Non-Insulin-Dependent Diabetes Mellitus:
Thrifty Genotype or Thrifty Phenotype?
© 1999 by James Q. Jacobs

There is presently a global epidemic of non-insulin-dependent diabetes mellitus (NIDDM) with morbidity and mortality of a tremendous magnitude. Diabetes, a chronic disease that has no cure, is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. In the United States 5.9 percent of the population have diabetes. Diabetes was the seventh leading cause of death listed on U.S. death certificates in 1996, according to the National Center for Health Statistics, registering more than 187,000 deaths in 1995. In the US, age-adjusted death rates reported for whites with diabetes are twice the rates for those without. People with NIDDM (Type 2) diabetes typically develop the disease after age 45. Over 18 percent of persons 65 and older have diabetes (American Diabetes Association 1999).

Diabetes is not one disease, rather there are two major forms, insulin-dependent or type I and non-insulin-dependent or type II. NIDDM as a disease with onset in middle age, in the 10-29 age interval. Children of parents who had NIDDM tend to have small departures from normality in glucose tolerance tests and to be obese. The causes of diabetes are not fully understood. Use of highly refined carbohydrates and sugars has altered dramatically with civilization. How this might influence the development of insulin resistance is a matter of active debate.

NIDDM has, until recently, been seen as a disease of genetic susceptibility triggered by environmental factors. The high prevalence of NIDDM in specific population led to this genetic association. The striking prevalence in various Amerindian groups created the suspicion that there might be a particular predisposition to the disease in some tribal groups, a predisposition that surfaced with reservation-style living. In 1962 Neel suggested that the quick insulin trigger in NIDDM was an asset to tribal hunter-gathers on feast-or-famine regimes (Neel 1999) but changing dietary patterns had compromised this mechanism. The environmental trigger is the change in lifestyle to inactivity and in diet to over alimentation, especially more carbohydrates and fats. The insulin trigger was seen as being under genetic control, with the genetic trait frequent in specific groups or tribes. This genetic adaptation was termed the "thrifty genotype."

The fundamental biochemical basis of diabetes is still unknown (Bennett 1999). NIDDM is not just a single entity. There are several forms of late onset, type II diabetes. In the Oji-Cree Native population in Ontario a genetic mutation has recently been associated with a form of NIDDM, maturity-onset diabetes of the young (MODY) (Hegele et al. 1999). This mutation is only known from this single population and only accounts for a portion of their incidence of NIDDM. A genetic mechanism, if one exists, remains to be discovered to explain the vast majority of high prevalences of NIDDM. The rare, inherited subtypes of NIDDM comprise no more than about 10 percent of what is commonly diagnosed as diabetes (Neel 1999).

While the "thrifty genotype" idea received wide acceptance the responsible gene or genes remained elusive. We do not yet know which genes determine the hypothesized inherited susceptibility, although genome-wide scans have been performed to define the location of these genetic factors. In the case of the Oji-Cree only several years elapsed from the time the high prevalence of NIDDM was noticed until the identification of the mutation associated with MODY in that population. During a far longer span efforts to find the associated genes in other populations have been unsuccessful (Neel 1999). So the question remains: Why is the predisposition to NIDDM so frequent and changing so markedly?

Explanations based on the "thrifty genotype" hypothesis continue to be invoked by many scientists. Nonetheless, recently the acceptance of the "thrifty genotype" theory has been eroding. According to its author, "it is now clear that the original thrifty genotype hypothesis, with its emphasis on feast or famine, presented an overly simplistic view" (Neel 1999). It is being replaced with a "thrifty phenotype" hypothesis (Hales et al. 1992). The concept underlying this new hypothesis is that poor fetal and early post-natal nutrition imposes mechanisms of nutritional thrift upon the growing individual. The resultant long-term consequences are impaired development of the endocrine pancreas and a far greater susceptibility to NIDDM.

Genes do not provide an unalterable blueprint, but conditional options and gene-environment (nutrient) interaction must be described in the context of development (Simopoulos 1999). The interaction of genes and nutrients determine phenotype and individual development. We know that changes in our adult diet are potential causes of diseases. Changes in nutrition affect heritability of variant phenotypes that are dependent on the nutrient environment for their expression (Simopoulos 1999). A study in 1970 showed that malnutrition may produce a permanent reduction in the capacity for insulin secretion (James et al. 1970).

The greatest portion of developmental life is gestative development (about 7/8th's in terms of cell divisions). Nearly all brain neurons are developed at birth. It follows that the fetal environment is a very important determinant of our phenotypic expression. Barker (1990) has proposed that cardiovascular disease results from restraint of growth during fetal life. Increased death rates had previously been linked to low birth weight. Restraint of fetal growth of certain tissues is due to an adverse environment related to poor maternal nutrition. Factors affecting early growth may lead to impaired glucose tolerance/type 2 diabetes (Hales 1992). Linkage of poor maternal nutrition might explain the high rates of glucose tolerance and diabetes in certain populations. Metabolic adaptations by the malnourished fetus increase fuel availability in utero. The adaptation persists and presents problems when a high energy diet is available in later life.

Studies in rats have shown that underfeeding the young lowers adult plasma insulin. Irreversible loss from an early growth failure applies generally to tissue growth (Hales 1992). Hales and Parker proposed that poor fetal nutrition is detrimental to the development and function of Beta cells and predispose to later NIDDM.

The effects of fetal undernourishment on adult life insulin responses and glucose tolerance has been studied in genetically normal rats (Martin et. al. 1999). Subjects were undernourished in utero and fed normal diets. Their offspring were also studied and study of the third generation continues. Both generations were fed adequate or high-energy, high-fat diets. The first generation displayed an elevated insulin response, the second generation displayed a markedly elevated insulin response. Insulin response was higher in the group fed the rich diet. Malnutrition during fetal development reduced the ability to increase insulin production to meet pregnancy needs. This results in increased glucose transfer to the fetus. Martin's group demonstrated that the second generation rats develop an insulin resistance typical of NIDDM in humans.

In the rat studies body weights were reduced in first generation pups. In humans an early life factor that influences the risk of developing type 2 diabetes is birth weight. Middle-aged men in the United Kingdom with a low birth weights had higher rates of diabetes (Hales 1992). Hales speculated that the excess of diabetes among the low-birth-weight group was due to maternal malnutrition during pregnancy, with a failure of the fetal pancreatic cells to develop fully. Earlier work had shown that infants who had high birth weights developed a high prevalence of diabetes at an early age (Bennett 1999).

In a study of the Pima Indians, the population with the highest prevalence of diabetes in the world, most of the diabetics were offspring of diabetic mothers, without evidence that the mothers were undernourished. Nevertheless, the observation of an excess prevalence of diabetes by the time these babies were 30 years of age was clear (Bennett 1999). Given the results by the Martin group it would be reasonable to look at the nourishment of earlier generations. Offspring exposed to the highest levels of amniotic fluid insulin (AFI) have a 13-fold increased risk of developing IGT by 10-16 years of age, and therefore NIDDM (Silverman et al. 1995). Abnormal intrauterine environments leads to early expression of diabetes (Bennett 1999). In the Pima, 10-15 percent of new cases are the children of diabetic pregnancies. Early onset of diabetes leads to increased diabetic pregnancies in the next generation and a further increase in the prevalence of diabetes, presenting a vicious cycle (Bennett 1999). This could explain the very high prevalence in the Pimas.

For the "thrifty genotype" model to work a genetic trait or set of traits that is presently doubling death rates must have conferred a significant survival advantage in the past. In the case of the very deleterious sickle cell anemia gene, which confers a survival advantage in areas with endemic malaria, the mechanism is very well known. No mechanism conferring greater survival advantage has been shown in cases of diabetes or diabetes prone populations.

Arguments offered in favor of the "thrifty genotype" model include that higher prevalences are seen in genetically related groups. Diabetes death rates vary considerably across race and ethnic groups. Recent estimates indicate that diabetes affects 6 percent of aboriginal adults compared with 2 percent of all Canadian adults (Hegele 1999). In the U. S., compared with white persons, diabetes death rates were 2.5 times higher among black persons (Center for Disease Control 1996). The highest prevalence rates are known among Pima and other Indians, followed be Nauruans and Aborigines (Center for Disease Control 1996). There is a wide range in the prevalence of diabetes among aboriginal groups. In Canada the parallel of latitude and the language phylum helps explain the prevalence. Both geographical location and language are likely to be associated with other shared environmental factors (Hegele 1999). Diabetes has reached epidemic proportions among Native Americans. The overall prevalence of NIDDM in Native Americans is 12.2 percent (American Diabetes Association 1999). In the Pima tribe 50 percent of adults between the ages of 30 and 64 having NIDDM (American Diabetes Association 1999).

In the general population diabetes tends to aggregate in families. The disease risk for relatives of afflicted individuals is much higher than that in the general population. Families share genes and environmental factors. Other metabolic factors have proven genetic determinants. Studies have shown that 50 percent of the variance in plasma cholesterol concentration and 30-60 percent of the variance in blood pressure is genetically determined (Simopoulos 1999).

These reasons seemed to make a very good case for the "thrifty genotype" scenario. Add to this the dramatic changes in lifestyle of the Pima, Nauruans and Aborigines in recent decades (the hypothesized environmental trigger) and it is obvious why the hypothesis enjoyed such favor for so long. Yet these arguments are not difficult to counter.

If a genetic cause is at work then the prevalence in genetic groups should be relatively predictable. This is not so. Prevalence of diabetes in the United Kingdom is about 2 percent compared to near 8 percent in the United States (Harris et al. 1987). A comparison of a variety of Native American groups reveals a broad range of NIDDM prevalence. A study of NIDDM in Native Canadians (Hegele et al. 1997) compared the Ontario Oji-Cree with the Inuit. The Oji-Cree have a frequency of near 40 percent, among the world's highest while the Inuit frequency is less than one percent. While there were significant differences in frequencies of "deleterious" alleles between the Oji-Cree, lnuit and the control sample of white subjects, genetics does not conform to the pattern nor sufficiently explain the difference in diabetes prevalence. The higher frequency in both the Oji-Cree and lnuit of the "deleterious" alleles would suggest that both of these groups might be genetically predisposed to diabetes, yet the incidence of diabetes in the lnuit is very low and, in the Oji-Cree, very high.

Hegel's group concluded that factors other than the alleles studied were the primary determinants of disease susceptibility, indicating the preeminence of environmental factors The different environments and recent histories of the Oji-Cree and Inuit are the most likely explanation. It is noteworthy that the Inuit lead a traditional lifeway, while the Oji-Cree are reservation dwellers who no longer have access to traditional resources.

It could be argued that the Inuit and the Oji-Cree are genetically distinct peoples. This argument can be countered by examining the Pima case more closely. A study compared 984 Arizona Pimas with 226 Mexican Pimas and a group of 198 non-Pima individuals living in the same environment as the Mexican Pimas. The results showed the following rates of diabetes: 38.2, 6.4 and 3.4 percent respectively (Valencia et al. 1999). The evidence supporting the genetic relatedness of the two Pima groups is based on linguistic similarities. It is estimated that the groups separated 700 to 1000 years ago. The vast prevalence differences in the genetically allied Pimas argues very strongly for an environmental causation. While the Mexican Pimas lead a traditional lifeway the Gila River Pimas are confined to a reservation. The Gila River residents were deprived of their irrigation water by floods in 1870 and suffered crop failures and severe malnutrition for decades (Hackenburg 1983). Ancestors of the present-day Pima were farmers, using the rivers to irrigate their crops. Anglo settlers diverted the water supply to irrigate land upriver. Their lifestyle probably changed little until the present century, when the Anglo settlers moved into the area and their traditional agricultural subsistence was disrupted (Bennett 1999).

In 1908, Hrdlicka, a physician and anthropologist, visited Indian reservations in the southwest and assessed the health of the people. He recorded one case of diabetes on the Gila River Reservation. The next evidence of diabetes among the Pima is from 1937, when Elliott Joslin identified 21 persons with diabetes, a frequency not dissimilar to that of the general population. In 1954, Parks and Waskow recorded 283 persons with diabetes, a 10-fold increase. In 1965 there were about 500 cases and the prevalence of diabetes has increased progressively up to the present time (Bennett 1999).

Prevalence of diabetes in Native American populations by regions and reservations varies widely. The rate per thousand is from four, seven and nine for the Northwest Territories Inuit, Northwest Territories Indians and Yukon Indians groups respectively (all ages, 1987), compared to 500 per thousand for the Gila River Pima (age 30-64, 1982-1987). Rates are consistently very low in the Far North group and low in the Pacific Northwest. The highest rates are in the Southwest. Nonetheless there is a considerable variation between Southwest tribes. Glucose tolerance and related tests were conducted on remote, unacculturated Amerindians, the Yanomamo and Marubo of the Brazilian Amazon Basin. Neither of these groups exhibited the dramatic glucose intolerance of the highly acculturated adult North American Pima. No evidence for a strong ethnic predisposition to NIDDM in the Amerindian group was found (Neel 1999).

Genetic change is not a rapid process, yet some Native populations have experienced a rapid increase in the prevalence of NIDDM over the past two to three decades. Exposure to the environmental risk factors must be responsible. The genetic constitution of a population cannot change over such a short period of time. What is interesting about these contrasting prevalences is that the differences point not only to environmental differences, but possibly historical differences. The Far North is the one region where the Native lifeway has continued unchanged to a great extent. Also, in the Far North the Natives have not been forced onto reservations with limited resources.

Does access to resources influence the incidence of disease? An individual's health status is the product of the interaction of his or her genetic endowment, age, nutrition, and other aspects of physical and cultural environment. Family history (including demographic and ethnic aspects) is an important predictor of disease (Simopoulos 1999). Demographic studies have revealed a relationship between income levels and diabetes prevalence in demographic groups, a pattern that is evident in various genetic groupings. Data from the National Longitudinal Mortality Study for 197989 show a strong relationship between diabetes mortality and family income. For persons 45 years of age and over, the age-adjusted death rate from diabetes decreased as family income increased. The diabetes death rate for women in families with incomes below $10,000 was 3 times the death rate for those with incomes of $25,000 or more.

We can also compare diabetes rates with Native American population statistics. According to the 1990 Census of Population and Housing, based on data from a sample of households, the following is known about Native American tribes (US Department of Commerce 1993). Sixty-nine percent of American Indian adult males were in the labor force compared with 74 percent nationally. A smaller proportion of American Indians were employed in managerial, professional, technical, sales, and administrative support jobs. The 1990 median income of American Indians families was 62 percent of the $35,225 population median. Twenty-seven percent of these families were maintained by a single, female householder with a median income of $10,742. In 1989 31 percent of American Indians were living below the poverty level, compared with the 13 percent national rate. Of American Indians residing on reservations 51 percent were living below the poverty level. About 2 in 3 persons on the Papago, Pine Ridge, Gila River, and San Carlos Reservations and trust lands were in poverty. Per capita income on reservations was about $4,478 and ranged from $3,100 to $4,718 on the 10 largest reservations. Papago and Pine Ridge per capita incomes were $3,100. These facts are supportive of the "thrifty phenotype" model.

The histories of other populations, and even families, can be examined to see if they also fit the pattern suggested by the "thrifty phenotype" hypothesis. This seems to be the case with the Nauruans and Aborigines. This area of investigation deserves further study and statistical analysis.

One of the most hopeful aspect the "thrifty phenotype" hypothesis is that it offers a cure to the escalating prevalence of NIDDM. Control of maternal diet offers a way to break the vicious cycle of diabetes. The "thrifty phenotype" hypothesis represents a hopeful new alternative to the genetic model.

Literature Cited.

American Diabetes Association, 1999, Diabetes Facts and Figures.

Barker, Osmond C., 1990. The intrauterine origins of cardiovascular and obstructive lung disease in adult life. Journal of the Royal College of Physics, 25:129-132.

Bennett, Peter H. 1999. Type 2 Diabetes Among the Pima Indians of Arizona: An Epidemic Attributable to Environmental Change? Nutrition Reviews, Volume 57:5, S51-S54.

Center for Disease Control, Prevalence of Diagnosed Diabetes Among American Indians/Alaskan Natives, 1996.

Hackenburg, Robert A. 1983. Pima and Papago Ecological Adaptations, In Handbook of North American Indians, Alfonso Ortiz, ed. Vol. 10, pp.161-177.

Hales, C. N., D. J. P. Barker, 1992. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35:595-601.

Harris, M. I., W. C. Hadden, W. C. Knowler, P. H. Bennet, 1987. Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. populations aged 24-74 yrs Diabetes 36:523-534.

Hegele, R. A., C. Henlan, S. Harrist, A. Hanley, B. Zinman, 1999, The Hepatic Nuclear Factor-1 a G319S Variant Is Associated with Early-Onset Type 2 Diabetes in Canadian 0ji-Cree. The Journal of Clinical Endocrinology & Metabolism, 84:3, pp. 1077-1082.

Hegele, Robert A. 1999. Lessons from Genetic Studies in Native Canadian Populations. Nutrition Reviews, Volume 57:5, S43-S49.

James, W. P. T., H. G. Goore, 1970. Persistent Impairment of Insulin Secretion and Glucose Tolerance after Malnutrition, The American Journal of Clinical Nutrition, 23:4, pp. 386-389.

Lee, E., B. Howard, P Savage, L Cowan, R. Fabsitz, J. Yeh, O. Go, D. Robbins, T Welty, 1995. Diabetes and Impaired glucose tolerance in three American Indian populations aged 45-74 years: the Strong Heart Study. Diabetes Care 18, pp. 599-610.

Martin, J. F., C. S. Johnson, C. Han, and D. C. Benyshek. 1999. Gestationally Undernourished, Genetically Normal Female Rats Produce Insulin Resistant Offspring, Manuscript. (Now published in The Journal of Nutrition, Nutritional Origins of Insulin Resistance: A Rat Model for Diabetes-Prone Human Populations 2000 130: 741-744.)

Neel, James V. 1999. The "Thrifty Genotype" in 1998, Nutrition Reviews 57:5 (Part II) S2-S9.

Sievers, M. L., W. Knowler, R. Nelson, P. Benneu, 1992, Impact of NIDDM on Mortality and Causes of Death in Pima Indians. Diabetes Care, 15:11, pp.

Silverman, B. P., N. M. Cho, B. E. Metzger, C. A. Loeb, 1995. Impaired Glucose Tolerance in Adolescent Offspring of Diabetic Mothers. Diabetes Care, 18:5, 611-617.

Simopoulos, Artemis P. 1999. Genetic Variation and Nutrition. Nutrition Reviews, Volume 57:5, S10-S19.

Steward, B. H., T. Woliever, J. Gittelson, J. Gao, A. Hanley. A. Logan, A Barnie, I. Zinman, 1997. The Prevalence of NIDDM and Associated Risk Factors in Native Canadians. Diabetes Care 20:1, pp.

U.S. Department of Commerce, 1993. We the First Americans, Economics and Statistics Administration, Bureau of the Census. Washington, D. C.

Valencia, Mauro E., P. Bennett, E. Ravussin, J. Esparza, C. Fox, and L. 0. Schulz, 1999. The Pima Indians in Sonora, Mexico. Nutrition Reviews, Volume 57:5, S55-S58.

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