Glucagon gene transcription is negatively regulated by insulin in a hamster islet cell line.

Abstract

Complex interrelationships exist between the four pancreatic islet cell types and their respective secretory products, insulin, glucagon, somatostatin, and pancreatic polypeptide. These hormones are known to interact with the different islet cells and modulate their functions. Insulin inhibits glucagon secretion from the A cell both in vivo and in vitro and, in states of insulin deficiency, high glucagon levels are observed that are normalized by insulin replacement. To determine if insulin also regulates glucagon biosynthesis, we studied its effects on glucagon gene expression. Our studies indicate that insulin, in a dose-dependent fashion decreases steady-state glucagon mRNA levels in a clonal hamster islet cell line, In-Rl-G9; this decrease is secondary to an inhibition of glucagon gene transcription as assessed by transcriptional run-on assays and does not involve detectable changes in mRNA stability. Inhibition of glucagon gene transcription is accompanied by corresponding decreases in glucagon immunoreactivity in both cell extracts and medium. We conclude that insulin may not only regulate glucagon secretion but also glucagon gene expression.

Insulin treatment and high-fat diet feeding reduces the expression of three Tcf genes in rodent pancreas

“…6A, insulin treatment led to a 95, 85, and 90% reduction in the level of expression of Tcf7, Tcf7l1, and Tcf7l2 respectively. Figure 6B shows that insulin treatment led to a significantly reduced expression of gcg, consistent with observation made by J Philippe two decades ago (Philippe 1989(Philippe , 1991. Figure 6C shows that in the pancreas of HFD fed mice, the expression level of Tcf7, Tcf7l1, and Tcf7l2 was significantly lower than those from mice fed with chow diet.…”

Glucagon regulates its own synthesis by autocrine signaling

“…Our data demonstrate that secreted glucagon stimulates its own resynthesis via a positive autocrine feedback mechanism. The increase in (prepro)glucagon mRNA levels is only transient, however, and the feedback loop is turned off by a lack of glucagon stimulus, leading to transient activation of protein kinases PKA and PKC in response to rising blood glucose levels, as well as to inhibition of glucagon gene transcription by insulin (33). Interestingly, GLP-1, another product of the (prepro)glucagon gene that is synthesized and secreted by intestinal L cells, is also able to activate the glucagon promoter in αTC1-9 cells (Fig.…”

TCF-4 Mediates Cell Type-specific Regulation of Proglucagon Gene Expression by β-Catenin and Glycogen Synthase Kinase-3β

“…Our previous studies have demonstrated that the GLUTag cell line responds appropriately to the regulatory factors known to control glu gene expression and GLP-1 synthesis and secretion in primary gut endocrine cells, including cAMP/protein kinase A, glucose-dependent insulinotropic peptide, and bethanechol (26,40,50,51). Likewise, the ␣-TC-1 and InR1-G9 cell lines have been routinely used as ␣ cell models to study glu gene expression and glucagon synthesis and secretion (19,20,30,(52)(53)(54)(55)(56). In these cell lines, for example, glucagon secretion is repressed by retinol and retinoic acid (52) and activated by phorbol esters (54), cytosolic calcium oscillations are inhibited by high glucose, and glu mRNA expression and glucagon synthesis are inhibited by insulin (55).…”