Highlights of the 15th Annual Meeting and Clinical Congress of the American Association of Clinical Endocrinologists

April 26-30, 2006

Zachary T. Bloomgarden, MD

Disclosures

August 08, 2006

In This Article

The Dynamic Fat Cell

Robert R. Henry, MD,[4] University of California, San Diego, took listeners from cellular responses to an understanding of the whole organism's response to diabetes, with a focus on PPAR gamma, the fat cell, adiponectin, and cardiovascular disease (CVD).

Dr. Henry reminded the audience that "the fat cell is a very dynamic organ, and it becomes more complex as we delve into it." Type 2 diabetes is associated with vascular inflammation, and lack of adiponectin is an important mediator. Insulin resistance and ectopic fat accumulation are directly related, as is impaired pancreatic insulin secretion. Increased islet fat may lead to decreased insulin secretion, and increased hepatic and intramyocellular fat may decrease insulin action in the liver and muscle.

Dr. Henry discussed the "in the beginning, difficult to understand" link between visceral obesity, insulin resistance, abnormalities of glucose and fat metabolism, and vascular inflammation. These associations are found in many different ethnic populations, and Dr. Henry reminded the audience that "you don't need to be obese to have visceral obesity" and to be at risk of cardiovascular complications. As visceral abdominal fat increases, there is a decrease in insulin sensitivity independent of body mass index (BMI), so that in persons of Indo-Asian ethnicity, normal BMI and excess visceral fat is associated with severe insulin resistance and vascular inflammation.

Dr. Henry also reviewed "lessons learned from the glitazones." The TZDs were developed in the 1980s as lipid-lowering agents and subsequently demonstrated glucose-lowering effects as well as numerous CVD risk factor benefits. There are 3 PPARs: alpha, which is expressed in liver and skeletal muscle; beta, which has many lipid effects; and gamma, the mediator of the TZD effect, which is expressed primarily in adipose tissue. It is not known if the insulin-sensitizing effects of the TZDs are direct or indirect. These agents bind to PPAR gamma in a heterodimeric fashion with the retinoid X receptor (RXR), which is activated by retinoic acid, acting on the nuclear hormone response element of a variety of genes, particularly those of fatty acid metabolism, to activate or deactivate transcription. Activation of PPAR gamma has pancreatic effects; lipid effects on low-density lipoprotein particle size, high-density lipoprotein (HDL), and triglyceride; vascular effects; and effects on insulin sensitivity.

A large part of the effects of TZDs has to do with stabilizing or reducing visceral adiposity. However, this comes with the cost of subcutaneous fat accumulation, which may in fact mediate the drugs' benefits. TZDs have both direct effects on liver, muscle, and vascular tissue, and indirect effects, particularly in their actions on the liver. Adipocytes are highly involved in energy metabolism, and are the primary site of deposition of excess calories but also the primary site of production of a large number of cytokines. PPAR gamma is highly abundant in adipose tissue, influencing its differentiation and the production of adipokines.

The fat cell "is clearly an endocrine organ," Dr. Henry reminded the audience, and it produces angiotensin II, leptin, resistin, C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and plasminogen activator inhibitor -1, as well as free fatty acids. Smaller fat cells produce greater amounts of adiponectin. As adipose tissue mass increases with accretion of triglyceride, the production of adipokines increases. There is, however, one important exception: the production of adiponectin, which is derived only from white adipose tissue, decreases with increasing adipocyte tissue mass.

Adiponectin is a 30-kD, 244-amino acid peptide with structural homology to collagen VIII and X, complement factor C1q, and TNF-alpha. Adiponectin is highly abundant in the circulation; it constitutes 0.01% of total plasma proteins, leading some to suggest that it may have roles other than its hormonal actions. Low adiponectin levels are associated with insulin resistance, type 2 diabetes, and premature vascular disease. Men have lower levels than women, and obesity, metabolic syndrome, polycystic ovary syndrome, CVD, and both type 2 diabetes and a family history of type 2 diabetes are associated with lower levels. There are adiponectin gene mutations with lower plasma levels, which increase rates of type 2 diabetes and CVD, with a diabetes-susceptibility locus mapped to chromosome 3q27, the site of the adiponectin gene. Type 2 diabetes and obesity have additive effects in lowering adiponectin levels. Adiponectin levels correlate with insulin sensitivity and extremely well with HDL cholesterol, independent of age, blood pressure, adiposity, or lipids. Adiponectin shows an inverse relationship to the degree of adiposity (BMI, fat mass), blood glucose, insulin, triglyceride, systolic blood pressure, intramyocellular lipid content, CRP, and TNF-alpha. Adiponectin levels increase with weight loss and with TZD therapy, but not with exercise.

Thus, Dr. Henry reflected that adiponectin may be a major mediator of TZD effects on insulin action and vascular inflammation. A functional PPAR response element has been identified in the region of the adiponectin gene. Administration of the TZD troglitazone and pioglitazone is associated with increased adiponectin, while metformin does not increase adiponectin levels, presumably because it does not have direct effects on the adipocyte. Adipocyte adiponectin production increases with TZD treatment, suggesting an effect on production rather than on clearance. There is a particularly good correlation between components of total adiponectin and changes in insulin sensitivity.

Adiponectin has a globular trimerization domain at the carboxy terminus. This is attached to a collagenous domain, exhibiting posttranslational sialation, while the amino terminal regions activate the adiponectin receptor. The adiponectin monomer is assembled into trimers and then into variable-sized oligomers, with the larger molecular weight oligomers of 2-6 trimers appearing to have greater receptor action. There are 3 major molecular-weight multimer groups: 67 kD, 138 kD, and greater than 300 kD. Women appear to have greater levels of the high molecular weight component. There are 2 adiponectin receptors: R1 (particularly expressed in skeletal muscle) and R2 (particularly expressed in liver). Both R1 and R2 are found in adipose tissue, suggesting an autocrine/paracrine effect. Activation of R1 and R2 mediates activation of adenosine monophosphate kinase (AMPK), acetyl CoA carboxylase, mitogen-activated protein kinase, PPAR alpha ligand, fatty acid oxidation, and glucose uptake in muscle and liver.

The current hypothesis is that the higher molecular weight components preferentially bind to the hepatic R2, activating AMPK, which (via effects on malonyl CoA) leads to decreased glucose production and changes in fat metabolism, ultimately decreasing insulin resistance. In skeletal muscle, R1 activates AMPK, leading to increased insulin-stimulated glucose uptake and a variety of additional insulin-sensitizing effects. AMPK, which appears to be the main site of adiponectin action, is also a site of action of insulin, of metformin, and perhaps of TZDs, although their effect on AMPK may be mediated via adiponectin.

The vascular effects of TZDs include decreased carotid intima-media thickness, decreased neointimal/vascular smooth muscle cell proliferation, macrophage migration, foam cell formation, and improved vascular reactivity and endothelial function. Other vascular effects include decreased vascular inflammation, CRP, matrix metalloproteinase-9, plasminogen activator inhibitor-1, and thrombolysis. There is clinical evidence of decreases in blood pressure and in microalbuminuria.

Adiponectin, like the TZDs, has vascular effects. Injured blood vessels rapidly accumulate adiponectin, which appears to bind to collagen components. Adiponectin has vascular antiinflammatory effects, decreasing adhesion molecules, decreasing monocyte adhesion and migration through endothelial cells, macrophage-to-foam cell transformation, and macrophage cytokine production. Stimulation of nitric oxide production occurs in vitro with adiponectin, involving AMPK phosphorylation, which is increased by adiponectin, a potential underlying mechanism of its action.

Dr. Henry advanced the concept that adiponectin is the mediator of TZD action, and that adiponectin may be a link between metabolic syndrome, insulin resistance, type 2 diabetes, and premature CVD.

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