Insulin sensitivity: modulation by nutrients and inflammation
Simon Schenk, Maziyar Saberi, Jerrold M. Olefsky
Simon Schenk, Maziyar Saberi, Jerrold M. Olefsky
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Insulin sensitivity: modulation by nutrients and inflammation

Abstract

Insulin resistance is a major metabolic feature of obesity and is a key factor in the etiology of a number of diseases, including type 2 diabetes. In this review, we discuss potential mechanisms by which brief nutrient excess and obesity lead to insulin resistance and propose that these mechanisms of action are different but interrelated. We discuss how pathways that “sense” nutrients within skeletal muscle are readily able to regulate insulin action. We then discuss how obesity leads to insulin resistance via a complex interplay among systemic fatty acid excess, microhypoxia in adipose tissue, ER stress, and inflammation. In particular, we focus on the hypothesis that the macrophage is an important cell type in the propagation of inflammation and induction of insulin resistance in obesity. Overall, we provide our integrative perspective regarding how nutrients and obesity interact to regulate insulin sensitivity.

Authors

Simon Schenk, Maziyar Saberi, Jerrold M. Olefsky

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Figure 1

Fatty acid metabolism and insulin action in skeletal muscle or liver.

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Fatty acid metabolism and insulin action in skeletal muscle or liver. Ob...
Obesity results in an increased flux of free fatty acids into the circulation and uptake by the myocyte or hepatocyte. Activated fatty acids (i.e., fatty acyl-CoAs) are “metabolized” primarily via one of two pathways, oxidation or storage. When fatty acid flux exceeds the ability of these pathways to dispose of fatty acyl-CoAs, intermediaries of fatty acid metabolism (e.g., DAG, PA, LPA, ceramide) accumulate. In turn, these fatty acid intermediates can activate a number of different serine kinases that can negatively regulate insulin action. Ceramide can also impair insulin action through interactions with PKB/Akt. An inability to completely oxidize fatty acids through β-oxidation, which leads to an accumulation of acylcarnitines, has also been hypothesized to cause insulin resistance, although the precise mechanisms leading to insulin resistance are, to date, unknown. AGPAT, acylglycerol-3-phosphate acyltransferase; PAP, PA phosphohydrolase.