Gluconeogenesis: Does Too Much Protein Convert to Sugar?

In nutrition, few topics stir as much curiosity and debate as the impact of dietary protein on blood sugar regulation and gluconeogenesis, or GNG. Keto dieters, fitness enthusiasts, and health-conscious individuals everywhere are trying to solve the seemingly mysterious underpinnings of protein metabolism and its influence on our metabolic health. Here, we’ll try to get to the root of it all, upend a few myths, and get you eating what your body needs to optimize your overall health.

QUICK REFERENCE

• The Inputs of Gluconeogenesis
• Dissecting Misconceptions
• Role of Protein in Gluconeogenesis
• Gaining a Better Understanding of the Relevance of Dietary Protein
• A Gluconeogenesis/Ketogenesis Recap
• A Challenge to Conventional Beliefs
• What Contributes to this Context?
• The Insulin-to-Glucagon Ratio
• So, Should You Worry About Gluconeogenesis?
• Put It Into Practice
• Discussion

The Inputs of Gluconeogenesis

Proteins are essential macronutrients composed of amino acids, which serve as building blocks for various bodily functions, including tissue repair and hormone synthesis. Blood sugar, or glucose, is the primary fuel source for the body's cells, and its regulation is tightly controlled by two hormones produced by the pancreas: insulin and glucagon. (1)

Blood sugar levels, or blood glucose levels, refer to the concentration of glucose present in the bloodstream. Maintaining blood sugar levels within a narrow range is crucial for overall health and well-being. When blood sugar levels are too high (hyperglycemia) or too low (hypoglycemia), it can lead to adverse health effects and complications. (2)

In healthy individuals, blood sugar levels are tightly regulated through a complex interplay of insulin and glucagon. Insulin helps lower blood sugar levels by facilitating glucose uptake into cells and promoting its storage as glycogen in the liver and muscles. Glucagon opposes insulin by stimulating the release of glucose from glycogen stores when blood sugar levels are low.

Factors such as diet, physical activity, stress, menstrual cycle, medications, and underlying health conditions can all influence blood sugar levels. Monitoring blood sugar levels regularly is a cornerstone for individuals with diabetes or other metabolic disorders (3). It is essential to manage these conditions and reduce the risk of complications. But even in healthy bodies, maintaining stable blood sugar levels is vital for supporting energy metabolism, cognitive function, and overall health.

As a super simple overview to start this deep dive, when you hear the word gluconeogenesis (GNG), you should think that it’s a metabolic pathway that allows the body to produce glucose from non-carbohydrate sources, such as amino acids (the building blocks of proteins), lactate, and glycerol. This process primarily occurs in the liver and, to a lesser extent, in the kidneys, serving as a vital mechanism for maintaining blood sugar levels during fasting or low-carb intake periods.

The debate surrounding gluconeogenesis centers on whether individuals should be concerned about its health implications, particularly its role in blood sugar and insulin regulation.

Dissecting Misconceptions

So, what does the Internet have to say about it? Well, as it turns out, quite a lot! Before we get heavy with the facts, let's address some common concerns and assumptions. Many worry that consuming excess protein might lead to undesirable outcomes, such as elevated blood sugar levels or increased fat storage. An article titled Diet Review: Ketogenic Diet for Weight Loss published on the Harvard T.H. Chan School of Public Health’s site states (4):

“Generally, popular ketogenic resources suggest an average of 70-80% fat from total daily calories, 5-10% carbohydrate, and 10-20% protein. For a 2000-calorie diet, this translates to about 165 grams fat, 40 grams carbohydrate, and 75 grams protein. The protein amount on the ketogenic diet is kept moderate in comparison with other low-carb, high-protein diets because eating too much protein can prevent ketosis. The amino acids in protein can be converted to glucose, so a ketogenic diet specifies enough protein to preserve lean body mass, including muscle, but that will still cause ketosis.”

This view of protein consumption is reiterated, discussed, and questioned board after board on various keto forums (Reddit or otherwise). I will use this thread from r/keto to illustrate how the protein debate often plays out and continuously ends without clarity. (5) The question is asked:

“How much protein is too much protein?”

And responses range from something like this:

“There are two points. Proteins are broken down to amino acids during digestion, to be used wherever proteins need to be synthesized. Excess amino acids cannot be stored. They get processed by the liver to make glucose. Secondly, there is some literature linking excessive protein intake to increased cancer risk. In general, 20-25% is considered a limit for an average person (that is 100-125 grams for a 2000 calorie diet.)” (6)

To the practical, yet perhaps not incredibly informed, response:

“When you have a hard time taking a poop. (lol jk)”
We’ll assume this user is saying, go wild on protein—no holds barred—until your bowels invariably decide you’ve had too much.

But after reading a wildly wide range of reactions across the Internet, I feel like many fellow keto dieters and others paying attention to nutrition will align with this middle-of-the-road (and very relatable) response:

“I've never had it effectively explained to me what happens to excess protein.
I doubt the body is so inefficient as to excrete it as waste.
I don't believe 100 grams of unused protein just floats around in our blood.
Not sure it can be converted to fat without first being converted to glucose?
Either way, taking things to excess is what got me fat in the first place, so I am wary of just going crazy on protein.I have felt the best on keto and maintained muscle eating in an 80–120 g per day window.”

This response effectively sums up that the topic breeds general confusion and uncertainty. The responder is approaching it from their context, and rightly so.

They have highlighted reasonable worries, and their response says it right from the start: the conversation seems to lack an ‘effective explanation,’ or at least one that’s easy to onboard.

Going into the scientific literature or reading about intricate biochemical processes like protein metabolism can be intimidating. Contrary to the beliefs of some, protein does not, under typical physiological circumstances, directly convert to glucose in large quantities. Instead, it undergoes gluconeogenesis. But the question remains: should we be worried about GNG? Let’s see if we can offer a simplification that will help you figure it all out once and for all!

Role of Protein in Gluconeogenesis

When we eat a hamburger or a hearty bacon and eggs breakfast, the protein provides the body with essential and non-essential amino acids necessary for various physiological processes. Certain amino acids, often considered gluconeogenic, can be converted into glucose precursors during gluconeogenesis.

In times of carbohydrate scarcity, like when the body is fasting, or someone is following a keto diet, the body relies on gluconeogenesis to maintain glucose levels for vital functions such as brain function and red blood cell metabolism. This process involves the conversion of amino acids into intermediates of the glycolytic pathway, ultimately leading to glucose synthesis.

While gluconeogenesis plays a crucial role in glucose homeostasis, excessive protein consumption can lead to elevated blood sugar and insulin levels, particularly in individuals with insulin resistance or metabolic disorders.

Gaining a Better Understanding of the Relevance of Dietary Protein

Even though these short synopses can help us lay the framework, these explanations always seem somewhat lacking, like they hang out on the surface but don’t get you (or any of us) to that Aha! Moment. In my search for a solid explanation of what’s going on with protein metabolism, Dr. Benjamin Bikman hits the nail on the head with his talk, titled ‘Insulin vs. Glucagon: The Relevance of Dietary Protein,’ published on Low Carb Down Under. (7, 8) If you can spare 36 minutes of your time, it is well worth the watch, and as the comments suggest, many viewers have given it multiple watches to let the information sink in. So, I will use this as a solid starting point to go deeper and get to the real meat of the matter.

Let’s head back to the beta and alpha cells in the pancreas, where we find the two hormones vital to these metabolic processes: insulin and glucagon. Understanding the intricate balance and antagonistic relationship between the two is essential.

Insulin promotes anabolism (“feeding and storage”), facilitating glycolysis and glucose uptake into cells, driving muscle synthesis and glycogenesis, and converting glucose into glycogen for storage in the liver and muscles. Additionally, insulin’s promotion of glycolysis and inhibition of gluconeogenesis lowers blood sugar levels.

Glucagon, in contrast, serves a catabolic function (“fasting and burning”), breaking down complex molecules into energy sources like glucose and ketones and promoting lipolysis, the breakdown of fats into fatty acids and glycerol for energy production. While glucagon generally increases blood sugar levels by promoting the release of glucose from glycogen stores in the liver (glycogenolysis) and stimulating gluconeogenesis, other factors that operate independently of glucagon are typically more influential on blood sugar levels.

This interplay, or antagonism, is particularly evident in muscle, adipose (fat) tissue, and the liver, where each hormone exerts distinct effects. Insulin's dominance in promoting anabolism is evident in muscle tissue, and adipocytes demonstrate a greater insulin sensitivity than glucagon. Conversely, glucagon's influence prevails in the liver, orchestrating processes geared towards energy mobilization and alternative fuel production, including gluconeogenesis and ketogenesis. (9)

A Gluconeogenesis/Ketogenesis Recap

Remember, carbs are the primary fuel for energy generation in the body's tissues. If carb consumption is limited to fewer than 50 grams per day, there is a significant drop in insulin secretion, causing the body to enter a catabolic state. Glycogen reserves are exhausted, leading to a sequence of metabolic changes. When carbs are scarce in the body's tissues, two critical metabolic processes occur: gluconeogenesis and ketogenesis. (10)

During GNG, the liver manufactures glucose to maintain blood sugar homeostasis. When glucose availability drops, endogenous glucose breakdown cannot generate enough ATP, so the metabolic pathway changes to ketogenesis to create ketone bodies. In this state, ketones fuel the body instead of glucose.

During ketogenesis, insulin secretion is low due to feedback from blood glucose levels, leading to decreased fat and glucose storage stimulation. Ketones accumulate in the body and provide energy during a metabolic state called "nutritional ketosis." As long as carbs are scarce, metabolism remains ketotic.

A Challenge to Conventional Beliefs

The interplay of macronutrients—carbohydrates, proteins, and fats—significantly modulates insulin and glucagon levels. Here’s a pictorial overview of the conventional belief:

During his lecture, Bikman challenges the conventional belief that protein consumption simultaneously increases insulin and glucagon. While carbs consistently raise insulin and decrease glucagon, the impact of protein is context-based, meaning that the insulinogenic effect is heavily influenced by an individual’s underlying glycemic status.

He points to a canine experiment investigating the body’s response to alanine, a gluconeogenic amino acid, under two. (11) There were significant increases in insulin levels in the presence of elevated glucose levels. However, in a fasted state where glucose levels were not elevated, insulin levels remained unchanged while glucagon levels doubled. This study illustrates the critical role of context, emphasizing the need to reconsider the oversimplified view of proteins' effects on insulin and glucagon secretion, especially in the context of metabolic health and disease prevention. This understanding points to a model that looks more like this:

Moreover, the study's findings underscore the intricate balance between insulin and glucagon to maintain normal glycemia, particularly during fasting. Without elevated glucose levels, the body prioritizes maintaining gluconeogenesis, a process crucial for sustaining blood glucose levels and preventing hypoglycemia. (12) And because of that? You guessed it. Insulin secretion remains unchanged, while glucagon levels increase to facilitate gluconeogenesis.

Understanding this dynamic relationship between macronutrients and hormonal responses can optimize our diets and nutritional interventions to promote metabolic health and prevent chronic diseases associated with dysregulated insulin and glucagon signaling.

What Contributes to this Context?

Underlying glycemic status refers to an individual's overall condition regarding blood sugar levels and glucose metabolism. It encompasses factors such as fasting blood sugar levels, postprandial (after-meal) glucose response, insulin sensitivity, and the presence or absence of conditions like prediabetes or diabetes. Understanding a person's underlying glycemic status is crucial for understanding what protein metabolism looks like for them, assessing their risk of developing metabolic disorders, and guiding appropriate nutritional interventions to maintain optimal blood sugar control. (13)

So, what other key factors contribute to a person's underlying glycemic status?

• Dietary habits
• Physical activity
• Current body weight and composition
• Belly fat
• Muscle mass
• Genetics
• Stress and sleep
• Medication use
• Hormonal imbalances (including cortisol) (14)
• Medical conditions (like polycystic ovarian syndrome) (15)
• Aging

The Insulin-to-Glucagon Ratio

If you’re still following along, great! The time has come for an in-depth analysis of the insulin-to-glucagon ratio. This refers to the balance between the levels of insulin and glucagon hormones in the bloodstream. This ratio is a crucial determinant of metabolic tone, reflecting whether anabolic (building) or catabolic (breakdown) processes predominate in the body.

A high insulin-to-glucagon ratio signifies anabolic pathways are favored, promoting processes like glycogen synthesis and fat storage. In contrast, a low ratio indicates a catabolic state, prompting actions like gluconeogenesis and lipolysis to release stored energy. This ratio regulates metabolic responses to dietary intake and fasting, influencing overall metabolic health and energy balance.

Let’s explore the variations in insulin-to-glucagon ratios (using Bikman’s numbers) across different dietary states to shed some light on their metabolic implications. (7) During fasting, a low insulin-to-glucagon ratio of around 0.8 indicates a state where catabolic processes like ketogenesis and gluconeogenesis predominate. This means that catabolic processes like ketogenesis and gluconeogenesis take over.

On the other hand, people who eat the Standard American Diet (SAD) have a high insulin-to-glucagon ratio of about 4. This means that they are in an anabolic state, which means they are storing fat and glucose while stopping processes like autophagy, cellular cleaning, and ketogenesis.

On the other hand, those adhering to a low-carb diet maintain a relatively lower insulin-to-glucagon ratio of around 1.3, akin to the fasted state, suggesting continued catabolic processes despite food intake.

What happens to the insulin-to-glucagon ratio when protein is introduced into each dietary state? In the fasted state, protein consumption lowers the ratio further, maintaining the catabolic state. In marked contrast, individuals eating the standard American diet experience a substantial increase in the ratio, demonstrating a heightened insulin response exacerbated by protein intake. However, in the low-carb diet context, the insulin-to-glucagon ratio remains relatively stable, showcasing minimal impact from protein consumption and indicating a unique metabolic response influenced by carbohydrate availability.

This nuanced understanding also highlights the role of hormonal balance in orchestrating metabolic responses, mainly when keeping context in mind. Maintaining a favorable insulin-to-glucagon ratio, like during fasting or when following a low-carb diet, confers profound metabolic benefits over the typically carb-heavy SAD. Here, SAD accentuates insulin secretion, compounded by protein consumption. At the same time, a low-carb diet maintains a more balanced hormonal profile and does not induce a similar, nor substantial, change in insulin secretion. As one commenter beneath Bikman’s video said, “So this is fascinating; if I understand correctly, in a fasted state, protein will increase blood glucose but NOT insulin relative to glucagon!”

The metabolic advantages of a low-carbohydrate diet, which mirrors aspects of the fasted state without necessitating complete food deprivation, include improved insulin sensitivity and activation of autophagy and mitophagy processes, enhanced lipolysis, and activation of brown adipose tissue (16). These metabolic adaptations, driven by hormonal signaling, contribute to metabolic flexibility and may confer various health benefits.

So, Should You Worry About Gluconeogenesis?

Considering that context is crucial, each person must understand how gluconeogenesis functions within the specific context of their body and diet, considering all the factors that impact their metabolic health.

In the initial stages of transitioning to a ketogenic diet, gluconeogenesis may increase as the body adapts to lower carbohydrate availability. (17) This can lead to temporary fluctuations in blood sugar levels and may impact ketone production and ketosis. Consuming adequate protein is essential for supporting muscle mass and metabolic function, but excessive protein intake may lead to gluconeogenesis and potential metabolic imbalances. However, gluconeogenesis typically decreases as the body adapts to using fat and ketones for energy, and blood sugar and ketone levels stabilize.

Put It Into Practice

Now, let’s use an example to see how a prediabetic, overweight individual might approach a low-carb diet while being mindful of their context. This individual must consider gluconeogenesis concerns regarding their overall metabolic health and weight management goals.

While gluconeogenesis may occur to some extent during ketosis, it does not necessarily hinder weight loss or metabolic improvements in most cases. The keto diet is effective for weight loss and improving many individuals' metabolic markers, such as insulin sensitivity and blood lipid levels.

It would be necessary for this individual to focus on fundamental principles, including:
Proper macronutrient balance: To take one last thing from Bikman, let’s employ his alliterative model that says:

1. Control Carbohydrate: Aim for low (or even very low) daily carb counts, between 20-50g per day, according to their needs.
2. Prioritize Protein: Prioritize high-quality proteins while moderating intake, considering that protein quantity can influence the degree of ketosis. During a transitional period, gluconeogenic amino acids can stimulate insulin secretion, potentially reducing ketone production in the liver.
3. Fill with Fats: Fill all remaining calories with fats, not just old fats. Choose monounsaturated or saturated fats over polyunsaturated fatty acids because the liver more readily converts them into ketone bodies.

Take an individualized approach: Monitor blood sugar, ketone levels, and overall health markers to assess the ketogenic diet's impact on gluconeogenesis and metabolic health. (18)

Consider lifestyle factors: Incorporate regular physical activity, stress management, and adequate sleep to support overall metabolic health and weight management efforts. (19)

Find support: Seek guidance from a functional practitioner experienced with ketogenic diets to address any concerns and tailor dietary and lifestyle recommendations to individual needs.

Gluconeogenesis is essential for maintaining blood sugar levels and supporting energy production, but excessive protein consumption can affect blood sugar and insulin regulation. Gaining a better understanding of the role of GNG in metabolic health can help you make informed dietary choices and manage blood sugar levels effectively. Understanding your current context and state of health is crucial to balancing protein intake with carbohydrate and fat consumption to optimize metabolic function and reduce your risk of metabolic disorders.

Sources:

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