TLDR: Excessive insulin sensitivity sets you up to become obese.
I have to apologise for citing Valter Fastingbar Longo, sometimes you have little choice. This paper
GH Receptor Deficiency in Ecuadorian Adults Is Associated With Obesity and Enhanced Insulin Sensitivity
documents the physiology of humans who are homozygous for a large growth hormone receptor gene defect. They make their GH, lots of it. It does absolutely nothing, having no receptor. GH normally works in opposition to insulin on adipocytes, causing both lipolysis and systemic insulin resistance.
Also, in the absence of GH signalling, these people make no IGF-1 so are of dwarf stature. They are exquisitely insulin sensitive. As in here are the OGTT results. Dark lines are the GHR deficient people:
Plasma glucose is comparable to that of controls throughout, matched for BMI (and lots of other things). But just look at that insulin level, peaking at 25microIU/ml vs 80microIU/ml in controls. The dwarves are very, very insulin sensitive.
And very fat.
Despite having a mean BMI of 27.6 (controls are higher at 29.4) the dwarves have 48% of their weight as fat mass compared to 41% in the controls.
Let's put this in to context: The GHr deficient people are fat because they are insulin sensitive. There is no paradox. We are not thinking that their obesity should have caused insulin resistance, it's that their failure to generate one type of physiological insulin resistance has allowed pathological insulin sensitivity to prevail, hence obesity.
Oh, and leptin:
Leptin in the dwarves with 48% body fat is 7.32ng/ml. Leptin in controls with 41% body fat is 10.36ng/ml, p is just over 0.02 if you are wondering or care.
It looks to me as if these excessively insulin sensitive individuals have yet to reach their "ideal" metabolic level of obesity to counteract their lack of GH signalling. Interesting to wonder what determines the level of adiposity at a given age in the absence of GH signalling. That's not simple.
We have no data on RER under fasting or post prandially. But we can be fairly confident that the fasting RER will be low, reflecting high basal lipolysis from distended adipocytes and post prandial RER will be high as insulin action facilitates glucose metabolism and locks lipids in to adipocytes.
A bit like those insulin sensitive pre-obese humans a couple of posts ago. But these dwarves will have to become very, very obese to behave like normal overweight insulin resistant people.
Addendum, not worth a post in its own right but on-topic:
Does Weight Gain Associated with Thiazolidinedione Use Negatively Affect Cardiometabolic Health?
Epic quote of failed perception:
"This review paper discussed the mechanism of action of TZDs on weight gain and the so-called “glitazone paradox”, the phenomenon that TZD-associated weight gain improves rather than exacerbates insulin resistance".
There is no paradox. Insulin signalling improves with glitazones, this makes you fat.