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3
Departments of
*
Anthropology and
Nutrition, Arizona State University, Tempe, AZ 85287
3To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • type 2 diabetes • insulin resistance • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Newman et al. 1987
). These findings, in conjunction with numerous
epidemiological studies which have consistently found high type-2
diabetes prevalence rates in populations moving from traditional,
non-Western diets and active lifestyles to rich, Western diets and
more sedentary lifestyles, provide the basis for the highly influential
"thrifty genotype" hypothesis (Neel 1962
).
Originally proposed to explain the unusually high incidence and
prevalence rates of type-2 diabetes among many Native American
populations after WWII, the "thrifty genotype" was hypothesized as
having been "selected for" when the earliest Native Americans
encountered particularly harsh feast or famine conditions as they moved
into North America from Asia thousands of years ago. This environment
was presumed to have favored individuals with a "quick insulin
trigger" which resulted in greater fat storage when plasma glucose
levels were highest during times of abundance. The fat then served as
an energy reserve to be called up in more difficult times.
However, while this special, genetically-based capacity promoted
survival advantage under aboriginal feast or famine conditions, when
coupled with stable, energy- adequate (or more than adequate) diets and
sedentary lifestyles (common in reservation communities beginning after
WWII), it promotes chronic hyperglycemia, hyperlipidemia, hypertension,
obesity and type-2 diabetes. Others have refined and reformulated the
original hypothesis (Brand Miller and Colagiuri 1994
,
O’Dea 1991
, Reaven 1998
,
Rittenbaugh and Goodby 1989
, Szathmary 1990
, Wendorf and Goldfine 1991
); however,
Neel’s emphasis on the role of genetics and natural selection in the
etiology of type-2 diabetes remains the central concept.
After years of intensive work by many laboratories, however,
there has been little success identifying type-2 diabetes
susceptibility genes (Elbein 1997
,Neel 1999
). Moreover, important questions have been raised as to the
methodological biases and conclusions drawn from
nonpopulation-based twin studies which have often been cited as
evidence of a strong genetic basis of the disease (Hopper 1999
). As a result, support for the "thrifty genotype"
hypothesis may be eroding. Hales and Barker (1992)
proposed an
alternative to Neel’s hypothesis, the "thrifty phenotype," to
accommodate the current epidemiological findings and experimental
animal data. The "thrifty phenotype" implicates fetal
undernutrition, not genetics, in the development of type-2 diabetes.
Hales and Barker (1992)
argue that metabolic adaptations by the
undernourished fetus serve to increase fuel availability in utero, but
this "programming" of pancreatic endocrine function persists
throughout life, elevating risk for the later development of type-2
diabetes.
In human populations, low birth weight is considered a reflection of
compromised nutrition in utero, and numerous reports have demonstrated
a relationship between a low birth weight and impaired glucose
tolerance in later life. In men aged 59 to 70 y (n
= 370), the prevalence of type-2 diabetes or impaired glucose
tolerance ranged from 40% if birth weight was less than or equal to
2.5 kg to < 14% if birth weight was > 4.3 kg (Hales et al. 1991
). A follow-up report in men and women aged 50
to 58 y (n = 266) indicated that the percentage of
subjects with type-2 diabetes or impaired glucose tolerance fell from
27 to 6% as birth weight increased from < 2.5 kg to over 3.4 kg
(Phipps et al. 1993
). Recently Rich-Edwards et al. (1999)
reported an inverse association between birth weight and risk
for type-2 diabetes in a cohort (n = 69,526) from the
Nurses’ Health Study. Relative risk for type-2 diabetes, adjusted for
age, adult body mass index and maternal history of diabetes, was
significantly greater at low birth weights (<2.3 kg) vs. high birth
weights (>3.2 kg) (relative risk: >1.8 and 
1.0,
respectively).
In addition to epidemiological research, rat studies have demonstrated
that the structure of the endocrine pancreas in undernourished fetuses
is altered: beta cell numbers are reduced as are islet size and
vascularization (Snoeck et al. 1990
). Insulin secretion
is impaired in these fetal islets when stimulated in vitro
(Dahri et al. 1991
). Furthermore, 70-d-old rats
undernourished in utero display impaired glucose tolerance and a
low-insulin response (Dahri et al. 1991
). Thus,
structural changes in the pancreata of undernourished fetuses lead to
functional deficiencies in adulthood.
In the present study, we examined the effects of fetal undernutrition on birth weights, insulin responses and glucose tolerance in adult life. Rats were undernourished in utero but consumed nutritionally adequate diets postweaning and throughout adulthood. The same variables were also examined in well-nourished second-generation animals, i.e., the offspring of rats undernourished in utero, to investigate the persistence of the "thrifty phenotype."
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The day after delivery, all litters were reduced to 10 pups. Control
pups consumed the N diet ad libitum postweaning (controls). Pups
undernourished during gestation consumed either the N diet ad libitum
postweaning (N: F1) or a high-fat (HF) diet (42% of energy from
fat, TD 88137; Harlan Teklad) ad libitum postweaning (HF: F1) (Table 1)
.
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Plasma glucose concentration was determined by a glucose oxidase method (kit #510-A; Sigma-Aldrich, St. Louis, MO), and plasma insulin concentration was measured using standard RIA procedures (ICN Pharmaceuticals, Costa Mesa, CA). Data are reported as the means ± SEM Differences between means were determined by one-way ANOVA followed by the Least Significant Difference posthoc test. The level of significance was set at 0.05. The Statistical Package for the Social Sciences (SPSS 7.5 for Windows, 1996, SPSS Inc., Chicago, IL) was used for all analyses.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). This difference in body weight persisted into adulthood. Body weights
at d 4 did not differ between N: F2 and control rats, but body weights
at d 4 for HF: F2 pups were significantly higher than that for all
other groups (Table 2)
. Body weights at 65 d did not differ in
second-generation rats consuming N or HF diets, while body weights
at 65 d were 20% higher in HF: F2 rats compared to control rats
(P < 0.05).
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). Furthermore, the baseline plasma insulin concentration in
second-generation experimental rats consuming the HF diet was twice
that of the second-generation experimental rats consuming the N
diet (P < 0.05). At 30-min postglucose challenge,
the plasma insulin concentration was insignificantly lower (-30%) in
N: F1 rats vs. controls (P = 0.395), whereas insulin
concentrations were significantly elevated in both sets of
second-generation rats compared to first-generation
experimental rats and controls. This pattern persisted at 120-min
postglucose challenge.
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. At 30-min postglucose
challenge, glucose concentrations were significantly reduced in all
experimental groups compared to controls. There were no differences
among groups at 120-min postglucose challenge.
The baseline insulin/glucose (I/G) ratio was significantly raised
in second- generation rats fed HF diets compared to controls and N: F1
animals (Fig. 1)
. At 30-min postglucose challenge,
second-generation rats fed HF diets had a significantly higher I/G
ratio than all other groups. By 120-min postglucose challenge, both
groups of second- generation rats had I/G ratios significantly higher
than those of control and N: F1 rats.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Snoeck et al. (1990)
observed that beta cells from neonates born to
dams fed low- protein diets had reduced proliferation and islet size
compared to control neonates. Additionally, islet vascularization was
reduced dramatically (-50%) in the low-protein-exposed neonates.
Thus, a low-protein diet during gestation impaired the normal
maturation of the fetal beta cell. Further investigation revealed that
in vitro stimulation of insulin secretion was reduced 20–30% in fetal
islets extracted from offspring of dams fed low-protein diets
(Dahri et al. 1991
). Islets from low-protein-exposed
offspring fed control diet from birth until d 84 also exhibited reduced
insulin secretion when challenged in vitro, indicating that the
functional deficit noted at birth persisted into adulthood
(Dahri et al. 1995
). An oral glucose challenge in these
rats generated a normal blood glucose and blood insulin response in the
male rats, but a hyperglycemic and hypoinsulinemic response in the
female rats (Dahri et al. 1995
).
Accordingly, adult female rats gestated by dams fed low-protein
diets but themselves fed the control diet throughout life developed
glucose intolerance during pregnancy (Dahri et al. 1995
). The endocrine pancreas of the offspring (the F2
generation) exhibited a higher proportion of large islets and a
significantly higher relative pancreatic insulin content vs. control
tissue (Dahri et al. 1995
, Eriksson and Swenne 1993
). Thus, protein-energy malnutrition during fetal
development reduced the ability of the rats to increase insulin
production to meet the needs of pregnancy; hence, increased amounts of
glucose and other nutrients were transferred to the fetus, stimulating
beta cell growth. Dahri et al. (1995)
postulated that these fetal
changes in the F2 generation would promote the development of a type-2
diabetes-like syndrome in adulthood. The data reported here expand
on these indications and demonstrate that adult F2 rats do indeed
develop an insulin resistance typical of type-2 diabetes in human.
Our findings are particularly interesting, given the fact that Native
American populations with high prevalence rates for type-2 diabetes,
such as the Pima, endured periods of starvation at the turn of the
century but did not experience high type-2 diabetes prevalence rates
until over 50 y later. The Pima suffered severe, general
malnutrition and even death due to starvation in the period 1870–1910
(Hackenberg 1983
). Subsequently, most Pimas escaped such
extreme privation, but income based on migratory labor remained low, as
did energy intake, through WWII. Just 21 cases of diabetes were
reported in 1940, and it has only been since the 1960s, when energy
intake approached and then surpassed the national level, that diabetes
became a major problem (Knowler et al. 1990
). By that
time, most of the 1870–1910 birth cohort had died, and the cases were
drawn from their children and grandchildren. Furthermore, Lillioja et al. (1991)
have demonstrated that nondiabetic Pimas are more
insulin-resistant and have exaggerated early insulin release and
elevated I/G ratios, compared to nondiabetic Caucasians.
This history of starvation and the subsequent development of diabetes
are observed also among the Havasupai of Arizona and the Nauruans of
Micronesia (Diamond 1992
, Martin 1986
,
Smith 1970
, Zimmet et al. 1991
), as well
as other indigenous and migrant populations around the world
(Griffiths 1995
, Kidd 1997
, Mayer 1961
). In light of our findings in rats, insulin resistance and
enhanced insulin secretory responses would be expected among offspring
born to mothers who were gestated under starvation conditions at the
turn of the century.
Obesity is a major risk factor for type-2 diabetes. Age-sex-specific
incidence rates of type-2 diabetes are 100–300% higher in individuals
with body mass index >35 kg/m2 vs. <25 kg/m2
(Knowler et al. 1990
). Total energy intake, particularly
from fat, is a strong predictor of obesity development. In the present
report, the consumption of HF, energy dense diets by rats gestated on
low-protein diets and by their offspring (the F2 generation) was
associated with a significant elevation in fasting blood glucose vs.
controls and a significant elevation in fasting blood insulin vs.
controls as well as F2 rats fed control diets. Hence, the
diet-induced insulin resistance of the present study appeared to be
exaggerated by feeding HF, high-energy diets, an association also
observed among diabetic Pimas (Bennett et al. 1984
).
Together, these data strongly indicate that fetal undernutrition in the
rat is a strong risk factor for the development of insulin resistance
in the subsequent F2 generation. Hattersley and Tooke (1999)
argue that
any association of low birth weight, an indication of poor maternal
nutrition, to diabetes is genetically determined and that the
"thrifty genotype" continues to be a valid hypothesis. Our data
counter this argument in that insulin resistance developed in
genetically normal rats via maternal undernutrition. The lack of a
gene-insulin resistance interaction suggests that careful maternal
monitoring may optimize human fetal development and break the familial
chain of diabetes (Godfrey 1998
). Buchanan et al. (1990)
and others (Algert et al. 1985
, Maresh et al. 1985
) have demonstrated the efficacy of brief energy
deprivation in mothers with gestational diabetes in terms of reducing
plasma glucose without creating a greater propensity for maternal
ketosis. Careful exploration of maternal diet intervention strategies
to reduce maternal hyperglycemia and optimize fetal environment is an
important consideration for future research.
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FOOTNOTES |
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2 Published in part in abstract form [Han, C. T., Martin, J. F. & Johnston, C. S. (1999) Insulin
resistance is promoted by protein malnutrition in utero. FASEB J. 13: A601].
4 Abbreviations used: HF, high fat; I/G, insulin/glucose; N, nutritionally adequate.
Manuscript received September 2, 1999. Revision accepted December 1, 1999.
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REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1. Algert S., Shragg P., Hollingsworth D. R. Moderate caloric restriction in obese women with gestational diabetes. Obstet. Gynecol. 1985;65:487-491[Medline]
2. Barnett A. H., Spiliopoulos A. J., Pyke D. A., Stubbs W. A., Burrin J., Alberti K. G. Metabolic studies in unaffected co-twins of non-insulin-dependent diabetics. Br. Med. J. 1981;23:1656-1658
3. Bennett P. H., Knowler W. C., Baird H. R., Butler W. J., Pettitt D. J., Reid J. Diet and development of non-insulin-dependent diabetes mellitus: an epidemiological perspective. Pozza G Micossi P. Catapano A. L. Paoletti R. eds. Diet, Diabetes and Atherosclerosis 1984:109-119 Raven Press New York.
4. Brand Miller J. C., and Colagiuri S. The carnivore connection: dietary carbohydrate in the evolution of NIDDM. Diabetologia 1994;37:1280-1286[Medline]
5. Buchanan T. A., Metzger B. E., Freinkel N. Accelerated starvation in late pregnancy: a comparison between obese women with and without gestational diabetes mellitus. Am. J. Obstet. Gynecol. 1990;162:1015-1020[Medline]
6. Dahri S., Reusens B., Remacle C., Hoet J. J. Nutritional influence on pancreatic development and potential links with non-insulin-dependent diabetes. Proc. Nutr. Soc. 1995;54:345-356[Medline]
7. Dahri S., Snoeck A., Reusens-Billen B., Remacle C., Hoet J. J. Islet function in offspring of mothers on low-protein diet during gestation. Diabetes 1991;40(Suppl. 2):115-120
8. Diamond S. M. Diabetes running wild. Nature 1992;357:362-363[Medline]
9. Elbein S. C. The genetics of human noninsulin-dependent (type 2) diabetes mellitus. J. Nutr. 1997;127:1891.S-1896S
10. Eriksson U. J., Swenne I. Diabetes in pregnancy: fetal macrosomia, hyperinsulinism and islet hyperplasia in the offspring of rats subjected to temporary protein-energy malnutrition early in life. Ped. Res. 1993;34:791-795[Medline]
11. Godfrey K. M. Maternal regulation of fetal development and health in adult life. Eur. J. Obstet. Gynecol. 1998;78:141-150[Medline]
12. Griffiths M. Aboriginal Affairs: A Short History 1995:1788-1995 Kangaroo Press NSW Australia.
13. Hackenberg R. Oritz A. eds. Handbook of North American Indians 1983:161-177 Smithsonian Washington, D. C.
14. Hales C. N., Barker D. J. P. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetol 1992;35:595-601
15. Hales C. N., Barker D. J. P., Clark P. M. S., Cox L. J., Fall C., Osmond C., Winter P. D. Fetal and infant growth and impaired glucose tolerance at age 64. Br. Med. J. 1991;303:1019-1022
16. Hattersley A. T., Tooke J. E. The fetal insulin hypothesis: an alternative explanation of the association of low birth weight with diabetes and vascular disease. Lancet 1999;353:1789-1792[Medline]
17. Hopper J. L. Is type II (non-insulin-dependent) diabetes mellitus not so "genetic" after all?. Diabetol 1999;42:125-127
18. Kidd R. The Way We Civilise 1997 University of Queensland Press Queensland, Australia
19. Knowler W. C., Pettitt D. J., Saad M. F., Bennett P. H. Diabetes mellitus in the Pima Indians: incidence, risk factors and pathogenesis. Diab. Metab. Rev. 1990;6:1-27[Medline]
20.
Lillioja S., Nyomba B. L., Saad M. F., Ferraro R., Castillo C., Bennett P. H., Bogardus C. Exaggerated early insulin release and insulin resistance in a diabetes-prone population: a metabolic comparison of Pima Indians and Caucasians. J. Clin. Endocrinol. Metab. 1991;73:866-876
21. Maresh M., Gillmer M. D., Beard R. W., Alderson C. S., Bloxham B. A., Elkeles R. S. The effect of diet and insulin on metabolic profiles of women with gestational diabetes mellitus. Diabetes 1985;34(Suppl 2):88-93
22. Martin J. F. The Havasupai. Plateau 1986;56:4 Museum of Northern Arizona Flagstaff, AZ.
23. Mayer A. Peasants of the Pacific 1961 University of California Press Berkeley
24. Neel J. V. Diabetes Mellitus: A "thrifty" genotype rendered detrimental by "progress"?. Am. J. Hum. Genet 1962;14:353-362[Medline]
25. Neel J. V. The "thrifty genotype" in 1998. Nutr. Rev. 1999;57:S2-S9[Medline]
26. Newman B., Selby J. V., King M. C., Slemenda C., Fabsitz R., Friedman G. D. Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins. Diabetol 1987;30:763-768
27. O’Dea K. Westernization, insulin resistance and diabetes in Australian Aborigines. Med. J. Aust. 1991;155:258-264[Medline]
28. Phipps K., Barker D. J. P., Hales C. N., Fall C. H. D., Osmone S., Clark P. M. S. Fetal growth and impaired glucose tolerance in men and women. Diabetol 1993;36:225-228
29. Reaven G. M. Hypothesis: muscle insulin resistance is the ("not-so") thrifty genotype. Diabetologia 1998;41:482-484[Medline]
30. Rich-Edwards J. W., Colditz G. A., Stampfer M. J., Willett W. C., Gillman M. W., Hennekens C. H., Speizer F. E., Manson J. E. Birth weight and the risk for type-2 diabetes mellitus in adult women. Ann. Inter. Med. 1999;130:278-284
31. Rittenbaugh C., Goodby C. Beyond the thrifty gene: metabolic implications of prehistoric migration into the New World. Med. Anthropol. 1989;11:227-236[Medline]
32. Smith C. G. Culture and diabetes among the upland Yuman Indians 1970 Unpublished Ph.D. Dissertation University of Utah.
33. Snoeck A., Remacle C., Reusens B., Hoet J. J. Effect of a low protein diet during pregnancy on the fetal rat endocrine pancreas. Biol. Neonate 1990;57:107-118[Medline]
34. Szathmary E. J. Diabetes in Amerindian populations: the Dogrib studies. Armelagos G. Swilling A. eds. Health and Disease of Populations in Transition 1990 Bergin & Garvey New York, NY.
35. Wendorf M., Goldfine I. D. Archaeology of NIDDM. Excavation of the "thrifty" genotype. Diabetes 1991;40:161-165
36. Zimmet P. Z., Finch C. F., Collins V. R. Decline in incidence of epidemic glucose intolerance in Nauruans: implications for the "thrifty genotype.". Am. J. Epidemiol. 1991;133:1097-1104
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