Diabetes, obesity, and Acrp30/adiponectin.

Diabetes mellitus (DM) is the clinical condition of inappropriate regulation of blood sugar by insulin, with resulting elevation of blood glucose and several other metabolic derangements. DM is comprised of two distinct entities: DM type 1 (DM-1), affecting the minority (5%–10%), is characterized by the destruction of insulin-secreting pancreatic β cells, leading to an absence of insulin. DM type 2 (DM-2), also called adult-onset DM and affecting 90%–95% of patients with diabetes, is characterized by peripheral defects in the response to insulin. Much work has focused on the underlying pathophysiology of these two diseases, related by a common metabolic defect—an absolute or functional loss of insulin action—but differing widely in pathogenesis. [For a recent review, see Saltiel (25)]. Insulin, as an anabolic hormone, acts to promote the clearance of glucose, chiefly in muscle through the stimulation of translocation of GLUT4 from intracellular pools to the plasma membrane; in liver by the inhibition of glycogenolysis and the enhancement of glycogen synthesis; and in adipose tissue by the uptake of free fatty acids (30) and its storage as fat. In adipose tissue, insulin also inhibits the breakdown of triglycerides and the resultant release of fatty acids by inhibiting hormone-sensitive lipase. The prevalence of DM-2 has continued to increase in recent years, with the number of patients in selected areas of the United States increasing 3-fold over an eight-year period (3), and is matched by a striking rise in childhood DM-2 (13). This increase has paralleled an increase in obesity, highlighting the intimate connection of these conditions. This link has been described in both the developed and increasingly in the developing world, demonstrating the influence of lifestyle on pathogenesis. However, strong genetic links between obesity and diabetes have also been described, and these links have been supported at the basic science level as well. In particular, derangements in lipid metabolism are a hallmark of DM-2. Much of the morbidity associated with obesity may be directly or indirectly associated with diabetes, as poorly controlled diabetes and obesity lead to a constellation of symptoms that are together known as the metabolic syndrome, or syndrome X (7,11,12). The term “the deadly quartet”, coined by Kaplan (11), refers to the abdominal obesity, insulin resistance, dyslipidemia, and hypertension found in the metabolic syndrome. Clearly, there are many factors underlying the development and progression of these two related conditions, and developing methods to counter them has become a major goal of contemporary medicine. Recent work has shown that adipose tissue, while long known for its capacity to store fat, has an additional important role as the source for a number of hormones and paracrine mediators, including resistin, adipsin, leptin, and TNF-α. Many groups are studying the physiologic role of these molecules and their connection to DM-2. Here we discuss a recently identified hormone produced only by adipocytes, Acrp30 (also called adiponectin), that may be central to the development of DM-2 and the metabolic syndrome. Acrp30 (adipocyte complement-related protein of 30 kDa) is a serum protein produced exclusively by adipose tissue. First identified in 1995 (28) in a subtractive hybridization screen to identify genes induced during differentiation of mouse 3T3-L1 preadipocytes to adipocytes, Acrp30 is up-regulated over 100-fold during adipocyte differentiation. Subsequently, other groups have identified the human homolog, called Apm1 (20). The predicted amino acid sequence (Figure 1) contains an amino-terminal signal sequence, followed by a nonconserved region of 28 amino acids, 22 collagen repeats, and a carboxyl-terminal domain with homology to the globular complement factor C1q. This segment is also homologous to Hib27, a member of a family of proteins found in the serum of animals capable of hibernation, but only when the animals are in the active state (15,28). Bacterially expressed full-length protein forms trimers, hexamers, and higher-order structures (31); similar species are also seen in serum, where the protein is found at high concentration, on the order of 5–10 μg/mL (1,28). The significance of these different species is further described below. The crystal structure of the globular head alone, expressed in bacteria, has similarity to TNF-α (29), forming a homotrimer with characteristic topology; the amino terminal and carboxyl termini are located in close proximity. Post-translational modifications include the addition of disialic acid residues (26) and hydroxylation and glycosylation at conserved lysine residues in the amino-terminal region of the molecule. Though the functional signifi-