Environment International 35 (2009) 987–993 Contents lists available at ScienceDirect Environment International j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e n v i n t Review article Influence of environment on insulin sensitivity Giuseppe Latini a,b,⁎, M. Loredana Marcovecchio c, Antonio Del Vecchio d, Francesco Gallo a, Enrico Bertino e, Francesco Chiarelli c a Division of Neonatology, Perrino Hospital, Brindisi, Italy Clinical Physiology Institute, National Research Council of Italy (IFC–CNR), Italy Department of Pediatrics, University of Chieti, via dei Vestini 5, Chieti, Italy d Division of Neonatology, Di Venere Hospital, Bari, Italy e Neonatal Unit, Department of Pediatrics, University of Turin, Turin, Italy b c a r t i c l e i n f o Article history: Received 30 December 2008 Accepted 23 March 2009 Available online 23 April 2009 Keywords: Insulin sensitivity Insulin resistance Environmental pollutants Endocrine disruptors Intrauterine environment Type 2 diabetes Obesity a b s t r a c t Genetic and environmental factors influence insulin sensitivity (IS) during one's lifetime. Actually, uterine environment may affect IS at birth and later in life. In particular, various exogenous toxic substances, coupled to a genetic predisposition, may remarkably influence the regulation of the hypothalamus–hypophysis–adrenal gland axis, and the production or the activity of insulin, cerebral incretins, pro-inflammatory cytokines, and placental hormones. Owing to this reaction against environmental injuries, fetal growth and endocrine system development may be impaired, leading to low or large birth weight, or prematurity. Reduced growth in early life has been related to insulin resistance, which can be silent for years and evident in predisposed adults. The incidence of type 2 diabetes mellitus and obesity associated with sedentary lifestyle patterns and inadequate dieting behaviors in children and adolescents has rapidly increased during the last decade. Recent evidences suggest that the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor(PPAR- ) gene and the angiotensin converting enzyme (ACE) I/D gene polymorphism combined with environmental factors, such as phthalates interfering with the post receptorial action of insulin, alter insulinsensible tissues. Therefore, IS, deriving from a complex interaction between genotype and environment, may change during life and depends on previous metabolic control, which is a sort of metabolic memory. The goal for the future is preventing the complications associated with impaired IS through the control of exogenous factors and the use of drugs selectively effective on its pathogenesis. © 2009 Elsevier Ltd. All rights reserved. Contents 1. 2. 3. 4. 5. Introduction . . . . . . . . . . . . . . . . . . Definition of insulin sensitivity . . . . . . . . . Pathogenesis of insulin resistance and risk factors Environmental pollutants and insulin sensitivity . The role of other environmental factors . . . . . 5.1. Diet. . . . . . . . . . . . . . . . . . . 5.2. Lack of exercise . . . . . . . . . . . . . 5.3. Body exposure to high or low temperature 5.4. Seasonality . . . . . . . . . . . . . . . 5.5. Sun exposure . . . . . . . . . . . . . . 5.6. Altitude. . . . . . . . . . . . . . . . . 5.7. Hypoxaemia. . . . . . . . . . . . . . . 6. Conclusions . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 988 988 988 989 990 990 990 990 991 991 991 991 991 991 Abbreviations: BPA, bisphenol A; DDE, p'-diphenyldichloroethene; DEHP, di-(2-ethylhexyl) phthalate; ER, estrogen receptor; IS, insulin sensitivity; IRS, insulin receptor substrates; LXR, liver X receptors; NP, nonylphenol; OC, organochlorine pesticides; P12A, proline12 → alanine variant; PBDEs, polybrominated diphenyl ethers; PCBs, nondioxin-like polychlorinated biphenyls; POPs, persistent organic pollutants; PPARs, peroxisome proliferator-activated receptors; SOCS, suppressors of cytokine signalling; TCDD, 2,3,7,8tetrachlorodibenzo-p-dioxin; WAT, white adipose tissue. ⁎ Corresponding author. Division of Neonatology, Ospedale A. Perrino, s.s. 7 per Mesagne, 72100 Brindisi, Italy. Tel.: +39 0831 537471; fax: +39 0831 537861. E-mail address: gilatini@tin.it (G. Latini). 0160-4120/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.envint.2009.03.008 988 G. Latini et al. / Environment International 35 (2009) 987–993 1. Introduction Normal glucose tolerance can be maintained when there is a balance between insulin sensitivity (IS) and beta-cell function. IS indicates the ability of insulin to exert its physiological effect on glucose, lipid and protein metabolism and to regulate cellular growth and differentiation and vascular function (Biddinger and Kahn, 2006). As IS and insulin secretion are traits that are both genetically and environmentally determined, a remarkable variability in insulin action has been reported in humans (Jensen, 2000). About one-third of subjects who are most insulin resistant are at higher risk of developing several adverse clinical outcomes, including the metabolic syndrome and type 2 diabetes (Reaven, 2005). Thus, gene variants that affect primarily insulin action and particularly their interaction with the environment, are important modulators of glucose metabolism and insulin resistance syndrome (LópezMiranda et al., 2007). Extensive growing epidemiological and experimental evidence indicates that an adverse intrauterine or postnatal environment at critical periods in both humans and animals increases the risk of developing various adult-onset diseases, whose nature varies with the timing of exposure, as a result of altered carbohydrate metabolism (De Blasio et al., 2007; Zambrano et al., 2006; de Rooij et al., 2006; Gorski et al., 2006). Thus, insulin secretion in adulthood reflects that early in life, suggesting that it is determined genetically or by persistent influences of the perinatal environment. Although risk of adult-onset diseases, such as glucose intolerance, insulin insensitivity, and obesity may occur with or without reduced birth weight (Poore et al., 2007) in humans, there is increasing epidemiological evidence, which associates low birthweight with later metabolic disorders that are likely a consequence of an early persistent reduction in IS (Hofman et al., 2006; Hofman and Cutfield, 2006; Mericq, 2006). Other environmental etiological factors, such as diet, sedentary lifestyle, high altitude and cold exposure have been shown to influence IS (Krampl et al., 2001; Vallerand et al., 1988; Cañete et al., 2007; Hamilton et al. 2007). However, endocrine-disrupting chemicals in the environment may also, at least partly, play a role in impairing IS, but to date little is known on their potential role(Newbold et al., 2008; Jurewicz et al., 2006; Latini et al., 2004; Davey et al., 2008). 2. Definition of insulin sensitivity IS indicates the ability of insulin to exert its physiological effect on glucose, lipid and protein metabolism and to regulate cellular growth and differentiation and vascular function (Biddinger and Kahn, 2006). In contrast, insulin resistance describes a state where there is reduced biological effect for any given concentration of insulin (Kahn, 1978; Matthaei et al., 2000). It is interesting to underline that the phenotype of insulin resistance varies on the basis of the specific component of the signalling pathway affected and on the tissue where the defect is more evident (Biddinger and Kahn, 2006). Several defects in the insulin signalling cascade have been implicated in the pathogenesis of insulin resistance, such as reduced synthesis or increased degradation of components of the system; an increased inhibitory serine phosphorylation of the insulin receptor or the insulin receptor substrates; interaction of components of the signalling pathway with inhibitory proteins or an alteration of the ratio of the different proteins of the system (Biddinger and Kahn, 2006; Matthaei et al., 2000; Bajaj and De Fronzo, 2003). Defects in the expression, binding, phosphorylation state or kinase activity of the insulin receptor can all account for insulin resistance (Pessin and Saltiel, 2000). However, defects in the insulin receptor are mainly responsible for rare forms of severe insulin resistance. Milder forms of insulin resistance are more likely related to defects in other components of the insulin signalling pathway, such as the insulin receptor substrates or other downstream mediators (Pessin and Saltiel, 2000; Hansen et al., 1997; Kawanishi et al., 1997). 3. Pathogenesis of insulin resistance and risk factors Insulin resistance is believed to have both genetic and environmental factors implicated in its etiology (Matthaei et al., 2000; Lee, 2006). Genetic factors have an important role in determining insulin resistance as supported by the finding of decreased insulin activity and hyperinsulinemia among first degree, non-diabetic relatives (Dannadian et al., 1999). To this regard, at least eighteen genes convincingly associated with type 2 diabetes have been identified. Many of these genes implicate pancreatic beta-cell function in the pathogenesis of the disease while only one is associated with insulin resistance (Ridderstråle and Groop, 2009; Florez, 2008). However, many other factors can influence IS, such as obesity, puberty, ethnicity, gender, perinatal factors as well as environmental factors (Lee, 2006). Obesity represents the major risk factor for the development of insulin resistance in children and adolescents, as in adults, and insulin resistance/hyperinsulinemia is believed to be an important link between obesity and the associated metabolic and cardiovascular risk (Caprio, 2002). Adipose tissue seems to play a key role in the pathogenesis of insulin resistance through several released metabolites, hormones and adipocytokines that can affect different steps in insulin action (Matsuzawa, 2005). Adipocytes produce non-esterified fatty acids, which inhibit carbohydrate metabolism and contribute to the pathogenesis of insulin resistance (Randle, 1998). Several ‘adipocytokines’ have been related to adiposity indexes as well as to insulin resistance (Matsuzawa, 2005). Adiponectin is one of the most common cytokines produced by adipose tissue, with an important insulin-sensitizing effect associated with anti-atherogenetic properties. Whereas obesity is generally associated with an increased release of metabolites by adipose tissue, levels of adiponectin are inversely related to adiposity (Gil-Campos et al., 2004). An altered partitioning of fat between subcutaneous and visceral or ectopic sites has been associated with insulin resistance. Visceral fat has a better correlation with IS than subcutaneous or total body fat, in both obese adults and children. Ectopic deposition of fat in the liver or muscle can also be responsible for insulin resistance in obese subjects, as the accumulation of fat in these sites impairs insulin signalling (Weiss and Kaufman, 2008). Gender is another important determinant of insulin resistance, with girls being more insulin resistant than boys. This difference in insulin resistance persists also after adjusting for body composition (Moran et al. 1999; Lee et al., 2006). Puberty is generally characterised by a physiological decrease in IS, that is reversible at the end of puberty. Cross-sectional as well as longitudinal studies have shown that puberty is associated with a 30– 50% decrease in IS and this is associated with an increased insulin secretion (Caprio et al., 1989). Epidemiological and clinical data indicate the existence of racial differences in insulin resistance, with the greatest prevalence among children and adolescents belonging to ethnic minorities: Native Americans, Mexican Americans, African Americans and Asian Americans (Lee, 2006; Svec et al., 1992). Risk of developing insulin resistance and type 2 diabetes appears to increase with either low or high birth weight, possibly because undernutrition or overnutrition in utero may cause permanent metabolic and hormonal changes that promote obesity, insulin resistance and β-cell dysfunction later in life (Phillips, 1998; Dabelea et al., 1999; Barker, 2005). Low birth weight, particularly when associated with a rapid postnatal weigh gain, has consistently been associated with insulin resistance and with other G. Latini et al. / Environment International 35 (2009) 987–993 adult-onset diseases. In addition, the risk for insulin resistance is increased not only among children born at term but small for gestational age, but also among children who had born prematurely independently of their birth weight (Hofman et al., 2004). Maternal diabetes is associated with increased birth weight and greater risk of childhood insulin resistance and type 2 diabetes (Silverman et al., 1995). 4. Environmental pollutants and insulin sensitivity Little is known on the potential role of environmental toxicants in impairing IS. Epidemiological and animal studies show that small changes in the developmental environment can induce phenotypic changes affecting an individual's responses to their later environment. As a consequence, environmental pollutants may induce greater risk of chronic disease, even at low exposure levels (Hanson and Gluckman, 2008) (Fig. 1). Several chemicals, such as arsenic, persistent organic pollutants (POPs), especially organochlorine (OC) pesticides and nondioxin-like polychlorinated biphenyls (PCBs), 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD), phthalates, bisphenol A (BPA) and nonylphenol (NP), and furans have been found to interfere with the function of the endocrine system, which is known to be responsible for growth, sexual development and many other essential physiological functions and therefore they are suspected of having endocrine-disrupting or modulating effects. These chemicals with hormone-like activity can disrupt the programming of endocrine signalling pathways, especially if exposure occurs early in life during critical stages of development, such as fetal life and infancy, thus determining adverse health consequences (Newbold et al., 2008; Jurewicz et al., 2006; Latini et al., 2004; Davey et al., 2008). The action of endocrine disruptors includes activation of nuclear receptors and metabolic sensors, such as the peroxisome proliferatoractivated receptors (PPARs), which together with liver X receptors 989 (LXR), have been shown to be involved in the control of IS (Feige et al., 2007; Latini et al., 2008). In particular, the PPARs are major regulators of lipid and glucose metabolism, allowing adaptation to the prevailing nutritional environment (Ferré, 2004). Among the above mentioned environmental pollutants, arsenic has been shown to induce diabetes mellitus in humans and it may impair pancreatic beta-cell function, particularly insulin synthesis and secretion (Lai et al., 1994; Dìaz-Villaseñor et al., 2006). Moreover, arsenic may affect IS in peripheral tissues, by modifying the expression of genes involved in insulin resistance, thus increasing risk for developing type 2 diabetes (Navas-Acien et al., 2006; Dìaz-Villaseñor et al., 2007). On the other hand, BPA may affect the glucose transport in mouse adipocytes (Alonso-Magdalena et al., 2006; Sakurai et al., 2004) and it has been shown to affect blood glucose homeostasis through different pathways thus increasing the risk of type 2 diabetes (Ropero et al., 2008). In addition, an increase in body weight that was apparent soon after birth and continued into adulthood was observed in the off springs of female rats prenatally exposed to BPA (Rubin et al., 2001). Moreover, BPA has been shown to directly affect pancreatic beta-cell function through Estrogens' receptor (ER) alpha activation outside the nucleus (Alonso-Magdalena et al., 2008). Jn addition, BPA inhibits the release from human adipocytes of adiponectin that protects humans from metabolic syndrome (Hugo et al., 2008). Furthermore, an association between serum BPA concentrations and metabolic disorders in adult men has been recently reported (Lang et al., 2008; vom Saal and Myers, 2008). With regard to TCDD, a dioxin contained in the herbicide mixture Agent Orange, it has been shown that high blood levels of this dioxin may promote an insulin resistant state (Kern et al., 2004; Cranmer et al., 2000). Exposure to POPs, xenobiotics accumulated in adipose tissue, such as PCBs, polychlorinated dibenzo-p-dioxins (PCDDs), dichloro Fig. 1. Influence of exogenous and endogenous factors on insulin sensitivity. 990 G. Latini et al. / Environment International 35 (2009) 987–993 diphenyl trichloroethane (DDT) and its major metabolite 1,1-dichloro2,2-bis (p-chlorophenyl)-ethylene (p,p' -DDE) is strongly associated with type 2 diabetes (Rignell-Hydbom et al., 2007) and consequently with higher risk of peripheral neuropathy, a common long-term complication of diabetes (Lee et al., 2008). In particular, p,p'diphenyldichloroethene (DDE) rather than OC pesticides or PCBs exposure may increase insulin resistance, thus leading to type 2 diabetes (Lee et al., 2007a,b; Jones et al., 2008; Turyk et al., 2009). However, it seems that POPs may mainly affect insulin secretion rather than being involved in the pathogenesis of insulin resistance (Jørgensen et al., 2008). In particular, most POPs have been shown to induce a great number and variety of genes, including several that alter insulin action (Carpenter, 2008). Moreover, the POPs can affect not only the physiological role of white adipose tissue (WAT), by modulating WAT differentiation, metabolism and function, but they may also influence the development of obesity-associated diseases (Müllerová and Kopeck , 2007). PCBs may affect the activities of gluconeogenic and lipogenic enzymes in rat liver, thus likely interfering with regulatory hormone actions (Boll et al., 1998). Furthermore, it has been shown that polybrominated diphenyl ethers (PBDEs), disrupt insulin in rats (Hoppe and Carey, 2007). Recently, phthalates have been associated with anti-androgenic effects in humans, including decreased testosterone levels. In male adults low testosterone has been associated with increased prevalence of obesity, insulin resistance and diabetes, and phthalate exposure with abdominal obesity and insulin resistance, thus suggesting that phthalates may contribute to the population burden of obesity, insulin resistance, and related clinical disorders (Stahlhut et al., 2007). Moreover, direct adverse effects of di-(2-ethylhexyl) phthalate (DEHP) on insulin receptor and glucose oxidation in Chang liver cells has been reported and suggests that DEHP exposure may have a negative influence on glucose homeostasis (Rengarajan et al., 2007). On the other hand, environmental phthalate monoesters have the potential of activating rodent and human PPARs, which may contribute to adipocyte differentiation and insulin sensitization (Latini et al., 2008; Hurst and Waxman, 2003). Moreover, it has been reported that the proline12 → alanine variant (Pro12Ala) of the PPAR-gamma2 gene may be a genetic marker of risk for obesity persisting into adolescence (Eriksson et al., 2002). There is also a well-established association between the PPAR-gamma2 gene and type 2 diabetes. It has been shown that the effects of the Pro12Pro and Pro12Ala polymorphisms of the PPAR-gamma2 gene in elderly people depends on their body size at birth. The well-known association between small body size at birth and insulin resistance was seen only in individuals with the high-risk Pro12Pro allele, thus suggesting a gene–environment interaction (Witchel et al., 2001). 5. The role of other environmental factors 5.1. Diet Diet composition has been suggested as an additional factor promoting and/or worsening insulin resistance. Animal and human studies suggest that a high energy intake as well as a diet rich in fat and carbohydrates and low in fiber could increase the risk of developing insulin resistance. It is known that a high protein intake is associated with an impairment in glucose metabolism due to insulin resistance. Based on the ‘early protein hypothesis’, a high protein intake during infancy can enhance weight gain and predispose to obesity and insulin resistance later in life (Cañete et al., 2007). However, it is also well known that different proteins can exert an opposite effect on IS. Soy proteins can improve IS and positively affect glucose homeostasis. Similarly fish proteins have a beneficial effect on IS (Tremblay et al., 2007). 5.2. Lack of exercise Lack of physical activity is another risk factor for the development of insulin resistance and its complications (Perseghin et al., 1996). Exercise can improve IS by acting on muscle, liver and adipose tissue. In the muscle, exercise can increase insulin dependent glucose transporter GLUT-4 expression. Exercise also determines increase in blood flow, therefore allowing insulin transport to peripheral tissues (Hespel et al., 1995). Nonetheless, exercise can stimulate the release of factors, such as bradikynin, which can in turn promote glucose uptake. Stimulation of glucose uptake also occurs in adipocytes as a consequence of exercise, whereas in the liver there is an exercisedependent reduction of glucose output (De Fronzo et al., 1987). In addition, exercise can contribute to achieve and maintain a normal body weight, which in turn can improve IS (Koivisto and Yki-Järvinen, 1987). 5.3. Body exposure to high or low temperature Outside temperature can influence IS by acting on insulin secretion, insulin receptor sensibility and counter-insular hormonal production. The long-term exposure to extreme environment induces possible psychophysiological mechanisms that increases peripheral IS, total cholesterol and hematocrit (due to the conditions of hypobaric hypoxia) (Farrace et al., 1999). Concentrations of plasma glucose, free fatty acids, insulin, and glucagon are influenced by cold exposure: plasma insulin concentration is reduced (Shephard, 1993) but insulin action on glucose metabolism is enhanced, so that blood glucose turnover rate is increased (Sano et al., 1999), particularly in the first period of life (Sanz Sampelayo et al., 2000), due to higher glucose uptake (Agosto et al., 1997); exposure to slightly higher temperature could increase insulin receptors affinity to glucose (Nagasawa et al., 1994). There is a tissue-specific regulation of the insulin signalling pathway: in white adipose tissue and skeletal muscle an impaired molecular response to insulin is detected, while in brown adipose tissue an enhanced response to insulin is evident. Muscle and white adipose tissues are able to take up large amounts of glucose, even in the face of an apparent molecular resistance to insulin (Gasparetti et al., 2003). The strategy is to favour heat-producing brown adipose tissue by changing its insulin status (content and binding to plasma membranes) but also to be ready for long periods of diet restriction (Okano et al., 1993). The molecular mechanisms explaining the temperature influence on IS are related to the release of insulin from beta cells and effects on insulin receptor exposition and binding. Solute permeability across membranes is higher with increasing temperature (Zhang and Wu, 2004): exocytosis of insulin granules already docked beneath the membrane is minimally affected by cooling; whereas insulin secretion is influenced by high overall temperature because the replenishment of the readily releasable insulin pool is temperature dependent (Renström et al., 1996). There is an inverse relationship between the receptor number and the degree of heat resistance of both receptors and whole cells: the binding is unaffected by temperatures below 43° C, but, above this temperature it is inhibited in a time– temperature dependent manner. Heating appears to act directly on the insulin receptor rather than indirectly on subsequent energy dependent processes, such as internalization (Calderwood and Hahn, 1983a). In particular, decreased insulin binding is due to receptor's loss, whereas thermal resistance of insulin binding is induced only when residual receptor loss (due to heating) occurs. In addition, decay of resistance is closely correlated with recovery of insulin binding capacity (Calderwood and Hahn, 1983b). A fundamental role should be played by the sympathetic reactivity: in multiple regression analyses, corrected for fasting glucose at entry, family history of diabetes, blood pressure-lowering medication, body mass index at entry, and level of exercise, norepinephrine response to cold pressure G. Latini et al. / Environment International 35 (2009) 987–993 test has been found to be a positive predictor of future HOMA–IR (Flaa et al., 2008). Maybe temperature influences the action of diet components on insulin sensitivity. Low magnesium diet can depress the enhanced tissue responsiveness to insulin in the cold environment, and decrease insulin-mediated glucose disposal (Achmadi et al., 2001). Chromium improves insulin binding, insulin receptor number, insulin internalization, beta cell sensitivity and insulin receptor enzymes with overall increases in insulin sensitivity (Anderson, 1997), but its supplementation seems not to influence glucose metabolism or insulin action in response to cold exposure in normoglycemic people (Sano et al., 2000), but only as chromium picolinate in few type 2 diabetic patients (Martin et al., 2006; Wang et al., 2007). Proteins could modify insulin action in response to cold exposure (Sano and Tarashima, 2001). 5.4. Seasonality Although plasma cortisol and tissue sensitivity to glucocorticoids varies with seasons (higher in winter) (Walker et al., 1997), no significant seasonal variation in IS and glucose effectiveness is evident (Gravholt et al., 2000). Forcada and Abecia (2006) supposed a seasonal modification of the insulin-induced orexogenic neuropeptide Y RNA levels, (Kos et al., 2007), and this can lead to a different glucose intake, a reduction of leptin blood levels and consequently a leptinmediated insulin sensitivity increase (Havel, 2002). Seasonality can influence insulin sensitivity through sun-dependent skin D3 conversion (Alemzadeh et al., 2008). 5.5. Sun exposure Insufficient sun exposure can lead to a deficient conversion of colecalciferol to vitamin D3 and may, at least partly, contribute to the impairment in insulin secretion and insulin action (Borissova et al., 2003; Dauncey et al., 2001), and probably contributes to the hypothalamic arousal syndrome, which is responsible for the development of endocrine abnormalities with parallel activation of the HPA axis and the central sympathetic nervous system (Björntorp et al., 1999). Possible mechanisms of action of vitamin D include stimulation of insulin secretion and effects on insulin sensitivity. Sun exposure usually implies greater outdoor physical activity, which in itself may have beneficial effects on insulin sensitivity, unrelated to serum 25hydroxyvitamin D concentrations(Tai, 2008a,b). 5.6. Altitude After short-term exposure to altitude, men and women appear to be less sensitive to insulin than at sea level (Braun et al., 2001; Jakobsson and Jorfeldt, 2006), but an almost-3-week altitude vacation intervention has a positive, but reversible influence on all key markers of the metabolic syndrome (Greie et al., 2006): fasting C-peptide levels and beta-cell function are similar, fasting concentrations of insulin and proinsulin are lower, and IS is higher at high altitude compared with sea level (Krampl et al., 2001). These improvements appear to be partially associated with a reduction in central fatness (Lee et al., 2004). Hypoxia in healthy subjects, induced by chronic altitude exposure, stimulates glucose production with decreased hepatic insulin sensitivity, but increases peripheral insulin sensitivity (Sauerwein and Schols, 2002). 5.7. Hypoxaemia In chronic lung affections there is an increased peripheral insulin sensitivity despite the existence of the long-term disease (Sauerwein and Schols, 2002). Severely hypoxaemic patients have altered glucose metabolism, which cannot be readily explained by changes in glucoregulatory hormones or short-term alterations in oxygenation 991 (Hjalmarsen et al., 1996). Normalization of oxygen saturation has an immediate effect on glucose tolerance and tissue sensitivity to insulin (Jakobsson and Jorfeldt, 2006). Many oxygen-sensitive regulatory mechanisms work through hypoxia inducible factor 1, that induces gene expression for fructose2-6-biphosphatase, an enzyme switching glucose metabolism towards glycolysis, allowing energy production in anaerobic conditions. Hypoxia inducible factor 1 also induces the promoter of the leptin gene, and then influences insulin sensitivity (Raguso et al., 2004). 6. Conclusions IS is a complex trait, influenced by both genetic and environmental factors, which may change during life. Impairments in IS are strictly related to the development of metabolic and cardiovascular diseases. The current available evidence is inadequate to establish a definitive causal role of environmental factors in influencing IS and consequently increasing type 2 diabetes risk. Further studies are needed, in order to (i) explore the contribution of genetic and environmental factors in influencing IS, (ii) evaluate genetic and environmental interactions and (iii) better understand the pathophysiological mechanisms leading adverse perinatal environmental factors to impaired IS. References Achmadi J, Sano H, Terashima Y. 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