Rabu, 04 Februari 2009

Pathophysiology of Diabetes Mellitus Type 2: Roles of Obesity, Insulin Resistance and -Cell Dysfunction

Physiology of Adipose Tissues

Adipose tissues are located throughout the body. Some of these depots are structural,
providing mechanical support but contributing little to energy homeostasis. Other
adipocytes exist in the skin as subcutaneous fat. Finally, several distinct depots are found within the body cavity, surrounding the heart and other organs, associated
with the intestinal mesentery, and in the retroperitoneum. This visceral fat drains
directly into the portal circulation and has been linked to morbidities, such as cardiovascular disease and T2D. Adipose tissues modulate energy balance by regulating
both food intake and energy expenditure. They a lso have a considerable effect on
glucose balance, which is mediated by endocrine (mainly through the synthesis
and release of peptide hormones, the so-called ‘adipokines’) and non-endocrine
mechanisms.

Among the endocrine factors, adipocyte-derived proteins with antidiabetic action
include leptin, adiponectin, omentin and visfatin. For instance, in addition to its wellcharacterized role in energy balance, leptin reverses hyperglycemia by improving
insulin sensitivity in muscles and the liver. According to the current view that intracellular lipids may contribute to insulin resistance, this occurs most likely by reducing intracellular lipid levels through a combination of direct activation of AMP-activated protein kinase (AMPK) and indirect actions mediated through central neural pathways [2]. Other factors tend to raise blood glucose, including resistin, tumor necrosis factor- (TNF-), interleukin-6 (IL-6) and retinol-binding protein 4 (RBP4). TNF- is produced in macrophages and reduces insulin action [3]. IL-6 is produced by adipocytes, and has insulin-resistance-promoting effects as well [4]. Such ‘adipocytokines’ can induce insulin resistance through several mechanisms, including c-Jun N-terminal kinase 1 (JNK1)-mediated serine phosphorylation of insulin receptor substrate-1 (IRS-1) (see below), IB kinase- (IKK-)-mediated nuclear factor-B (NF-B) activation, induction of suppressor of cytokine signaling 3 (SOCS3) and production of ROS [for review, see 5]. RBP4, a secreted member of the lipocalin superfamily, is regulated by the changes in adipocyte glucose transporter 4 (GLUT4) levels. Studies have shown that overexpression of RBP4 impairs hepatic and muscle insulin action, and Rbp4/mice show enhanced insulin sensitivity [6]. Furthermore,
high serum RBP4 levels are associated with insulin resistance in obese humans and
patients with T2D [7]. The exact mechanisms how RBP4 impairs insulin action are,
however, not clear. Adipocytes also release non-esterified fatty acids (NEFAs) into the circulation, which may therefore be viewed as an adipocyte-derived secreted non-endocrine product. They are primarily released during fasting, i.e. when glucose is limiting, as a nutrient source for most organs. Circulating NEFAs reduce adipocyte and muscle glucose uptake, and also promote hepatic glucose output, consistent with insulin resistance. The net effect of these actions is to promote lipid burning as a fuel source in most tissues, while sparing carbohydrate for neurons and red blood cells, which depend on glucose as an energy source. Several mechanisms have been proposed to account for the effects of NEFAs on muscle, liver and adipose tissue, including protein kinase C (PKC) activation, oxidative stress, ceramide formation, and activation of Toll-like receptor 4 [for review, see 5, 8]. Because lipolysis in adipocytes is repressed by insulin, insulin resistance from any cause can lead to NEFA elevation, which, in turn, induces additional insulin resistance as part of a vicious cycle. -Cells are also affected by NEFAs, depending in part on the duration of exposure; acutely, NEFAs induce insulin secretion (as after a meal), whereas chronic exposure to NEFAs causes a decrease in insulin secretion [9] (see below), which may involve lipotoxicityinduced apoptosis of islet cells [10] and/or induction of uncoupling protein-2 (UCP- 2), which decreases mitochondrial membrane potential, ATP synthesis and insulin secretion [10, 11]. The ability to store large amounts of esterified lipid in a manner
that is not toxic to the cell or the organism as a whole may therefore be one of the
most critical physiological functions of adipocytes.

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