Synergistic inhibition of hepatic ketogenesis in the presence of insulin and a cAMP antagonist

Olivieri, M C; Botelho, L

doi:10.1016/0006-291x(89)90057-0

Biochemical and Biophysical Research Communications

1989

DOI: 10.1016/0006-291x(89)90057-0

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Synergistic inhibition of hepatic ketogenesis in the presence of insulin and a cAMP antagonist

M C Olivieri¹,

L Botelho²

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Cited by 3 publications

(1 citation statement)

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“…Insulin strongly inhibits ketosis, predominantly by reducing lipolysis in adipocytes and reducing the supply of free fatty acids, the substrate for ketone body production. In addition, insulin may have direct effects at the level of the hepatocyte by lowering intracellular cAMP (21). In contrast, glucagon potently increases cAMP in hepatocytes, a signal that has been tied to both lipid and glucose metabolism (22).…”

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confidence: 99%

The Limited Role of Glucagon for Ketogenesis During Fasting or in Response to SGLT2 Inhibition

et al. 2020

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Glucagon is classically described as a counterregulatory hormone that plays an essential role in the protection against hypoglycemia. In addition to its role in the regulation of glucose metabolism, glucagon has been described to promote ketosis in the fasted state. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are a new class of glucose-lowering drugs that act primarily in the kidney, but some reports have described direct effects of SGLT2i on α-cells to stimulate glucagon secretion. Interestingly, SGLT2 inhibition also results in increased endogenous glucose production and ketone production, features common to glucagon action. Here, we directly test the ketogenic role of glucagon in mice, demonstrating that neither fasting- nor SGLT2i-induced ketosis is altered by interruption of glucagon signaling. Moreover, any effect of glucagon to stimulate ketogenesis is severely limited by its insulinotropic actions. Collectively, our data suggest that fasting-associated ketosis and the ketogenic effects of SGLT2 inhibitors occur almost entirely independent of glucagon.

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confidence: 99%

The Limited Role of Glucagon for Ketogenesis During Fasting or in Response to SGLT2 Inhibition

et al. 2020

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GLP-1 mimetics and diabetic ketoacidosis: possible interactions and clinical consequences

Forouzanmehr,

Hemmati,

Atkin

et al. 2024

Naunyn-Schmiedeberg's Arch Pharmacol

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AMPKα2 regulates fasting-induced hyperketonemia by suppressing SCOT ubiquitination and degradation

Zhang,

Lu,

et al. 2024

Sci Rep

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Ketone bodies serve as an energy source, especially in the absence of carbohydrates or in the extended exercise. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a crucial energy sensor that regulates lipid and glucose metabolism. However, whether AMPK regulates ketone metabolism in whole body is unclear even though AMPK regulates ketogenesis in liver. Prolonged resulted in a significant increase in blood and urine levels of ketone bodies in wild-type (WT) mice. Interestingly, fasting AMPKα2–/– and AMPKα1–/– mice exhibited significantly higher levels of ketone bodies in both blood and urine compared to fasting WT mice. BHB tolerance assays revealed that both AMPKα2–/– and AMPKα1–/– mice exhibited slower ketone consumption compared to WT mice, as indicated by higher blood BHB or urine BHB levels in the AMPKα2–/– and AMPKα1–/– mice even after the peak. Interestingly, fasting AMPKα2–/– and AMPKα1–/– mice exhibited significantly higher levels of ketone bodies in both blood and urine compared to fasting WT mice. . Specifically, AMPKα2ΔMusc mice showed approximately a twofold increase in blood BHB levels, and AMPKα2ΔMyo mice exhibited a 1.5-fold increase compared to their WT littermates after a 48-h fasting. However, blood BHB levels in AMPKα1ΔMusc and AMPKα1ΔMyo mice were as same as in WT mice. Notably, AMPKα2ΔMusc mice demonstrated a slower rate of BHB consumption in the BHB tolerance assay, whereas AMPKα1ΔMusc mice did not show such an effect. Declining rates of body weights and blood glucoses were similar among all the mice. Protein levels of SCOT, the rate-limiting enzyme of ketolysis, decreased in skeletal muscle of AMPKα2–/– mice. Moreover, SCOT protein ubiquitination increased in C2C12 cells either transfected with kinase-dead AMPKα2 or subjected to AMPKα2 inhibition. AMPKα2 physiologically binds and stabilizes SCOT, which is dependent on AMPKα2 activity.

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Synergistic inhibition of hepatic ketogenesis in the presence of insulin and a cAMP antagonist

Cited by 3 publications

References 21 publications

The Limited Role of Glucagon for Ketogenesis During Fasting or in Response to SGLT2 Inhibition

The Limited Role of Glucagon for Ketogenesis During Fasting or in Response to SGLT2 Inhibition

GLP-1 mimetics and diabetic ketoacidosis: possible interactions and clinical consequences

AMPKα2 regulates fasting-induced hyperketonemia by suppressing SCOT ubiquitination and degradation

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