Obesity and Type 2 Diabetes

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During the last 20 years, obesity has reached epidemic proportions in the United States and worldwide. Recent data from the National Center for Health Statistics indicate that 30% of U.S. adults 20 years of age and older (over 60 million people) are obese (Ogden, Carroll, Curtin, McDowell, Tabak, and Flegal 2006). Visceral obesity and three other pathologic conditions (dyslipidemia, hypertension, and insulin resistance) comprise the so-called "metabolic syndrome," also known as "Syndrome X." Syndrome X is a major risk factor for type 2 diabetes (T2D; also called non-insulin-dependent diabetes mellitus, or NIDDM) (Haffner, Ruilope, Dahlof, Abadie, Kupfer, and Zannad 2006).

A common feature of obesity, insulin resistance, and T2D is chronic, low-grade inflammation (Dandona, Aljada, and Bandyopadhyay 2004; Dandona, Aljada, Chaudhuri, Mohanty, and Garg 2005; Weisberg et al. 2006; Weisberg, McCann, Desai, Rosenbaum, Leibel, and Ferrante 2003; Wellen and Hotamisligil 2005). Markers of chronic subclinical inflammation (e.g., C-reactive protein and IL-6) are closely linked to insulin resistance and obesity (Finegood 2003; Temelkova-Kurktschiev, Henkel, Koehler, Karrei, and Hanefeld 2002). In addition, proinflammatory cytokines such as TNF-a, monocyte chemotactic protein-1 (MCP-1), IL-6, IL-8, and macrophage inflammatory peptide (MIP)-1aare often increased in patients with obesity, insulin resistance and T2D (Gerhardt, Romero, Cancello, Camoin, and Strosberg 2001; Mohamed-Ali et al. 1997; Sartipy and Loskutoff 2003; Takahashi et al. 2003; Uysal, Wiesbrock, Marino, and Hotamisligil 1997; Weisberg et al. 2003, 2006; Xu et al. 2003; Yudkin, Kumari, Humphries, and Mohamed-Ali 2000). In obesity, MCP-1, a member of the chemokine family, is thought to play a key role in the recruitment of monocytes/macrophages to adipose tissue, thereby contributing to the proinflammatory environment (Weisberg et al. 2003). Furthermore, adipose tissue itself secretes immune-modulatory proteins (i.e., leptin, adiponectin, and resistin) that are collectively known as adipokines. Leptin promotes macrophage production of IL-1P, IL-6, IL-12, and TNF-a and decreases the antiinflammatory cytokine IL-10 both in vitro and in vivo (Loffreda et al. 1998). In contrast, adiponectin has anti-inflammatory properties and its plasma concentrations are positively and strongly associated with insulin sensitivity and negatively associated with TNF-a levels (Abbasi et al. 2004; Ajuwon and Spurlock 2005). Adipokines have been implicated in the pathogenesis of obesity, metabolic syndrome and T2D (reviewed in Fantuzzi (2005), Fernandez-Real (2006), Vettor, Milan, Rossato, and Federspil (2005)).

The pathogenesis of T2D is complex and multifactorial. However, recent studies support a role for chronic inflammation in the development of metabolic syndrome and T2D. Furthermore, many of the proinflammatory substances associated with chronic inflammation also modulate sleep (Cannon 2000; Elenkov, Iezzoni, Daly, Harris, and Chrousos 2005; Kapsimalis, Richardson, Opp, and Kryger 2005). A number of studies have revealed interactions between obesity and sleep in both people and mice. For example, C57BL/6J mice rendered obese via access to a high fat diet show increased total sleep, more bouts of sleep, and shorter periods of waking (Jenkins, Omori, Guan, Vgontzas, Bixler, and Fang 2005; O'Donnell et al. 1999). Obese leptin-deficient mice also show abnormal sleep architecture (i.e., more frequent arousals, more frequent but shorter bouts of sleep, greater total daily sleep time, and a flattened diurnal rhythm of sleep-wake) (Laposky, Shelton, Bass, Dugovic, Perrino, and Turek 2006).

In people, metabolic syndrome and its associated panoply of problems (obesity, dyslipidemia, insulin resistance) are also often associated with fragmented sleep. Analogously, reduced sleep is associated with metabolic perturbations, glucose intolerance, and insulin resistance. A landmark study demonstrated relative glucose intolerance in healthy men after a single night of sleep loss (Spiegel, Leproult, and Van Cauter 1999a). Additional laboratory-based and epidemiologic studies have since supported a relationship of impaired or reduced sleep to insulin resistance and T2D (Al-Delaimy, Manson, Willett, Stampfer, and Hu 2002; Ayas et al. 2003; Elmasry, Janson, Lindberg, Gislason, Tageldin, and Boman 2000; Elmasry et al. 2001; Ip, Lam, Ng, Lam, Tsang, and Lam 2002; Punjabi, Sorkin, Katzel, Goldberg, Schwartz, and Smith 2002; Resnick et al. 2003; Spiegel, Knutson, Leproult, Tasali, and Van Cauter 2005). In fact, the frequent association of sleep apnea, which causes reduced or fragmented sleep, with the other facets of "Syndrome X" has led to the suggested alternative title of "Syndrome Z" (Wilson, McNamara, and Collins 1998).

These relationships have fostered speculations that reduced, impaired or disrupted sleep, which are common in today's society, may contribute to the development of both obesity and diabetes. Recent work has established that sleep loss and sleep disorders alter normal endocrine diurnal rhythms and metabolic function (Leproult, Copinschi, Buxton, and Van Cauter 1997; Qin, Li, Wang, Wang, Xu, and Kaneko 2003; Spiegel, Tasali, Penev, and Van Cauter 2004; Van Cauter, Blackman, Roland, Spire, Refetoff, and Polonsky 1991), perhaps contributing to obesity. This clustering of pathophysiologic conditions suggests positive (reinforcing) interactive metabolic feedback mechanisms that link sleep loss, obesity, and glucose intolerance via common neuroendocrine and immune mediators (Bjorntorp and Rosmond 2000; Boethel 2002).

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