Limits...
FoxO6 integrates insulin signaling with gluconeogenesis in the liver.

Kim DH, Perdomo G, Zhang T, Slusher S, Lee S, Phillips BE, Fan Y, Giannoukakis N, Gramignoli R, Strom S, Ringquist S, Dong HH - Diabetes (2011)

Bottom Line: This effect stems from inept insulin suppression of hepatic gluconeogenesis.FoxO6 stimulates gluconeogenesis, which is counteracted by insulin.Insulin inhibits FoxO6 activity via a distinct mechanism by inducing its phosphorylation and disabling its transcriptional activity, without altering its subcellular distribution in hepatocytes.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. dongh@pitt.edu

ABSTRACT

Objective: Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. This effect stems from inept insulin suppression of hepatic gluconeogenesis. To understand the underlying mechanisms, we studied the ability of forkhead box O6 (FoxO6) to mediate insulin action on hepatic gluconeogenesis and its contribution to glucose metabolism.

Research design and methods: We characterized FoxO6 in glucose metabolism in cultured hepatocytes and in rodent models of dietary obesity, insulin resistance, or insulin-deficient diabetes. We determined the effect of FoxO6 on hepatic gluconeogenesis in genetically modified mice with FoxO6 gain- versus loss-of-function and in diabetic db/db mice with selective FoxO6 ablation in the liver.

Results: FoxO6 integrates insulin signaling to hepatic gluconeogenesis. In mice, elevated FoxO6 activity in the liver augments gluconeogenesis, raising fasting blood glucose levels, and hepatic FoxO6 depletion suppresses gluconeogenesis, resulting in fasting hypoglycemia. FoxO6 stimulates gluconeogenesis, which is counteracted by insulin. Insulin inhibits FoxO6 activity via a distinct mechanism by inducing its phosphorylation and disabling its transcriptional activity, without altering its subcellular distribution in hepatocytes. FoxO6 becomes deregulated in the insulin-resistant liver, accounting for its unbridled activity in promoting gluconeogenesis and correlating with the pathogenesis of fasting hyperglycemia in diabetes. These metabolic abnormalities, along with fasting hyperglycemia, are reversible by selective inhibition of hepatic FoxO6 activity in diabetic mice.

Conclusions: Our data uncover a FoxO6-dependent pathway by which the liver orchestrates insulin regulation of gluconeogenesis, providing the proof-of-concept that selective FoxO6 inhibition is beneficial for curbing excessive hepatic glucose production and improving glycemic control in diabetes.

Show MeSH

Related in: MedlinePlus

Beneficial effect of FoxO6 inhibition on glucose metabolism in diabetes. Diabetic male db/db mice (aged 12 weeks) were stratified by body weight and fasting blood glucose levels and randomly assigned to two groups (n = 7), which were treated with 1.5 × 1011 plaque forming units of FoxO6-siRNA or Sc-siRNA control vector. One group of male age-matched heterozygous db/+ littermates (n = 8) was used as a normal control. A: Blood glucose levels. B: Plasma insulin levels. After 5 days of vector administration, mice were fasted for 16 h, followed by the determination of blood glucose and plasma insulin levels. C: Blood glucose profiles in response to glucose tolerance test (GTT). After a 16-h fast, mice were injected with glucose (3 g/kg i.p.), followed by the determination of blood glucose levels. Data were obtained from day 5, and similar results were reproduced at day 10 after vector administration. D: Blood glucose profiles in response to insulin tolerance test (ITT). Mice were injected with insulin (2 IU/kg i.p.) at day 10 after vector administration, followed by determination of blood glucose levels. E: Hepatic G6Pase activity. F: Hepatic G6Pase mRNA levels. G: Hepatic PEPCK mRNA levels. H: Hepatic FoxO6 mRNA levels. I: Hepatic FoxO1 mRNA levels. J: Body weight. Mice were killed at day 12 after vector administration, and liver tissues were collected for the determination of hepatic G6Pase activity and hepatic mRNA levels corresponding to G6Pase, PEPCK, FoxO6, and FoxO1 by real-time quantitative RT-PCR assay using β-actin mRNA as control. *P < 0.05 and **P < 0.005 vs. control by ANOVA; NS, not significant.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3198083&req=5

Figure 8: Beneficial effect of FoxO6 inhibition on glucose metabolism in diabetes. Diabetic male db/db mice (aged 12 weeks) were stratified by body weight and fasting blood glucose levels and randomly assigned to two groups (n = 7), which were treated with 1.5 × 1011 plaque forming units of FoxO6-siRNA or Sc-siRNA control vector. One group of male age-matched heterozygous db/+ littermates (n = 8) was used as a normal control. A: Blood glucose levels. B: Plasma insulin levels. After 5 days of vector administration, mice were fasted for 16 h, followed by the determination of blood glucose and plasma insulin levels. C: Blood glucose profiles in response to glucose tolerance test (GTT). After a 16-h fast, mice were injected with glucose (3 g/kg i.p.), followed by the determination of blood glucose levels. Data were obtained from day 5, and similar results were reproduced at day 10 after vector administration. D: Blood glucose profiles in response to insulin tolerance test (ITT). Mice were injected with insulin (2 IU/kg i.p.) at day 10 after vector administration, followed by determination of blood glucose levels. E: Hepatic G6Pase activity. F: Hepatic G6Pase mRNA levels. G: Hepatic PEPCK mRNA levels. H: Hepatic FoxO6 mRNA levels. I: Hepatic FoxO1 mRNA levels. J: Body weight. Mice were killed at day 12 after vector administration, and liver tissues were collected for the determination of hepatic G6Pase activity and hepatic mRNA levels corresponding to G6Pase, PEPCK, FoxO6, and FoxO1 by real-time quantitative RT-PCR assay using β-actin mRNA as control. *P < 0.05 and **P < 0.005 vs. control by ANOVA; NS, not significant.

Mentions: To test this hypothesis, we stratified diabetic db/db mice by body weight and fasting blood glucose levels into two groups, which were treated with FoxO6-siRNA or scrambled Sc-siRNA vector. Compared with age- and sex-matched heterozygous db/+ littermates (n = 8), diabetic db/db mice (n = 7) exhibited fasting hyperglycemia (Fig. 8A) and hyperinsulinemia (Fig. 8B), accompanied by glucose intolerance (Fig. 8C). These metabolic abnormalities were significantly improved in FoxO6-siRNA vector-treated db/db mice (n = 7) (Fig. 8A–C). Furthermore, db/db mice in the FoxO6-siRNA groups displayed significantly improved blood glucose profiles in response to insulin tolerance (Fig. 8D).


FoxO6 integrates insulin signaling with gluconeogenesis in the liver.

Kim DH, Perdomo G, Zhang T, Slusher S, Lee S, Phillips BE, Fan Y, Giannoukakis N, Gramignoli R, Strom S, Ringquist S, Dong HH - Diabetes (2011)

Beneficial effect of FoxO6 inhibition on glucose metabolism in diabetes. Diabetic male db/db mice (aged 12 weeks) were stratified by body weight and fasting blood glucose levels and randomly assigned to two groups (n = 7), which were treated with 1.5 × 1011 plaque forming units of FoxO6-siRNA or Sc-siRNA control vector. One group of male age-matched heterozygous db/+ littermates (n = 8) was used as a normal control. A: Blood glucose levels. B: Plasma insulin levels. After 5 days of vector administration, mice were fasted for 16 h, followed by the determination of blood glucose and plasma insulin levels. C: Blood glucose profiles in response to glucose tolerance test (GTT). After a 16-h fast, mice were injected with glucose (3 g/kg i.p.), followed by the determination of blood glucose levels. Data were obtained from day 5, and similar results were reproduced at day 10 after vector administration. D: Blood glucose profiles in response to insulin tolerance test (ITT). Mice were injected with insulin (2 IU/kg i.p.) at day 10 after vector administration, followed by determination of blood glucose levels. E: Hepatic G6Pase activity. F: Hepatic G6Pase mRNA levels. G: Hepatic PEPCK mRNA levels. H: Hepatic FoxO6 mRNA levels. I: Hepatic FoxO1 mRNA levels. J: Body weight. Mice were killed at day 12 after vector administration, and liver tissues were collected for the determination of hepatic G6Pase activity and hepatic mRNA levels corresponding to G6Pase, PEPCK, FoxO6, and FoxO1 by real-time quantitative RT-PCR assay using β-actin mRNA as control. *P < 0.05 and **P < 0.005 vs. control by ANOVA; NS, not significant.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198083&req=5

Figure 8: Beneficial effect of FoxO6 inhibition on glucose metabolism in diabetes. Diabetic male db/db mice (aged 12 weeks) were stratified by body weight and fasting blood glucose levels and randomly assigned to two groups (n = 7), which were treated with 1.5 × 1011 plaque forming units of FoxO6-siRNA or Sc-siRNA control vector. One group of male age-matched heterozygous db/+ littermates (n = 8) was used as a normal control. A: Blood glucose levels. B: Plasma insulin levels. After 5 days of vector administration, mice were fasted for 16 h, followed by the determination of blood glucose and plasma insulin levels. C: Blood glucose profiles in response to glucose tolerance test (GTT). After a 16-h fast, mice were injected with glucose (3 g/kg i.p.), followed by the determination of blood glucose levels. Data were obtained from day 5, and similar results were reproduced at day 10 after vector administration. D: Blood glucose profiles in response to insulin tolerance test (ITT). Mice were injected with insulin (2 IU/kg i.p.) at day 10 after vector administration, followed by determination of blood glucose levels. E: Hepatic G6Pase activity. F: Hepatic G6Pase mRNA levels. G: Hepatic PEPCK mRNA levels. H: Hepatic FoxO6 mRNA levels. I: Hepatic FoxO1 mRNA levels. J: Body weight. Mice were killed at day 12 after vector administration, and liver tissues were collected for the determination of hepatic G6Pase activity and hepatic mRNA levels corresponding to G6Pase, PEPCK, FoxO6, and FoxO1 by real-time quantitative RT-PCR assay using β-actin mRNA as control. *P < 0.05 and **P < 0.005 vs. control by ANOVA; NS, not significant.
Mentions: To test this hypothesis, we stratified diabetic db/db mice by body weight and fasting blood glucose levels into two groups, which were treated with FoxO6-siRNA or scrambled Sc-siRNA vector. Compared with age- and sex-matched heterozygous db/+ littermates (n = 8), diabetic db/db mice (n = 7) exhibited fasting hyperglycemia (Fig. 8A) and hyperinsulinemia (Fig. 8B), accompanied by glucose intolerance (Fig. 8C). These metabolic abnormalities were significantly improved in FoxO6-siRNA vector-treated db/db mice (n = 7) (Fig. 8A–C). Furthermore, db/db mice in the FoxO6-siRNA groups displayed significantly improved blood glucose profiles in response to insulin tolerance (Fig. 8D).

Bottom Line: This effect stems from inept insulin suppression of hepatic gluconeogenesis.FoxO6 stimulates gluconeogenesis, which is counteracted by insulin.Insulin inhibits FoxO6 activity via a distinct mechanism by inducing its phosphorylation and disabling its transcriptional activity, without altering its subcellular distribution in hepatocytes.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. dongh@pitt.edu

ABSTRACT

Objective: Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. This effect stems from inept insulin suppression of hepatic gluconeogenesis. To understand the underlying mechanisms, we studied the ability of forkhead box O6 (FoxO6) to mediate insulin action on hepatic gluconeogenesis and its contribution to glucose metabolism.

Research design and methods: We characterized FoxO6 in glucose metabolism in cultured hepatocytes and in rodent models of dietary obesity, insulin resistance, or insulin-deficient diabetes. We determined the effect of FoxO6 on hepatic gluconeogenesis in genetically modified mice with FoxO6 gain- versus loss-of-function and in diabetic db/db mice with selective FoxO6 ablation in the liver.

Results: FoxO6 integrates insulin signaling to hepatic gluconeogenesis. In mice, elevated FoxO6 activity in the liver augments gluconeogenesis, raising fasting blood glucose levels, and hepatic FoxO6 depletion suppresses gluconeogenesis, resulting in fasting hypoglycemia. FoxO6 stimulates gluconeogenesis, which is counteracted by insulin. Insulin inhibits FoxO6 activity via a distinct mechanism by inducing its phosphorylation and disabling its transcriptional activity, without altering its subcellular distribution in hepatocytes. FoxO6 becomes deregulated in the insulin-resistant liver, accounting for its unbridled activity in promoting gluconeogenesis and correlating with the pathogenesis of fasting hyperglycemia in diabetes. These metabolic abnormalities, along with fasting hyperglycemia, are reversible by selective inhibition of hepatic FoxO6 activity in diabetic mice.

Conclusions: Our data uncover a FoxO6-dependent pathway by which the liver orchestrates insulin regulation of gluconeogenesis, providing the proof-of-concept that selective FoxO6 inhibition is beneficial for curbing excessive hepatic glucose production and improving glycemic control in diabetes.

Show MeSH
Related in: MedlinePlus