Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? 1962.

FOR THE POPULATION CENETICIST, diabetes mellitus has long presented an enigma. Here is a relatively frequent disease, often interfering with reproduction by virtue of an onset during the reproductive or even pre-reproductive years, with a well-defined genetic basis, perhaps as simple in many families as a single recessive or incompletely recessive gene (cf. Allan, 1933; Pincus and White, 1933, 1934; Harris, 1950; Steinberg and Wilder, 1952; Lamy, Frezal and de Grouchy, 1957; Steinberg, 1959; Post, 1962a). If the considerable frequency of the disease is of relatively long duration in the history of our species, how can this be accounted for in the face of the obvious and strong genetic selection against the condition? If, on the other hand, this frequency is a relatively recent phenomenon, what changes in the environment are responsible for the increase? Current developments in the study of this disease suggest an explanation with important biological ramifications. "THRIFTINESS" OF DIABETIC GENOTYPE PRIOR TO ONSET OF DIABETES MELLITUS There is now much evidence to indicate that the individual predisposed to diabetes differs metabolically from the non-predisposed from birth onward. The frequency of over-sized infants among the offspring of women with overt or subclinical diabetes is well known (e.g., Bowcock and Greene, 1928; Bix, 1933; Allen, 1939; Miller, 1945, 1956; Kriss and Futcher, 1948; Gonce, 1949; Gilbert, 1949; Brosset and Werko, 1950; Moss and Mulholland, 1951; Jackson, 1952; Pirart, 1955; Hsia and Gellis, 1957, etc.). This phenomenon, which may antedate the development of clinical diabetes by 30),ears, has customarily been regarded as an expression of the mother's diabetes. The difficulties in duplicating this phenomenon in experimental animals rendered diabetic by alloxan (Miller, 1947, but see Lazarow, Kim and Wells, 1960) leaves some room for doubt as to whether this concept offers a complete explanation. Maternal genotype and phenotype may be only one factor in the etiology of the phenomenon. Inasmuch as from the genetic standpoint these children constitute a high risk group, and in view of the report that the juvenile diabetic at birth averages some 100 grams heavier than his non-diabetic siblings (Nilsson, 1962, but see White, 1960), the possibility must be considered that this phenomenon is also in part an expression of the infant's predisposition. Some evidence to this effect may be drawn from the observations of Sheldon (1949) on rapidly developing maternal obesity, in that women who presented with this problem, of whom a significant proportion had overt or subclinical diabetes and to whom large infants were often born, themselves often had been large infants. What is lacking is evidence concerning the relative risk of the development of diabetes in the normal-birthweight siblings of these individuals. Somewhat more cogent evidence regarding the role of infant genotype in birthweight comes from the reports that the infants born to normal mothers with diabetic husbands also have an increased birthweight (Jackson, 1952; Siegeler and Siegeler, 1960; Pyke, 1961; Nilsson, 1962). Children who develop diabetes tend to be somatically advanced for their age (White, 1939; Wagner, White and Bogan, 1942; Nilsson, 1962). The menarche has occurred, on the average, about a half to three-quarters of a year earlier in the diabetic woman who developed her disease after the age of 20 than in her siblings who did not later develop diabetes (Arduino and Ferreira, 1958; Post and White, 1958; Post, 1962). Theoretically (cf. Post and White, 1958) this might lead to earlier onset of childbearing and even to an increase in average fertility on the part of those with late-onset diabetes, capable of offsetting, at ]east in part, the impaired reproductive performance of those with early onset diabetes. The actual data on this point are consistent with a fertility differential in favor of the diabetic, but, as pointed out by Post and White (1958), are inadequate in several respects. …