Controversy continues to rage regarding the underlying causes of insulin resistance and type 2 diabetes. Although low-carbohydrate diets reliably improve multiple markers of these conditions (to the point where some researchers have asserted that carbohydrate restriction should be the default treatment) it has not been proven that excess carbohydrate per se is the primary cause of these metabolic derangements. Theories abound: excess carbohydrate consumption is one but there’s also excess total energy excess dietary fat insufficient physical activity environmental factors and more. Skeletal muscle insulin resistance is sometimes cited as a factor: when skeletal muscle no longer responds to insulin by taking up glucose more insulin is secreted and glucose lingers in the blood for an extended period of time resulting in hyperglycemia and it may be returned to the liver for conversion into triglycerides and eventual storage in adipose tissue. But this model is unsatisfactory for a number of reasons.

First consider that a 155-pound person stores only about 120 grams of carbohydrate as glycogen in the skeletal muscle. That’s really not much since a New York City bagel can pack a 50-60 gram wallop of carbs all by itself. And considering that millions of people do little to nothing most days to make a dent in those glycogen stores it’s really not surprising that the muscles don’t have much room to spare for even more glucose. It may be less that skeletal muscle is resistant to insulin and more that their storage capacity is already full.

Second while many individuals with metabolic syndrome or type 2 diabetes are overweight or obese many are not. And while obesity is often considered a cause of diabetes and metabolic syndrome the accumulation of excess adipose tissue is more likely an effect of issues with insulin signaling. Obesity may be thought of as a symptom of metabolic dysfunction rather than its driver. Clinicians know that millions of people without obesity display many other hallmarks of metabolic derangement such as elevated triglycerides low HDL hypertension elevated hemoglobin A1c and fasting glucose. So even if skeletal muscle insulin resistance contributes to this why do only some individuals gain significant body fat while others don’t.

There’s a different paradigm of insulin resistance and metabolic syndrome present in the medical literature but which remains underappreciated and underexplored. It is an adipose-centric model and it explains some of the contradictions and “paradoxes” that have come to light in the past few years. In a nutshell the adipose-centric model posits that adipose tissue itself is the regulator of how much body fat an individual will store and where it will be stored with the results governing who becomes obese versus who remains lean and who will experience dysregulated blood glucose and insulin.

Each person has what we can think of as an individual threshold for fat storage in adipose tissue. Individuals who have a very large capacity for storage may become obese to the tune of carrying an extra 100 200 or 300 pounds. Because their adipose tissue has such a large storage capacity the glucose and fatty acids have “somewhere to go.” They do not linger in the blood nor get deposited ectopically. This may explain at least in part the “obesity paradox” wherein individuals with higher body weights seem to have lower risks for certain health outcomes than would be expected based on their size. If someone’s adipose tissue is able to continually expand and accommodate excess triglyceride then the fat accumulates where it is “supposed to” rather than being deposited in and around the organs.

Contrast this with “normal weight obese” individuals (a.k.a. “TOFI” – thin outside fat inside). For these people—the ones with multiple markers for metabolic syndrome or cardio-metabolic disease minus being overweight or obese—if their unique adipose storage threshold is low then they will not store the excess triglyceride in their adipose tissue but rather viscerally and ectopically such as in the liver and pancreas. And the adipose-centric model of type 2 diabetes posits that this accumulation of triglyceride in the liver and pancreas is the main driver of dysregulated insulin signaling and consequent elevated blood glucose. (Triglyceride in the adipose tissue is unable to accommodate may also be deposited in skeletal muscle resulting in a kind of “marbling.” When fat ends up in muscle tissue in a cow it makes for a juicy and delicious steak; when it happens in humans it’s bad news.)

This explains why an otherwise lean individual can present with non-alcoholic fatty liver disease. From the standpoint of the 21^st Century western world where we are obsessed with image and physique these folks are “lucky” because they remain slender. But the outside appearance hides the insidious effects happening on the inside.

Returning to the individuals who do become overweight or obese their adipose tissue is more accommodating and as such it may serve as a “buffer” for energy flux and a storage tank for excess energy regardless of whether that energy originated as carbohydrate fat or protein. As long as they can keep storing this energy in what we can say is its “proper place” then the excess does not need to be deposited elsewhere as a last resort. This may be what offers heavier individuals the modest degree of protection observed in the aforementioned obesity paradox. Based solely on body size these folks appear to be unhealthy but on the inside they have better cardio-metabolic risk profiles than individuals who have a lower body weight but whose adipose tissue has reached its storage limit and therefore excess triglyceride must instead be stored viscerally where it will affect the function of organs involved in blood sugar regulation. Indeed researchers have noted “limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease” and the link between insulin resistance phenotypes and “higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments.” 

Another mystery this model explains is how individuals with lipodystrophy or lipoatrophy—conditions of adipose tissue deficiency—often exhibit the same markers we would expect in obese type 2 diabetics including manifesting type 2 diabetes itself. “Any plausible explanation for the link between excess adipose tissue and insulin resistance needs to be able to account for this observation.” If adipose tissue serves as the buffer for energy flux then individuals with insufficient adipose would suffer the same effects as those with a “normal” or an excessive amount of adipose but the storage capacity of which has been exceeded causing glucose to linger in the blood and triglycerides to be deposited ectopically. 

These are fascinating insights but they haven’t as of yet garnered the attention they deserve.