Viewpoints on the Way to the Consensus Session
Where does insulin resistance start? The adipose tissue
- Patricia Iozzo, MD, PHD
- From the Institute of Clinical Physiology, National Research Council (CNR), Pisa, Italy.
- Corresponding author: Patricia Iozzo, patricia.iozzo{at}ifc.cnr.it.
Adipose tissue is a heterogeneous organ with respect to embryonic origin, body distribution, and function. In addition to playing a major role in the regulation of nutrient and energy homeostasis, it is involved in the modulation of the immune response, reproductive function, hemostasis, mechanical support, bone mass growth, and thermogenesis.
To postulate that insulin resistance starts in adipose tissue, there should be evidence of 1) potential mechanisms for such a causal relationship, 2) the manifestation of such mechanisms in insulin-resistant individuals, and 3) their early occurrence in the development of insulin resistance.
PLAUSIBILITY: ADIPOSE TISSUE CAN CAUSE INSULIN RESISTANCE
Adipose tissue releases a variety of factors known to modulate insulin sensitivity, and their effects are summarized in Fig. 1.
Adipose tissue is the largest endocrine organ in the body. The diagram summarizes the main roles and effects of representative fat-derived products that have been related to insulin resistance and metabolic risk. BP, blood pressure; HR, heart rate.
Fatty acids
The concept that fatty acids (FAs) provoke cardiac, skeletal muscle, and hepatic insulin resistance and impair β-cell function has been extensively confirmed in humans, and mechanisms are reviewed in detail elsewhere (1). A sustained pharmacologic inhibition of lipolysis, with reduction in the plasma FA concentration, reverses these defects (2–4). Elevated FA levels also promote the synthesis and release of VLDL by the liver by 1) increasing substrate availability, 2) inhibiting insulin-mediated apoB degradation (5), and 3) reducing hepatic insulin clearance, contributing to hyperinsulinemia. In the brain, excessive FA uptake and its response to weight loss have been documented in subjects with the metabolic syndrome (6), and FAs are implicated in the central regulation of glucose production (7).
FA overflow from adipocytes to skeletal muscle and other tissues may result in free radical formation during oxidative phosphorylation, the intramyocellular accumulation of triglyceride, and the production of toxic …
