do nienaruszonej masy komórek wyspowych, co przypisane zostało wyższej wewnątrzkomórkowej zawartości cAMP w zgrupowanych komórkach, nasilającej ich reaktywność wydzielniczą [70,71].…”

“…Zgodnie z tym DEX wywiera negatywny efekt regulatorowy na poziom mRNA oceniany w izolowanych rozproszonych wyspach trzustkowych pochodzących od szczurów [70]. Natomiast odwrotne działanie DEX odnotowano w odniesieniu do nienaruszonej masy komórek wyspowych, co przypisane zostało wyższej wewnątrzkomórkowej zawartości cAMP w zgrupowanych komórkach, nasilającej ich reaktywność wydzielniczą [70,71]. Podobne stymulacyjne działanie DEX na transkrypcję genu insuliny opisywano w obrębie wysp trzustkowych szczurów we wcześniejszych badaniach [72].…”

Effect of adrenalectomy on the development of a pancreatic islet lesion in fa/fa rats

“…The data obtained in the current study are evidence that pancreatic glucokinase activity is also regulated by the HPA axis but does not indicate whether glucocorticoids directly modulate glucokinase or exert their effects via their influence on the anterior pituitary or hypothalamic nuclei. Results of studies investigating direct glucocorticoid action on insulin secretion or biosynthesis, and on pancreatic glucokinase activity are not conclusive [31][32][33][34]. However, glucocorticoids may increase pancreatic islet beta-cell glucokinase activity indirectly either by increasing glucose production by the liver or by acting through the HPA axis [35,36].…”