Arthur G. Steinberg

Diabetes in the Pima Indians: Evidence of Bimodality in Glucose Tolerance Distributions

Venous plasma glucose levels two hours after a 75 gm. carbohydrate load were determined on over 2,900 Pima Indians, a population known to have an extremely high prevalence of diabetes mellitus. In each sex and in each decade above twenty-five years of age, the frequency distributions of the logarithms of the glucose levels were clearly bimodal, but below this age a single symmetrical unimodal distribution was found. A maximum likelihood procedure was used to derive the best fitting theoretical gaussian distributions for each group of data, together with the parameters of each distribution. The observed bimodal distributions were found to be in satisfactory agreement with a model of two overlapping gaussian distributions, indicating that a logical separation between those with normal and high levels of glucose is possible, although the presence of overlap indicates that some misclassification will occur if any finite level is used to subdivide the population. The data indicate that among the Pima: 1. The frequency distributions of two-hour glucose tolerance levels can be used to identify objectively and describe a hyperglycemic population without recourse to other criteria for diabetes. 2. There are small changes in the parameters of “normal” glucose tolerance between the ages of twenty-five and sixtyfour years. 3. The increase in mean glucose level found with rising age in this population is mainly the result of an increasing proportion of subjects who are in the group characterized by marked glucose intolerance. The bimodal distributions of plasma glucose levels The bimodal distributions of plasma glucose levels among the Pima Indians contrast with those described so far in other groups. It seems likely that differences are attributable to the lower prevalence of diabetes elsewhere which would obscure the identification of bimodality.

Hereditary Globulin Factors and Immune Tolerance in Man

Eight nontransfused donors of antibodies against a hereditary γ-globulin factor lacked the factor, but each donors mother had it. The probability that this is a chance observation is .00003. A ninth donor had been transfused, and she and her mother both lacked the factor. It is assumed that each nontransfused donors antibody was formed against his mothers γ-globulin and that immune tolerance had not been induced.

The distribution of HLA antigens and phenotypes among donors and patients in the UNOS registry.

We have analyzed HLA data from the UNOS registry on 20,230 patients on the renal waiting list in 1991 and 18,708 donors from 1988-1992. Significant differences were found in the distribution of HLA antigens for comparisons of the total donor pool and the various racial groups of patients as well as for inter- and intraracial comparisons of donors and patients. Within a racial group, the frequencies of blanks and of broad antigens were usually higher in patients while those of splits were usually higher in donors. Comparisons between the total donor pool and the various racial groups of patients showed that the likelihood of mismatch was greater for African-Americans and Hispanics than for Caucasians but that the chance of mismatch is high for all groups and the average number of antigens mismatched will not vary greatly among the different races. Heterogeneity, as measured by the percentage of the population with different phenotypes, was higher in African-Americans (97.2-99.7%) and Hispanics (97.7-99.4%) than in Caucasians (83.3-86.5%) because of multiple occurrences of a few phenotypes, most containing A1, B8 and DR3, in Caucasians. However, the most common phenotypes of Caucasian donors differed from those of Caucasian patients. All phenotypes were rare (0.007-0.61%) and, with the exception of a small group of Caucasian patients, the likelihood of achieving a good match is low, regardless of race. These data explain the observations that, with the exception of the phenotypically identical match, HLA matching does not influence organ distribution significantly.

THE GENETICS OF DIABETES: A REVIEW*

According to Foster (1912), the earliest report of a familial incidence of diabetes mellitus was by Rlorton in 1696. Morton reported a family in which four children were diabetic. It seems reasonable to assume that the familial nature of diabetes was known long before this, because diabetes mellitus was apparently recognized by the sweet taste of the urine as early as 500 A.D. (Saundby, 1908). Be that as it may, daily experience early convinced clinicians that diabetes mellitus is frequently familial. I t was not until the fourth decade of this century, however, that it was quantitatively established that the increased incidence is statistically significant (Pincus and White, 1933). These observations strongly indicated that susceptibility to diabetes is genetically determined because the necessary and sufficient criterion for establishing the presence of a genetic component in the causation of a character (disease) is an increased familial incidence in the absence of environmental factors that can explain this increase. Further evidence for the hereditary nature of diabetes mellitus is offered by the many studies of twins (Then Berg, 1938; J o s h and White in J o s h el al., 1946; and many others). In general, these studies show a greater frequency of concordance among monozygous twins than among dizygous ones. Since monozygous twins are genetically identical, and dizygous twins are no more alike than ordinary sibs, these observations indicate a genetic factor in determining susceptibility to diabetes. Concordance among identical twins is not complete; hence, postnatal environmental factors are important in determining the occurrence of frank diabetes. Pincus and White (1933) showed that the familial incidence of diabetes may be explained by assuming that susceptibility to diabetes is due to homozygosity for a recessive gene. Independently, and a t essentially the same time, William Allan (1933) arrived a t the same conclusion from his highly skilled and toofrequently overlooked analysis of the family data from 143 cases. These pioneering studies have been followed by numerous studies of large samples. The several investigators have advanced a variety of interpretations to explain their data. Prominent among them are hypotheses that distinguish the early-onset, severe, brittle diabetes from the late-onset, mild, stable type. These hypotheses are attractive on a priori grounds because of the clinical heterogeneity of the disease. Three broad categories of diabetes appear to be recognized: (1) juvenile, with acute onset, severe course, and sensitivity to insulin; (2) late, with gradual onset, generally in obese individuals, mild course, and often no need of insulin;

The frequencies of HLA alleles and haplotypes and their distribution among donors and renal patients in the UNOS registry.

HLA allele and haplotype frequencies are used in transplantation, anthropology, forensic medicine, and studies of the associations between HLA factors and the immune response. The cost of determining these frequencies through family studies can be avoided by estimating them from population data. We have utilized the data in the UNOS donor registry and kidney transplant waiting list to estimate allele and haplotype frequencies for the HLA-A, -B, and -DR(B1) loci and report the allele and a portion of the haplotype data here. Using programs written in A Program Language (APL) we were able to perform all analyses on a personal computer. We have found that the distribution of haplotype frequencies varies among the races, with Caucasians having a greater number of both more common and extremely rare haplotypes. Despite the sizes of the groups studied, only one-third to two-thirds of the haplotypes theoretically possible were actually observed. Although the data confirm the well-known fact that the distributions of alleles and haplotypes varies among races, they also reveal that certain common haplotypes are shared among all racial groups and represent an opportunity for well-matched transplants between donors and recipients of different races.

DEPENDENCE OF A GM(B) ANTIGEN ON THE QUATERNARY STRUCTURE OF HUMAN GAMMA GLOBULIN.

The antigens associated with the Gm(b) factor of human 7S γ-globulin differ in Caucasoids and Negroids. The studies reported here show that an antigen, Gm(bw), associated with the Gm(b) of whites but not with that of Negroes, is present on the S (slow) fragment of 7S γ-globulin obtained by digestion with papain or pepsin. All other Gm antigens thus far studied have been found on the F (fast) fragment. The antigens Inv(a) and Inv(b) were detected on isolated L-chains, and Gm(a) and Gm(b) were detected on isolated H-chains, but Gm(bw) was detected on neither. Recombining the H- and L-chains restored activity for Gm(bw) comparable to that of intact γ-globulin

ACID PHOSPHATASES OF HUMAN RED CELLS: PREDICTED PHENOTYPE CONFORMS TO A GENETIC HYPOTHESIS.

Analysis of data from 80 families and 369 unrelated individuals confirms the hypothesis that human red cell acid phosphatase phenotypes are determined by three codominant alleles at a single autosomal locus. Further confirmation is afforded by the finding of the predicted sixth phenotype.

A new human gamma globulin factor determined by an allele at the Inv locus.

Fifty‐three Negro families and 165 unrelated Negroes were tested for the γ‐globulin factor, Inv, discovered by Ropartz et al. [7] and for a new γ‐globulin factor herein named Inv(b). Analysis of these data established that Inv(b) is inherited by an allele (Invb) of the one determining InV. The latter allele is renamed Inva The finding of Ropartz et al. [7] that the Inv locus is genetically independent of Gm‐like was confirmed.

Gamma-Globulin Factors (Gm and Inv) in New Guinea: Anthropological Significance

Analysis of the hereditary Gm and Inv γ-globulin factors of 1669 New Guineans from the Morobe and Eastern Highlands districts and Bougainville Island demonstrates thatthe frequencies of the three Gm alleles present (Gma, GMab, and Gmax) are similar in general to those in Mongoloids and in particular to those in Southeast Asians and Micronesians. The New Guinea frequencies are distinct from those in other populations, including Australian aborigines. Highly significant differences in frequencies of Gm and Inv alleles occur between Melanesian-and non-Austronesian-speaking New Guineans.

Comparison of the Value of the Two- and One-hour Glucose Levels of the Oral GTT in the Diagnosis of Diabetes in Pima Indians

In many population and screening studies of diabetes, the onehour glucose level of the GTT has been used to define the diabetic status of subjects. The one-hour postglucose load determination has been preferred over the two-hour value by many investigators primarily because of convenience and justified on the basis of the high correlation between the two values. Venous plasma glucose levels, one and two hours after a 75-gm. carbohydrate load, were determined on over 1,600 Pima Indians. In most sex and age groups, the frequency distributions of both the one-hour and two-hour glucose levels were clearly bimodal. By the logarithms of the glucose values these distributions were consistent with a model of two overlapping Gaussian distributions. The data indicate that for the Pima the amount of overlap of the distributions was greater for the one-hour than for the two-hour values. For each sex and decade the probabilities of misclassification of a normal as “hyperglycemic” and vice versa were smaller for the two-hour than for the one-hour values. Such misclassifications for the two-hour levels averaged 6.6 per cent and 11.6 per cent for the one-hour levels. The reproducibility of the GTT taken one to three weeks apart in a sample of ninety-nine Puna Indians showed that the two-hour level was superior to the one-hour level as measured by the mean values of the absolute difference between log GTT levels for test and retest values. The one-hour measurements also gave more disagreements between the classifications of diabetic status than the two-hour test values. If a single measure of glucose tolerance is to be selected for the diagnosis of diabetes among Pima Indians, these data provide a mathematical rationale for preferring the two-hour level to the one-hour determination.