One of the only clinical diagnostic criteria for type II diabetes mellitus (T2DM) is a persistently elevated blood glucose (BG) level. Chasing down the cause of this BG elevation has been the subject of an enormous investigation for many decades. Many researchers disagree about the ultimate pathogenesis and pathophysiology of the disease state, and in the 21st century we have the fortune of being able to see these disagreements play out in real time online. Actual PhDs doing actual pivotal research have taken to using social media platforms like Twitter and publicly accessible academic platforms like Research Gate to debate the merits and consistency of the available data. In these places you will find an enormous breadth of opinions— some plausible, some preposterous, and some that surely reflect reality quite accurately.
Some people argue that sugar causes the disease. Others blame fat and animal products. Some even say it is merely an inescapable consequence of aging. People have many conflicting opinions about T2DM. I'm not a researcher. I'm not an expert. But for what it's worth, I'd like to share my thoughts on this subject. To do this, I want to use a bit of a different format with this post. I'm going to state my position in point form, and then I'm going to defend it by breaking each point down. So let's get to it.
- Fatty acids cause insulin resistance, but glucose shows it to you.
- Diabetes is a disease of excess calories.
- Carbohydrate restriction is therapeutic, not curative.
- Ketosis is functional diabetes, therefore also therapeutic.
Before we dive into dissecting each one of these points, we need a little crash course in cellular physiology. It won't be painful, I promise. We're just going to briefly review the Randle cycle.
The Randle cycle is basically a series of biochemical pathways inside of your cells that signal which fuel substrates are to be burned. In one arrangement, a cell will preferentially burn glucose. In the other arrangement, a cell will preferentially burn fatty acids (FA). Under normal conditions, the arrangement is dependent on the relative proportions of each available substrate. For example, after a carbohydrate rich meal, the cycle will favour burning carbohydrates. After a fat rich meal, the cycle will favour burning FAs. Here we see a diagram of these mechanisms in action.
On the left and right we see glucose and long-chain fatty acids (LCFA) being transported into the cytosol of an adipocyte. Here we see how the availability of either substrate dictates which substrate is to be burned as fuel. Let's start with glucose.
When glucose enters through glucose transporter type 4 (GLUT4), it is driven through an enzymatic pathway known as glycolysis and cleaved in half. This gives us two three-carbon units of pyruvate, which enter the mitochondria. Not seen here, one pyruvate goes on to participate in the Citric Acid (TCA) cycle, and the other pyruvate gets converted to a two-carbon unit called Acetyl-CoA by the pyruvate dehydrogenase complex (PDH). The extra carbon is lost as CO2. If there is too much pyruvate, this drives up Acetyl-CoA and inhibts PDH. This is a form of negative feedback. When the PDH complex is inhibited by Acetyl-CoA, excess pyruvate is shunted out of the cell as lactate.
When LCFA enter the cell, they're broken apart into two-carbon units called long chain fatty Acyl-CoA (LC-FAC) by long chain fatty Acyl-CoA synthetase (LC-FACS). These enter the mitochondria through carnitine palmitoyltransferase 1 (CPT1). From there, each LC-FAC is converted to Acetyl-CoA through beta-oxidation (β-ox). Notice how excess Acetyl-CoA does not have a negative feedback system inside the mitochondria. Instead, excess Acetyl-CoA drives up mitochondrial citrate, and thus drives up cytosolic citrate. Cytosolic citrate is the signal to inhibit GLUT4 and phosphofructokinase 1 (PFK-1). This means that if enough citrate is generated, glucose is both inhibited from entering the cell and inhibited from entering glycolysis.
Further downstream we discover that FAs do in fact have their own negative feedback system. The consequence of continuing to drive up cytosolic citrate is to eventually produce Malonyl-CoA. Which stimulates fatty acid synthase (FAS) for the purposes of storing excess fatty acids through the synthesis of new triglycerides (TG). Malonyl-CoA also inhibits CPT-1, preventing LC-FAC from being transported into the mitochondria.
There we go. We now understand the basics of the Randle cycle. Now let's talk about how this is fundamentally relevant for understanding my position on T2DM.
1. Fatty acids cause insulin resistance, but glucose shows it to you.
Let's refer back to the graphic above. We know that FAs in the cell uniquely inhibit GLUT4. It all depends on the relative proportions of FAs to glucose that are available to the cell. The more FAs you have in the cell, the more resistant that cell will be to translocating GLUT4 to the cell surface to take up glucose. Thus, the activity of the PDH complex will be impaired as the cell begins to preferentially burn FAs as fuel . This impairs oxidative glucose disposal and increases non-oxidative glucose disposal . Essentially, when you eat a high-fat diet, you lose glycogen in your liver, your cells will make the switch to FA-burning, and oxidative disposal of glucose will go down. When you finally do get a bolus of glucose, it will serve to replete glycogen stores and will be disposed of through non-oxidative pathways. More astute individuals in the low-carb community will recognize this whole situation as "physiological insulin resistance", which they rightly state is a non-pathological state.
However, since merely increasing the availability of FAs to a cell will powerfully reduce its sensitivity to insulin , we can surmise that the relative insulin sensitivity of a cell is dictated by its FA burden. As such, if one's cells are overburdened with FAs, glucose concentrations in the blood will be higher due to the Randle cycle's effects on insulin sensitivity and glucose disposal . When you challenge the body with glucose while the body is attempting to burn through a surplus of FAs, glucose is going to have to wait outside the cell in the blood until those FAs are burned. When we see this happen in T2DM, it is very tempting to blame the carbs in the diet as being the ultimate cause of the persistently elevated glucose we see in the blood. But the glucose isn't actually to blame. The elevated BG is merely reflecting the competition between energy substrates based on the relative availability of each substrate to the body's cells, particularly the adipocytes. When there is too much fat, glucose cannot be burned.
Am I attempting to imply that a high-fat diet causes T2DM? No, not at all. But the effects of high-fat feeding on glucose metabolism gives us insight into the roles of carbs and fats in T2DM. Which leads me to my next point.
2. Diabetes is a disease of excess calories.
We can confidently say that the symptoms of T2DM are made uniquely worse by carbohydrates, as removing them has profound utility with regards to symptom management . Nobody can really dispute this credibly at this point. However, there is a massive amount of evidence indicating that the primary source of insulin resistance in T2DM at the cellular level is the FA burden of the actual cell . So, what determines the FA burden of a cell? By and large, the answer is every Taubesian acolyte's least favourite word—calories. Calories, calories, calories.
But isn't insulin a fat storage hormone? Aren't the carbohydrates responsible for sequestering fat into our fat tissue? Yes and no. Insulin stores fat and displaces lipolysis proportionate to the energy provided by the carbohydrates that stimulated the insulin. So yes, if you were somehow able to learn the history of each TG in your adipose tissue, you'd discover that the vast majority of those TGs originated as FAs consumed in the diet. However, insulin wasn't really required to store any of them. If we refer back to the diagram of the Randle cycle for a moment, we discover that merely overburdening an adipocyte with FAs will stimulate TG synthesis. Whether those TGs were stored in the adipocyte through insulin or stored passively by merely consuming fat, it is the total calorie balance of the diet that determines the TG content of the adipocyte at the end of the day .
There is a growing body of evidence that suggests that sufficient caloric restriction leads to the remission and perhaps the reversal of T2DM in a manner that is entirely predicted by fat mass loss . Fat mass loss is dictated by caloric intake. No more, no less.
So, to recap. If you overeat carbohydrates, you will indeed store every ounce of fat you consume. However, calorie for calorie, if you overconsume fat, you will drive up TG synthesis and store every ounce of excess fat you consume as well. At the end of the day, total calorie intake minus your total energy expenditure determines fat loss or fat gain. If you overeat enough calories chronically, eventually your adipocytes become so overloaded with FAs that they're indefinitely stuck in the FA-burning position. It is similar to only being able to turn one handle on a faucet, when you should be able to turn both.
3. Carbohydrate restriction is therapeutic, not curative.
Let's go back to BG for a moment. Why is carbohydrate restriction beneficial for T2DM? If it's the fat inside the cell that's causing the problem, why should there be benefits to restricting carbohydrates at all? The short answer is that consuming excess fat carries fewer short-term negative symptoms when compared to glucose in the context of T2DM. When we consume excess fat, it may be readily stored in a number of places. Even though some of these storage depots are problematic, like the liver or even the blood, fat stored in these places causes very few noticeable symptoms under certain conditions. Don't get me wrong, though. It's still not a good thing to store ectopic fat, or to store fat in the blood. However, when you consume glucose while adipocytes and visceral fat stores are experiencing an overload of fat (as with T2DM), all hell breaks loose.
The body does not prefer to store glucose as fat . It never has, and it never will. Glucose that can't be burned is shunted out of cells as lactate. Once the lactate is in the blood it goes to the liver and participates in the Cori cycle to be recycled into glucose. It is then sent back into the blood . Typically, lactate is returned to the liver to be converted to glucose to replete hepatic glycogen. The body knows that while you're burning FAs as fuel, the liver needs extra glucose. But T2DM typically presents with a scenario wherein both subcutaneous fat stores as well as hepatic fat stores are maxed. This impairs the liver's ability to store glycogen. The liver and the adipose are both paddles in a game of Pong, with glucose and lactate as the ball. This is confirmed by the higher levels of plasma and urinary lactate associated with T2DM . As one would expect, this effect can be observed in people with certain glycogen storage disorders as well . In T2DM, this merry-go-round repeats itself indefinitely, until the FA burden on the adipocytes can be resolved.
But, at this point you might be wondering why this merry-go-round is damaging. Personally, I don't actually think the glucose itself is damaging, but what inevitably results from that glucose is damaging. In this state, you cannot have a glut of BG without a glut of blood lactate, and that is problematic. Lactate can cause anything from hypoxia to tissue necrosis, and pretty much any of the comorbidities associated with T2DM. In fact, some people with T2DM have experienced acute lactic acidosis from taking metformin, a drug that inhibits the Cori cycle . Inhibiting the Cori cycle increases lactate levels in the blood . I'm not trying to scare diabetics out of taking metformin. Not at all. In fact, one of the reasons metformin is beneficial is because it opens the loop. If the lactate can't go to the liver to be converted to glucose, it may be redirected to the kidney to be excreted in the urine. This is because the liver and the kidney are two of the body's largest lactate disposal sites. If you take the liver out of the equation, you may very well urinate the excess lactate more easily, or even metabolize it in the kidney more easily.
I suspect that a combination of metformin and a low-carbohydrate diet could be a powerful tool for reducing many of the comorbidities associated with T2DM. In my estimation, the lactate probably has more to do with these comorbidities than does the glucose itself. But removing the glucose removes the lactate. So, removing the glucose has tremendous utility in T2DM symptom management. Until the FA burden on the adipocytes can be rectified, one cannot expect to be able to tolerate a glucose challenge. It is for this reason that I'm willing to say that the reduction in diabetic symptoms associated with carbohydrate-restriction may very well constitute T2DM remission. However, this is not T2DM reversal. Reversal would imply that one has restored glucose tolerance. Mechanistically, the only durable path toward genuine T2DM reversal would be rigorous calorie restriction, regardless of the macronutrient ratio of the diet. Though, a low carbohydrate diet would likely be less rocky along the way.
Additionally, as a consequence of the body not preferring to store glucose as fat, you have an innate preference to dispose of glucose through oxidative pathways. This generates a lot of metabolites and byproducts of metabolism that are inherently damaging, and even more damaging in the context of T2DM. Substances like methylglyoxal, reactive oxygen species, and other breakdown products. These products disrupt metabolism and can damage a number of tissues. They can also further disrupt insulin signalling through oxidative damage of the insulin receptor substrate proteins. When you swap the carbohydrates for fat in the diet, there is a greater opportunity to safely store the energy you've consumed. Because the body can safely store this energy, and there is no pressing need to burn it immediately, there is considerably greater leeway with carbohydrate-restrictive diets when we're considering T2DM and its associated comorbidities.
4. Ketosis is functional diabetes, therefore also therapeutic.
This statement may seem provocative and hyperbolic, but I'm absolutely serious. If you compare ketotic metabolism to diabetic metabolism, there are some spooky similarities.
Pretty much all of the hallmarks of T2DM overlap with the hallmarks of nutritional ketosis, with the exception of glucose, insulin, and lactic acid. This is why ketosis is therapeutic for T2DM. Ketosis removes the primary source of the bulk of the comorbidities associated with T2DM, but the underlying pathology still remains. The insulin resistance persists. The high energy status, and many of its long-term consequences, likely persists as well. In short, ketosis is T2DM without the hyperglycemia. Ketosis takes a dysfunctional state, and makes it more functional by removing the challenge to the glucose disposal system while it is impaired. It doesn't reverse the dysfunctional state. It merely improves the situation by masking some of the associated symptoms.
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 Chokkalingam K., et al. High-fat/low-carbohydrate diet reduces insulin-stimulated carbohydrate oxidation but stimulates nonoxidative glucose disposal in humans: An important role for skeletal muscle pyruvate dehydrogenase kinase 4. J Clin Endocrinol Metab. January 2007. https://www.ncbi.nlm.nih.gov/pubmed/17062764
 Bisschop P.H., et al. Dietary fat content alters insulin-mediated glucose metabolism in healthy men. Am J Clin Nutr. March 2001. https://www.ncbi.nlm.nih.gov/pubmed/11237931
 Stephen F. Burns, Sheryl F. Kelsey, and Silva A. Arslanian. Effects of an Intravenous Lipid Challenge and Free Fatty Acid Elevation on In Vivo Insulin Sensitivity in African American Versus Caucasian Adolescents. Diabetes Care. February 2009. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628707
 Siôn A. Parry, Rachel M. Woods, Leanne Hodson, and Carl J. Hulston. A Single Day of Excessive Dietary Fat Intake Reduces Whole-Body Insulin Sensitivity: The Metabolic Consequence of Binge Eating. Nutrients. August 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579612/
 Sarah J. Hallberg, et al. Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study. Diabetes Ther. April 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104272/
 Taylor R., et al. Remission of Human Type 2 Diabetes Requires Decrease in Liver and Pancreas Fat Content but Is Dependent upon Capacity for β Cell Recovery. Cell Metab. October 2018. https://www.ncbi.nlm.nih.gov/pubmed/30078554
 Kevin D. Hall and Juen Guo. Obesity Energetics: Body Weight Regulation and the Effects of Diet Composition. Gastroenterology. May 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568065/
 Lean M.E., et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. February 2018. https://www.ncbi.nlm.nih.gov/pubmed/29221645
 Roy Taylor. Calorie restriction for long-term remission of type 2 diabetes. Clin Med (Lond). January 2019. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399621/
 Acheson K.J., Schutz Y., Bessard T., Anantharaman K., Flatt J.P., Jéquier E. Glycogen storage capacity and de novo lipogenesis during massive carbohydrate overfeeding in man. Am J Clin Nutr. August 1988. https://www.ncbi.nlm.nih.gov/pubmed/3165600
 Chen Y.D., Varasteh B.B., and Reaven G.M. Plasma lactate concentration in obesity and type 2 diabetes. Diabetes Metab. August 1993. https://www.ncbi.nlm.nih.gov/pubmed/8293860
 Jean L. J. M. Scheijen, et al. L(+) and D(−) Lactate Are Increased in Plasma and Urine Samples of Type 2 Diabetes as Measured by a Simultaneous Quantification of L(+) and D(−) Lactate by Reversed-Phase Liquid Chromatography Tandem Mass Spectrometry. Exp Diabetes Res. March 2012. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310144/
 Hagen T., Korson M.S., and Wolfsdorf J.I. Urinary lactate excretion to monitor the efficacy of treatment of type I glycogen storage disease. Mol Genet Metab. July 2000. https://www.ncbi.nlm.nih.gov/pubmed/10924273
 E. Fitzgerald. Metformin associated lactic acidosis. BMJ. September 2009. https://www.bmj.com/content/339/bmj.b3660
 Huang W., Castelino R.L., and Peterson G.M. Lactate Levels with Chronic Metformin Use: A Narrative Review. Clin Drug Investig. November 2017. https://www.ncbi.nlm.nih.gov/pubmed/28836132
 DeFronzo R., Fleming G.A., Chen K., and Bicsak T.A. Metformin-associated lactic acidosis: Current perspectives on causes and risk. Metabolism. February 2016. https://www.ncbi.nlm.nih.gov/pubmed/26773926