Perspectives in Diabetes
Archaeology of NlDDM
Excavation of the "Thrifty" Genotype
- .
MICHAEL WENDORF AND IRA D. GOLDFINE
Since the 1940s, numerous cases of non-insulindependent diabetes mellitus (NIDDM) have been
observed in certain American lndian populations.
Extremely high prevalence rates of NlDDM occur most
strikingly in several tribes of Paleo-Indians, whose
ancestors migrated to North America >I
1,000 yr ago.
Archaeological evidence from that period indicates
that certain groups of Paleo-Indians maintained an
arcticlike hunter-gatherer life-style in an area in
temperate North America ranging from Wyoming
to Arizona. This life-style featured a reliance on
unpredictable big game species as a major food
source. However, at this time, big game species were
becoming extinct. It is hypothesized that thosepaleolndians who relied on big game as a food source
developed a "thrifty" genotype that allowed a selective
advantage during the periods of fasting that occurred
between big game kills. It also is hypothesized that
this thrifty genotype in these lndians may contribute to
NlDDM when a sedentary life-style is adopted and food
sources are constant. Because insulin resistance in
muscle is a major feature of NIDDM, it is possible that
insulin resistance per se is the phenotypic expression
of the thrifty genotype. Diabetes 40:161-65, 1991
I
n the last century, non-insulin-dependent diabetes mellitus (NIDDM) was uncommon among all American lndian
tribes. Since the 1940% some but not all tribes have developed very high prevalence rates of NlDDM (1). NIDDM
is very common among the Pimas of Arizona, who have the
highest reported NlDDM prevalence in the world (-50% of
From the 4rchaeological Research Fac~l~ty,
University of Cal~fornia,Berkeley;
the D~visionof Diabetes and Endocrine Research, Mount Zion Medcal Center
of the Unversity of California, and the Departments of Medicine and Physiology, University of California. San Francisco, California.
Address correspondence and reprint requests to Michael Wendorf, PhD,
Div~s~on
cf Diabetes and Endocrine Research. Mount Zion Medical Center.
PO Box 7921, San Francisco, CA 94120.
Received for publication 5 July 1990 and accepted in rev~sedform 25
Septembr?r1990.
DIABETES, VOL. 40, FEBRUARY 1991
adults >35 yr old; 2) and have been the subject of several
epidemiological studies (3-10). NlDDM is also prevalent
among many other lndian tribes, e.g., the Papagos, Yumas,
and Comanches (1 1.12). However. Alaskan and Canadian
Athapaskans, Aleuts, Eskimos, Navajo, and some Apache
tribes have lower NlDDM rates than the Pimas (1 1,13,14).
The recent appearance of NlDDM among many American
lndian tribes may be due to the interaction of a susceptible
genotype and life-style changes. In this perspective, we use
the archaeological record of early American lndians to provide clues as to how a susceptible genotype might have
been selected in American lndians and why it might be more
common among some tribes than others.
AMERICAN INDIAN SElTLEMENT OF NORTH AMERICA
The high prevalence of NlDDM among many American Indians, who before the 1900s lived in widely different environments, suggests that the susceptible genotype was selected during an event in the remote past common to most
American Indians, i.e., before or during the initial settlement
of North America (12). It is widely held that the settlement
of North America began near the end of the Pleistocene,
thousands of vears aao, and involved three seDarate miarations of Asian hunter-gatherers into Alaska: ~aleo-lndian,NaDene or Athapaskan, and Aleut-Eskimo (15,16).
The Paleo-Indian migration may have occurred during the
late Wisconsin glacial period (after -23,000 yr ago) when
hunter-gatherers crossed the now-submerged Bering land
bridge (an 1800-km-wide land mass that extended from Saint
Lawrence island to the Diomede islands, connecting Asia
and North America) (17). The route south through the interior
of Canada was blocked until only -12,000 yr ago by the
occlusion of the Canadian continental glaciers (18). Shortly
afterward, the Paleo-Indians were able to move south into
what is now Montana and the rest of North America through
a narrow ice-free tundra corridor that opened between the
retreating continental glaciers (19; Fig. 1).
The Na-Denes or Athapaskans may have migrated from
Asia into Alaska -10,000 yr ago, just before the Bering land
bridge was submerged by rising sea levels (20). However,
161
Present
Diabetes appears
Navajo and Apache arrive in Southwest
5.000
Eskimos enter North America
Athapaskans migrate into Alaska
and Canada as glaciers recede
Big game extinctions
-
_
Paleoindians move south into continental U.S.
through tundra 'ice free corridor'
I
'Thrifty' genotype selected
during period of big game
reliance
Paleoindians blocked from moving south into Canada and cont~nental
U.S. by glaciers
Paleoindians migrate from Asia into Alaska
25.000
m s
Aa,
FIG. 1. Time line of American Indian settlement of North America.
"Thrifty" genes may have been selected between 11,500 and 10,000 yr
ago during period of reliance on vanishing big game. Diabetes appears
only recently with changes in diet and life-style. First Paleo-Indian
migration from Asia into Alaska is estimated to have occurred 23,000
yr ago or thereafter.
the Athapaskans remained in Alaska and Canada until relatively recently, when they migrated into the southwest as
Navajo and Apache groups in the 17th century (17).
Ancestral Aleut-Esklmo groups first appeared in North
America -4500 yr ago (20). They have since remained in
the northern latitudes, where they developed an economy
based on marine resources and caribou. Because the American Indians that have the highest prevalence of NlDDM are
descendants of the Paleo-Indians, we propose that the archaeological record of the Paleo-Indian settlement of North
America provides evidence of the stresses that selected a
diabetic genotype.
SPECIALIST VS. GENERALIST
The 11,000- to 12,000-yr-old archaeological record of the
early Paleo-Indians, who lived as hunter-gatherers (agriculture had not yet been developed), can be interpreted through
the use of ethnographic studies of living hunter-gatherers.
As the archaeologist Binford (21) noted, "Archaeology is not
a field that can study the past directly. . . On the contrary, it
is a field wholly dependent upon inference to the past from
things found in the contemporary world." Ethnographic studies of hunter-gatherers have shown that foraging strategies
range in a continuum from specialized to generalized in response to a latitudinal gradient in the number of prey species
that can be used productively (22-25). In high-latitude highly
seasonal environments, which have few species but many
individuals per species (26), hunter-gatherers specialize and
often camp near the food resource that is most abundant in
each season. As a result, camps are moved frequently to
be near the seasonally abundant resource (27), e.g., a caribou crossing (28).
In contrast, in temperate-latitude environments, which
have numerous species but fewer individuals per species,
hunter-gatherers generalize by foraging among a wide range
of species and camp in such a way that foods can be brought
back to camp as they are found by foraging parties. The
result is a largely sedentary life-style with large campsites
that are somewhat removed from any single food source.
Examining the archaeological record of the early Paleolndians (-1 1,000 yr ago), two life-styles are seen. The first
IS a generalist life-style that is evident throughout much of
temperate North America. Most of these sites are campsites
to which food was evidently returned by foraging parties,
and some campsites even have evidence of housing, implying a relatively sedentary life-style (29,30).
However, in low elevations from Wyoming to Arizona and
Texas, a second specialist life-style is evident. Small campsites near big game kills are seen. These camps were evidently being moved from one big game kill to another as if
they were in the high arctic (31-38; Figs. 2 and 3). This
settlement pattern is not only anomalous in the Upper Paleolithic (from -40,000 to 10,000yr ago), it is not what would
be expected given what is known about hunter-gatherers
living today.
What could have caused this articlike pattern of camping
near game kills in the temperate latitudes for this second
group of specialist Paleo-lndlans? Modern arctic huntergatherers provide clues. For instance, Eskimos today might
move their camp to the site of a caribou kill to allow the entire
group, including women and children, to take part in processing the game. Although other foods, such as an occasional ptarmigan (an arctic game fowl), are available and
are included in the diet, it is crucial that the single food item
that is sufficiently abundant to support the group (l.e., caribou) be quckly and efficiently processed. Like the Eskimo,
these Paleo-Indians were moving their camps from one big
game kill to another because big game (e.g., bison) was
considered crucial to their survival, and the whole group took
part in processing the game.
Why would big game be so crucial to the survival of this
group of early Paleo-Indians? Like hunter-gatherers in temperate latitudes today, they should have relled more on the
numerous species of small game and plant foods around
them.
Because big game species are less diverse than small
game species from one environment to another, blg game
would remain familiar prey as the Paleo-Indians moved south
along the Rocky Mountains. However, new species of smaller
game and plant foods would have been encountered as the
Paleo-Indians moved from the tundras near the Canadian
glaciers to the forests and parklands south of Montana. The
change in smaller game and plant foods was too abrupt to
allow for a gradual adaptation, leading to this unusual temperate-latitude reliance on big game (39). The other generalist Paleo-Indians, who moved east and west along the
ice margins, did not have to adapt to a radical change in
environment. Consequently, big game hunting was not as
crucial to these Paleo-Indians as it was to the specialist
Paleo-Indians
DIABETES. VOL 40, FEBRUARY 1991
FIG. 2. Map of North America and northeastern
Siberia --11,500 yr ago showing Bering land
bridge, Canadian glaclers (lightly shaded areas),
and ice-free corridor. Specialized Paleo-Indian
campsites with adjacent big game hunting
activities (i.e., hunter-gatherer) occurred in dark/y
shaded area from Wyoming t o southern Arizona.
Several well-known sltes such as Lahner,
Arizona, are indicated. Generalized Paleo-Indian
campsites without adjacent big game kills have
been found in numerous locations in east, far
west, and near hlgh elevations within area of
specialized Paleo-Indian activity (not shown).
(Modified from ref. 56.)
Although big game is a high-risk resource even when it is
abundant, many species, e.g., horses, camels, and mammoths, were becoming extinct throughout North America at
this time (-1 1.000-10,000 yr ago). However, the specialist
Paleo-Indians continued to rely on the only remaining big
game species, the bison, for several hundred years, even
though these animals were not as numerous as they would
later become (17). Thus, the extinction of most specles of
big game did not cause these Paleo-Indians to abandon
their reliance on large game. This reliance ended hundreds
of years later as the specialists, who were no longer camping
near big game kills, learned to hunt smaller game and process plant foods efficiently.
THRIFTY GENOTYPE AND NlDDM
The result of this big game reliance would have been frequent but short-lived food shortages as the specialist PaleoIndians extracted the food energy from one kill and then
waited for the next fortunate hunt. Due to the lack of preservation, little evidence of the use of plant foods by these
Paleo-Indians has been found. However, it is likely that carbohydrates were included in the diet and could have prevented outright starvation during these periods of food shortage (40). A thrifty genotype metabolism, such as proposed
by Neel (41; see below), could have allowed a survival advantage during these alternating periods of feast and famine.
Because certain Paleo-Indians, i.e.. the Pimas, now have
FIG. 3. Paleo-Indian artlfacts found In association
with mammoth remains at Lehner site, southern
Arizona, dated 1200 yr ago. Top row, 5 stone
clovis projectile points (spear tips) used to kill
mammoths; bottom row, center, quartz clovls
point; bottom row, left and right, scrapers used
to butcher mammoths. These artifacts provide
strong evidence that Paleo-Indians of this period
were specialized huntergatherers who preyed on
large game. (Photo courtesy Arlzona State
Museum, The University of Arizona, Tucson.)
DIABETES, VOL. 40. FEBRUARY 1991
163
a sedentary life-style and a constant food source, their thrifty
genotype may now be disadvantageous and lead to obesity
and NIDDM. In contrast, the Athapaskans, Aleuts, and Eskimos, who either remained in high latitudes or migrated
south after the glaciers had retreated, did not experience
the sudden change in environment that confronted these
Paleo-Indians. Consequently, in the former group, the thriftygenotype metabolism would not have conveyed as much
survival advantage as in the Paleo-Indians.
A major feature of NIDDM in both white and Indian populations is insulin resistance in muscle, which IS primary and
antedates the onset of the disease (42-45). However, this
resistance is not sufficient to produce the symptoms of
NIDDM. Concomitant decreased insulin secretion is also
necessary (43,44). Both population surveys and prospective
studies of prediabetic Pima lndians indicate that insulin resistance predates the onset of NlDDM (5,46). Also, studies
of glucose metabolism indicate that the major site of ~nsulin
resistance is in muscle (47).
To explain the presence of NlDDM genes in all populations, Neel (41) first postulated that a thrifty genotype existed
that had a selection advantage as hunter-gatherers fluctuated between feast and famine. As he first proposed, the
thrifty genotype involved a "quick insulin trigger" that reduced urinary calorie loss and allowed more fat storage,
thus providing an adaptation to periods of famine. In a modern environment with access to a constant food supply, he
suggested that the quick ~nsulintrigger was overstimulated,
leading to the production of circulating insulin antagonists,
with p-cell decompensation and eventual diabetes. Although
his original pathophysiological mechanism of insulin oversecretion and the subsequent development of insulin antagonists has been retracted (48), the thrifty genotype concept
may still be valid.
HYPOTHESIS
We propose that the thrifty genotype in NlDDM could in fact
be (or contribute to) the insulin resistance seen in muscle.
A selective insulin resistance In muscle would have the effect
of blunting the hypoglycemia that occurs during fasting but
would allow energy storage in fat and liver during feeding.
Both of these features could allow hunter-gatherers to have
survival advantages during periods of food shortage. However, in sedentary individuals allowed free access to food,
this genotype would be disadvantageous; these individuals
would become obese with concomitant secondary insulin
resistance in fat and liver (46). Also, significant postprandial
hyperglycemia would occur. Postprandial hyperglycemia
would then lead to glucose toxicity with decreased insulin
secretion from the p-cell (45,49-51). The effect of chronically
high glucose concentrations in decreasing insulin secretion
has been demonstrated both in vitro and in vivo (45,49-51).
Thus, in those individuals with the thrifty genotype, increased
insulin resistance and concomitant decreased insulin secretion could contribute to the expression of NIDDM.
Parallels to the NIDDM seen in the Pimas and other tribes
of Paleo-Indians can be found in animal models of NIDDM,
i.e.,the spiny mouse and the Egyptian sand rat (52,53). Both
are desert animals that. In their native state, are nondiabetic.
However, when placed in a laboratory environment and allowed unrestricted access to food, they become obese and
164
diabetic. Furthermore, both have been shown to be insulin
resistant (52,53). Thus, in both animals and humans, a genotype that has a selective advantage in a food-scarce environment can contribute to NlDDM in a food-abundant environment.
Most likely, in the obese form of NlDDM such as is seen
in Pima Indians, multiple genes are involved, and thus, the
basic cellular mechanism of insulin resistance remains unknown. Studies of the insulin receptor in tissues of typical
NlDDM patients have revealed defects, but these defects
have been relatively small and are believed to be secondary
to the metabolic alterations of this disease (54). Therefore.
the receptor abnormalities are probably not the primary defect in NIDDM. More likely is that cellular signaling events
that occur after the insulin binds to its receptor cause the
insulin resistance. Recent studies focused on postreceptor
mechanisms in muscle such as the activation of glucose
transport or glycogen synthesis (55) or insulin-receptor tyrosine kinase antagonists (Sbraccia et al., this issue, p. 295).
Defects in either of these steps in muscle glucose metabolism could expla~nin part the impaired glucose metabolism
seen in Paleo-Indians and other groups with NIDDM.
ACKNOWLEDGMENTS
This work was supported in part by National Institutes of
Health Grant POI-DK-38985.
We thank P. Goodman, G. Reaven, D. Estrich, and C. Grunfeld for critical reading of this manuscript.
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