Foxa2 regulates multiple pathways of insulin secretion
Kristen A. Lantz, Marko Z. Vatamaniuk, John E. Brestelli, Joshua R. Friedman, Franz M. Matschinsky, Klaus H. Kaestner
Kristen A. Lantz, Marko Z. Vatamaniuk, John E. Brestelli, Joshua R. Friedman, Franz M. Matschinsky, Klaus H. Kaestner
View: Text | PDF
Article Metabolism

Foxa2 regulates multiple pathways of insulin secretion

Abstract

The regulation of insulin secretion by pancreatic β cells is perturbed in several diseases, including adult-onset (type 2) diabetes and persistent hyperinsulinemic hypoglycemia of infancy (PHHI). The first mouse model for PHHI has a conditional deletion of the gene encoding the winged-helix transcription factor Foxa2 (Forkhead box a2, formerly Hepatocyte nuclear factor 3β) in pancreatic β cells. Using isolated islets, we found that Foxa2 deficiency resulted in excessive insulin release in response to amino acids and complete loss of glucose-stimulated insulin secretion. Most PHHI cases are associated with mutations in SUR1 (Sulfonylurea receptor 1) or KIR6.2 (Inward rectifier K+ channel member 6.2), which encode the subunits of the ATP-sensitive K+ channel, and RNA in situ hybridization of mutant mouse islets revealed that expression of both genes is Foxa2 dependent. We utilized expression profiling to identify additional targets of Foxa2. Strikingly, one of these genes, Hadhsc, encodes short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase, deficiency of which has been shown to cause PHHI in humans. Hadhsc is a direct target of Foxa2, as demonstrated by cotransfection as well as in vivo chromatin immunoprecipitation experiments using isolated islets. Thus, we have established Foxa2 as an essential activator of genes that function in multiple pathways governing insulin secretion.

Authors

Kristen A. Lantz, Marko Z. Vatamaniuk, John E. Brestelli, Joshua R. Friedman, Franz M. Matschinsky, Klaus H. Kaestner

×

Figure 3

Options: View larger image (or click on image) Download as PowerPoint
Foxa2loxP/loxP;Ins.Cre islets exhibit misregulated hormone secretion in ...
Foxa2loxP/loxP;Ins.Cre islets exhibit misregulated hormone secretion in response to glucose and amino acids. (A) Control islets (filled symbols) immediately secrete insulin in response to 25 mM glucose but do not respond to amino acids alone. In contrast, Foxa2loxP/loxP;Ins.Cre islets (open symbols) secrete insulin in a dose-dependent manner upon exposure to increasing concentrations of a mixture of all 20 amino acids (0.55 mM/min for 30 minutes up to 17 mM) followed by 20 minutes at 17 mM, with no additional response to 25 mM glucose. Data shown are mean ± SEM of 2 identical experiments. Similar responses were seen in 8 additional trials (data not shown). (B) Control islets do not respond to amino acid stimulation, but 300 nM glyburide closes KATP channels and leads to insulin secretion. As in A, Foxa2loxP/loxP;Ins.Cre islets respond to the identical amino acid ramp, but glyburide has no additional effect. Trace shown is representative of 2 similar experiments. (C) Control islets secrete glucagon in response to low concentrations of an amino acid ramp (0.55 mM/min for 30 minutes up to 17 mM), but Foxa2loxP/loxP;Ins.Cre islets do not. While the amino acid concentration is held constant at 17 mM, additional exposure to 25 mM glucose for 20 minutes has no effect on secretion from either control or mutant islets. Mean ± SEM of two identical experiments is shown. Downward arrows indicate times of reagent administration.