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Molecular characterization of insulin-mediated suppression of hepatic glucose production in vivo.

Ramnanan CJ, Edgerton DS, Rivera N, Irimia-Dominguez J, Farmer B, Neal DW, Lautz M, Donahue EP, Meyer CM, Roach PJ, Cherrington AD - Diabetes (2010)

Bottom Line: Insulin-mediated suppression of hepatic glucose production (HGP) is associated with sensitive intracellular signaling and molecular inhibition of gluconeogenic (GNG) enzyme mRNA expression.Net GNG flux was restored to basal by 4 h, despite a substantial reduction in PEPCK protein, as gluconeogenically-derived carbon was redirected from lactate efflux to glycogen deposition.In response to acute physiologic hyperinsulinemia, 1) HGP is suppressed primarily through modulation of glycogen metabolism; 2) a transient reduction in net GNG flux occurs and is explained by increased glycolysis resulting from increased F2,6P(2) and decreased fat oxidation; and 3) net GNG flux is not ultimately inhibited by the rise in insulin, despite eventual reduction in PEPCK protein, supporting the concept that PEPCK has poor control strength over the gluconeogenic pathway in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. chris.ramnanan@vanderbilt.edu

ABSTRACT

Objective: Insulin-mediated suppression of hepatic glucose production (HGP) is associated with sensitive intracellular signaling and molecular inhibition of gluconeogenic (GNG) enzyme mRNA expression. We determined, for the first time, the time course and relevance (to metabolic flux) of these molecular events during physiological hyperinsulinemia in vivo in a large animal model.

Research design and methods: 24 h fasted dogs were infused with somatostatin, while insulin (basal or 8 x basal) and glucagon (basal) were replaced intraportally. Euglycemia was maintained and glucose metabolism was assessed using tracer, (2)H(2)O, and arterio-venous difference techniques. Studies were terminated at different time points to evaluate insulin signaling and enzyme regulation in the liver.

Results: Hyperinsulinemia reduced HGP due to a rapid transition from net glycogen breakdown to synthesis, which was associated with an increase in glycogen synthase and a decrease in glycogen phosphorylase activity. Thirty minutes of hyperinsulinemia resulted in an increase in phospho-FOXO1, a decrease in GNG enzyme mRNA expression, an increase in F2,6P(2), a decrease in fat oxidation, and a transient decrease in net GNG flux. Net GNG flux was restored to basal by 4 h, despite a substantial reduction in PEPCK protein, as gluconeogenically-derived carbon was redirected from lactate efflux to glycogen deposition.

Conclusions: In response to acute physiologic hyperinsulinemia, 1) HGP is suppressed primarily through modulation of glycogen metabolism; 2) a transient reduction in net GNG flux occurs and is explained by increased glycolysis resulting from increased F2,6P(2) and decreased fat oxidation; and 3) net GNG flux is not ultimately inhibited by the rise in insulin, despite eventual reduction in PEPCK protein, supporting the concept that PEPCK has poor control strength over the gluconeogenic pathway in vivo.

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Arterial blood lactate concentrations (A) and net hepatic lactate uptake (B) in 24 h fasted conscious dogs during the basal (−30 to 0 min) and experimental (0–240 min) periods. Data are means ± SEM; n = 7 in control (CTR) and n = 20 in 8× insulin (8X INS) groups. *P < 0.05 vs. CTR group; †P < 0.05 vs. basal period.
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Figure 3: Arterial blood lactate concentrations (A) and net hepatic lactate uptake (B) in 24 h fasted conscious dogs during the basal (−30 to 0 min) and experimental (0–240 min) periods. Data are means ± SEM; n = 7 in control (CTR) and n = 20 in 8× insulin (8X INS) groups. *P < 0.05 vs. CTR group; †P < 0.05 vs. basal period.

Mentions: In control animals, there was no significant change in arterial blood lactate levels (Fig. 3A) or net hepatic lactate balance (Fig. 3B) over time. Conversely, hyperinsulinemia caused a transient increase in arterial blood lactate levels and a switch from net hepatic lactate uptake to net hepatic lactate output that was evident between 30 and 120 min. By 240 min, net hepatic lactate uptake had returned to baseline rates.


Molecular characterization of insulin-mediated suppression of hepatic glucose production in vivo.

Ramnanan CJ, Edgerton DS, Rivera N, Irimia-Dominguez J, Farmer B, Neal DW, Lautz M, Donahue EP, Meyer CM, Roach PJ, Cherrington AD - Diabetes (2010)

Arterial blood lactate concentrations (A) and net hepatic lactate uptake (B) in 24 h fasted conscious dogs during the basal (−30 to 0 min) and experimental (0–240 min) periods. Data are means ± SEM; n = 7 in control (CTR) and n = 20 in 8× insulin (8X INS) groups. *P < 0.05 vs. CTR group; †P < 0.05 vs. basal period.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2874690&req=5

Figure 3: Arterial blood lactate concentrations (A) and net hepatic lactate uptake (B) in 24 h fasted conscious dogs during the basal (−30 to 0 min) and experimental (0–240 min) periods. Data are means ± SEM; n = 7 in control (CTR) and n = 20 in 8× insulin (8X INS) groups. *P < 0.05 vs. CTR group; †P < 0.05 vs. basal period.
Mentions: In control animals, there was no significant change in arterial blood lactate levels (Fig. 3A) or net hepatic lactate balance (Fig. 3B) over time. Conversely, hyperinsulinemia caused a transient increase in arterial blood lactate levels and a switch from net hepatic lactate uptake to net hepatic lactate output that was evident between 30 and 120 min. By 240 min, net hepatic lactate uptake had returned to baseline rates.

Bottom Line: Insulin-mediated suppression of hepatic glucose production (HGP) is associated with sensitive intracellular signaling and molecular inhibition of gluconeogenic (GNG) enzyme mRNA expression.Net GNG flux was restored to basal by 4 h, despite a substantial reduction in PEPCK protein, as gluconeogenically-derived carbon was redirected from lactate efflux to glycogen deposition.In response to acute physiologic hyperinsulinemia, 1) HGP is suppressed primarily through modulation of glycogen metabolism; 2) a transient reduction in net GNG flux occurs and is explained by increased glycolysis resulting from increased F2,6P(2) and decreased fat oxidation; and 3) net GNG flux is not ultimately inhibited by the rise in insulin, despite eventual reduction in PEPCK protein, supporting the concept that PEPCK has poor control strength over the gluconeogenic pathway in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA. chris.ramnanan@vanderbilt.edu

ABSTRACT

Objective: Insulin-mediated suppression of hepatic glucose production (HGP) is associated with sensitive intracellular signaling and molecular inhibition of gluconeogenic (GNG) enzyme mRNA expression. We determined, for the first time, the time course and relevance (to metabolic flux) of these molecular events during physiological hyperinsulinemia in vivo in a large animal model.

Research design and methods: 24 h fasted dogs were infused with somatostatin, while insulin (basal or 8 x basal) and glucagon (basal) were replaced intraportally. Euglycemia was maintained and glucose metabolism was assessed using tracer, (2)H(2)O, and arterio-venous difference techniques. Studies were terminated at different time points to evaluate insulin signaling and enzyme regulation in the liver.

Results: Hyperinsulinemia reduced HGP due to a rapid transition from net glycogen breakdown to synthesis, which was associated with an increase in glycogen synthase and a decrease in glycogen phosphorylase activity. Thirty minutes of hyperinsulinemia resulted in an increase in phospho-FOXO1, a decrease in GNG enzyme mRNA expression, an increase in F2,6P(2), a decrease in fat oxidation, and a transient decrease in net GNG flux. Net GNG flux was restored to basal by 4 h, despite a substantial reduction in PEPCK protein, as gluconeogenically-derived carbon was redirected from lactate efflux to glycogen deposition.

Conclusions: In response to acute physiologic hyperinsulinemia, 1) HGP is suppressed primarily through modulation of glycogen metabolism; 2) a transient reduction in net GNG flux occurs and is explained by increased glycolysis resulting from increased F2,6P(2) and decreased fat oxidation; and 3) net GNG flux is not ultimately inhibited by the rise in insulin, despite eventual reduction in PEPCK protein, supporting the concept that PEPCK has poor control strength over the gluconeogenic pathway in vivo.

Show MeSH
Related in: MedlinePlus