Type II Diabetes, Essential Hypertension, and Obesity as "Syndromes of Impaired Genetic Homeostasis": The "Thrifty Genotype" Hypothesis Enters the 21st Century
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TYPE II DIABETES, ESSENTIAL HYPERTENSION, AND OBESITY AS "SYNDROMES OF IMPAIRED GENETIC HOMEOSTASIS": THE "THRIFTY GENOTYPE" HYPOTHESIS ENTERS THE 21st CENTURY JAMES V. NEEL*, ALAN B. WEDER**, and STEVO JULIUS** Introduction In 1962, under the title "Diabetes mellitus: A 'thrifty' genotype rendered detrimental by 'progress'?" one of us published the suggestion that the basic defect in diabetes mellitus was a quick insulin trigger [I]. This was an asset to our tribal, hunting-and-gathering ancestors, with their intermittent , sometimes feast-or-famine alimentation, since it should have minimized renal loss of precious glucose. Currently, however, it was hypothesized , the pattern of over-alimentation in the technologically advanced nations resulted in insulin levels that elicited the insulin antagonists popularized by Vallance-Owen and colleagues [2-4] , and the result was diabetes mellitus. The changing dietary patterns of Western Civilization had compromised a complex homeostatic mechanism. The paper was written before the clear distinction between type I and type II diabetes had been drawn, but in retrospectwas directed at type II or non-insulin dependent diabetes (NIDDM). This quick insulin trigger was under a (still) poorly defined genetic control. Since too quick an insulin trigger might be as disadvantageous as too slow a trigger, it was suggested that this genetic control might take the form of a balanced polymorphism, by analogy with the polymorphisms for the sickle cell allele (ßs) then receiving so much attention. When other laboratories could not confirm Vallance-Owen's insulin antagonists (except in rare cases), the original physiological basis for the hypothesis collapsed. Although alternative "balance" hypotheses came to mind [5], they were neither as simple nor as intellectually satisfactory. However, the problem remained: why is the predisposition to NIDDM so frequent? Explanations based on the "thrifty genotype" hypothesis continue to be frequently invoked. *Departments of Human Genetics and **Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.© 1998 by The University of Chicago. All rights reserved. 0031-5982/98/4201-1082$01.00 44 Neel, Weder andJulius ¦ Type II Diabetes, Essential Hypertension, and Obesity Over the past 35 years, it has become increasingly clear that essential hypertension and obesity share many of the epidemiological features of NIDDM. Both are diseases of civilization, with a very gradual onset. Both are familial, with the disease the result of a complex interplay of genetic and environmental factors. This essay will compare and contrast current facts concerning the genetic bases for all three diseases and their pathophysiology , and will review the arguments for regarding the genetic predisposition to all three of these conditions as formerly adaptive genotypes whosefunctioningisnowcompromisedbythe changinglifestyles ofthe technologically advanced nations. Finally, we will discuss the probable relative effectiveness in the future ofageneticallybased as contrasted to an "environmentally " based program of prevention and therapy for these diseases. Some Recent Developments Concerning NIDDM In recent years, the concept of NIDDM has been evolving rapidly. (Although impairment in glucose metabolism in populations is a continuous distribution, the usual cut-point for the diagnosis of NIDDM is a one-hour post-glucose-challenge blood glucose concentration greater than 224 mg/ dl or a casual level greater than 124 mg/dl.) Five developments are of especial relevance to this presentation. NIDDM IN AMERINDIANS Although NIDDM obviously blossomed with inactivity and over-alimentation , 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, i.e., that the thrifty genotype hypothesis was of limited ethnic applicability [6-14]. With some difficulty, we were able to carry out glucose tolerance and related tests on representatives of two groups of remote and relatively unacculturated Amerindians, the Yanomama and Marubo of the Brazilian Amazon Basin [15] . Although there were statistically significant differences between the plasma glucose, insulin, pancreatic polypeptide, and growth hormone responses of the two Amerindian groups, neither of these groups exhibited the dramatic glucose intolerance of the highly acculturated (and quite obese) adult North American Pima. Although the study was limited, we saw no evidence for a strong ethnic predisposition to NIDDM in Amerind groups pursuing a traditional lifestyle. A more telling observation involves the Pima Indians of Southern Arizona and...