Everything you didn’t know about Gluconeogenesis

If you’re like a lot of people in the keto community, you’ve heard plenty about gluconeogenesis (GNG). The most common topics of discussion are how too much protein can be detrimental to ketosis because gluconeogenesis will turn it into glucose and stop you from burning fat.

In general, the idea is that GNG is in competition with ketogenesis (KG) for the production of energy. Fat vs. Protein, in a never-ending battle.

What if it wasn’t that way at all? What if GNG was in fact, complementary to KG and enhanced the metabolic efficiency of being in ketosis?

Gluconeogenesis – The Basics

The dictionary definition of GNG is “formation of glucose within the animal body especially by the liver from substances (such as fats and proteins) other than carbohydrate”.

Notice, “such as fats and proteins”? 

Wait!!!! GNG can use fats to create glucose?!?!?!?!

Yes. GNG is not a specific, protein-driven process. It can use other substances to generate energy.

One of the biggest concerns people have with GNG is that protein consumption will increase glucose production. This isn’t true. GNG doesn’t rely on protein and if there are other substances it can use it will use them first. Protein metabolism is energy expensive. Protein is also prioritized for muscle protein synthesis, cellular repair, metabolic function, and a bunch of other, non-energy-related systems in the body. Your body doesn’t want to use protein for fuel unless it absolutely needs to.

GNG is an umbrella term for all of the processes your body uses to produce glucose for energy. 

Yes, there is more than one. 

Gluconeogenesis – A little deeper

There are 4 main substances that are used in GNG. Three of them are byproducts of KG. One is amino acids.

  • Acetate
  • Pyruvate
  • Lactate
  • Glucogenic Amino Acids

There are 2 main cycles of metabolism GNG uses to create glucose from these 4 substances.

Krebs Cycle – Energy production with Oxygen

    • Acetate
    • Pyruvate
      • Pyruvic acid supplies energy to living cells through the Krebs cycle when oxygen is present (aerobic respiration); when oxygen is lacking, it ferments to produce lactic acid (lactate).
    • Glucogenic Amino Acids

Cori Cycle – Energy production without Oxygen

    • Lactate
      • Anaerobic work creates lactate as a byproduct of glycolysis (the breakdown of muscle glycogen). Lactate is re-used in the Cori Cycle to create glucose.
      • Lactate is also a byproduct of the breakdown of Acetone from KG

If GNG can use other substances besides amino acids, where do they come from? 

Acetate, Pyruvate, and Lactate can come from a few different sources. In a fat-adapted person, a lot of it comes from metabolizing fatty acids during ketogenesis.

What is Ketogenesis really?

The dictionary definition of ketogenesis is “the production of ketone bodies.

That’s fairly anti-climatic.  

The three ketone bodies created by KG are:

  • Acetoacetate – It’s the first ketone body and it is broken up into the other two.
  • Β-hydroxybutyrate (BHB) – This is the most abundant ketone body and it is the main source of fuel for the body. (commonly referred to as ketones)
  • Acetone – is not an “active” metabolite it, breaks down into Acetate, Pyruvate, and Lactate.

The major benefits we get from KG are the abundance of BHB for fuel. Reducing carbohydrates as the main source of fuel allows for BHB to take over. KG, by producing and breaking down Acetone, facilitates access to the three metabolites that can be added back into the energy cycles for the creation of glucose.

Ketogenesis and Glucoegenesis work together to provide either source of energy the body needs when it is needed. Being fat-adapted feeds BOTH ketone AND glucose production. GNG is happening all the time. Carbs are more of a risk to being in ketosis than protein will ever be.

It’s not one or the other. GNG doesn’t cancel out ketosis. If you’re fat-adapted and making sure to keep carbs from becoming the dominant source of fuel, then staying in ketosis should never be a problem.

Notes and References

Biochemistry, Ketogenesis

https://www.ncbi.nlm.nih.gov/books/NBK493179/ 

Ketogenesis produces acetone, acetoacetate, and beta-hydroxybutyrate molecules by breaking down fatty acids.

Ketogenesis

https://en.wikipedia.org/wiki/Ketogenesis

Acetone, which is generated through the decarboxylation of acetoacetate, either spontaneously or through the enzyme acetoacetate decarboxylase. It can then be further metabolized either by CYP2E1 into hydroxyacetone (acetol) and then via propylene glycol to pyruvate, lactate and acetate (usable for energy) and propionaldehyde, or via methylglyoxal to pyruvate and lactate.

You Can Get There From Here: Acetone, Anionic Ketones and Even-Carbon Fatty Acids can Provide Substrates for Gluconeogenesis

https://web.archive.org/web/20130926031021/http://www.bioline.org.br/request?np10002

Although the literature contains studies published more than 30 years ago showing that acetone is not metabolically inert, it is common to find biochemistry textbooks and current research publications asserting that acetone is a ‘dead-end’ metabolite. In fact, acetone derived from the non-enzymatic breakdown of acetoacetate in ketotic individuals or from the oxidation of ingested isopropanol can be metabolized to D-lactate and pyruvate, and ultimately glucose. This report describes the reactions and pathways that account for the metabolism of acetone in humans.

Ketogenesis

https://www.sciencedirect.com/topics/medicine-and-dentistry/ketogenesis

Acetate can be utilized by muscle and other peripheral tissues (Pouteau et al., 1996). Complete oxidation of acetate requires thiamin, riboflavin, niacin, pantothenate, lipoate, ubiquinone, iron, and magnesium.

First, free acetate must be conjugated to coenzyme A by acetate-CoA ligase (thiokinase; EC6.2.1.1). Most acetyl-CoA is utilized in mitochondria via the tricarboxylic acid (Krebs) cycle. Citrate synthase (EC4.1.3.7) joins acetyl CoA to oxaloacetate. The citrate from this reaction can then be metabolized further providing FADH, NADH, and succinate for oxidative phosphorylation and ATP or GTP from succinyl CoA.

Pyruvic Acid and Metabolism

https://bio.libretexts.org/Bookshelves/Microbiology/Book%3A_Microbiology_(Boundless)/5%3A_Microbial_Metabolism/5.03%3A_Catabolism/5.3B%3A_Pyruvic_Acid_and_Metabolism

  • Pyruvic acid can be made from glucose through glycolysis, converted back to carbohydrates (such as glucose) via gluconeogenesis, or to fatty acids through acetyl-CoA.
  • Pyruvic acid supplies energy to living cells through the citric acid cycle (also known as the Krebs cycle ) when oxygen is present (aerobic respiration); it ferments to produce lactic acid when oxygen is lacking ( fermentation ).
  • Pyruvate is the output of the anaerobic metabolism of glucose known as glycolysis.
  • Pyruvate can be converted into carbohydrates via gluconeogenesis, to fatty acids or energy through acetyl-CoA, to the amino acid alanine, and to ethanol.

Physiology, Gluconeogenesis

https://www.ncbi.nlm.nih.gov/books/NBK541119/

The major substrates of gluconeogenesis are lactate, glycerol, and glucogenic amino acids.

  • Lactate is a product of anaerobic glycolysis. When oxygen is limited (such as during vigorous exercise or in low perfusion states) cells must perform anaerobic glycolysis to produce ATP. Cells that lack mitochondria (e.g., erythrocytes) cannot perform oxidative phosphorylation, and as a result rely strictly on anaerobic glycolysis to meet energy demands. Lactate generated from anaerobic glycolysis gets shunted to the liver, where it can be converted back to glucose through gluconeogenesis. Glucose gets released into the bloodstream, where it travels back to erythrocytes and exercising the skeletal muscle to be broken down again by anaerobic glycolysis, forming lactate. This process is called the Cori cycle.[2]
  • Glycerol comes from adipose tissue. The breakdown of triacylglycerols in adipose tissue yields free fatty acids and glycerol molecules, the latter of which can circulate freely in the bloodstream until it reaches the liver[3]. Glycerol is then phosphorylated by the hepatic enzyme glycerol kinase to yield glycerol phosphate. Next, the enzyme glycerol phosphate dehydrogenase oxidizes glycerol phosphate to yield dihydroxyacetone phosphate, a glycolytic intermediate.
  • Glucogenic amino acids enter gluconeogenesis via the citric acid cycle. Glucogenic amino acids are catabolized into citric acid cycle metabolites such as alpha-ketoglutarate, succinyl CoA, and fumarate. Through the citric acid cycle, these alpha-ketoacids converts to oxaloacetate, the substrate for the gluconeogenic enzyme PEP carboxykinase.

Additional Resources

The stimulation of hepatic gluconeogenesis by acetoacetate precursors. A role for the monocarboxylate translocator

https://pubmed.ncbi.nlm.nih.gov/6736017/ 

Glucose feeds the TCA cycle via circulating lactate

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898814/ 

Citric Acid cycle (Krebs Cycle)

https://en.wikipedia.org/wiki/Citric_acid_cycle#Glucose_feeds_the_TCA_cycle_via_circulating_lactate 

Which way does the citric acid cycle turn during hypoxia?

http://real.mtak.hu/56447/1/Which_way_does_the_citric_acid_cycle_turn_during_hypoxia_u.pdf

Krebs’ citric acid cycle : half a century and still turning

https://archive.org/details/krebscitricacidc0000unse/page/25/mode/2up

What is Acetoacetate and Why is it Important on Keto?

https://www.ruled.me/what-is-acetoacetate/

Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes

https://pubmed.ncbi.nlm.nih.gov/10634967/

Cori Cycle

https://en.wikipedia.org/wiki/Cori_cycle

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