Chronic insulin resistance over time can lead to pre-diabetes and ultimately to type II diabetes. Insulin resistance occurs primarily in overweight and obese subjects. Excess fat in adipose tissue increases the overflow of fatty acids into the blood. This leads to increased concentrations of fatty acyl-CoA or diacylglycerols in muscle or liver cells that activate protein kinase C (PKC). PKC phosphorylates the insulin receptor (at serine residues) preventing the proper translocation of GLUT-4 to the membrane decreasing glucose uptake and thus inducing a state of insulin resistance.
Chronic low-grade inflammation present in overweight and obese subjects also increases insulin resistance. For example TNF-alpha increases serine phosphorylation of IRS-1 (as does PKC), decreasing the activity of IRS-1 necessary for the progression of intracellular insulin signaling.
This occurs not only because of excess fat, but also because of a concomitant decrease in muscle tissue, present in sedentary subjects and/or with hypercatabolic pathologies. Muscle tissue is the main organ that contributes to blood glucose clearance as it is the main glycogen store in our body.
In summary, what I am saying is that insulin resistance and type II diabetes occur mainly in overweight/obese and/or sedentary subjects with low muscle mass, also known as “metabolically obese lean”. There is also sarcopenic obesity which is a combination of excess body fat and low muscle mass in proportion.
Recent evidence shows that simple weight loss is shown to be the most potent tool for remission of type II diabetes. In fact, a weight loss of about 15 kg achieved by calorie restriction can lead to remission of type II diabetes in about 80% of patients (Magkos et al 2020).
Weight loss (~ 5% of initial body weight) in non-diabetic individuals with obesity and metabolic dysfunction lowers blood glucose and dramatically improves fasting insulin.
The DiRECT diabetes remission clinical trial (Lean et al 2018), which was conducted in the UK, showed how caloric restriction leading to a weight loss of about 15 kg, achieved diabetes remission in obese subjects of up to 86% . The really interesting thing about this study is that the dietary formula given to the subjects was composed of 59% carbohydrates, 13% fat, 26% protein and 2% fiber, i.e., it was high in carbohydrates in relation to other nutrients, although being hypocaloric, the total amount of carbohydrates was not too high either.
In addition, after the first 3-5 months of following this low-calorie, high-carbohydrate replacement diet, a food reintroduction plan was followed for 2-8 weeks, increasing caloric intake. This dietary reintroduction plan was composed of approximately 50% carbohydrate, 35% total fat and 15% protein, i.e., it was still relatively high in carbohydrate, although now providing slightly more calories. Remember that we are talking about subjects with type 2 diabetes.
And what happened? Well, apart from the weight loss they had, the most interesting thing is that there was a remission of diabetes. Yes, you read that right, they remitted practically all the metabolic abnormalities associated with this disease.
When combined with dietary calorie restriction and exercise, the results are optimal, since physical exercise not only contributes to facilitate the caloric deficit necessary for weight loss, but exercise by itself will improve insulin resistance and glucose uptake by muscle regardless of whether there is weight loss or not. Muscle contraction leads to translocation of GLUT4 to the cell membrane independently of insulin action. In addition, exercise increases the expression of anti-inflammatory cytokines that also exert a positive role on insulin sensitivity such as IL-6, which when expressed by skeletal muscle, plays an important role in improving insulin sensitivity and interestingly has anti-inflammatory actions. In addition, strength training will be key here because it will help us to maintain muscle mass in the weight loss intervention, because it is not about losing weight per se, but about losing body fat and not muscle mass.
Therefore, caloric restriction, physical exercise and weight loss are the key tools to improve and reverse insulin resistance and type II diabetes in subjects with these alterations linked to sedentary lifestyle, poor diet, overweight, etc.
In these specific subjects, reducing carbohydrates in the diet is an appropriate tool, since they present poor tolerance to them due to insulin resistance, and this will improve post-prandial glucose peaks. In fact, in the Gardner et al 2018 study, it was found that people with insulin resistance had greater benefits with a low-carbohydrate diet, while those without insulin resistance would do better with a low-fat diet.
But does this happen in healthy subjects who are athletes and/or have an adequate body composition?
Well, no, in subjects without pathologies, who do physical exercise and maintain an adequate body composition, it is very difficult or almost impossible for them to have insulin resistance, much less type II diabetes.
However, nowadays there is a tendency to extrapolate what a person with pathologies or obese subjects needs to what a healthy, lean and athletic subject needs. To make a healthy, lean athlete believe that he or she has insulin resistance and therefore must follow carbohydrate-restricted diets is ridiculous. This does not mean that athletic subjects can eat anything, because as I always say, carbohydrates should be commensurate with the type of exertion involved in the sport the athlete is playing and their overall physical activity.
Astrup et al 2017, in their study, found that normoglycemic individuals (healthy subjects without insulin resistance) lost more weight on a low-fat, high-carbohydrate diet, while prediabetic (insulin-resistant) individuals seem to be much more susceptible to weight loss on a diet with a greater focus on the quality of carbohydrate content, i.e., a diet with a lower glycemic load, more fiber, and more whole grains.
Nowadays we have high-intensity elite athletes eating fewer total calories and fewer carbohydrates than they need for fear of getting fat or getting sick, when they are precisely the ones who need them the most. On the other hand, we have overweight sedentary subjects eating sugars as if they were going to run a marathon, which leads to overweight, obesity and different diseases.
To want to create a need where there is none is to deceive the patient in order to sell an intervention. The same applies to the issue of metabolic flexibility, which is nothing more than the organic flexibility we have to use different energy substrates indistinctly and efficiently depending on the activity.
In a world with a high prevalence of obesity, sedentary lifestyle and a Westernized diet based on ultra-processed products rich in poor quality fats and refined sugars, metabolic flexibility in relation to the use of fats as a source of energy is being lost. Therefore, low-carbohydrate or ketogenic diets are proposed with the aim of improving this metabolic flexibility. But this presents several questions to be clarified that are sometimes overlooked.
- Although sedentary and/or obese subjects can benefit from a low-carbohydrate diet to improve their metabolic flexibility, it will really be the caloric deficit and the inclusion of physical exercise in their daily habits (along with the fat loss that this entails) that will give them the benefits mainly in this sense. Reducing carbohydrates will also be a good strategy in these subjects obviously, but secondary to the main thing: caloric restriction-physical exercise-weight loss.
- We must pay attention to the context, since in this case we are talking about subjects with insulin resistance or type II diabetes, something that is anecdotal in healthy, athletic subjects with good body composition. Therefore, these subjects already start with a good metabolic flexibility, since physical exercise, especially practiced in a significant way as it occurs in athletic subjects, will be THE MAIN mechanism that leads to metabolic flexibility, far ahead of the dietary manipulation you employ. Obviously both together will add up to more than by themselves, but…does a low carb ketogenic type diet really improve long term metabolic flexibility in athletic subjects? Precisely NO, since metabolic flexibility is always referred to in relation to low fat-oxidizing flexibility. This stems from the fact that there is a high prevalence of obese subjects in the world, but not everyone is obese. Athletic subjects need to be flexible by obtaining energy from glucose as well, especially at times or peaks of high intensity. Eating a very low carbohydrate diet may help oxidize fat but may limit glucose oxidation, as very low carbohydrate diets decrease the PDH enzyme that is key in the glucose energy pathways.
Therefore, this low-carbohydrate nutritional strategy used in a prolonged manner to improve metabolic flexibility in subjects who practically do not need it (physical exercise already takes care of it for the most part) can make them less efficient in the long term at oxidizing glucose, something that is in the interest of these athletes, thus making them less metabolically flexible. Another thing is “train low” strategies in a punctual way in athletes, which could make sense (or not), but I am referring to chronic carbohydrate restrictions (ketogenic diets) in athletes.