Chapter 5: Obesity, Diabetes, and the Metabolic Syndrome Conserve Energy

The Metabolic Syndrome Defined:

The metabolic syndrome is closely linked to obesity and inactivity. It is a cluster of conditions that occur together, increasing risk of heart disease, stroke, and type 2 diabetes. Treatment includes lifestyle changes and medication. A healthy diet and regular exercise can result in weight loss and improved outcomes. If lifestyle changes aren’t enough, medications can help. Here are some defining elements of the metabolic syndrome:   Increased blood pressure High blood sugar Excess body fat around the waist Abnormal cholesterol or triglyceride levels Insulin resistance

Chapter Summary

The modern epidemics of obesity, cardiovascular disease, and diabetes mellitus are essentially a product of our modern environment. Artificially high levels of sugars, fats, processed foods, and sedentary behavior constitute an “obesogenic” environment that makes us more susceptible to the metabolic syndrome today than our foraging ancestors were millennia ago. However, early experiences play a role as well. It has become clear that poor nutrition early in life can increase a person’s propensity for developing the metabolic syndrome. It is thought that the fetus has an adaptive ability to perceive nutritional deprivation and reprogram its metabolic systems for energy efficiency as a predictive response to expected environmental scarcity. These metabolic alterations are thought to be beneficial in times of poor nutritional quality but, unfortunately, have consistently been shown to result in adverse health outcomes and metabolic disease when food is calorie-dense and readily available. Besides the various metabolic changes, animals programmed for thrift have been shown to exhibit neurological changes resulting in increased hunger, sedentariness, and volume reductions in the cerebral cortex. A great deal of evidence, including countless animal studies and a worldwide series of epidemiological investigations, has supported the close relationship between early nutritional status and susceptibility to the major risk factors (increased adiposity, hypertension, and insulin resistance) for the metabolic syndrome in later life. The perspectives originated by James Neel (the thrifty genotype hypothesis) and David Barker (the thrifty phenotype hypothesis) have remained meaningful interpretations through which to view the nature of the genetic, structural, and adaptive facets of the programming of metabolic function. Moreover, these perspectives, and the integrative conceptualizations they promote, have begun to provide valuable direction for research and health care.

The Metabolic Syndrome: Obesity, Insulin Resistance, and Hypertension

The metabolic syndrome is a combination of medical disorders that present in a clustered fashion and result in an increased risk for cardiovascular disease and diabetes. This disease was identified over 80 years ago but has shown a striking increase worldwide in the last two decades. The rise in international prevalence is closely associated with the global epidemic of obesity and diabetes. Symptoms and features include glucose intolerance (type 2 diabetes, impaired glucose tolerance); high blood pressure (hypertension); central obesity (visceral adiposity); increased LDL cholesterol; and dyslipidemia (elevated triglycerides). These conditions tend to co-occur in individuals more often than they present alone. For this reason, they have been grouped into the encompassing diagnosis of the metabolic syndrome.

Table 1

Disorders Comprising the Metabolic Syndrome

Obesity	increased total body fat, abdominal or central fat distribution, increased visceral fat
Insulin resistance	hyperinsulinemia
Dyslipidemia	hypertriglyceridemia, decreased HDL cholesterol, increased LDL cholesterol
Impaired glucose tolerance	type 2 diabetes mellitus
Increased waist circumference	>102 cm in men, >88 cm in women
Elevated triglycerides	>150 mg/dL or 1.7 mmol/l
Decreased HDL cholesterol	<40 mg/dL in men, <50 mg/dL in women
Blood pressure (hypertension)	>130/85 mgHg or active treatment for hypertension
Fasting glucose	> 110 mg/dL or active treatment for hyperglycemia

The defining disorders of the metabolic syndrome and their components

The majority of diagnoses are given to older, obese individuals. Until recently, the metabolic syndrome was regarded as a disease of old age, yet now, with increasing rates of obesity and diabetes in young people, it is commonly diagnosed in children.

Table 2

Behavior Associated with the Metabolic Syndrome

Pituitary adrenal abnormalities: hypercoritisolemia, stress behaviors

Reduced physical activity, sedentariness

Reduced ability to cope with stress, elevated stress hormone levels

Substance abuse: smoking, alcohol, others

Increased food intake: hyperphagia, increased dietary fat content

Sex hormone abnormalities

A brief list of some of the behavioral abnormalities closely associated with the metabolic syndrome.

The disorder, like its features, is highly heritable, and the large genetic component helps health practitioners to identify at-risk individuals if their family medical history is known. The main treatments include calorie restriction, dieting, physical exercise, and occasional drug prescription.

Table 3

Therapy for the Metabolic Syndrome

Obesity	behavior modification, caloric restriction, regular exercise
Atherogenic diet	reduce trans fats, saturated fats, dietary cholesterol and total fat
Cigarette smoking	complete smoking cessation
Hypertension	lifestyle therapy, advise antihypertensive drugs
LDL	advise LDL cholesterol lowering drugs
Elevated glucose	lifestyle therapy, advise hypoglycemic agents
Physical inactivity	60 minutes of moderate-intensity exercise daily

A very brief summary of clinical recommendations for the individual disorders of the metabolic syndrome.

The prevalence of the metabolic syndrome has increased severalfold in the last few decades. In these same decades fast food and processed foods have become internationally ubiquitous, and physical exercise has been engineered out of our daily routines. The metabolic syndrome is a product of the modern environment, which has done much to increase sedentary behavior and the overconsumption of unhealthy foods. It is thought that humans were not “designed” to live this lifestyle, which is to say that we were not naturally selected to have genes that prepare us for it. Our hunting and gathering ancestors were probably only rarely afflicted by such unhealthy lifestyles or their metabolic consequences.

The Thrifty Genotype: Genes for Feast and Famine

The same genes that cause humans to be susceptible to diabetes, heart disease, and obesity in modern times may have protected us from starvation and famine during ancestral times. This hypothesis was first put forward in 1962 by James Neel in an article entitled: “Diabetes mellitus: a ‘thrifty’ genotype rendered detrimental by ‘progress.’” Neel coined the phrase “thrifty genotype,” referring to the probably substantial complement of genes that would have helped our ancestors’ metabolisms to be economical and prudent with the foods they hunted and gathered for (Neel, 1982). Not only did their meals contain a smaller proportion of sugar and fat, but our ancestors also had to engage in prolonged physical activities to obtain them. Interestingly, adopting a “paleolithic diet” consisting primarily of fruit, vegetables, and meat is an increasingly popular dietary regimen.

Neel pointed out that not only are our bodies engineered to expect a different diet, but they are also probably expecting extreme food shortages, which modern people only rarely encounter. His thesis, refined in subsequent articles, was that adaptations that allowed organisms to minimize metabolism and providently lay down fat reserves would produce a survival advantage during nutritional scarcity (Neel, 1999). A good deal of research has indicated that the environment of human adaptedness, and wild environments in general, are marked by periods of “boom and bust,” where periods of plenty are interspersed among periods of food shortage or famine. This concept was initially generated to allow an evolutionary explanation for the existence of diabetes but has since been generalized toward the metabolic syndrome and become widely adopted. The mainstay of this conceptual standpoint is that our inherited propensity for energy conservation probably only translates into obesity and metabolic disease in modern times and may have protected individuals, particularly those with the “thriftiest genotypes,” from starvation in ancestral times.

Table 5

Diet and Behavior, Then and Now

Prehistoric Foraging Individual	Modern Day Individual
Caloric uncertainty	Caloric stability
Moderate to high physical activity	Low physical activity
Dietary balance	Dietary excess
Insulin sensitivity in muscle cells	Insulin resistance in muscle cells
Metabolic efficiency	Metabolic dysregulation
Reproductive advantage	Presumed reproductive disadvantage

A comparison of health and ecological features between a typical forager and modern individual on a Westernized diet with an inactive lifestyle.

Thrifty benefits have been attributed to the individual components of the metabolic syndrome. A smaller, weaker, yet less energy-expensive heart may confer the ability to minimize energy expenditure in the heart in order to mitigate the risk of starvation (Barker, 1998; Barker et al., 2002). In modern times people that express this once adaptive phenotype no longer enjoy the benefits because the excess of fat and cholesterol consumed by these individuals puts a severe strain on their “thrifty” heart, making them susceptible to cardiovascular disease (Ridley, 2003).

A similar tradeoff is presumed to exist for insulin signaling. The beta cells of the pancreas release insulin in response to carbohydrate intake, facilitating the metabolism of carbohydrates. An exaggerated pancreatic response (seen in the metabolic syndrome) results in hyperinsulinemia (high circulating insulin levels) that leads to increased lipogenic activity and, ultimately, the storage of fats in adipose tissue. Such metabolic tendencies for increased adiposity may have helped individuals in the past to be frugal with fats and to store more fat, yet today they lead to obesity.

Type 2 diabetes mellitus has been characterized as a disorder that is a prototypic example of this kind of evolutionary tradeoff. It has been thought for decades now that, on a cellular and organ system level, the disorder represents a thrifty condition – insulin resistance – that would have only rarely manifested as a disease in the ancestral environment because, at that time, individuals had no access to refined sugar or processed foods. The current literature holds that insulin resistance, brought about by genes for type 2 diabetes, represents a finely tuned physiological state and that its cellular and molecular pathways have been refined by natural selection over millions of years to help organisms conserve blood sugar. Insulin causes cells to rapidly take up blood sugars and increase the rate of their cellular processes, thereby increasing total metabolic output. The defective insulin receptors seen in cells of people with insulin resistance might have helped to conserve these blood sugars in the past, but now that our diets feature dramatically higher levels of refined sugar, insulin resistance results in blood sugar levels that are vastly too high. Elevated blood sugar (hyperglycemia) can cause various systemic and organ problems by damaging important biomolecules (glycation), which is seen frequently in diabetes. In all these examples, biological mechanisms malfunction badly once they are forced to face our unhealthy modern diets. It is now thought that many individual physiological pathways involved in the metabolic syndrome may represent ancient methods of energy conservancy (Eriksson et al., 2001).

Table 6

The Medical Risks Associated with a Westernized Diet

Metabolic State	Implications for Foragers	Implications for Moderns
Adiposity	Healthy fat retention	Excessive fat retention
Insulin resistance	Healthy levels of blood sugar	Excessive levels of blood sugar
Beta Cell Responsiveness	Metabolism of carbohydrates	Hyperinsulinemia
Thrifty heart	Healthy, efficient heart	Heart burdened by high body fat
Glucose intolerance	Normoglycemia	hyperglycemia

A comparison between a typical forager and an obese modern individual with respect to the end result of individual metabolic states.

Population genomics has identified some interesting trends in geographic susceptibility to the metabolic syndrome that provide corroborating evidence for the thrifty genotype theory. This widely accepted interpretation emphasizes that populations of preagricultural, foraging individuals that live in areas where, until recently, food has been relatively unpredictable have a much higher prevalence of thrifty genes (Neel, 1982). The traits these genes code for probably helped these individuals survive during prolonged periods of scarcity or were maintained because, historically, these individuals were not exposed to high-calorie diets (Valencia, 1999). Today, the incidence of the metabolic disease remains highest among populations where an economy of foraging existed until recently. Unfortunately, people in these areas, such as Native Americans, Aboriginal Australians, and Pacific Islanders, have an unusually high prevalence of the metabolic syndrome now that they have been exposed to the modern “diet of affluence.” This genetic variation between human populations is akin to other known forms of anthropological adaptation to the environment.

Unbeknownst to many, there are several examples of selective pressures acting on humans even in the last 50,000 years. Lactase persistence is one example, where populations in Europe and elsewhere retained the ability to digest lactose into adulthood because of the domestication of cattle and the importance of the ability to derive calories from milk. 

The Pima Indians in Arizona and the Nauru people from the Micronesian South Pacific Islands appear to have particularly thrifty genotypes (Dowse et al., 1991). Both populations are thought to have endured repeated episodes of food shortage and starvation. They have long lived in relatively isolated, unpredictable, and in the case of the Pima, desolate areas. Fascinatingly, the Nauru people have traveled among remote islands in the Pacific during many several-week-long canoe voyages. Historical accounts attest that many individuals in these canoes died of starvation during the trips, perhaps creating a Nauru founder population of highly starvation-adapted people. When exposed to a Western lifestyle in the twentieth century, obesity and diabetes increased drastically in the Pima and Nauru. For some time, these two groups had among the highest rates of type 2 diabetes (Schulz et al., 2006).

A variety of animal studies echo these genographic studies in humans. Diabetes commonly afflicts zoo animals, and an epidemic has been described of captive populations of primates whose lifestyle approximates the sedentary, high-calorie lifestyle of First World, urban humans (Diamond, 2003). Certain animals that are well adapted to frequent food shortages, such as desert mammals, show increased susceptibility to the features of the metabolic syndrome when they can feed ad libitum. The Israeli sand rat is a prime example. It is highly predisposed to developing metabolic diseases, including insulin resistance, obesity, and diabetes, when put on the western lab rat diet. The symptoms quickly reverse when its food is restricted or placed back in its natural environment (Haines et al., 1965). Fascinatingly, it is known that the facets of the metabolic syndrome in humans, including diabetes, can be reversed by diet, exercise, and weight loss. This decline and even disappearance of diabetes symptoms happened to thousands of Parisians during the 1870-1871 famine associated with the siege of Paris (Zimmet, 1997).

Even though the thrifty gene hypothesis has been challenged in its particulars, the aspects discussed here have been well accepted in the medical and ethological literature. Far from being a liability, a tendency to be fine-tuned for having a lower metabolism would have been an asset to survival in the Plio-Pleistocene because it would have helped individuals to conserve calories. That individual species or some individuals within a species have this tendency has important biomedical ramifications. Further research and experimentation in this area should help clarify the underpinnings and tradeoffs involved in energy homeostasis. Several successful animal models, like the ones mentioned, are thought to have helped to elucidate some of the key genes and pathways involved in impaired energy balance regulation. Interestingly, the genes that one is born with are not the only predisposing factors. As the next section will illustrate, the environment can also play a significant role.

Glycation is the bonding of sugar molecules to proteins which occurs during long periods of high blood sugar. Glycation can damage proteins changing how they function. It also damages tissues, and it creates some of the complications seen in diabetes.

Epigenetics, Phenotypic Plasticity, and the Metabolic Syndrome

It is now widely accepted that the risk for a number of metabolic diseases may be affected by circumstances before birth. Professor David Barker and colleagues have produced a large amount of data since 1994, showing that low birth weight increases susceptibility to diabetes mellitus, hypertension, and coronary heart disease (Barker, 1998) later in life. By analyzing epidemiological data for cohorts whose birth records are available and following these individuals into adulthood, Barker, Hales, and others have shown that birthweight, length, body proportions, and placental weight are highly associated with later metabolic disease incidence (Barker, 1994; Barker, 1998). In addition to having increased adipose tissue in adulthood, low birth weight individuals tend to have less muscle. Reduced muscle has been reported to contribute heavily to a lowered basal metabolic rate and is expected to reduce the capacity for exercise (Kensara et al., 2006). These associations between birth size and disease are often apparent from childhood, hold in a large number of different populations, and have given rise to the term “fetal origins of adult disease” (FOAD) (Law & Shiell, 1996; McKeigue, 1997).

The biological changes responsible for the metabolic alterations are attributed to phenotypic plasticity and epigenetic programming. As you know, epigenetic programming occurs when an environmental cue changes gene expression. Even small changes in gene expression and protein regulation early on can cause large phenotypic changes with time. Developmental geneticists closely adhere to the idea that a single genotype can give rise to a variety of different phenotypes depending on the programming effects of the early environment. In this case, an environmental stimulus experienced during gestation is thought to lead to impaired fetal growth and diminution in size at birth. However, “catch-up” growth in childhood is the norm. This stimulus or cue also leads to altered homeostatic mechanisms, such as the regulation of blood pressure or insulin sensitivity, which in turn results in susceptibility to the metabolic syndrome later in life (Langley, 1997).

A reliable way to decrease a rat’s size at birth is by reducing protein in the diet of their pregnant mothers. Like humans and other mammals, these rats show catch-up growth in youth but soon thereafter exhibit tendencies toward obesity, elevated blood pressure (Langley & Jackson, 1994), and impaired glucose tolerance (Desai et al., 1995). The presence of obesity worsens these symptoms in an additive manner (Petry et al., 1997), and, as in humans, worsened symptoms lead to reduced longevity in rats and mice (Ozanne & Hales, 2004).

Restriction of total calories during pregnancy, without respect to protein composition, has resulted in rat offspring that are hyperphagic, hyperinsulinemic, obese, hypertensive, and significantly less physically active (Harding, 2001). They are also more ravenous eaters because they are less responsive to the hormone leptin, which inhibits hunger. Again, analogous to what we see in our own species, these symptoms are made worse if the animal is given a high-fat diet later in life (Cettour-Rose et al., 2005). Similar studies designed to reduce maternal nutrition during pregnancy have yielded comparable results in rats, mice, guinea pigs, and sheep.

The second source of evidence for the efficacy of maternal undernutrition in programming the metabolic syndrome comes from historical pseudo-experiments. A popular example, the Dutch Hunger Winter, was a season of extreme food shortage in the Netherlands between 1944 and 1945. Ravelli and colleagues compared data on 300,000 19-year-old males born before, during, or after this famine (Ravelli et al., 1976). The study revealed that the nutritional limitations imposed by severe nutritional deprivation led to offspring with reduced birth size and increased risk of obesity and diabetes in adult life. The most affected cohorts were the offspring of the mothers whose first two trimesters of pregnancy coincided with the famine. Similar historical pseudo-experiments, with well-documented medical data consistent with the findings of the Dutch Hunger Winter, have occurred in Asia and elsewhere.

Another body of literature has taken this programming concept a step further and attributed adaptive or evolutionary value to sensitivity to programming (Barker et al., 2002).

The Thrifty Phenotype: Bodies Built for Feast and Famine

It is clear that Hales and Barker, like Neel before them, appreciated the evolutionary implications of their hypotheses. They explicitly proposed that this metabolic response to a nutritionally poor early environment was a predictive, adaptive response that would maximize chances of surviving postnatally in conditions of ongoing deprivation. Also, like Neel, they appreciated the fact that this prediction represents a tradeoff and is subject to being inaccurate. If unexpectedly the postnatal environment provides ample nutrition, these individuals will be at increased risk of metabolic disease.

The thrifty phenotype hypothesis (Hales, 1992; 2001) has been used widely by researchers from different disciplines to interpret studies showing that maternal malnutrition is a decisive risk factor for the metabolic syndrome (Wells, 2003). According to this hypothesis, phenotypes that are programmed by prenatal malnutrition to express low metabolic rates enjoy a survival advantage under deprived circumstances; however, if such a thrifty fetus is born into an environment marked by nutritional abundance, it will face an increased risk of adverse health consequences (Bateson et al., 2004). Conversely, robust phenotypes that express larger size and rapid metabolism are thought to increase reproductive success when resources are more plentiful but are more susceptible to starvation if exposed to nutritional shortage. Specialists now believe that the association between maternal malnourishment and the offspring’s proclivity for a low metabolism is adaptive, specifically because the mother’s deprived condition during pregnancy is often predictive of the environment into which the fetus will be born. It has been established that many animals share similar metabolic responses to environmental cues. This requires us to concede that our own tendency to react plastically may derive from phylogenetically earlier forms because of a shared evolutionary history (Crespi & Denver, 2005).

Epigenetic processes are the biological basis for programming effects. Chemicals such as acetyl or methyl groups attach themselves to promoter regions of genes in specific tissues. Fine and intricate control of gene expression has been taken to suggest that the programming effects have been maintained through evolution because of their adaptive advantage rather than representing maladaptive effects of developmental disruption such as teratogenesis (Hanson & Gluckman, 2008). It has been shown that, in animals, these epigenetic effects, for instance, DNA methylation, can be passed down to successive generations along with the altered phenotypic expressions. In fact, due to alterations in the epigenome that are maintained during the creation of gametes, the effects of early life under-nutrition may be transmitted to subsequent generations without repetition of the immediate insult in the second generation (Drake & Walker, 2004). Many researchers believe there may be an adaptive advantage in long-term intergenerational programming and that information about a grandparent’s environment will help a developing animal in its “environmental forecasting.”   

Many fully grown animals are well known to demonstrate consistent adaptive responses to starvation that help to minimize energy expenditure, even on the order of a few days. Starvation evokes several immediate physiological changes, the most dramatic of which include suppression of metabolic rate, increased adiposity, reduction of thyroid hormone levels and growth hormone levels, a reduction in fertility (through the suppression of gonadal function), and increased activation of the hypothalamic-pituitary-adrenal axis (Schwartz et al., 1995; Flier, 1998). Unlike animals programmed prenatally for thrift, these predictive metabolic measures reverse largely after the animal resumes its regular diet. It is also well-accepted that seasonal cycles of metabolic alterations occur in hibernating mammals. Many animals that hibernate are insulin insensitive for months before they go into hibernation and exhibit increased adiposity. When they wake up in the spring, they are lean and insulin sensitive once again (Scott & Grant, 2006). These other examples of phenotypic plasticity are very comparable to intrauterine programming in many ways and researchers could potentially learn much from contrasting these models.

The brains of experimental animals that were exposed to early nutritional deprivation seem to be buffered from growth restriction in moderate cases but can show definite changes in severe ones. Reductions in the number of cells in certain regions, as well as in synapses and white matter, evince that programming effects that may involve thrift take place in the brain as well. Recent studies using imaging techniques show that gray matter is reduced in humans subjected to intrauterine growth restriction and that catch-up growth may not occur (Tolsa et al., 2004). Of course, this book offers explanatory hypotheses for these and related observations. It is possible that a large number of different metabolic and organ systems may be affected by epigenetic programming involving predictive adaptive responses.

Discussion

The thrifty genotype hypothesis posits that specific human genes associated with increased risk for metabolic disease today were naturally selected in the past because they helped their bearers to be more ‘thrifty’ with energy stores. According to this hypothesis, phenotypes that express low metabolic rates enjoy a survival advantage under deprived circumstances. However, they face an increased risk of negative health consequences when sugars and fats are artificially abundant, as they are in many countries today. The thrifty phenotype hypothesis posits that we all have windows of susceptibility to thrifty programming that enable us to create permanent readjustments in homeostatic systems in an obsolete attempt to aid survival.

Today, the costs of the metabolic syndrome are well documented and well understood. However, the prehistoric, defensive manifestations are obscured, at least at first glance, because of discrepancies between the ancestral environment and the modern environment.

The merits of the thrifty genotype and phenotype hypotheses include the implications they generate for understanding past, current, and future trends in disease (Pollard). The historical and evolutionary forces that are apparent are still largely abstract when measured against our biomedical knowledge. It is clear that during our journey of reconciling the two, they will continue to influence and provide predictions for each other. The notion that the human genome bears witness to past struggles for survival against starvation allows us a new context to view the human body’s responses. A person’s physiological response to dieting will reflect our ancestors’ adaptive responses to seasonal hunger, just as their response to abundant calories and fats will reflect our ancestors’ beneficial responses to harvest seasons. Furthermore, the thrifty phenotype hypothesis informs us that early prenatal effects and even effects that were inherited from grandparents can cause the same anachronistic responses. 

Identifying and mapping both thrifty genes and epigenetic markers will help evaluate these hypotheses, but more importantly, will help inform medical research. Many critical aspects remain to be explored: 1) where are the alleles for thrifty genes? 2) at what points during development do these windows of susceptibility exist? 3) what are the signaling pathways through which an environmental cue is translated into a developmental response? 4) which developmental responses persist beyond a single generation and how? Please keep these questions in mind as you continue to read this book.

The observations discussed here have been extensively replicated and the theories discussed have been widely espoused, but both are- and perhaps for good reason- still discussed, questioned, and debated. Many of these observations are not invariable, and the causal pathways are still quite far from being transparent. It is thought that the concepts of the “thrifty genotype” and “thrifty phenotype” can be consistent and reconciled with one another. The validity and applicability of these hypotheses are undoubtedly open for dispute.

Animal models are not always directly comparable to the human situation but should continue to offer insight into mechanisms. Long-term human studies are expensive and time-consuming, but they will help clarify the pertinent issues too. It is evident that this line of research has major ramifications for public health policy. Health care funding may be more prudently spent on informing and improving pregnancy care rather than on the contingent metabolic disorders which manifest decades later and cost many times more to treat. If overeating and sedentary behavior are determined during prenatal development to the degree that this literature implies, this may explain why public health initiatives to improve exercise and dieting in adults with metabolic symptoms are largely ineffective.

An extensive literature addresses these concepts from different angles, and much is known about the similarities in the predisposition for metabolic disease between people and animals (Gluckman & Hanson, 2004). There is still much that is unknown, though. Whether the broad, ultimate, evolutionary hypotheses have to be largely altered or just fine-tuned, it is becoming clear that metabolic disease may very simply stem from the fact that our behavior, diet, and nutrition are so different from how they used to be.                                                                          

Definitions

Dyslipidimia: Refers to a disruption of the levels of lipid in the blood. In western societies, most dyslipidemias are hyperlipidemias; an elevation of lipids often due to diet, lifestyle or prolonged elevations of insulin.

Glucose Tolerance: The ability of the body to adapt to a relatively large dose of glucose. This ability is usually diminished in diabetics and is used to diagnose diabetes mellitus. A fasting subject ingests around 75 grams of glucose and blood glucose is measured at intervals. In diabetics the concentration is higher and takes longer to return to baseline value.

Genotype: The genetic constitution of a cell or organism. The genotype contains the information, in the form of DNA, that dictates how the cell or organism develops and interacts with its environment.

Hypercortisolemia: High amounts of circulating cortisol, an essential glucocorticoid steroid hormone, and the major hormone secreted by the adrenal glands.

Hyperglycemia: A complex metabolic condition  characterized by high levels of blood glucose in the circulation, usually a result of insufficient or ineffective insulin production in either type 1 or type 2 diabetes mellitus.

Hyperphagia: Refers to an abnormal appetite or increased eating of food, often associated with abnormalities in the hypothalamus.

Hypertension: High blood pressure or force of blood on the vessel walls of the arteries.

Hypothalamic-pituitary-adrenal Axis: This is a neuroendocrine system in the body responsible for regulating stress physiology. Brain areas that sense threat, signal the hypothalamus which communicates hormonally to the pituitary which hormonally signals the adrenal glands to secrete adrenaline and cortisol.

Insulin Resistance: A condition in which cells, especially those comprising muscle, fat and liver tissue, fail to be properly receptive to the messages of the hormone insulin. Because insulin promotes the extraction of glucose from the blood, allowing cells to meet their metabolic needs, insulin resistance is associated with elevated levels of blood glucose.

Metabolic Syndrome: A combination of metabolic disorders that commonly present together and increase the risk of developing diabetes and cardiovascular disease.

Phenotype: An observable characteristic of an organism such as a trait, property or behavior. Phenotypes develop from the interaction between an organism’s genes and its environment.

Visceral Fat: The accumulation of fat around the internal organs of the torso. Associated with the “apple shape,” belly fat, central obesity and a high waist to hip ration.

Summary Points for the Developmental Origins of the Metabolic Syndrome

• The metabolic syndrome represents a cluster of metabolic derangements that are risk factors for obesity, type 2 diabetes mellitus and cardiovascular disease.
• There is currently a world wide epidemic of obesity and diabetes that is due to unhealthy eating and poor exercise. These are probably issues that our hunting and gathering ancestors would rarely have been exposed to because they were probably only rarely exposed to excess but commonly exposed to famine.
• The human gene pool probably contains many thrifty genes that would have helped our ancient ancestors to survive food shortages and starvation. For example, a tendency to efficiently take up ingested fats into fat stores would have increased the likelihood of survival.
• The physiologic states that cause us to be susceptible to the facets of the metabolic syndrome probably all had ecological utility in the past. This is supported by animal models.
• Many mammals, and it seems humans too, can be programmed for thrift if they are exposed to severe under nutrition early in development. This programming may be a predictive, adaptive response to environmental cues signaling that the environment is nutritionally poor.
• The thrifty phenotype that is created from these programming effects is highly susceptible to metabolic disease.
• Future findings in this literature should have serious implications for public health and the treatment of the metabolic syndrome.
  
  

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