The regulatory role of insulin in energy metabolism and leukocyte functions

Abstract

Insulin is the hormone responsible for maintaining glucose homeostasis in the body, in addition to participating in lipid metabolism, protein synthesis, and the inhibition of gluconeogenesis. These functions are well characterized in the classic organ target cells that are responsible for general energy regulation: the liver, skeletal muscle, and adipose tissue. However, these actions are not restricted to these tissues because insulin has been shown to affect most cells in the body. This review describes the role of insulin in leukocyte signaling pathways, metabolism and functions, and how insulin resistance could affect this signaling and deteriorate leukocyte metabolism and function, in addition to showing evidence that suggests leukocytes may substantially contribute to the development of systemic insulin resistance.

Keywords: insulin; insulin resistance; insulin signaling; leukocytes.

FIGURE 1

Regulation of metabolism and leukocytes functions by insulin. Leukocytes express the insulin receptor. Once insulin binds to its receptor, it activates two signal transduction pathways. The MAPK pathway results in ERK‐1/2 activation, in leukocytes it participates in adhesion, chemokinesis, chemotaxis and cytokine production. PI3K pathway, activating AKT and phosphoryling different substrates downstream of the signaling cascade in functions such as protein synthesis, inflammatory response, metabolic rewiring, and chemotaxis

FIGURE 2

Molecular mechanisms involved in insulin resistance. Insulin signaling requires IRS‐1/2 phosphorylation at tyrosine residues and subsequent AKT phosphorylation at Thr308 and Ser473. Kinases such as JNK, IKK and PKC phosphorylate IRS in serine residues activating transcription factors wich improving pro‐inflammatory genes expression, deteriorating insulin signaling and producing insulin resistance. These kinases are activated by molecular mechanisms involving hyperglycemia, AGEs production, pro‐inflammatory cytokines, LPS, the increasing of free fatty acids and endoplasmic reticulum stress. Another mechanism described involve NE, wich can intake into the cell and degrade IRS, producing insulin resistance