How the body produces glucose via gluconeogenesis during ketosis | Dominic D'Agostino
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Ketosis, whether induced by fasting or by following a ketogenic diet, is associated with a reduction in dietary glucose. The body has elegant mechanisms that allow it to utilize non-carbohydrate substrates to generate glucose. Gluconeogenesis is a metabolic pathway in which the liver produces glucose from non-carbohydrate substrates including glucogenic amino acids (from protein) and glycerol (from lipids). In athletes, skeletal muscle is constantly being remodeled and may serve as a source of glucogenic amino acids. In this clip, Dr. Dominic D'Agostino describes how gluconeogenesis fills an important role during ketosis to maintain a basal level of glucose.
Rhonda: You mentioned when you were talking about gluconeogenesis, you triggered something in my mind. I wanted to ask you, I forgot. So when you're in nutritional ketosis or fasting-induced ketosis, you need to make glucose you still need glucose, your red blood cells have no mitochondria and your red blood cells are important, right? So you're making glucose through this process that you mentioned called gluconeogenesis.
Dom: Glucose does not bottom out. It's not like one or the other. You're pulling fuel source from...
Rhonda: So I wanted to ask you about, like, how... Has anyone looked at where...so if you are on a pretty strict ketogenic diet or whatever it is you're doing to get into ketosis, what...so does the liver use, like, glycerol, lactate, like, both as a primary source to make glucose? Is that glucose predominantly going to red blood cells or does it go has that been looked at to see, like, where, you know...? So red blood cells, like, are they getting enough of their glucose or they, you know?
Dom: I think so. I mean, you'd probably have to severely calorie restrict. In those cases, you could become anemic or impair...your immune system is also, too, highly dependent to some extent on glucose and glutamate. So, yeah, you have lactate, you have the glycerol backbone, the fats...
Rhonda: But they always have mitochondria.
Dom: Yes, yes. So glycerol backbone of fatty acids or of triglycerides, for sure, lactate, yes, and amino acids, gluconeogenic amino acids in your diet also are a source of glucose. So gluconeogenic amino acids in your skeletal muscle your muscles constantly breaking down or remodeling especially in athletes. So they're all sources.
The contribution of each of these gluconeogenic sources in each individual probably varies tremendously, but I would say that... So glucose is always going to be there, and the body ensures through very powerful homeostatic mechanisms that your glucose is going to stay, rarely go below three, maybe 2.5 millimolar, mine will drop two, go to four and stay within a very tight range, but what does change considerably from a glucose regulation standpoint is the insulin.
Insulin bottoms out to the point where I've seen enough blood work to show that in many cases, insulin and IGF-1 is below the reference range. So insulin signaling goes down. So if insulin's down, all those insulin pathways that you see on your flowcharts are all going to be suppressed and IGF-1, obviously, it's going to be lower and I think that's a really important consideration to factor in as it relates to cancer therapeutics, cancer biology, cancer prevention, even. But also from the perspective of muscle metabolism. And I think by keeping insulin signaling sort of low, you upregulate factors that make you more responsive to insulin. So I think, and ketones can kind of compensate for a deficiency in insulin, and that was, a lot of the reviews by Richard Veech talked about that.
And the ketones themselves are anti-catabolic for protein sparing. So if you're in a state of ketosis, you're protecting gluconeogenic amino acids and skeletal muscle from being degraded. So you are as a metabolic fuel, but you're also, there's evidence that you're inhibiting proteolytic enzymes and pathways that would otherwise be chewing up your muscle tissue over time.
Rhonda: That's super-cool.
Dom: So it's anti-catabolic, yeah, so ketones are anti-catabolic in that part.
Rhonda: So then you're probably not using, I mean, the gluconeogenic amino acids as much...
Dom: From skeletal muscle, yeah, not as much. So the idea is that you want to keep pumping in the fat, too, if you're on a ketogenic diet. If it's not sufficient with ample amounts of fat, you're probably much more catabolic. So you want to ensure that you're using the fatty acids, go to the mitochondria that uses fuel, they keep the mitochondria happy as do the ketones. Then the glycerol is kind of,shuttled and it's a very nice kind of an elegant pathway to ensure that we have that flux of glucose for vital functions like the red blood cells and making...there's an number of neurotransmitters and hormones that require a baseline level of insulin or glucose to be used.
The practice of long-term restriction of dietary intake, typically characterized by a 20 to 50 percent reduction in energy intake below habitual levels. Caloric restriction has been shown to extend lifespan and delay the onset of age-related chronic diseases in a variety of species, including rats, mice, fish, flies, worms, and yeast.
Referring to the set of metabolic pathways that break down molecules (such as polysaccharides, lipids, nucleic acids, and proteins) into smaller units to be oxidized to release energy or used in other anabolic reactions.
Any of a group of complex proteins or conjugated proteins that are produced by living cells and act as catalyst in specific biochemical reactions.
A molecule composed of carboxylic acid with a long hydrocarbon chain that is either saturated or unsaturated. Fatty acids are important components of cell membranes and are key sources of fuel because they yield large quantities of ATP when metabolized. Most cells can use either glucose or fatty acids for this purpose.
A metabolic pathway in which the liver produces glucose from non-carbohydrate substrates including glycogenic amino acids (from protein) and glycerol (from lipids).
An amino acid found in high concentration in every part of the body. In the nervous system, glutamate is by a wide margin the most abundant neurotransmitter in humans. It is used by every major excitatory information-transmitting pathway in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain.
A sugar-alcohol compound that is the backbone of the triglycerides.
A peptide hormone secreted by the beta cells of the pancreatic islets cells. Insulin maintains normal blood glucose levels by facilitating the uptake of glucose into cells; regulating carbohydrate, lipid, and protein metabolism; and promoting cell division and growth. Insulin resistance, a characteristic of type 2 diabetes, is a condition in which normal insulin levels do not produce a biological response, which can lead to high blood glucose levels.
A diet that causes the body to oxidize fat to produce ketones for energy. A ketogenic diet is low in carbohydrates and high in proteins and fats. For many years, the ketogenic diet has been used in the clinical setting to reduce seizures in children. It is currently being investigated for the treatment of traumatic brain injury, Alzheimer's disease, weight loss, and cancer.
Lactate is thought to participate in a sort of "lactate shuttle" where, after being produced in muscle from exercise, it is transported in to tissues like the heart, and brain, where it is used as an energy source. Lactate is one of many molecules that falls under a loose group of molecules referred to as exerkines, a broad group of exercise-induced hormonal-like factors. Evidence suggests that lactate is the preferred fuel of the brain. Additionally, rodent studies suggest that lactate mediates some of the benefits of exercise on learning and memory via inducing neuronal brain-derived neurotrophic factor (BDNF) expression.[1] In clinical studies, lactate shows promise as a treatment for inflammatory conditions including traumatic brain injury and as a means to deliver fuel to working muscles.
- ^ Helge, Jørn Wulff; Moritz, Thomas; Morville, Thomas; Clemmensen, Christoffer; Dela, Flemming (2020). Plasma Metabolome Profiling Of Resistance Exercise And Endurance Exercise In Humans Cell Reports 33, 13.
The thousands of biochemical processes that run all of the various cellular processes that produce energy. Since energy generation is so fundamental to all other processes, in some cases the word metabolism may refer more broadly to the sum of all chemical reactions in the cell.
Tiny organelles inside cells that produce energy in the presence of oxygen. Mitochondria are referred to as the "powerhouses of the cell" because of their role in the production of ATP (adenosine triphosphate). Mitochondria are continuously undergoing a process of self-renewal known as mitophagy in order to repair damage that occurs during their energy-generating activities.
A molecule composed of a glycerol molecule bound to three fatty acids. Triglycerides are the primary component of very-low-density lipoproteins (VLDL). They serve as a source of energy. Triglycerides are metabolized in the intestine, absorbed by intestinal cells, and combined with cholesterol and proteins to form chylomicrons, which are transported in lymph to the bloodstream.
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