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 . . . . . . . . . . . . . . . . . . . . .
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988
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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.
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