I wanted to thank Ratzo for a great question and also for tracking down a citation for further discussion. Here is the original question:
Hi Robb,I posted this question on Art Devany’s site, since I am very curious about it.If insulin is the key to body composition, then how are there people in studies who are insulin sensitive yet who are obese?
He then provided this abstract:
Robb,Here is a good review study on the subject where Gerald Reaven (who wrote about Syndrome X) mentions there are a substantial number of overweight/obese people who are insulin sensitive:
Diab Vasc Dis Res. 2005 Oct;2(3):105-12.
All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals.
Reaven G. Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. [email protected]
The ability of insulin to mediate glucose disposal varies more than six-fold in an apparently healthy population, and approximately one third of the most insulin-resistant of these individuals are at increased risk to develop cardiovascular disease. Differences in degree of adiposity account for approximately 25% of this variability, and another 25% varies as a function of level of physical fitness. The more overweight/obese the person, the more likely they are to be insulin-resistant and at increased risk of cardiovascular disease, but substantial numbers of overweight/obese individuals remain insulin-sensitive, and not all insulin-resistant persons are obese. Of greater clinical relevance is evidence that the metabolic benefit and decrease in risk of cardiovascular disease following weight loss occurs primarily in those overweight/obese individuals that are also insulin-resistant. The relationship between insulin resistance and overall obesity, as assessed by measurement of body mass index, is essentially the same as the relationship between insulin action and abdominal obesity as quantified by determining waist circumference. Finally, there appears to be a comparable relationship between insulin-mediated glucose disposal and amount of visceral fat, subcutaneous fat, and total fat as quantified by various imaging techniques, and the magnitude of these relationships is no greater than that between insulin action and simple measure of body mass index.
There are some really interesting points to be made from that paper, perhaps most significant being: Variables from person to person can be enormous. Another point to be made is that “insulin resistance” or “insulin sensitivity” are relative terms that are constructed by testing and drawing somewhat arbitrary lines as to what constitutes normal and abnormal. Obviously there are some parameters under-which most people function but that does not address what is optimal for a given individual. Reavens work and much of what Taubes discusses in his book deals with these confounding findings. It is natural to paint as simplistic a picture as possible, the media is especially prone to this, but few situations boil down as nicely as “this is good, that is bad”. Lets look at two populations Reavens mentions that appear at odds with the notion of insulin resistance and obesity. Lean individuals who are insulin resistant and obese individuals who are insulin sensitive.
The lean individual who is insulin resistant could result from sleep deprivation, stress or excessive exercise oddly enough. Introduce enough of a stressor and the individual will head towards insulin resistance. I suspect these individuals although technically “lean” show a propensity towards abdominal adiposity and if they revers the insulin resistance the hip/waist ratio will improve. Why are these individuals not obese? Honestly, I’m not sure on that one. These individuals show blood profiles similar to obese insulin resistant individuals but they manifest the condition in a different way. Similar to the obese however, these individuals must reduce the action of whatever is contributing to their insulin resistance, be it food, stress or lack of sleep.
There is likely some differences in tissue insulin resistance levels…and here is an interesting study looking at this very situation. Congenital generalized lipodystrophy (CGL) is a genetic condition in which the individual LACKS virtually all body fat, yet is HIGHLY insulin resistant. These individuals are remarkably muscular and have an athrogenic blood profile typical of the insulin resistant, however the condition progresses at a dramatically accelerated rate. The individuals also, not surprisingly, have very low circulating leptin levels. It’s all a bit chicken and egg but the lack of Leptin due to a nearly absent fat mass may play into the pronounced insulin resistance. Leptin plays a role in energy regulation and usage mainly (it is thought) by monitoring energy storage levels. Caloric restriction can decrease leptin, this will tend to increase appetite and this is part of why it’s so damn hard to stay on a calorie restricted diet. Interestingly a ketogenic diet does not lower leptin levels yet it does emulate other elements of fasting. An interesting observation with these folks is that insulin resistance is obviously not a player in obesity (the folks have virtually no body fat) but it absolutely is a player in a blood lipid profile that is unhealthy and will lead to an early death. Not surprisingly, I have found no indication that a ketogenic diet has been explored as a therapy for this condition. We might sum up this condition as “not insulin resistant in the fat mass, highly resistant in the muscle mass.”
Lets now look at the obese yet insulin sensitive individual. One interesting hallmark with these folks is a hip/waist ratio that is “normal”. Adiposity is generally distributed and not centralized to the midsection. This becomes a bit chicken and egg again but if insulin sensitivity is good then we see glucose disposal (either in the muscles or the adipose) and a consequent lack the conversion of glucose to triglycerides in the liver. In the instance of insulin resistance we see significant fatty liver deposits and a tendency for fat to be deposited in and around the viscera. The obese, insulin sensitive individual is partitioning nutrients into the fat mass and apparently staying ahead of insulin resistance. I think this is just one of the phenotypes possible and it reflects a situation in which insulin levels may not be at a pathological level with regards to athrogenic blood profile, however things are sufficiently buggared to induce fat gain. A decreased inslulin level via glycemic control will fix this situation. The fact the individual is not technically insulin resistant is a bit moot and if that fat mass continues to grow it will derange hormonal function at some point sufficiently such that overt insulin resistance occurs.
It’s complex stuff and it shows quite a spectrum of genetic responses to various environmental cues. Chines medicine is “OK” with the notion that one type of irritant may result in differing pathology from person to person. Our false reductionist approach to many questions leaves little or no ability to see the shades of grey that reflect reality.