Amid prevalence rates of type 2 Diabetes mellitus in the United States doubling between 1990 and 2005, the Center for Disease Control (CDC) has officially declared an epidemic (Gerberding 2007). With both genetic and lifestyle factors affecting the onset of the disease, how has the human race and certain populations reached this point? The recent outbreak of type 2 Diabetes can be easily explained by the lifestyle changes that have occurred in the past century, but a full and accurate explanation requires a complete understanding of the evolutionary mechanisms to account for the genetic predisposition that has occurred through evolution. An analysis of the ultimate hypotheses that explain the evolutionary origins is necessary in forming one succinct notion of why the rates are increasing taking into account the shortfalls and paradigms of each.
Formerly called adult-onset diabetes or non-insulin-dependent Diabetes mellitus (NIDDM), Diabetes mellitus type 2 is a disorder that interferes with the breakdown of sugar and causes an accumulation of glucose in the blood. The disorder involves a general resistance to insulin and insulin deficiency (Cotran and Robbins). The disease usually arises in people that have a poor diet and get little to know exercise. Type 2 diabetes used to be only an adult condition, but there has been a recent problem with children developing diabetes at increasingly younger ages due in large part of the skyrocketing obesity rates. Unlike Type 1 diabetes, which is an autoimmune disorder that results in the "destruction of insulin-producing beta cells of the pancreas" and is irreversible, type 2 can be managed and eliminated by increasing exercise and maintaining a healthy diet (Cihakova). The three classic symptoms of diabetes are "polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger)" (Cooke 2008). Fatigue and weight loss are also symptoms, but the latter is associated more with type 1 (Cooke 2008). In type 2 diabetes, the major biological problem is insulin resistance. This means that cells do not respond appropriately with the presence of insulin. Unlike type 1 diabetes, insulin resistance is generally 'post-receptor', "meaning it is a problem with the cells that respond to insulin rather than a problem with the production of insulin" (Cotran et al 1999). Although there is considerable debate as to the relative contributions of beta-cell dysfunction and reduced insulin sensitivity to the pathogenesis of diabetes, it is generally agreed that both these factors play important roles (Scheen 2003). However, the mechanisms controlling the interaction of the two impairments are unclear. Since a majority of patients with type 2 diabetes are obese, researchers have been trying to find the link between the increased adipose tissue (fat) and the dysfunction of the insulin response in beta cells. The most popular explanation for this link is "the portal/visceral hypothesis giving a key role in elevated non-esterified fatty acid concentrations; two new emerging paradigms are the ectopic fat storage syndrome (deposition of triglycerides in muscle, liver and pancreatic cells) and the adipose tissue as endocrine organ hypothesis (secretion of various adipocytokins, i.e. leptin, TNF-alpha, resistin, adiponectin, implicated in insulin resistance and possibly beta-cell dysfunction)" (Scheen 2003). The portal/visceral hypothesis is named from the hepatic portal system and visceral fat. The hepatic portal system is the collection of veins that travel from the gastrointestinal tract to the liver. Visceral refers to fat that is deposited deep in the abdomen near the organs. The hypothesis theorizes that this type of adipose tissue increases the amount of free fatty acids in the blood, which are brought to the liver where they compete with glucose for substrates thus increasing resistance to an insulin response. The theorized paradigm of the ectopic fat syndrome is simply based on the discovery that decreased adipose tissue also has an affect on insulin resistance and therefore must be connected in some way to the amount of fat found in the body. Finally, the endocrine hypothesis is based on the finding that fat cells release resistant (and other protein signals) that dampen insulin receptor substrates (IRS) lessening the affects of an adequate blood glucose response. These models provide the framework for further research into insulin resistance and the obesity of patients.
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The rate of type 2 diabetes worldwide has skyrocketed in the last century. "There are an estimated 220 million people worldwide living with type 2 diabetes" ("Diabetes"). In the United States there are about 23.6 million people with diabetes (7.8% of the population), 90% of whom are type 2 (Inzucchi et al). "In 2005, an estimated 1.1 million people died from diabetes worldwide" ("Diabetes"). The actual number is much larger because although people live with diabetes for many years, their cause of death is one of its many complications including heart disease or kidney failure. Almost 80% of diabetes deaths occur in low- and middle-income countries ("Diabetes"). In addition, type 2 diabetes is more commonly seen in non-white groups. "American Indian youths have the highest prevalence of type 2 diabetes" ("Children and Diabetes"). Based on the statistics, diabetes is a growing problem, but more for the lower economic classes and ethnic groups. Researchers have been trying to find an explanation for these findings and genetics have been found to provide some evidence for the occurrence of type 2 diabetes.
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There is a strong inheritable connection in type 2 diabetes. If a person has kin (especially mother or father) with type 2 diabetes, the risk of developing the disease increases significantly (Sakagashira et al 1996). In twin studies, the presence of the traits that cause diabetes in identical twins is nearly 100% and 25% of those diagnosed have a family history of the illness (Lyssenko et al 2008). In type 2 diabetes, many genes are thought to be involved. "Diabetes genes" may show only a subtle variation in the gene sequence, and these variations may be extremely common. "The difficulty lies in linking such common gene variations, known as single nucleotide polymorphisms (SNPs), with an increased risk of developing diabetes" (Dean and McEntyre). One method of finding the diabetes susceptibility genes is by whole-genome linkage studies. The entire genome of affected family members is scanned, and the families are followed over several generations and/or large numbers of affected sibling-pairs are studied (Dean and McEntrye). Associations between parts of the genome and the risk of developing diabetes are looked for. Two genes have been identified using this method, calpain 10 (CAPN10) and hepatocyte nuclear factor 4 alpha (HNF4A) (Dean and McEntyre). CAPN10 is a calcium-activated enzyme that breaks down proteins. "Variation in the non-coding region of the CAPN10 gene is associated with a threefold increased risk of type 2 diabetes in Mexican Americans" (Dean and McEntrye). The HNF4A gene encodes a transcription factor that is found in the liver and pancreas. Since "HNF4A maps to a region of chromosome 20 that is linked with type 2 diabetes and because mutations of this gene cause a rare form of autosomal dominant diabetes", the HNF4A gene is considered to be a strong candidate for involvement in type 2 diabetes (Dean and McEntyre). Various hereditary conditions feature diabetes as one of many affects of the disease. Myotonic dystrophy, Friedreich's ataxia, and Wolfram's syndrome feature diabetes mellitus as one of it's symptoms (Barrett 2001). There are also epigenetical factors that affect the onset of diabetes from gene expression. Epigenetics is the study of changes in phenotype of genes from factors independent of the DNA sequence. For example, a diet high in fat and glucose "as well as high levels of inflammation related cytokines found in the obese results in cells that produce fewer and smaller mitochondria than is normal, and are thus prone to insulin resistance" ("The Origin of Diabetes"). The fact that gene expression and resultant protein production can be changed due to diet is one of the reasons why behavioral decision-making can be another risk factor.
The other main cause of type 2 diabetes is lifestyle. There are a number of different factors that play a role in increasing the risk of developing diabetes and one study found that those who exercised regularly, maintained a healthy diet, did not smoke, and did not consume alcohol in excess showed a decreased rate of diabetes of 82% (Mozzaffarian et al 2009). The study used a "healthy diet" as consumption of food had a lower mean glycemic index, high fiber content, and a high ratio of polyunsaturated to saturated fat (Mozzaffarian et al 2009). The glycemic index is simply a measure of the effects of carbohydrates on blood sugar levels. "Carbohydrates that break down quickly during digestion and release glucose rapidly into the bloodstream have a high GI; carbohydrates that break down more slowly, releasing glucose more gradually into the bloodstream, have a low GI" (DJ Jenkins et al 1981).
The first person to propose an evolutionary explanation for the rise in the rates of diabetes was James V. Neel in 1962 in his paper, "Diabetes Mellitus: A 'Thrifty' Genotype Rendered Detrimental by 'Progress'? He proposed this hypothesis because he noticed that a clearly harmful disease was quite common, which could lead to the assumption that it has a strong genetic basis. However, a phenotype that produces the effects of diabetes would not be favored through the process of natural selection. Neel suggested in the paper that the problem lie with 'thrifty genes' that were once advantageous in the evolution of humans were "rendered detrimental by 'progress'" (Neel 1962). These 'thrifty genes' were genes that processed food efficiently and deposited fat for energy storage during times of food abundance (Neel 1962). Since our ancestors didn't have a continual occurrence of abundant food or 'feast' the incidence of diabetes and obesity was rare and it was necessary to take advantage of the food available. During times of feast, hunter-gathers and especially child-bearing women could increase the amount of their adipose tissue so they could survive the long periods of famine and be able to reproduce. In modern society, this gene could possibly still be in effect causing increased fat production and diabetes from constant levels of food consumption.
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When Neel wrote the paper, he only intended for it to provoke further contemplation and discussion; he wanted research to be conducted on the possible evolutionary and genetic causes of diabetes "among populations that had only recently come into regular contact with Westerners" (Neel 1962). Neel also proposed a counter-hypothesis in his 1962 paper that discusses the possibility that the frequency of obesity and diabetes is a relatively recent phenomenon, which leads to the question, "what changes in the environment are responsible for the increase?" (Neel 1962). In the decades following the publication of his first paper, Neel researched the frequency of diabetes and obesity in a number of populations to see if it his thrifty gene hypothesis was valid and had evidential support. He theorized that if the tendency to develop diabetes had become an evolutionary adaptation, then there would be occurrences of diabetes throughout a population's existence as an industrialized society where the diet has not changed drastically from hunter-gatherer ancestors. Instead, he found that the exponential rise in diabetes are only a recent phenomenon and are not the same as earlier in the century (Neel 1982). Although there have been changes in diet in the last couple of decades that have increased the consumption of sugar and saturated fats, under his hypothesis, the rates of diabetes still should have increased when society developed the constant availability of food and was no longer nomadic. The reason is because the genes are from early ancestors who had markedly different lives and the hypothesis is based on feast and famine not necessarily fat-rich foods. In addition, he tested younger members of at-risk native populations for glucose intolerance, which could show a predisposition for diabetes and found no evidence (Spielman et al). Neel published an additional paper in 1989 titled, "Update to 'The Study of Natural Selection in Primitive and Civilized Human Populations," where he discussed his further research into his 'thrifty gene hypothesis.' In the paper he says, "The data on which that (rather soft) hypothesis was based has now largely collapsed" (Neel 1989). However, he doesn't completely dismiss the thrifty gene hypothesis and maintains that it should refer to a genotype that is altered in these populations and affects other metabolic disorders (Neel 1989). The 'thrifty genes' could now be understood as being more susceptible to environmental changes than other genes and cause the effects seen in the last 50 years from an altered diet. This understanding was the beginning of the study of epigenetics and the fact that a person's genetic expression could be altered. Neel hypothesized that carbohydrates were the source of the problem with developing diabetes and theorized it was the use "of highly refined carbohydrates" that could provide an answer (Neel 1999). Neel has dismissed and altered his 'thrifty gene hypothesis' since first publishing it in 1962. The lasted incarnation though is getting closer to a better evolutionary explanation and makes sense for explaining the staggering rates seen in native populations. Since their diet has only recently changed relative to the rest of society and often mate within their community allowing for little genetic alteration, changes in lifestyle affect them to a greater degree. In addition, another hypothesis looks at the changes that can occur in the development of humans in response to environmental factors received from the mother that could also shed light on the discrepancies of differing type 2 diabetes rates.
The thrifty phenotype on the other hand, proposed in 1997 by David J. P. Barker, looks at the development of the infant in the womb as where the changes occur that cause the predisposition to diabetes and other disorders. Supporters of the hypothesis, propose that the pregnant mother modifies a developing baby if resources are scarce so as to be adapted to this environment by giving it a 'thrifty phenotype' (Hales and Barker 1992). The thrifty phenotype results in "a smaller body size, a lowered metabolic rate and a reduced level of behavioral activityâ€¦ adaptations to an environment that is chronically short of food" (Bateson and Martin 1999). This leads to a higher possibility of becoming obese, developing type 2 diabetes, and a host of other conditions. The thrifty phenotype can occur because of three adaptive processes: developmental plasticity, niche construction and maternal effects. Only developmental plasticity is based on the brain of the offspring. It is the process where development of the brain can be altered based on what environmental signals it receives (nutrients, stimulation, etc). Both niche construction and maternal effects are all dependent on the signals the mother sends to the developing fetus. Thus, the experience of the mother during development of the offspring directly affects the future adaptive fitness of the infant to its environment (Wells 2007). For example, if a mother has a poor diet when pregnant, this leads fetal malnutrition, decreased fetal growth, and subsequent defects in insulin responsiveness. These factors make the offspring more susceptible in developing type 2 diabetes.
Yet another theory discusses the possibility that famines did not play a role in selecting 'thrifty genes' and there has been enough time for humans to even evolve genes of that sort. John Speakman proposed the 'drifty gene hypothesis' in 2008 as a response to the 'thrifty gene hypothesis' citing data that shows that mortality rates of early humans during periods of famine were relatively low, which would eliminate natural selection pressure (Speakman 2008). Instead, it is hypothesized that a genetic drift occurred that affected the upper limit of our obese phenotype. Speakman theorizes, "Such a drift may have started because around 2 million years ago ancestral humans effectively removed the risk of predation, which was probably a key factor maintaining the upper boundary of the regulation system" (Speakman 2008). With these genes that code for a more obese population separated by others in the human gene pool and with almost no existence of environmental pressure, this phenotype was allowed to reproduce and proliferate. The genetic drift theory depends on the notion that there was "variability of basal fat oxidation" among ancestral individuals of which there is little to no evidence (Speakman 2008). The genetic drift hypothesis does little to prove its own ideas and more to just disprove the thrifty gene hypothesis.
Although the 'thrifty gene hypothesis' was the first attempt of describing an evolutionary mechanism, it is still widely discussed and debated by researchers today. A portion of the scientific community still believes in Neel's original hypothesis and refers to more native cultures as support even though Neel conducted research and found that support for his original hypothesis was lacking. The 'thrifty phenotype' hypothesis on the other hand has evidence to support its main point that maternal diet and environment has an impact on fetal development, which could predict the development of type 2 diabetes. However, there is still some speculation about the extent that 'nature' plays a role in an infant's life as opposed to their environment. Twin studies have revealed that there are differences in the occurrence of disease between people with the same genetic code. This has led researchers to the thrifty epigenotype, which is a continuation of Neel's most current hypothesis and is the best ultimate explanation of type 2 diabetes. It maintains that humans have the innate ability and trait to conserve and expend energy. Moreover, the genetic code of humans is well protected against mutations, but epigenetic variations can affectively change the phenotype of traits. This susceptibility to certain variations can also be inherited across generations. One gene that has been researched extensively that plays a role in the development of diabetes and obesity is Leptin (Stöger 2008). Leptin has been discovered has a possible gene that accounts for the "thrifty" traits. If flawed, the leptin response pathway cannot effectively produce a feeling satiety and stop the desire for food (Stöger 2008). As a result, people become obese and the excess adipose tissue induces diabetes as explained earlier.
With differing hypothesizes on the evolutionary mechanism for the occurrence and exponential increase of type 2 diabetes, an accurate hypothesis takes into account the theories that have the most evidence and predict the proximate mechanisms that researches are still trying to fully understand. Epigenetics does this the best and is just one stop in the continued search for evolutionary origins. It is well understood now the lifestyle factors that increase a person's chances of developing type 2 diabetes, but the exact pathway where increased adipose tissue affects the renal and liver function and causes insulin resistance is still not completely understood. What is beginning to be mapped are the exact genes involved in inheritance of a predisposition of type 2 diabetes. Knowledge of the exact genes involved in the development of type 2 diabetes helps with discussing the genetic factors that could have existed during the evolution of humans and that could have survived natural selection pressures. The world is rapidly becoming "westernized" and soon there will not be any native populations exposed to industrialized society. Are these populations doomed to the same fate as others before them? The likely answer is yes unless researchers can act proactively to stop this epidemic.