CIDeRplusGeneral Information:
| Id: | 6,393 |
| Diseases: |
Diabetes mellitus, type II
- [OMIM]
Insulin resistance |
| Mus musculus | |
| article | |
| Reference: | Mutel E et al.(2011) Control of blood glucose in the absence of hepatic glucose production during prolonged fasting in mice: induction of renal and intestinal gluconeogenesis by glucagon Diabetes 60: 3121-3131 [PMID: 22013018] |
Interaction Information:
| Comment | Since the pioneering work of Claude Bernard, the scientific community has considered the liver to be the major source of endogenous glucose production in all postabsorptive situations. Nevertheless, the kidneys and intestine can also produce glucose in blood, particularly during fasting and under protein feeding. The aim of this study was to better define the importance of the three gluconeogenic organs in glucose homeostasis. G6Pase activity was disrupted specifically in the liver by temporal and tissue-specific deletion of the G6pc gene based on a CRE-lox strategy. These mice are unable to mobilize their glycogen stocks during fasting. Consistent with the role of hepatic glycogenolysis as an important pathway of glucose production in the early postabsorptive state, EGP levels were found to be lower in 6 h‚Äďfasted L-G6pc -/- animals than in control animals. This was correlated with a lower blood glucose in 6 h‚Äďfasted L-G6pc-/- mice. |
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Formal Description Interaction-ID: 60242 |
gene/protein affects_activity of process endogenous glucose production |
| Comment | Since the pioneering work of Claude Bernard, the scientific community has considered the liver to be the major source of endogenous glucose production in all postabsorptive situations. Nevertheless, the kidneys and intestine can also produce glucose in blood, particularly during fasting and under protein feeding. The aim of this study was to better define the importance of the three gluconeogenic organs in glucose homeostasis. G6Pase activity was disrupted specifically in the liver by temporal and tissue-specific deletion of the G6pc gene based on a CRE-lox strategy. These mice are unable to mobilize their glycogen stocks during fasting. Consistent with the role of hepatic glycogenolysis as an important pathway of glucose production in the early postabsorptive state, EGP levels were found to be lower in 6 h‚Äďfasted L-G6pc -/- animals than in control animals. This was correlated with a lower blood glucose in 6 h‚Äďfasted L-G6pc-/- mice. |
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Formal Description Interaction-ID: 60553 |
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| Comment | Concomitant with this drop in blood glucose observed at 6 h fasting, ketogenesis was rapidly induced in L-G6pc-/- animals. At 6 h fasting, the amounts of ketone bodies (beta-hydroxybutyrate) in L-G6pc-/- mice were fivefold greater compared with the control mice that were able to produce high levels of glucose by inducing glycogenolysis. These results were accounted for by fast induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (Hmgcs2) expression in 6 h-fasted L-G6pc-/- mice. It is important to recall here that ketone bodies provide an alternative form of cellular energy fuel in postabsorptive situations characterized by low glucose availability. This is true notably for the brain, which may derive up to 70% of its energy from ketone bodies, and for the kidney and intestine, the two alternative gluconeogenic organs, which derive 50% of their energy from ketone bodies in postabsorptive state. It therefore seems unlikely that L-G6pc-/- mice lacked energy fuels for these essential organs. |
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Formal Description Interaction-ID: 60554 |
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| Comment | Concomitant with this drop in blood glucose observed at 6 h fasting, ketogenesis was rapidly induced in L-G6pc-/- animals. At 6 h fasting, the amounts of ketone bodies (beta-hydroxybutyrate) in L-G6pc-/- mice were fivefold greater compared with the control mice that were able to produce high levels of glucose by inducing glycogenolysis. These results were accounted for by fast induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (Hmgcs2) expression in 6 h-fasted L-G6pc-/- mice. It is important to recall here that ketone bodies provide an alternative form of cellular energy fuel in postabsorptive situations characterized by low glucose availability. This is true notably for the brain, which may derive up to 70% of its energy from ketone bodies, and for the kidney and intestine, the two alternative gluconeogenic organs, which derive 50% of their energy from ketone bodies in postabsorptive state. It therefore seems unlikely that L-G6pc-/- mice lacked energy fuels for these essential organs. |
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Formal Description Interaction-ID: 60557 |
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| Comment | Concomitant with this drop in blood glucose observed at 6 h fasting, ketogenesis was rapidly induced in L-G6pc-/- animals. At 6 h fasting, the amounts of ketone bodies (beta-hydroxybutyrate) in L-G6pc-/- mice were fivefold greater compared with the control mice that were able to produce high levels of glucose by inducing glycogenolysis. These results were accounted for by fast induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (Hmgcs2) expression in 6 h-fasted L-G6pc-/- mice. It is important to recall here that ketone bodies provide an alternative form of cellular energy fuel in postabsorptive situations characterized by low glucose availability. This is true notably for the brain, which may derive up to 70% of its energy from ketone bodies, and for the kidney and intestine, the two alternative gluconeogenic organs, which derive 50% of their energy from ketone bodies in postabsorptive state. It therefore seems unlikely that L-G6pc-/- mice lacked energy fuels for these essential organs. |
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Formal Description Interaction-ID: 60558 |
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| Comment | The study assessed the expression of gluconeogenic genes in the kidneys and intestine of fed animals. Renal G6pc mRNA levels of fed L-G6pc-/- mice were about 1.7-fold higher than those in control mice. This was associated with an increase in renal G6PC protein. Specific G6Pase activity in the kidney was 40% higher in L-G6pc-/- than in control mice. On the contrary, renal Pck1 expression and PEPCK activity were not modified. In the fed state, no modification of G6PC and PEPCK-c expression was observed in the intestine of L-G6pc-/- compared with control mice. Thus, only G6Pase was upregulated in the kidneys of L-G6pc-/- mice in the fed state, reflecting constitutive induction of the gluconeogenic pathway in the kidneys of L-G6pc-/- compared with WT mice. |
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Formal Description Interaction-ID: 60559 |
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| Comment | The study assessed the expression of gluconeogenic genes in the kidneys and intestine of fed animals. Renal G6pc mRNA levels of fed L-G6pc-/- mice were about 1.7-fold higher than those in control mice. This was associated with an increase in renal G6PC protein. Specific G6Pase activity in the kidney was 40% higher in L-G6pc-/- than in control mice. On the contrary, renal Pck1 expression and PEPCK activity were not modified. In the fed state, no modification of G6PC and PEPCK-c expression was observed in the intestine of L-G6pc-/- compared with control mice. Thus, only G6Pase was upregulated in the kidneys of L-G6pc-/- mice in the fed state, reflecting constitutive induction of the gluconeogenic pathway in the kidneys of L-G6pc-/- compared with WT mice. The results strongly suggested that the L-G6pc-/- mouse rapidly upregulated gluconeogenesis in the kidneys and intestine once food glucose was lacking. |
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Formal Description Interaction-ID: 60560 |
process hepatic glucose production affects_activity of process |
| Comment | After 6 h fasting, the expression of the genes encoding major regulatory enzymes of extrahepatic gluconeogenesis [G6Pase, PEPCK-c, and glutaminase] was dramatically induced in both the kidneys and intestine of L-G6pc-/- mice. In the kidneys, amounts of G6pc mRNA and protein were about twice those in the control, and specific G6Pase activity was 36% higher than in control mice. Renal PEPCK-c expression was increased concomitantly, resulting in a threefold increase of Pck1 mRNA and protein and specific PEPCK-c activity more than twice that of L-G6pc-/- mice. There was also an induction of glutaminase in the kidneys of L-G6pc-/- mice. A similar pattern of induction of gluconeogenic gene expression was observed for the three enzymes in the intestine of L-G6pc-/- mice. Thus, the expression of gluconeogenic genes was rapidly induced in both the kidneys and intestine of L-G6pc-/- mice in post-absorptive state. |
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Formal Description Interaction-ID: 60561 |
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| Drugbank entries | Show/Hide entries for PCK1 |
| Comment | After 6 h fasting, the expression of the genes encoding major regulatory enzymes of extrahepatic gluconeogenesis [G6Pase, PEPCK-c, and glutaminase] was dramatically induced in both the kidneys and intestine of L-G6pc-/- mice. In the kidneys, amounts of G6pc mRNA and protein were about twice those in the control, and specific G6Pase activity was 36% higher than in control mice. Renal PEPCK-c expression was increased concomitantly, resulting in a threefold increase of Pck1 mRNA and protein and specific PEPCK-c activity more than twice that of L-G6pc-/- mice. There was also an induction of glutaminase in the kidneys of L-G6pc-/- mice. A similar pattern of induction of gluconeogenic gene expression was observed for the three enzymes in the intestine of L-G6pc-/- mice. Thus, the expression of gluconeogenic genes was rapidly induced in both the kidneys and intestine of L-G6pc-/- mice in post-absorptive state. |
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Formal Description Interaction-ID: 60562 |
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| Comment | After 6 h fasting, the expression of the genes encoding major regulatory enzymes of extrahepatic gluconeogenesis [G6Pase, PEPCK-c, and glutaminase] was dramatically induced in both the kidneys and intestine of L-G6pc-/- mice. In the kidneys, amounts of G6pc mRNA and protein were about twice those in the control, and specific G6Pase activity was 36% higher than in control mice. Renal PEPCK-c expression was increased concomitantly, resulting in a threefold increase of Pck1 mRNA and protein and specific PEPCK-c activity more than twice that of L-G6pc-/- mice. There was also an induction of glutaminase in the kidneys of L-G6pc-/- mice. A similar pattern of induction of gluconeogenic gene expression was observed for the three enzymes in the intestine of L-G6pc-/- mice. Thus, the expression of gluconeogenic genes was rapidly induced in both the kidneys and intestine of L-G6pc-/- mice in post-absorptive state. |
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Formal Description Interaction-ID: 60563 |
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| Drugbank entries | Show/Hide entries for GLS |
| Comment | After 6 h fasting, the expression of the genes encoding major regulatory enzymes of extrahepatic gluconeogenesis [G6Pase, PEPCK-c, and glutaminase] was dramatically induced in both the kidneys and intestine of L-G6pc-/- mice. In the kidneys, amounts of G6pc mRNA and protein were about twice those in the control, and specific G6Pase activity was 36% higher than in control mice. Renal PEPCK-c expression was increased concomitantly, resulting in a threefold increase of Pck1 mRNA and protein and specific PEPCK-c activity more than twice that of L-G6pc-/- mice. There was also an induction of glutaminase in the kidneys of L-G6pc-/- mice. A similar pattern of induction of gluconeogenic gene expression was observed for the three enzymes in the intestine of L-G6pc-/- mice. Thus, the expression of gluconeogenic genes was rapidly induced in both the kidneys and intestine of L-G6pc-/- mice in post-absorptive state. |
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Formal Description Interaction-ID: 60564 |
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| Drugbank entries | Show/Hide entries for GLS2 |
| Comment | In mammals, sophisticated hormonal control by insulin, glucagon, glucocorticoids, and cathecholamines maintains blood glucose within narrow limits, orchestrating the uptake and production of glucose. In both the fed state and after 6 h fasting, glucagon levels were higher in L-G6pc-/- mice than in control mice. On the contrary, L-G6pc-/- mice exhibited a lower insulin level than that of control mice after 6 h fasting, but were not hypoinsulinemic in fed state. Corticosterone levels were markedly increased in L-G6pc-/- mice compared with the control mice after 6 h fasting, but not in the fed state. However, the epinephrine and norepinephrine plasma concentrations were similar in both L-G6pc-/- and control mice. This is in agreement with the observation that a hypoglycemic state around 60 mg/dL is mild and does not represent a stressed condition from the metabolic viewpoint, especially in the light of the concomitant increased availability of ketone bodies. |
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Formal Description Interaction-ID: 60566 |
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| Comment | In mammals, sophisticated hormonal control by insulin, glucagon, glucocorticoids, and cathecholamines maintains blood glucose within narrow limits, orchestrating the uptake and production of glucose. In both the fed state and after 6 h fasting, glucagon levels were higher in L-G6pc-/- mice than in control mice. On the contrary, L-G6pc-/- mice exhibited a lower insulin level than that of control mice after 6 h fasting, but were not hypoinsulinemic in fed state. Corticosterone levels were markedly increased in L-G6pc-/- mice compared with the control mice after 6 h fasting, but not in the fed state. However, the epinephrine and norepinephrine plasma concentrations were similar in both L-G6pc-/- and control mice. This is in agreement with the observation that a hypoglycemic state around 60 mg/dL is mild and does not represent a stressed condition from the metabolic viewpoint, especially in the light of the concomitant increased availability of ketone bodies. |
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Formal Description Interaction-ID: 60567 |
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| Comment | In mammals, sophisticated hormonal control by insulin, glucagon, glucocorticoids, and cathecholamines maintains blood glucose within narrow limits, orchestrating the uptake and production of glucose. In both the fed state and after 6 h fasting, glucagon levels were higher in L-G6pc-/- mice than in control mice. On the contrary, L-G6pc-/- mice exhibited a lower insulin level than that of control mice after 6 h fasting, but were not hypoinsulinemic in fed state. Corticosterone levels were markedly increased in L-G6pc-/- mice compared with the control mice after 6 h fasting, but not in the fed state. However, the epinephrine and norepinephrine plasma concentrations were similar in both L-G6pc-/- and control mice. This is in agreement with the observation that a hypoglycemic state around 60 mg/dL is mild and does not represent a stressed condition from the metabolic viewpoint, especially in the light of the concomitant increased availability of ketone bodies. |
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Formal Description Interaction-ID: 60568 |
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| Comment | In mammals, sophisticated hormonal control by insulin, glucagon, glucocorticoids, and cathecholamines maintains blood glucose within narrow limits, orchestrating the uptake and production of glucose. In both the fed state and after 6 h fasting, glucagon levels were higher in L-G6pc-/- mice than in control mice. On the contrary, L-G6pc-/- mice exhibited a lower insulin level than that of control mice after 6 h fasting, but were not hypoinsulinemic in fed state. Corticosterone levels were markedly increased in L-G6pc-/- mice compared with the control mice after 6 h fasting, but not in the fed state. However, the epinephrine and norepinephrine plasma concentrations were similar in both L-G6pc-/- and control mice. This is in agreement with the observation that a hypoglycemic state around 60 mg/dL is mild and does not represent a stressed condition from the metabolic viewpoint, especially in the light of the concomitant increased availability of ketone bodies. |
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Formal Description Interaction-ID: 60569 |
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| Comment | In mammals, sophisticated hormonal control by insulin, glucagon, glucocorticoids, and cathecholamines maintains blood glucose within narrow limits, orchestrating the uptake and production of glucose. In both the fed state and after 6 h fasting, glucagon levels were higher in L-G6pc-/- mice than in control mice. On the contrary, L-G6pc-/- mice exhibited a lower insulin level than that of control mice after 6 h fasting, but were not hypoinsulinemic in fed state. Corticosterone levels were markedly increased in L-G6pc-/- mice compared with the control mice after 6 h fasting, but not in the fed state. However, the epinephrine and norepinephrine plasma concentrations were similar in both L-G6pc-/- and control mice. This is in agreement with the observation that a hypoglycemic state around 60 mg/dL is mild and does not represent a stressed condition from the metabolic viewpoint, especially in the light of the concomitant increased availability of ketone bodies. |
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Formal Description Interaction-ID: 60570 |
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| Comment | The study shows that the absence of hepatic glucose release had no major effect on the control of fasting plasma glucose concentration. Instead, compensatory induction of gluconeogenesis occurred in the kidneys and intestine, driven by glucagon, glucocorticoids, and acidosis. Moreover, the extrahepatic action of glucagon took place in wild-type mice. The study provides a definitive quantitative estimate of the capacity of extrahepatic gluconeogenesis to sustain fasting endogenous glucose production under the control of glucagon, regardless of the contribution of the liver. |
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Formal Description Interaction-ID: 60572 |
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