At its most simple, gluconeogenesis is when excess protein, beyond what your body needs for cell growth and repair, converts into glucose. “Gluconeogenesis is a process by which the liver converts non-carbohydrates (fats, amino acids, glycerol, lactic acid, etc.) into glucose. The purpose of this is to regulate your blood sugar.”1 People with an aggressive exercise regimen need more protein than sedentary people.

The liver manufactures new glucose from amino acids in a process called “gluconeogenesis” in 24 hours to 2 days. “Literally, this is translated as ‘making new glucose.’ In non-diabetic persons, glucose levels fall but stay within the normal range.”2

“During gluconeogenesis, the liver (and occasionally the kidneys) turns non-sugar compounds like amino acids (the building blocks of protein), lactate, and glycerol into sugar that the body uses as fuel.”3 Gluconeogenesis (abbreviated GNG) is “a metabolic process of making glucose, a necessary body fuel, from non-carbohydrate sources such as protein (amino acids), lactate from muscle cell energy metabolism, and the glycerol component of fatty acids.”4

A Diapedia entry for “glycolysis and gluconeogenesis” says: “Gluconeogenesis is the reverse [of glycolysis], a metabolic pathway that generates glucose from non-carbohydrate carbon substrates…. Gluconeogenesis (with glycogenolysis) is one of the two main mechanisms which keep blood glucose levels from dropping too low (hypoglycemia). Gluconeogenesis takes place mainly in the liver and, to a lesser extent, in the cortex of kidneys. Gluconeogenesis occurs during fasting, low-carbohydrate intake, or intense exercise, often in association with ketosis.”5

“Glycolysis and gluconeogenesis refer to the breakdown of glucose and the synthesis of new glucose, respectively. Both are absolutely essential metabolic processes, as the amount of glucose your body consumes in a day is astronomical in molecular terms…. The main difference between glycolysis and gluconeogenesis is in their basic function: one [glycolysis] depletes existing glucose, while the other [gluconeogenesis] replenishes it from both organic (carbon-containing) and inorganic (carbon-free) molecules. This makes glycolysis a catabolic [breaking down of compounds to release energy] process of metabolism, while gluconeogenesis is anabolic [building of compounds, which uses energy].”6

WikiBooks, on “Principles of Biochemistry/Gluconeogenesis and Glycogenesis,” says: “Gluconeogenesis is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In animals, gluconeogenesis takes place mainly in the liver.”7

So, in practical terms, what does this mean? It means we require insulin to metabolize carbohydrate, fat, and protein. Protein has a minimal effect on blood glucose levels with adequate insulin. However, “with insulin deficiency, gluconeogenesis proceeds rapidly and contributes to an elevated blood glucose level.”8 Also, “low insulin will promote gluconeogenesis (breakdown of various substrates to release glucose).”9

Gluconeogenesis is the endogenous production of glucose in the body, especially in the liver, primarily from lactic acid, glycerol, and the amino acids alanine and glutamine. When glucose availability drops further, the endogenous production of glucose cannot keep up with the needs of the body and ketogenesis begins in order to provide an alternate source of energy as ketone bodies. Ketone bodies replace glucose as a primary source of energy. “One diet regimen that has proven to be very effective for rapid weight loss is a very-low-carbohydrate and high-fat ketogenic diet.”10

“Recently, an increasing number of people trying to achieve nutritional ketosis have found that they need to moderate protein in addition to limiting carbohydrates to reduce insulin to the point where significant levels of ketones can be measured in the blood,”11 writes Marty Kendall of Optimising Nutrition in his article, “The Blood Glucose, Glucagon, and Insulin Response to Protein.”

Jimmy Moore sums it up like this:12 “One of the basic tenets of a well-formulated ketogenic diet is the moderation of protein intake to upwards of 15 percent of total caloric intake as a means for reducing the effect of gluconeogenesis that comes from excessive protein beyond what that body needs.”

And Chris MasterJohn, PhD, quips in his article entitled, “We Really Can Make Glucose From Fatty Acids After All! O Textbook, How Thy Biochemistry Hast Deceived Me!”13 “Thus, when insulin levels fall and ketone levels rise, as occurs when our carbohydrate intake is low, our cells increase their supply of CYP2E1 and thereby activate the conversion of fatty acids to glucose…. It is worth noting that when this pathway is activated, we not only convert fatty acids to glucose, but methylglyoxal concentrations rise and inhibit the breakdown of glucose.”

I think I’ll stick to Jimmy Moore’s explanation for the real world!

Endnotes

1Pagano, Mandy. “What is gluconeogenesis?” Ketovangelist, n.d. https://www.ketovangelist.com/what-is-gluconeogenesis/ (accessed on 7/31/2020).

2Fung, Dr. Jason. “Fasting Physiology – Part II,” The Fasting Method, n.d. https://idmprogram.com/fasting-physiology-part-ii/ (accessed on 7/31/2020).

3Clarke, Craig. “What is Gluconeogenesis?” Ruled.me (updated June 2, 2020). https://www.ruled.me/what-is-gluconeogenesis/ (accessed on 7/31/2020).

4Davis, Ellen. “Gluconeogenesis,” Ketogenic Diet Resource, n.d. https://www.ketogenic-diet-resource.com/gluconeogenesis.html (accessed on 7/31/2020).

5“Glycolysis and gluconeogenesis,” Diapedia, n.d. https://www.diapedia.org/metabolism-insulin-and-other-hormones/51040851107/glycolysis-and-gluconeogenesis (accessed on 2/20/2020).

6Beck, Kevin. “The Difference Between Glycolysis and Gluconeogenesis,” Sciencing (June 4, 2019). https://sciencing.com/difference-between-glycolysis-gluconeogenesis-8711255.html (accessed on 7/31/2020).

7“Principles of Biochemistry/Gluconeogenesis and Glycogenesis,” WikiBooks (February 8, 2019). https://en.wikibooks.org/wiki/Principles_of_Biochemistry/Gluconeogenesis_and_Glycogenesis (accessed on 7/31/2020).

8Franz, M. J. “Protein: metabolism and effect on blood glucose levels,” Diabetes Educ. Nov-Dec 1997; 23(6):643-6, 648, 650-1. doi: 10.1177/014572179702300603. https://www.ncbi.nlm.nih.gov/pubmed/9416027 (accessed on 7/31/2020).

9Mandel, Dr. Ananya, MD; reviewed by April Cashin-Garbutt, MA, Editor. “Diabetes Pathophysiology,” News Medical (February 26, 2019). https://www.news-medical.net/health/Diabetes-Pathophysiology.aspx (accessed on 7/31/2020.

10Masood, Wajeed; Pavan Annamaraju; and Kalyan R. Uppaluri. “Ketogenic Diet,” StatPearls Publishing (June 22, 2020). https://www.ncbi.nlm.nih.gov/books/NBK499830/ (accessed on 7/31/2020).

11Kendall, Marty. “The Blood Glucose, Glucagon and Insulin Response to Protein,” Optimising Nutrition, n.d. https://optimisingnutrition.com/2015/06/15/the-blood-glucose-glucagon-and-insulin-response-to-protein/ (accessed on 7/31/2020).

12Moore, Jimmy. “The Gluconeogenesis Effects of a Low-Carb, High-Protein Diet,” Jimmy Moore’s Livin’ La Vida Low-Carb (April 1, 2018). https://www.facebook.com/livinlowcarbman/posts/title-the-gluconeogenesis-effects-of-a-low-carb-high-protein-dietauthor-moore-ja/10156588170931320/ (accessed on 7/31/2020).

13“We Really Can Make Glucose From Fatty Acids After All! O Textbook, How Thy Biochemistry Hast Deceived Me!” Chris MasterJohn, PhD (January 7, 2012). https://chrismasterjohnphd.com/2012/01/07/we-really-can-make-glucose-from-fatty/ (accessed on 7/31/2020).

Additional Information and References

Gluconeogenesis (abbreviated GNG) is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids…. Gluconeogenesis is one of several main mechanisms used by humans and many other animals to maintain blood glucose levels, avoiding low levels (hypoglycemia).

Reference: Principles of Biochemistry/Gluconeogenesis and Glycogenesis
https://en.wikibooks.org/wiki/Principles_of_Biochemistry/Gluconeogenesis_and_Glycogenesis

So, in practical terms, what does this mean? It means that insulin is required for carbohydrate, fat, and protein to be metabolized. Protein has a minimal effect on blood glucose levels with adequate insulin. However, with insulin deficiency, gluconeogenesis proceeds rapidly and contributes to an elevated blood glucose level.

Reference: Protein: metabolism and effect on blood glucose levels.
https://www.ncbi.nlm.nih.gov/pubmed/9416027

THE BLOOD GLUCOSE, GLUCAGON AND INSULIN RESPONSE TO PROTEIN
Recently, an increasing number of people trying to achieve nutritional ketosis have found that they need to moderate protein in addition to limiting carbohydrates to reduce insulin to the point where significant levels of ketones can be measured in the blood.
https://optimisingnutrition.com/2015/06/15/the-blood-glucose-glucagon-and-insulin-response-to-protein/

Fasting Physiology – Part II
Gluconeogenesis – 24 hours to 2 days – The liver manufactures new glucose from amino acids in a process called “gluconeogenesis.” Literally, this is translated as “making new glucose.” In non-diabetic persons, glucose levels fall but stay within the normal range.
https://idmprogram.com/fasting-physiology-part-ii/

Gluconeogenesis
https://www.ketogenic-diet-resource.com/gluconeogenesis.html

What is gluconeogenesis?
https://www.ketovangelist.com/what-is-gluconeogenesis/

Diabetes Pathophysiology
https://www.news-medical.net/health/Diabetes-Pathophysiology.aspx

Glycolysis and gluconeogenesis
https://www.diapedia.org/metabolism-insulin-and-other-hormones/51040851107/glycolysis-and-gluconeogenesis

Diabetes, Insulin Resistance 
Fructose-Induced Liver Gluconeogenesis Nearly Normalized by L-Carnitine
http://www.life-enhancement.com/magazine/article/2308-diabetes-insulin-resistance

We Really Can Make Glucose From Fatty Acids After All! O Textbook, How Thy Biochemistry Hast Deceived Me!
Thus, when insulin levels fall and ketone levels rise, as occurs when our carbohydrate intake is low, our cells increase their supply of CYP2E1 and thereby activate the conversion of fatty acids to glucose…. it is worth noting that when this pathway is activated, we not only convert fatty acids to glucose, but methylglyoxal concentrations rise and inhibit the breakdown of glucose.
https://chrismasterjohnphd.com/2012/01/07/we-really-can-make-glucose-from-fatty/

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