He proposed the hypothesis in 1962 to resolve a fundamental problem: diabetes is clearly a very harmful medical condition, yet it is quite common, and it was already evident to Neel that it likely had a strong genetic basis.
[citation needed] According to the hypothesis, the 'thrifty' genotype would have been advantageous for hunter-gatherer populations, especially child-bearing women, because it would allow them to fatten more quickly during times of abundance.
Neel intended the paper to provoke further contemplation and research on the possible evolutionary and genetic causes of diabetes among populations that had only recently come into regular contact with Westerners.
In its original form the theory more specifically stated that diabetes may be due to a rapid insulin response which would prevent loss of glucose from the urine.
[7] Neel in a 1998 review described an expanded form of the original hypothesis, diabetes being caused by "thrifty genes" adapted specifically for intermittent starvation, to a more complex theory of several related diseases such as diabetes, obesity, and hypertension (see also metabolic syndrome) being caused by physiological systems adapted for an older environment being pushed beyond their limits by environmental changes.
Thus, one possible remedy for these diseases is changing diet and exercise activity to more closely reflect that of the ancestral environment.
[8] The thrifty genotype hypothesis has been used to explain high, and rapidly escalating, levels of obesity and diabetes among groups newly introduced to western diets and environments, from South Pacific Islanders,[9] to Sub Saharan Africans,[10] to Native Americans in the Southwestern United States,[11] to Inuit.
[14][15] However, this implies that the period after which humans migrated out of Africa would have provided sufficient time to reverse any pre-existing famine-adapted alleles, for which there is little to no evidence.
Data on the body mass index of hunter-gatherer and subsistence agriculturalists show that between famines they do not deposit large fat stores.
[18] Hence, one of the main causes of type 2 diabetes has been attributed to poor fetal and infant growth and the subsequent development of the metabolic syndrome.
In response to the criticisms of the original thrifty genotype theory, several new ideas have been proposed for explaining the evolutionary bases of obesity and related diseases.
Subtle, epigenetic modifications at many genomic loci (gene regulatory networks) alter the shape of the canal in response to environmental influences and thereby establish a predisposition for complex diseases such as metabolic syndrome.
[21] Watve and Yajnik suggested that changing insulin resistance mediates two phenotypic transitions: a transition in reproductive strategy from "r" (large number of offspring with smaller investment in each) to "K" (smaller number of offspring with greater investment in each) (see r/K selection theory); and a switch from a lifestyle dependent upon muscular strength to one dependent on brain power ("soldier to diplomat").
[18] The main problem with this idea is the timing at which the transition is presumed to have happened, and how this would then translate into the genetic predisposition to type 2 diabetes and obesity[citation needed].
For example, the decline in reproductive investment in human societies (the so-called r to K shift) has occurred far too recently to have been caused by a change in genetics.
Sellayah et al. argue that ethnic groups whose ancestors were adapted to hot climates have low metabolic rates due to lack of thermogenic capacity, whereas those groups whose ancestors were cold-adapted were endowed with greater thermogenic capacity and higher metabolic rates.
Sellayah and colleagues provide evidence of thermogenic capacity, metabolic rates and obesity prevalence in various indigenous populations in support of their argument.
Such drift may have started because around 2 million years ago ancestral humans effectively removed the risk from predators, which was probably a key factor selecting against fatness.
It is argued by Prentice that famine may actually have only been a force driving evolution of thrifty genes for the past 15,000 years or so (since the invention of agriculture), but because famines exert effects on both survival and fertility the selection pressure may have been sufficient even over such a short timescale to generate a pressure for "thrifty" genes.