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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 gotten to this point? The recent outbreak of type 2 Diabetes can be easily explained by the lifestyle changes that have occurred in the past decade, but a full and accurate explanation requires a complete understanding of the evolutionary mechanism to account for the genetic predisposition that has occurred through evolution. This necessitates an analysis of the ultimate hypotheses and forming one complete proposition that takes into account the shortfalls and paradigms of each.
Formerly called non-insulin-dependent Diabetes mellitus (NIDDM) or adult-onset diabetes, 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). Unlike type 1, which is an autoimmune disorder that results in the "destruction of insulin-producing beta cells of the pancreas", type 2 can be managed 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 biological problem that results 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). These two models provide the framework for research into insulin resistance and the obesity of patients.
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" ("Diabetes"). The actual number is much larger because although people live with diabetes for many years, their cause of death is often recorded as 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 provide some evidence for the occurrence of type 2 diabetes.
There is a strong inheritable connection in type 2 diabetes. If a person has relatives (especially first degree) with type 2 diabetes, the risk of developing the disease increases substantially (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. To 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. A diet of 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 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 had high levels of physical activity, a healthy diet, did not smoke, and consumed alcohol in moderation had an 82% lower rate of diabetes" (Mozzaffarian et al 2009). The study defined a healthy diet as "one high in fiber, with a high polyunsaturated to saturated fat ratio, and a lower mean glycemic index" (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. When Neel wrote the paper, he only intended for it to provoke further contemplation and discussion. More specifically, 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. Instead, he found that the rates of diabetes are only a recent phenomenon and are not the same as earlier in the century (Neel 1982). In addition, he tested younger members of the 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). This understanding was the beginning of the study of epigenetics and the fact that a person's genetic expression could be altered. Neel found that carbohydrates lay at the base of the problem with developing diabetes and theorized it was the use "of highly refined carbohydrates" that could provide an answer (Neel 1999).
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: maternal effects, niche construction and developmental plasticity. Only developmental plasticity is based on the brain of the offspring, while 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). Taking into account both the thrifty gene and thrifty phenotype hypotheses, researchers have now turned to the thrifty epigenotype to explain the occurrences and discrepancies of both theories. 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).
Yet another theory discusses the possibility that famines did not play 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 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. 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 function of the kidney and causes insulin resistance is not fully 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.