Introduction: our very own sugar factory
Step into the low-carb world and soon enough you’ll hear the term GlucoNeoGenesis. GNG for short, is your body’s ability to construct glucose, a kind of sugar, out of molecules that aren’t glucose. It does this to ensure that, if you don’t eat any carbs, the cells in your body that need glucose will still get enough of it. It’s one reason why humans are so good at fasting or delaying death from starvation for weeks or months. We can meet our own need for glucose by producing it ourselves.
A quick note on Optimal vs Sufficient…
What do I mean by cells in your body that need glucose? I mean a reliance on glucose to accomplish its basic physiological for a long time. You then might ask, but is there a difference when meeting your glucose needs with GNG versus by eating carbs? Fair question. You could also ask – although no one seems to – is it better to meet your glucose needs through GNG than by eating carbs? Also a fair question I think but one people will most likely scoff at. These questions deserve more space than I’m according them here, so they’ll have to be wrestled with in a follow-up post.
Background: why do we make our own glucose?
As mentioned in the introduction, it helps us handle a lack of calories or carbohydrates – but that can only be because at least some of our cells depend on glucose (or other monosaccharides) to some significant degree.
Most cells in your body do just fine using varying amounts of fatty acids, glucose, amino acids, lactate, ketones etc… However, a few cell types we’ll call obligate glucose users can’t use any other fuel but glucose. Then there are what we’ll call quasi obligate glucose users whose metabolisms are adapted to specialized functions requiring mostly glucose be used.
Obligate glucose users
- Red blood cells 
- Medulla cells of the kidney 
- Activated T-cells of the immune system [3, 4, 5]
- Sertoli cells of the testis 
Glucose fiends (but not obligate users)
- Retinal cells, previously thought of as obligate glucose users, have recently been discovered to use non-trivial amounts of fatty acids too 
- Neurons, now thought to be less dependent on glucose because they can also use considerable amounts of ketones and lactate 
- Fibroblasts, they produce more glucose-rich glycosaminoglycans in a high-glucose (25mM) medium than in a low one (4mM) 
- Smooth muscle cells of your vascular system 
Any old tissue in your body cannot make glucose. The liver, kidney and intestines all contribute more or less to GNG. This depends on whether or not you’re eating and what you’re eating [11, 12]. Hat tip to Raymund Edwards for noting the apportioning of GNG between these organs.
Before we look at 2 competing theories of how GNG works, I want to point out that we know mitochondria to be involved in the process. The pyruvate dehydrogenase complex can bind a mitochondrion and send pyruvate send down the path of providing ATP. Alternatively, pyruvate carboxylase complex can bind a mitochondria and send pyruvate down the path for GNG .
Liver as the metabolic hub theory
The liver is often described as the metabolic hub (or nexus) where decisions to make more or less glucose happen. This is supported by the fact that the pancreas’ beta and alpha-cells release insulin and glucagon, respectively. Insulin brings blood sugar down and glucagon raises it. This insulin-to-glucagon ratio is largely responsible for how much glucose the liver will release.
Tyler Cartwright explains it like this, saying
“So what regulates GNG? The presence of higher amounts of glucagon seems to be sufficient to globally regulate the rate of GNG”
This is illustrated below
In a general sense I think it’s fair to call the liver a metabolic hub, in that it can store glycogen, store fat (although it shouldn’t have to really), as well as make ketones, glucose, cholesterol, phospholipids, fatty acids and triglycerides. If glycogen levels change in your muscles or liver, yes your GNG activity can respond accordingly.
Dr.Fung gives a good conceptual overview of how this liver-centric theory is understood by those who subscribe to it, saying 
the liver lies at the nexus of food energy storage and production
insulin pushes glucose into the liver cell, gradually filling it up
insulin resistance is an overflow phenomenon, where glucose is unable to enter the cell that is already overfilled
It’s well known that insulin resistant people have poor and worsening blood sugar control and that dysregulated GNG is part of that. GNG seems to be how the ‘overflow phenomenon’ in insulin resistance actually manifests; hence why it’s described as a “supply” driven process. And because protein can supply some of the substrate for GNG, protein restriction is often recommended to further lower blood sugars that may persist despite an already low intake of carbohydrates (say <80g/day).
On the other hand, others emphasize that low levels of liver or muscle glycogen can be replenished through GNG, and that this de facto makes it a “demand” driven process (too?).
These examples of GNG occurring from supply or demand driven processes will mean to some people that it is must be a process of both supply and demand, or simply one or the other. I don’t ascribe to any of these conclusions because I think they all confuse a descriptive theory with an explanatory one. The point is moot actually, these are merely smaller components of one mechanism (GNG) feeding into the larger task of energy homeostasis.
Adipose-centric theory (1.0)
I’m biased towards a theory Gabor Erdosi of the Lower Insulin Facebook group brought to my attention. You might call it the adipose-centric theory of….GNG, diabetes, obesity or Metabolic Syndrome (if you’re feeling cocky). The big picture behind this theory of GNG can be thought of as a triangle, starting with fat tissue, then the liver and finally the pancreas. If you remember just one thing about it, it’s that
there’s no gluconeogenesis without lipolysis
Lipolysis happens inside the fat cell (adipocyte) where stored fat (triglyceride) is broken down into its individual components (1 glycerol backbone, 3 fatty acids) for release into the bloodstream.
This theory hinges on a 2-man job: insulin working with adipocytes to manage our largest energy reserves (fat). Much of that management involves carefully buffering substrate delivery to various tissues. Part of how this is accomplished smoothly, involves adipocytes releasing free fatty acids into the bloodstream continuously, sort of in a drip-fed manner. It allows for quick adjustments to be made. Think of how it’s easier to park your car with the engine running during your maneuver rather than having to turn it on and off every time you put shift into reverse. This ‘keeping the fat cycling’ going (the ‘car running’) is called futile cycling. it’s ill-named. It’s ill-named because it’s actually a clever energy saving mechanism, not a random energy wasting one.
Fat cells together and insulin really get around to regulating quite a lot. From this perspective the liver is ‘merely’ carrying out the orders coming from the adipose tissue. GNG is really more of a slave to adipocytes than hepatocytes per se.
The complete quote from the diagram above comes from a paper by Perry et al. (2015) we’ll keep referring to. It actually says
“suppression of hepatic gluconeogenesis could entirely be ascribed to suppression of lipolysis, with 85% of the suppression of HGP [hepatic glucose production] attributed to reduced conversion of oxaloacetate to glucose and the remainder attributed to reduced conversion of glycerol to glucose”
This way of thinking about gluconeogenesis is quite a departure from more popular one contending that it fundamentally results from a handful of inputs with more or less equal contributions. A diagram from University of California San Francisco illustrates this 
As you can see, it all starts from a dual signal in the pancreas whereby insulin secretion is reduced and glucagon secretion is increased. Glucagon acts somewhat top down on the fat and muscle cells to get them to release their glucose precursors for assembly of glucose in the liver. This diagram is not meant to exhaustively show every variable and its network, but it does suggest that if you turned glucagon off, the fat cell couldn’t release it’s glucose precursors (free fatty acids and glycerol).
In both rodents and humans Perry et al. again found that this is not the case [emphasis mine]
“This reduction in HGP [hepatic glucose output] was associated with […] no changes in plasma lactate, glucagon, or liver glycogen concentrations”
Ah, so hepatic glucose output, which for simplicity simply just means GNG, was not reduced by turning the glucagon tap off, nor by the ‘GNG demand’ sent by the liver’s low glycogen levels. The metabolic hub theory would predict that without glucagon there, GNG derived glucose cannot be release by the liver. It’s a failed basic prediction. What actually happens is that
there’s no gluconeogenesis without lipolysis […not glucagon !]
Perry et al., again, illustrate this showing lipolytic activity (=> adipocyte + insulin) acts top down on the liver’s glucose output
So does the adipose theory of GNG completely disregard the energy store signals coming from low glycogen levels in the liver and muscle? No. Low glycogen levels do in fact signal a need for GNG derived glucose to replenish them. But how that actually happens is not a glucagon story but one of insulin acting on the adipocyte (again). Insulin goes up, lipolysis goes down (fat leaving adipocytes). Whether insulin is high or low makes no difference to the absolute rate of primary FFA reesterification (fat entering adipocytes) .
So say the adipocytes start releasing more free fatty acids because there’s less insulin around, maybe because the pancreas secretes less of it in response to low blood glucose. These fatty acids reach the liver where they go through beta-oxidation, contributing to the acetyl-CoA pool. The bigger the pool the more can get pushed through GNG pathways. See the Perry paper for details.
But again, what about other glucose mediators, surely they count for something right? Is it really as straightforward as
insulin => lipolysis => FFAs => liver acetyl-CoA => liver GNG ?
It was in rats at least (still Perry et al. 2015) [emphasis mine]
“Liver concentrations of other putative mediators of gluconeogenesis, including the ratios of ATP to ADP, ATP to AMP, NAD+ to NADH, and four TCA cycle intermediates were also unchanged in high-fat-fed or clamped rats” (Figures S5A–S5G)”
And what about supply side of GNG?
A prediction of the metabolic hub theory would be that if I feed you lots of protein, it’ll just be pushed through to the liver and leave it as glucose for the most part, right? That’s not what happens. Supplying lots of protein does not have the same consequences on postprandial plasma glucose levels as does straight glucose does. The figure below shows that compared to ingesting 80g of glucose, ‘normal’ non-diabetics ingesting 80 or 160g of protein from lean beef, egg whites or casein don’t see raised blood sugar levels. In fact it barely budges from their starting ~ 80 mg/dL .
Glucose is not the whole story
Glucose is indeed an important metabolic substrate reflecting the state of affairs in adipocytes between total primary free fatty acid reesterification and lipolysis, but other substrates, enzymes and TCA cycle intermediates have something to tell us too.
For instance, what does the supply of amino acids do to ketogenesis? More amino acids can increase oxaloacetate and this matters because when the oxaloacetate-to-acetyl-CoA ratio dips under 1 ketogenesis shifts into a higher gear. Said another way 
“free oxaloacetate calculated from the contents of malate and ketone bodies measured in the mitochondrial compartment was found to be correlated in an inverse manner with the rate of ketone body production”
So the less oxaloacetate, the more acetyl-CoA gets diverted away from GNG and more into ketogenesis (amongst other possibilities). Some people see this to mean that ketosis is the direct antithesis of gluconeogenesis. It’s not quite the case, ketone levels and GNG activity have seesaw like relationship, but not a linear one.
Keep in mind that this doesn’t change the fact that GNG itself does not directly hinge on the available supply of amino acids and glucose – lipolysis still reigns. We’re best served not conflating questions of GNG-supply with ketogenesis. Lets keep them separate for now.
Fatty acids push GNG – what else does?
Just to recap, fatty acids push GNG since 1 mole of oxaloacetate (needed for GNG) can be produced from 2 moles of acetyl-CoA (provided by fatty acids). Ketone bodies contribute to GNG too. Acetone can also provide 4 – 11% of GNG derived glucose alone .
Blood glucose regulation really has a lot to do with the integrity of your fat tissue. And the acetyl-CoA content of one’s liver too. This interesting rat study by Perry and Shulman et al. (2007) showed the importance of hepatic acetyl-CoA, saying [emphasis mine]
“It should be noted that all of these studies were performed following a 16-hr overnight fast, which almost totally depletes hepatic glycogen content. Therefore, rates of hepatic glucose production in these studies almost entirely reflect rates of hepatic gluconeogenesis.”
So once again it’s shown that the GNG demand is a secondary signal, one that can increase GNG output but lipolysis can still override it.
Oh and alcohol, the fourth macronutrient, it can also supply GNG substrate. It does that with glycerol. Recall however, that drinking (low sugar/sugar-free) alcohol can actually increase ketogenesis…if you drink just enough. This happens mainly through oxaloacetate depletion, increased NADH/NAD ratio, and ethanol’s release of free fatty acid feeding the pool of hepatic acetyl-CoA .
Insulin doesn’t just act on adipocytes but on the liver too
Insulin communication with the liver. Some studies point to insulin regulating hepatic GNG through 2 pathways, hepatic IR-Akt-Foxo1 (direct) and (absent Foxo1) extra-hepatic insulin-responsive tissue communicates with the liver to regulate glucose output (indirect)… somehow. This is supported by the fact that reducing Foxo1 activity in insulin resistant disorders can have beneficial effects .
Like many processes in the body, GNG receives input from the the hormonal and metabolic levels. This leads to a tendency for theories about such processes to fall into the groove of one or the other. Ultimately it’s our job to reconcile all levels of mechanism.
For more on the metabolic and hormonal mechanisms underlying GNG please take a look at the following references kindly organized by Gabor. Also check out our first podcast where we pick apart the Perry paper I kept referencing.
1993, human study
Demonstration of a critical role for free fatty acids in mediating counterregulatory stimulation of gluconeogenesis and suppression of glucose utilization in humans.
In vitro studies indicate that FFA compete with glucose as an oxidative fuel in muscle and, in addition, stimulate gluconeogenesis in liver. During counterregulation of hypoglycemia, plasma FFA increase and this is associated with an increase in glucose production and a suppression of glucose utilization. To test the hypothesis that FFA mediate changes in glucose metabolism that occur during counterregulation, we examined the effects of acipimox, an inhibitor of lipolysis, on glucose production and utilization ([3-3H]glucose), and incorporation of [U-14C]-alanine into glucose during insulin-induced hypoglycemia.
2000, human study
Effects of free fatty acid elevation on postabsorptive endogenous glucose production and gluconeogenesis in humans.
Effects of free fatty acids (FFAs) on endogenous glucose production (EGP) and gluconeogenesis (GNG) were examined in healthy subjects (n = 6) during stepwise increased Intralipid/heparin infusion (plasma FFAs 0.8+/-0.1, 1.8+/-0.2, and 2.8+/-0.3 mmol/l) and during glycerol infusion (plasma FFAs approximately 0.5 mmol/l). Rates of EGP were determined with D-[6,6-2H2]glucose and contributions of GNG from 2H enrichments in carbons 2 and 5 of blood glucose after 2H2O ingestion. Plasma glucose concentrations decreased by approximately 10% (P < 0.01), whereas plasma insulin increased by approximately 47% (P = 0.02) after 9 h of lipid infusion.
1992, human study
Quantitative analysis of amino acid oxidation and related gluconeogenesis in humans
Significant gaps remain in our knowledge of the pathways of amino acid catabolism in humans.
Further quantitative data describing amino acid metabolism in the kidney are especially needed as are further details concerning the pathways utilized for certain amino acids in liver. Further quantitative data describing amino acid metabolism in the kidney are especially needed as are further details concerning the pathways utilized for certain amino acids in liver. Sufficient data do exist to allow a broad picture of the overall process of amino acid oxidation to be developed along with approximate quantitative assessments of the role played by liver, muscle, kidney, and small intestine. Our analysis indicates that amino acids are the major fuel of liver, i.e., their oxidative conversion to glucose accounts for about one-half of the daily oxygen consumption of the liver, and no other fuel contributes nearly so importantly.
1999, human study
The effects of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects.
We have quantitatively determined gluconeogenesis (GNG) from all precursors, using a novel method employing 2H20 to address the question of whether changes in plasma free fatty acids (FFA) affect GNG in healthy, nonobese subjects. In the first study (n = 6), plasma FFA were lowered at 16 to 20 hours with nicotinic acid (NA) and were then allowed to rise at 20 to 24 hours (FFA rebound after administration of NA). FFA decreased from 387 μM at 16 hours to 43 μM at 20 hours, and then rebounded to 1,823 μM at 24 hours. GNG decreased from 58.1% at 16 hours to 38.6% of endogenous glucose production at 20 hours (P < 0.005) and then rebounded to 78.9% at 24 hours (P < 0.05).
1996, dog study
Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs.
Suppression of hepatic glucose output (HGO) has been shown to be primarily mediated by peripheral rather than portal insulin concentrations; however, the mechanism by which peripheral insulin suppresses HGO has not yet been determined. Previous findings by our group indicated a strong correlation between free fatty acids (FFA) and HGO, suggesting that insulin suppression of HGO is mediated via suppression of lipolysis. To directly test the hypothesis that insulin suppression of HGO is causally linked to the suppression of adipose tissue lipolysis, we performed euglycemic-hyperinsulinemic glucose clamps in conscious dogs (n = 8) in which FFA were either allowed to fall or were prevented from falling with Liposyn plus heparin infusion (LI; 0.5 ml/min 20% Liposyn plus 25 U/min heparin with a 250 U prime). Endogenous insulin and glucagon were suppressed with somatostatin (1 microgram/min/kg), and insulin was infused at a rate of either 0.125 or 0.5 mU/min/kg.
1996, dog study
Importance of peripheral insulin levels for insulin-induced suppression of glucose production in depancreatized dogs.
It is generally believed that glucose production (GP) cannot be adequately suppressed in insulin-treated diabetes because the portal-peripheral insulin gradient is absent. To determine whether suppression of GP in diabetes depends on portal insulin levels, we performed 3-h glucose and specific activity clamps in moderately hyperglycemic (10 mM) depancreatized dogs, using three protocols: (a) 54 pmol.kg-1 bolus + 5.4 pmol.kg-1.min-1 portal insulin infusion (n = 7; peripheral insulin = 170 +/- 51 pM); (b) an equimolar peripheral infusion (n = 7; peripheral insulin = 294 +/- 28 pM, P < 0.001); and (c) a half-dose peripheral infusion (n = 7), which gave comparable (157 +/- 13 pM) insulinemia to that seen in protocol 1.
Indirect effect of insulin to suppress endogenous glucose production is dominant, even with hyperglucagonemia.
Suppression of endogenous glucose production (EGP) is one of insulin’s primary metabolic effects and failure of this action is a major contributor to fasting hyperglycemia of type 2 diabetes mellitus. Classically, insulin was thought to suppress the liver directly, via hyperinsulinemia in the portal vein. Recently, however, we and others have demonstrated that at least part, and possibly most of insulin’s action to suppress EGP is normally mediated via an extrahepatic (i.e., indirect) mechanism. We have suggested that this mechanism involves insulin suppression of adipocyte lipolysis, leading to lowered FFA and reduced EGP (“Single Gateway Hypothesis”).
2000, dog study
Inhibition of lipolysis causes suppression of endogenous glucose production independent of changes in insulin.
We have shown that insulin controls endogenous glucose production (EGP) indirectly, via suppression of adipocyte lipolysis. Free fatty acids (FFA) and EGP are suppressed proportionately, and when the decline in FFA is prevented during insulin infusion, suppression of EGP is also prevented. The present study tested the hypothesis that suppression of lipolysis under conditions of constant insulin would yield a suppression of EGP. N 6-cyclohexyladenosine (CHA) was used to selectively suppress adipocyte lipolysis during euglycemic clamps in conscious male dogs.
2016, rat and in vitro study
Direct Hepatocyte Insulin Signaling Is Required for Lipogenesis but Is Dispensable for the Suppression of Glucose Production.
During insulin-resistant states such as type II diabetes mellitus (T2DM), insulin fails to suppress hepatic glucose production (HGP) yet promotes lipid synthesis. This metabolic state has been termed “selective insulin resistance” to indicate a defect in one arm of the insulin-signaling cascade, potentially downstream of Akt. Here we demonstrate that Akt-dependent activation of mTORC1 and inhibition of Foxo1 are required and sufficient for de novo lipogenesis, suggesting that hepatic insulin signaling is likely to be intact in insulin-resistant states.