Norman B. Rushforth

Epidemiologic studies of diabetes in the Pima Indians.

Publisher Summary This chapter reviews the results of the epidemiologic studies of diabetes in the Pima Indians. It also gives the details of the subjects taken up for these studies and the tests conducted on these subjects. These studies present an extraordinarily high prevalence of hyperglycemia and the specific complications of diabetes, such as retinopathy, in abundance in the Pima Indians. These studies examined the prevalence of glucose intolerance, the distribution of glucose tolerance levels, the characteristics of diabetes, the etiologic factors in diabetes, the factors influencing the pathogenesis of diabetic microangiopathy, and the development of glucose intolerance. Glucagon levels, renal disease, and protein uria and serum creatinine levels were also assessed in these studies. Diabetes mellitus is well recognized as it produces characteristic effects on pregnancy and its outcome. The past pregnancies of females aged 25–44 years were reviewed to determine whether diabetes mellitus produced similar effects in the Pima Indians. Insulin responses among Pima Indians showed different patterns according to the level of glucose tolerance. These studies have enhanced the knowledge of the distribution and determinants of diabetes and its specific complications.

Hyperinsulinemia and hypoinsulinemai. Insulin responses to oral carbohydrate over a wide spectrum of glucose tolerance.

Oral glucose tolerance tests using a 75 gm. carbohydrate load were performed on 396 Pirna Indians. Subjects were divided into groups on the basis of two-hour plasma glucose levels and the patterns of insulin response examined. Two-hour insulin levels were highest in the group with two-hour plasma glucose levels between 140–169 mg./100 ml. and then fell progressively until levels above 400 mg./100 ml. were reached. Half and one-hour insulin levels showed little change in the groups with two-hour glucose levels up to 170 mg./100 ml., but at higher glucose levels these insulin levels also progressively diminished. Fasting insulin levels were relatively unchanged over the entire range of glucose tolerance. Obesity was the most important factor influencing the fasting insulin levels. Glucose level was the major determinant of post-load insulin responses, but these were also significantly influenced by obesity. No effect of age or sex on insulin levels was demonstrated. Comparison with other published data indicates that different interpretations of insulin response in subjects with “mild diabetes” have resulted from comparisons of groups with different degrees of glucose intolerance.

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.

Unexplained hyperinsulinemia in normal and "prediabetic" Pima Indians compared with normal Caucasians. An example of racial differences in insulin secretion.

The pattern of insulin response to oral and/or intravenous glucose has been claimed to be characteristic of diabetes and even prediabetes. To determine if differences in insulin secretion might explain the exceptionally high prevalence of diabetes in the Pima Indians, 26 genetically normal Pimas (nondiabetic offspring of nondiabetic parents), 32 genetically prediabetic Pimas (nondiabetic offspring of diabetic parents), 10 diabetic Pimas, and 29 normal Caucasians were studied. All subjects received an intravenous glucose tolerance test (IVGTT) to examine the acute-phase insulin response, and all nondiabetic subjects received an oral glucose tolerance test (OGTT) and arginine infusion (AI). The prediabetics also received a cortisone-primed oral glucose tolerance test (CGTT) and were classified by the result of this test. While acute-phase insulin release during the IVGTT was absent in the diabetics, there was a rapid response in all nondiabetics. Prediabetic Pimas with normal or abnormal CGTT had insulin levels similar to normal Indians during the IVGTT, OGTT, and AI. Thus, no evidence of impairment of acute- or late-phase insulin release was found. The normal and prediabetic Indians had fasting and stimulated insulin levels during all the tests two-to-threefold greater than the Caucasians. Differences in insulin levels between the two races could not be explained by differences in glucose level, age, or obesity.

Fasting and two-hour post-load glucose levels for the diagnosis of diabetes. The relationship between glucose levels and complications of diabetes in the Pima Indians.

SummaryThe frequency distributions of both the fasting and two-hour post-load plasma glucose levels were bimodal in the Pima Indian population aged 25 years and over. The hyperglycaemic component of this distribution represents those with diabetes mellitus, as some 30 percent of this group had evidence of the specific vascular complications of the disease, whereas these abnormalities were virtually absent in those with lower glucose levels. The bimodal characteristics of the frequency distributions were utilized to define optimal criteria to separate those with and without diabetes. The sensitivity and specificity of these criteria for fasting and two-hour glucose levels were compared and were found to be similar. The fasting glucose determination, however, was more reproducible and stable, as well as being easier to obtain, indicating that it is the better measurement for diagnostic purposes. The optimal level for diagnosis of 7.5 mmol/l (136 mg/dl) for the fasting glucose and the equivalent two-hour value of 14 mmol/l (250 mg/dl), were higher than many previously recommended diagnostic levels. Nevertheless, there was no evidence that subjects with lower levels were at appreciable risk of developing the specific complications of diabetes. Subjects with impaired glucose tolerance (IGT), but without fasting hyperglycaemia, shouldnot be diagnosed as having diabetes mellitus.

Violent death in a metropolitan county. Changing patterns in homicide (1958-74).

Analysis of homicide patterns in Cuyahoga County, Ohio (metropolitan Cleveland), for 1958-1974 discloses the following major trends: a dramatic rise in overall homicide rates in the city (320 per cent) and suburbs (200 per cent); an increase in justifiable homicide; a doubling of the percentage of homicides incident to other felonies; a markedly increased incidence of homicide among younger persons; a conspicuous rise in firearm killings (now 81 per cent of all homicides); and a continued preponderance of intraracial homicide, with the highest rates among nonwhite males in the city. The trends in Cuyahoga County are consistent with those in other United States metropolitan counties. Homicide is responsible for a major part of the decreased life expectancy among young, urban, non-white men. The factor most consistently associated with these trends is the increased use of handguns.

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.

Behavior in Hydra: Contraction Responses of Hydra pirardi to Mechanical and Light Stimuli

Hydra pirardi contracts in response to light and mechanical agitation. The animals show a reduction in the number of contractions in response to mechanical agitation on repeated testing but continue to contract in response to a light stimulus. Excision of all the tentacles of the animal completely inhibits contraction in response to mechanical agitation but does not affect contraction in response to light. The results of these experiments suggest that H. pirardi has different receptors for light and for mechanical agitation and that the control mechanisms for the contraction responses to these two stimuli are independent.

Bimodality of Glycosylated Hemoglobin Distribution in Pima Indians: Relationship to Fasting Hyperglycemia

Glycosylated hemoglobin (HbA1) concentrations were determined in 300 Pima Indians aged 15 yr and older. Frequency distributions of HbA, were unimodal in the 15-24-yr-old age group, but were bimodal in those aged 25 yr and over. The bimodality indicated that the subpopulation with diabetes could be identified by the presence of elevated HbA1 levels. This group was comprised primarily of subjects who also had fasting plasma glucose levels of < 140 mg/dl, but subjects with impaired glucose tolerance without fasting hyperglycemia had HbA1 levels that were not significantly higher than those with normal glucose tolerance. The prevalence of diabetic retinopathy was much higher in the subgroup with elevated HbA1 levels and increased with increasing HbA1 level. HbA1 levels and triglyceride concentrations showed only a modest association. HbA1 determinations provided no advantage over fasting or post challenge glucose levels in the diagnosis Of diabetes.

Urinary excretion and renal clearance of specific plasma proteins in diabetes of short and long duration.

To characterize the renal handling of protein in diabetics, the 24-h total protein excretion (Shevky-Stafford method), as well as urinary excretion, plasma concentration, and clearance of each of 17 proteins (radial immunodiffusion technique) were determined in 25 nondiabetic and 31 diabetic Pima Indians and in 25 nondiabetic Caucasians. Determination of 24-h total protein excretion demonstrated similar levels in nondiabetic Pimas [8.6 mg/24 h (median), 5.0-18.0 mg/24 h (95% confidence interval)] and nondiabetic Caucasians [10.1 mg/24 h, 7.0-24.0 mg/24 h] but significantly elevated levels in Pima diabetics [41.0 mg/24 h, 24.0-163.0 mg/24 h]. Total protein excretion was significantly greater among those with diabetes of 10 or more yr duration with retinopathy [163.0 mg/24 h, 24.0-436.0 mg/24 h] and those with recent onset of diabetes [39.5 mg/24 h, 24.7-81.0 mg/24 h], whereas long-duration diabetics without retinopathy [11.5 mg/24 h, 6.7-29.0 mg/24 h] and nondiabetic Pimas had similar values. Mean blood pressure and fasting plasma glucose levels were positively correlated with total protein excretion in the diabetic Pimas. Measurable quantities of only 9 of the 17 individual proteins were detected in the urine in more than 50% of all nondiabetic and diabetic subjects. They were β2- microglobulin, β2-glycoprotein I, α1-acid glycoprotein, α2 HS-glycoprotein, α1-antitrypsin, albumin, hemopexin, transferrin, and IgG. The excretions and clearances ofthese proteins were comparable in nondiabetic Pimas and Caucasians. Compared with nondiabetic Pimas, diabetics had significantly higher clearance and excretion of each of these proteins, except β2-microglobulin (mol. wt. = 11,600) and α-glycoprotein I (mol.wt. = 40,000). Long-duration diabetics with retinopathy and recent-onset diabetics both had significantly elevated clearance and excretion of the same proteins. In contrast, long-duration diabetics without retinopathy had significant increases of clearance and excretion only of hemopexin, transferrin, and IgG. The IgG/transferrin clearance ratios were not significantly different among the nondiabetic and diabetic groups. The other eight proteins were detected in the urine in measurable quantities in less than 50% of all subjects. These were prealbumin, gc-globulin, antithrombin III, plasminogen, haptoglobin, C3 activator, C4- component, and C3-component. While for statistical reasons, clearance data could not be analyzed for these proteins, a significantly higher percentage of diabetic Pimas had detectable excretion of these proteins except for C3 activator. In conclusion, diabetics, even of recent onset, have increased urinary excretion and clearance of proteins with a molecular weight greater than 40,000 compared with nondiabetics. This increased glomerular permeability appears to be nonselective for the larger proteins and can be detected shortly after the onset of diabetes. It might be predictive of the development of more severe renal disease after longer duration of diabetes.