TGF-β1/Smad3 Pathway Targets PP2A-AMPK-FoxO1 Signaling to Regulate Hepatic Gluconeogenesis

Maintenance of glucose homeostasis is essential for normal physiology. Deviation from normal glucose levels, in either direction, increases susceptibility to serious medical complications such as hypoglycemia and diabetes. Maintenance of glucose homeostasis is achieved via functional interactions among various organs: liver, skeletal muscle, adipose tissue, brain, and the endocrine pancreas. The liver is the primary site of endogenous glucose production, especially during states of prolonged fasting. However, enhanced gluconeogenesis is also a signature feature of type 2 diabetes (T2D). Thus, elucidating the signaling pathways that regulate hepatic gluconeogenesis would allow better insight into the process of normal endogenous glucose production as well as how this process is impaired in T2D. Here we demonstrate that the TGF-β1/Smad3 signaling pathway promotes hepatic gluconeogenesis, both upon prolonged fasting and during T2D. In contrast, genetic and pharmacological inhibition of TGF-β1/Smad3 signals suppressed endogenous glucose production. TGF-β1 and Smad3 signals achieved this effect via the targeting of key regulators of hepatic gluconeogenesis, protein phosphatase 2A (PP2A), AMP-activated protein kinase (AMPK), and FoxO1 proteins. Specifically, TGF-β1 signaling suppressed the LKB1-AMPK axis, thereby facilitating the nuclear translocation of FoxO1 and activation of key gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. These findings underscore an important role of TGF-β1/Smad3 signaling in hepatic gluconeogenesis, both in normal physiology and in the pathophysiology of metabolic diseases such as diabetes, and are thus of significant medical relevance.

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Acute inhibition of lipolysis does not affect postprandial suppression of endogenous glucose production

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00195.2005 ◽

2005 ◽

Vol 289 (6) ◽

pp. E941-E947 ◽

Cited By ~ 9

Author(s):

Peter E. Carey ◽

Jean Gerrard ◽

Gary W. Cline ◽

Chiara Dalla Man ◽

Philip T. English ◽

...

Keyword(s):

Fatty Acids ◽

Glucose Homeostasis ◽

Plasma Glucose ◽

Peak Plasma ◽

Serum Insulin ◽

Glucose Production ◽

Significant Negative Correlation ◽

Endogenous Glucose Production ◽

Liver Fat ◽

Endogenous Glucose

To test the hypothesis that intrahepatic availability of fatty acid could modify the rate of suppression of endogenous glucose production (EGP), acipimox or placebo was administered before and during a test meal. We used a modified isotopic methodology to measure EGP in 11 healthy subjects, and 1H magnetic resonance spectroscopic measurement of hepatic triglyceride stores was also undertaken. Acipimox suppressed plasma free fatty acids markedly before the meal (0.05 ± 0.01 mmol/l at −10 min, P = 0) and throughout the postprandial period (0.03 ± 0.01 mmol/l at 150 min). Mean peak plasma glucose was significantly lower after the meal on acipimox days (8.9 ± 0.4 vs. 10.1 ± 0.5 mmol/l, P < 0.01), as was mean peak serum insulin (653.1 ± 99.9 vs. 909 ± 118 pmol/l, P < 0.01). Fasting EGP was similar (11.15 ± 0.58 μmol·kg−1·min−1 placebo vs. 11.17 ± 0.89 mg·kg−1·min−1 acipimox). The rate of suppression of EGP after the meal was almost identical on the 2 test days (4.36 ± 1.52 vs. 3.69 ± 1.21 μmol·kg−1·min−1 at 40 min). There was a significant negative correlation between the acipimox-induced decrease in peak plasma glucose and liver triglyceride content ( r = −0.827, P = 0.002), suggesting that, when levels of liver fat were low, inhibition of lipolysis was able to affect glucose homeostasis. Acute pharmacological sequestration of fatty acids in triglyceride stores improves postprandial glucose homeostasis without effect on the immediate postprandial suppression of EGP.

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Protein Feeding Promotes Redistribution of Endogenous Glucose Production to the Kidney and Potentiates Its Suppression by Insulin

Endocrinology ◽

10.1210/en.2008-0601 ◽

2009 ◽

Vol 150 (2) ◽

pp. 616-624 ◽

Cited By ~ 48

Author(s):

Bruno Pillot ◽

Maud Soty ◽

Amandine Gautier-Stein ◽

Carine Zitoun ◽

Gilles Mithieux

Keyword(s):

Insulin Sensitivity ◽

Glucose Uptake ◽

Phosphoenolpyruvate Carboxykinase ◽

Glucose Production ◽

Glycogen Storage ◽

Endogenous Glucose Production ◽

Diabetic Patients ◽

Type 2 Diabetic Patients ◽

Protein Feeding ◽

Endogenous Glucose

The aim of this study was to assess in rats the effect of protein feeding on the: 1) distribution of endogenous glucose production (EGP) among gluconeogenic organs, and 2) repercussion on the insulin sensitivity of glucose metabolism. We used gene expression analyses, a combination of glucose tracer dilution and arteriovenous balance to quantify specific organ release, and hyperinsulinemic euglycemic clamps to assess EGP and glucose uptake. Protein feeding promoted a dramatic induction of the main regulatory gluconeogenic genes (glucose-6 phosphatase and phosphoenolpyruvate carboxykinase) in the kidney, but not in the liver. As a consequence, the kidney glucose release was markedly increased, compared with rats fed a normal starch diet. Protein feeding ameliorated the suppression of EGP by insulin and the sparing of glycogen storage in the liver but had no effect on glucose uptake. Combined with the previously reported induction of gluconeogenesis in the small intestine, the present work strongly suggests that a redistribution of glucose production among gluconeogenic organs might occur upon protein feeding. This phenomenon is in keeping with the improvement of insulin sensitivity of EGP, most likely involving the hepatic site. These data shed a new light on the improvement of glucose tolerance, previously observed upon increasing the amount of protein in the diet, in type 2 diabetic patients. Protein feeding increases kidney gluconeogenesis without increasing global endogenous glucose production, and improves insulin suppression of the latter, likely at the hepatic site.

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