Loss of insulin-induced inhibition of glucagon gene transcription in hamster pancreatic islet alpha cells by long-term insulin exposure

Abstract

Aims/hypothesis Diabetes mellitus type 2 is characterised by hyperglucagonaemia, resulting in hepatic glucose production and hyperglycaemia. Considering that insulin inhibits glucagon secretion and gene transcription, hyperglucagonaemia in the face of hyperinsulinaemia in diabetes mellitus type 2 suggests that there is insulin resistance also at the glucagon-producing pancreatic islet alpha cells. However, the molecular mechanism of alpha cell insulin resistance is unknown. Therefore, the effect of molecules implicated in conferring insulin resistance in some other tissues was investigated on insulin-induced inhibition of glucagon gene transcription in alpha cells. Methods Reporter gene assays and biochemical techniques were used in the glucagon-producing hamster pancreatic islet alpha cell line InR1-G9.Results From among 16 agents tested, chronic insulin treatment was found to abolish insulin-induced inhibition of glucagon gene transcription. Overproduction of constitutively active protein kinase B (PKB) still inhibited glucagon gene transcription after chronic insulin treatment; together with a markedly reduced insulin-induced phosphorylation and, thus, activation of PKB, this indicates that targets upstream of PKB within the insulin signalling pathway are affected. Indeed, chronic insulin treatment markedly reduced IRS-1 phosphorylation, insulin receptor (IR) autophosphorylation and IR content. Cycloheximide and in vivo labelling experiments attributed IR downregulation to enhanced degradation. Conclusions/interpretation These results show that an extended exposure of alpha cells to insulin induces IR downregulation and loss of insulin-induced inhibition of glucagon gene transcription. They suggest that hyperinsulinaemia, through IR downregulation, may confer insulin resistance to pancreatic islet alpha cells in diabetes mellitus type 2.

Leptin downregulates expression of the gene encoding glucagon in alphaTC1-9 cells and mouse islets

“…Our results show that glucagon is another target gene downregulated by leptin. This is consistent with the suppressive effect of other cytokines on glucagon gene expression [35]. Additionally, we also showed that STAT3 is involved in the leptin regulation of glucagon mRNA levels.…”

Insulin Signaling in α Cells Modulates Glucagon Secretion In Vivo

“…The alterations in glucagon gene expression in the αIRKO islets exposed to different concentrations of glucose indicates a regulatory role for insulin signaling in α-cells at the level of transcription consistent with previous studies (Gonzalez et al, 2008; Philippe, 1989). Since glucose is an important physiological suppressor of glucagon secretion in vivo (Gromada et al, 2007) the paradoxical stimulation of glucagon secretion by high glucose (Salehi et al, 2006) has led to the suggestion that additional modulator(s) exist for glucagon suppression in vivo .…”

Podocyte GSK3α is important for autophagy and its loss detrimental for glomerular function

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