The role of saturation of fat depots in the pathogenesis of insulin resistance.
Insulin resistance is the earliest observable abnormality in individuals who are predisposed to, and who later develop type 2 diabetes mellitus. We hypothesize that saturation of the subcutaneous fat depot is the primary event in the pathophysiology of insulin resistance in the majority of patients and postulate that this seminal event may lead to the development of hypertension, hypertriglyceridemia and depressed HDL levels (i.e., the metabolic syndrome). Our hypothesis has the following clinical implications: (1) differing responses to weight loss may be seen with regards to insulin resistance depending on the size of the fat depot; individuals with small fat depots having to maintain an extremely low body mass to preserve an insulin sensitive phenotype while individuals with a large fat depot may become insulin sensitive even when still clinically obese with some amount of weight loss; (2) peroxisome proliferator activated receptor gamma agonists, such as thiazoledinediones which expand the subcutaneous fat depot, may be especially useful in improving insulin resistance in individuals with small fat depots; (3) expanding alternate storage sites for triglycerides by a variety of techniques, such as resistance training-induced muscle hypertrophy, may also improve insulin resistance; (4) drugs, such as beta 3 adrenergic receptor agonists which promote lipolysis and have been suggested as possible agents in the treatment of obesity may actually increase insulin resistance by releasing free fatty acids into the circulation. Similarly, inhibitors of the beta oxidation of free fatty acids (e.g., carnitine palmitoyl transferase inhibitors) may also actually cause insulin resistance by sparing fat from oxidation and thus worsening fat depot saturation and (5) liposuction, by reducing the size of the subcutaneous fat depot may actually worsen insulin resistance, thus increasing the risk of type 2 diabetes mellitus.
Cherian
Mathew A
MA
Department of Medicine, University of North Dakota, School of Medicine and Health Sciences, 1919 Elm Street North, Fargo, ND 58102, USA. amprayilcm@gmail.com
Santoro
Thomas J
TJ
D005223:Fats / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D024821:Metabolic Syndrome / Q000209:etiology*
D005223:Fats