Long-term effects of a randomised trial of a 6-year lifestyle intervention in impaired glucose tolerance on diabetes-related microvascular complications: the China Da Qing Diabetes Prevention Outcome Study.

AIMS/HYPOTHESIS: We determined the effects of 6 years of lifestyle intervention in persons with impaired glucose tolerance (IGT) on the development of retinopathy, nephropathy and neuropathy over a 20 year period. METHODS: In 1986, 577 adults with IGT from 33 clinics in Da Qing, China were randomly assigned by clinic to a control group or one of three lifestyle intervention groups (diet, exercise, and diet plus exercise). Active intervention was carried out from 1986 to 1992. In 2006 we conducted a 20 year follow-up study of the original participants to compare the incidence of microvascular complications in the combined intervention group vs the control group. RESULTS: Follow-up information was obtained on 542 (94%) of the 577 original participants. The cumulative incidence of severe retinopathy was 9.2% in the combined intervention group and 16.2% in the control group (p = 0.03, log-rank test). After adjusting for clinic and age, the incidence of severe retinopathy was 47% lower in the intervention group than the control group (hazard rate ratio 0.53, 95% CI 0.29-0.99, p = 0.048). No significant differences were found in the incidence of severe nephropathy (hazard rate ratio 1.05, 95% CI 0.16-7.05, intervention vs control, p = 0.96) or in the prevalence of neuropathy (8.6% vs 9.1%, p = 0.89) among the 20 year survivors. CONCLUSIONS/INTERPRETATION: Lifestyle intervention for 6 years in IGT was associated with a 47% reduction in the incidence of severe, vision-threatening retinopathy over a 20 year interval, primarily due to the reduced incidence of diabetes in the intervention group. However, similar benefits were not seen for nephropathy or neuropathy.

Relatively low plasma leptin concentrations precede weight gain in Pima Indians.

Leptin, the product of the ob gene, is a hormone, produced by adipose cells, that inhibits food intake and increases energy expenditure in rodents. In humans, plasma leptin concentrations correlate closely with the size of the adipose tissue depot; however, there is considerable variation in plasma leptin concentrations at any given degree of fatness. To investigate whether individuals prone to weight gain are hypoleptinemic, we measured fasting plasma leptin concentrations in two groups of weight-matched nondiabetic Pima Indians followed for approximately 3 years, 19 of whom subsequently gained weight and 17 of whom maintained their weight. After we adjusted for initial percent body fat, mean plasma leptin concentration was lower in those who gained weight than in those whose weight was stable. These data indicate that relatively low plasma leptin concentrations may play a role in the development of obesity in Pima Indians, a population prone to obesity.

Glomerular function in Pima Indians with noninsulin-dependent diabetes mellitus of recent onset.

Differential solute clearances were used to characterize glomerular function in 20 Pima Indians with noninsulin-dependent diabetes mellitus (NIDDM) of less than 3 yr duration. 28 Pima Indians with normal glucose tolerance served as controls. In the diabetic group, the glomerular filtration rate (GFR, iothalamate clearance) exceeded the control value by 15% (140 +/- 6 vs. 122 +/- 5 ml/min, P less than 0.01). A corresponding 12% increase in renal plasma flow (RPF) was not statistically significant and did not account fully for the observed hyperfiltration, suggesting a concomitant elevation of the ultrafiltration pressure or coefficient. The median albumin excretion ratio in NIDDM exceeded control by almost twofold (10.1 vs. 5.8 mg/g creatinine), a trend which just failed to achieve statistical significance (P = 0.06). Fractional clearances of dextrans of broad size distribution were also elevated in diabetic subjects, significantly so for larger dextrans of between 48 and 60 A radius. A theoretical analysis of dextran transport through a heteroporous membrane revealed glomerular pores in NIDDM to be uniformly shifted towards pores of larger size than in controls. We conclude that an impairment of barrier size selectivity combined with high GFR elevates the filtered protein load in NIDDM of recent onset. We propose that enhanced transglomerular trafficking of protein may predispose to sclerosis of glomeruli in those Pima Indians with NIDDM who ultimately develop diabetic nephropathy.

An amino acid substitution in the human intestinal fatty acid binding protein is associated with increased fatty acid binding, increased fat oxidation, and insulin resistance.

The intestinal fatty acid binding protein locus (FABP2) was investigated as a possible genetic factor in determining insulin action in the Pima Indian population. A polymorphism at codon 54 of FABP2 was identified that results in an alanine-encoding allele (frequency 0.71) and a threonine-encoding allele (frequency 0.29). Pimas who were homozygous or heterozygous for the threonine-encoding allele were found to have a higher mean fasting plasma insulin concentration, a lower mean insulin-stimulated glucose uptake rate, a higher mean insulin response to oral glucose and a mixed meal, and a higher mean fat oxidation rate compared with Pimas who were homozygous for the alanine-encoding allele. Since the FABP2 threonine-encoding allele was found to be associated with insulin resistance and increased fat oxidation in vivo, we further analyzed the FABP2 gene products for potential functional differences. Titration microcalorimetry studies with purified recombinant protein showed that the threonine-containing protein had a twofold greater affinity for long-chain fatty acids than the alanine-containing protein. We conclude that the threonine-containing protein may increase absorption and/or processing of dietary fatty acids by the intestine and thereby increase fat oxidation, which has been shown to reduce insulin action.

An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians.

Type 2 diabetes mellitus is a common chronic disease that is thought to have a substantial genetic basis. Identification of the genes responsible has been hampered by the complex nature of the syndrome. Abnormalities in insulin secretion and insulin action predict the development of type 2 diabetes and are, themselves, highly heritable traits. Since fewer genes may contribute to these precursors of type 2 diabetes than to the overall syndrome, such genes may be easier to identify. We, therefore, undertook an autosomal genomic scan to identify loci linked to prediabetic traits in Pima Indians, a population with a high prevalence of type 2 diabetes. 363 nondiabetic Pima Indians were genotyped at 516 polymorphic microsatellite markers on all 22 autosomes. Linkage analyses were performed using three methods (single-marker, nonparametric multipoint [MAPMAKER/SIBS], and variance components multipoint). These analyses provided evidence for linkage at several chromosomal regions, including 3q21-24 linked to fasting plasma insulin concentration and in vivo insulin action, 4p15-q12 linked to fasting plasma insulin concentration, 9q21 linked to 2-h insulin concentration during oral glucose tolerance testing, and 22q12-13 linked to fasting plasma glucose concentration. These results suggest loci that may harbor genes contributing to type 2 diabetes in Pima Indians. None of the linkages exceeded a LOD score of 3.6 (a 5% probability of occurring in a genome-wide scan). These findings must, therefore, be considered tentative until extended in this population or replicated in others.

Effect of hypertension on mortality in Pima Indians.

BACKGROUND: The effect of hypertension on mortality was examined in 5284 Pima Indians, 1698 of whom had type 2 diabetes at baseline or developed it during follow-up. METHODS AND RESULTS: During a median follow-up of 12.2 years (range, 0.01 to 24.8 years), 470 nondiabetic subjects and 488 diabetic subjects died. In the nondiabetic subjects, 45 of the deaths were due to cardiovascular disease, 208 to other natural causes, and 217 to external causes; in the diabetic subjects, 106 of the deaths were due to cardiovascular disease, 85 to diabetic nephropathy, 226 to other natural causes, and 71 to external causes. In the nondiabetic subjects, after adjusting for age, sex, body mass index, and serum cholesterol concentration in a proportional hazards model, hypertension predicted death from cardiovascular disease (death rate ratio [DRR]=2.8; 95% CI, 1.4 to 5. 6; P=0.003). In the diabetic subjects, after additional adjustment for duration of diabetes, plasma glucose concentration, and proteinuria, hypertension strongly predicted deaths from diabetic nephropathy (DRR=3.5; 95% CI, 1.7 to 7.2; P<0.001), but it had little effect on deaths from cardiovascular disease (DRR=1.4; 95% CI, 0.88 to 2.3; P=0.15). CONCLUSIONS: We propose that the weak relationship between hypertension and cardiovascular disease in diabetic Pima Indians is not because of a diminished effect of hypertension on cardiovascular disease in diabetes, but because of a relatively greater effect of hypertension on the progression of diabetic nephropathy. Factors that may account for this finding in Pima Indians include a younger age at onset of type 2 diabetes, a low frequency of heavy smoking, favorable lipoprotein profiles and, possibly, enhanced susceptibility to renal disease.

Intrauterine diabetes exposure and the risk of renal disease in diabetic Pima Indians.

The association between the diabetic intrauterine environment and renal disease was examined cross-sectionally in 503 Pima Indians with type 2 diabetes. Subjects were selected from participants in an ongoing study of diabetes and its complications in the Gila River Indian Community of Arizona. Subjects' exposure to diabetes in utero was established from periodic examinations conducted as part of the study. The prevalence of elevated urinary albumin excretion (UAE) (albumin-to-creatinine ratio > or = 30 mg/g) was 40% (83 of 207) in the offspring of nondiabetic mothers, 43% (105 of 246) in the offspring of prediabetic mothers (i.e., women who were not diabetic at the time of the pregnancy but who developed diabetes after the pregnancy), and 58% (29 of 50) in the offspring of mothers who had diabetes during pregnancy. After controlling for age, sex, duration of diabetes, HbA1c, and mean arterial pressure in the offspring in a logistic regression analysis using generalized estimating equations, maternal diabetes during pregnancy was strongly associated with elevated UAE. The odds of elevated UAE in the offspring of mothers who had diabetes during pregnancy was 3.8 times (95% CI 1.7-8.4) that of the offspring of prediabetic mothers; the odds of elevated UAE in the offspring of nondiabetic and prediabetic mothers were similar (odds ratio of 0.94; 95% CI 0.59-1.5). We concluded that exposure to a diabetic intrauterine environment increases the risk of elevated UAE in diabetic Pima Indians. The effect of this exposure appears to be independent of other susceptibility factors that lead to nephropathy in diabetes.

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 insluin 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.

A simplified method using somatostatin to assess in vivo insulin resistance over a range of obesity.

Twenty-one nondiabetic subjects, their weights ranging from 56 to 165 kg, received an infusion of glucose (420 mg/min), insulin (0.77 mU/kg/min), and somatostatin (500 microgram/h) for 150 min. A steady state level of plasma insulin and glucose was attained after 90 min. Endogenous insulin secretion determined by C-peptide measurement, and glucagon secretion remained suppressed throughout the period. With similar steady state levels of plasma insulin (SSPI) maintained in all subjects, the height of the steady state plasma glucose concentration (SSPG) was considered an index of total body sensitivity to insulin-mediated glucose uptake. A positive correlation between SSPG and the degree of obesity, as determined by the body mass index (BMI), was demonstrated (r = 0.70, P less than 0.001). No correlation was found between SSPI and BMI. The fasting plasma insulin concentration correlated with BMI (r = 0.82, P less than 0.0001) and SSPG (r = 0.80, P less than 0.0001). This method provides a simple safe measure of total body insulin resistance over a wide range of obesity and is independent of endogenous insulin secretion.

High prevalence of diabetes in young Pima Indians: evidence of phenotypic variation in a genetically isolated population.

Medical records of the Pima Indian population aged 0--24 yr were reviewed for a diagnosis of diabetes before initiation of glucose tolerance testing. None of 1556 subjects below age 15, but 6 of 657 aged 15--24, had a previous diagnosis. Of the six known diabetics, five had been treated with insulin and four had had ketoacidosis. Subsequently, plasma glucose levels were determined after a 75-g oral carbohydrate load in 1712 subjects aged 5--24 yr, which is about 78% of the eligible population. Previously diagnosed diabetes and asymptomatic hyperglycemia were more frequent in subjects 15--24 yr old than were reported in other populations. Glucose intolerance in young Pimas was associated with obesity. In Pima offspring, the presence of diabetes in both parents was related to glucose tolerance in those above but not below the age of 15 yr. Both asymptomatic hyperglycemia and insulin-requiring diabetes occurred frequently in young Pimas, suggesting that these syndromes represent the clinical spectrum of a single disease in the Pima Indian.

Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged 20-74 yr.

The prevalence of physician-diagnosed diabetes and of undiagnosed diabetes and impaired glucose tolerance (IGT) that meet National Diabetes Data Group (NDDG) and World Health Organization (WHO) criteria have been estimated for the U.S. population aged 20-74 yr from the 1976-1980 National Health and Nutrition Examination Survey. This survey included a demographic/medical history questionnaire administered in the participant's home and a detailed examination composed of a physician's exam, special clinical procedures, other tests, and collection of blood and urine specimens. Survey participants were selected from 1970 census data through a stratified multistage probability sampling scheme. Of 17,390 eligible residents aged 20-74 yr, 15,357 (88.3%) participated in the interview and are the basis for estimates of diagnosed diabetes; 11,858 (68%) participated in the exam. A half sample of 5901 examinees was selected to receive a 75-g oral glucose tolerance test (OGTT) performed in the morning after an overnight 10- to 16-h fast. Of these examinees, valid OGTT data were obtained for 3772 people without a medical history of diabetes, and these are the basis for estimates of undiagnosed diabetes and IGT. The major reasons for incomplete OGTT data were inability of participants to attend the examination center in the morning and lack of adherence to the fasting instructions. Despite the relatively low response rates, evidence is presented that data on both the interviewed sample and those receiving the OGTT, when adjusted for the 1970-1980 census characteristics by age, race, sex, income, and geographic location, are representative of the U.S. population. Extrapolation of these data to the U.S. population aged 20-74 yr indicates a total diabetes prevalence of 6.6% by NDDG criteria, or more than 8 million people with diabetes. The prevalence of undiagnosed diabetes (3.2%) was almost equal to that of previously diagnosed diabetes (3.4%). Total rates of diabetes increased with age, from 2.0% at age 20-44 yr to 17.7% at age 65-74 yr. Rates were approximately equal by sex but were greater in Blacks than in Whites. The prevalence of undiagnosed diabetes by WHO criteria (3.4%) was similar to that by NDDG criteria, but the rate of impaired glucose tolerance (11.2%) was more than twice the NDDG estimate (4.6%). Both obesity and parental history of diabetes were associated with significantly higher rates of diabetes and IGT. Fasting plasma glucose was relatively insensitive to age, but 1-h and 2-h post-75-g glucose values increased significantly with age.

Duration of obesity increases the incidence of NIDDM.

The effect of duration of obesity on incidence of non-insulin-dependent diabetes mellitus (NIDDM) was determined among Pima Indians. Duration of obesity was defined as the time since body mass index (BMI) was first known to be at least 30 kg/m2. Among 1057 participants eligible for study, there were 224 incident cases of NIDDM in 5975 person-yr of follow-up. The association of duration of obesity with incidence of diabetes adjusted for age, sex, and current BMI was highly significant (P less than 0.0001). This adjusted incidence of diabetes in cases/1000 person-yr of obesity was 24.8 for people with less less than 5 yr of obesity, 35.2 for people with 5-10 yr of obesity, and 59.8 for people with at least 10 yr of obesity. There was no apparent excess risk of diabetes for people who had a BMI of at least 30 kg/m2 and then lost weight. They had a slightly nonsignificantly higher rate than people who had not attained a BMI of at least 30 kg/m2 and a lower rate than people whose BMI remained 30-35 kg/m2. The relationship of duration of obesity with serum insulin concentrations among nondiabetic people was determined controlling for sex and age, BMI, and plasma glucose concentrations at the time of a glucose tolerance test. Duration of obesity was inversely associated with fasting serum insulin concentration through most of the range of fasting plasma glucose concentrations (P less than 0.001) and tended to be inversely associated with 2-h postload serum insulin concentration through the entire range of postload plasma glucose concentrations (P = 0.058).

Effect of glycemia on mortality in Pima Indians with type 2 diabetes.

The effect of plasma glucose concentration on overall and cause-specific mortality was examined in 1,745 Pima Indians (725 men, 1,020 women) > or = 15 years old with type 2 diabetes. During a median follow-up of 10.6 years (range 0.1-24.8), 533 subjects (275 men, 258 women) died; 113 of the deaths were attributable to cardiovascular disease, 96 to diabetes-related diseases (diabetic nephropathy for 92 of these), 249 to other natural causes, and 75 to external causes. After adjusting for age, sex, duration of diabetes, and BMI in a generalized additive proportional hazards model, higher baseline 2-h postload plasma glucose concentration predicted deaths from cardiovascular disease (P = 0.007) and diabetes-related diseases (P = 0.003), but not from other natural causes (P = 0.73). An increment of 5.6 mmol/l (100 mg/dl) in the 2-h plasma glucose concentration was associated with 1.2 times (95% CI 1.1-1.4) the death rate from cardiovascular disease, 1.3 times (95% CI 1.1-1.5) the death rate from diabetes-related diseases, and almost no change in the death rate from other natural causes (rate ratio = 1.0; 95% CI 0.94-1.1). In Pima Indians with type 2 diabetes, higher plasma glucose concentration predicts deaths from cardiovascular and diabetes-related diseases but has little or no effect on deaths from other natural or external causes.

Retinopathy in Pima Indians. Relationships to glucose level, duration of diabetes, age at diagnosis of diabetes, and age at examination in a population with a high prevalence of diabetes mellitus.

The occurrence of retinopathy and its relationship to diabetes in 1,640 Pima Indians age 15 and over has been determined. Eighteen per cent of those with two-hour postload plasma glucose levels of equal to or greater than 200 mg./dl. had some evidence of retinopathy. Of those with retinopathy and diabetes, 7 per cent were found to have proliferative or neovascular changes, the remainder having microaneurysms and/or exudates. The frequency of retinopathy increased from 3 per cent among newly diagnosed diabetics to 47 per cent among those with diabetes of 10 or more years duration. No relationship was found with sex, age at diagnosis of diabetes, or age at time of examination when duration of diabetes was taken into account. The occurrence of retinopathy was confined largely to those who fell into the second or hyperglycemic component of the frequency distribution of plasma glucose levels in the population, indicating the significance of the bimodal glucose tolerance frequency distribution.

Coronary heart disease in the Pima Indians. Electrocardiographic findings and postmortem evidence of myocardial infarction in a population with a high prevalence of diabetes mellitus.

The frequency of electrocardiographic evidence of coronary heart disease (CHD) and the rate of autopsy-proved myocardial infarction were determined in the Pima, a tribe of American Indians with a high prevalence of diabetes mellitus. The electrocardiograms of 701 Pimas, aged 40 years and over (85 per cent of the adult reservation population, 45 per cent of whom had diabetes) were read according to the Minnesota Code, and 120 postmortem examinations were reviewed for evidence of myocardial infarction. The frequency of CHD as evidenced by major Q-wave changes in the Pima (1.6/100) was about one-half that found in Tecumseh, Michigan (p less than 0.10). The relatively low rate of myocardial infarction at autopsy (15 per cent of males and 8 per cent of females aged 40 years and over) was consistent with the low prevalence of Q-wave changes. The subjects with diabetes had a higher rate of CHD than nondiabetics, both electrocardiographically and at postmortem examination, although the differences were not statistically significant. The low prevalence of CHD in the living Pima and the low rate of infarction at autopsy indicate that this tribe has a low frequency of CHD despite the extraordinarily high prevalence of diabetes mellitus.

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 one-hour 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 75-gm. carbohydrate load, were determined on over 1600 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 reproducivility of the GTT taken one to three weeks apart in a sample of ninety-nine Pima 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.

Gestational diabetes mellitus and impaired glucose tolerance during pregnancy. Long-term effects on obesity and glucose tolerance in the offspring.

The effects of disturbances in carbohydrate metabolism during gestation were studied in the offspring of 1049 Pima Indian women who had no previous diagnosis of diabetes. Rates of fetal and maternal complications of pregnancy among women with diabetes first diagnosed during the pregnancy were similar to those among women in whom diabetes was recognized before gestation. Offspring, aged 5-19 yr, of women with abnormal glucose tolerance during pregnancy had a higher mean percent desirable weight and a higher mean postchallenge plasma glucose concentration than did offspring of women with normal glucose tolerance. Percent desirable weight and glucose concentration, however, were both lower than found in offspring of women with diabetes diagnosed before the pregnancy. Thus, metabolic events during pregnancy, as indicated by the detection of abnormal glucose tolerance during gestation, appear to have long-term effects on obesity and glucose tolerance in the offspring.

Genome-wide linkage analysis assessing parent-of-origin effects in the inheritance of type 2 diabetes and BMI in Pima Indians.

We examined the hypothesis that imprinted genes may affect the propensity to type 2 diabetes and obesity in Pima Indians. Multipoint variance component methods were used to assess linkage of BMI (kg/m(2)) and age-adjusted diabetes to loci derived from either father (LOD(FA)) or mother (LOD(MO)) in a genome-wide scan. Tentative evidence of loci where imprinted genes might be acting was found for diabetes with maternally derived alleles on chromosomes 5 (LOD(MO) = 1.5) and 14 (LOD(MO) = 1.6). Evidence of linkage of BMI to maternally derived alleles was found on chromosome 5 (LOD(MO) = 1.7) and to paternally derived alleles on chromosome 10p (LOD(FA) = 1.7). Additional analyses of sibling pairs who were affected by diabetes and younger than 25 years of age showed an increase of sharing of maternally derived alleles on chromosome 6 (LOD(MO) = 3.0). We also examined sites of a priori interest where action of imprinted genes has been proposed in diabetes or obesity. We found no evidence of parent-specific linkage (of either diabetes or BMI) on chromosome 11p, a region that contains several imprinted genes, but observed weak evidence of linkage of diabetes to paternally derived alleles (LOD(FA) = 0.9) in the region of chromosome 6q, believed to contain an exclusively paternally expressed gene or genes that cause transient neonatal diabetes mellitus. In conclusion, we determined regions of interest on chromosomes 5, 6, and 10 where imprinted genes might be affecting the risk of type 2 diabetes or obesity in Pima Indians.

Gamma globulin levels predict type 2 diabetes in the Pima Indian population.

It has been proposed that inflammation or infection may contribute to the development of type 2 diabetes. We examined whether serum gamma globulin, a nonspecific measure of the humoral immune system, predicted changes in glucose tolerance in 2,530 members of the Pima Indian population, a group with a marked predisposition to type 2 diabetes. Cross-sectionally, gamma globulin was positively related to age (r = 0.08, P < 0.0005), BMI (r = 0.09; P < 0.0001), and female sex (P < 0.0001). Gamma globulin concentrations were familial, being positively correlated among siblings (r = 0.23; P < 0.0001) and between parents and their children (mother/child: r = 0.17, P < 0.0001; father/child: r = 0.25, P < 0.0001). Gamma globulin concentrations were higher with greater degrees of American Indian heritage (P < 0.004, with adjustment for age, sex, and BMI) and in the presence of a family history of type 2 diabetes (P < 0.04). Higher gamma globulin levels predicted risk of diabetes. In univariate analysis, a 1 SD difference in gamma globulin was associated with a 20% higher incidence of diabetes in those who were normal glucose tolerant at baseline (hazard rate ratio 1.20 [CI 1.11-1.30]; P < 0.0001) and remained as a significant predictor of diabetes, even when controlled for effects of sex, BMI, and 2-h glucose as additional predictors (hazard rate ratio for 1 SD difference in gamma globulin, 1.14 [1.05-1.24]; P = 0.002). Gamma globulin was also associated in univariate analysis with later development of impaired glucose tolerance (IGT) (hazard rate ratio 1.15 [1.07-1.23]; P < 0.0001), but not with the transition from IGT to diabetes (hazard rate ratio 1.04 [0.90-1.20]; P = 0.6). Thus, gamma globulin levels predict increased risk of diabetes in the Pima population. We suggest that immune function or activation may play a role in the development of type 2 diabetes.

Segregation analysis of diabetic nephropathy in Pima Indians.

Familial aggregation of diabetic nephropathy suggests the existence of genes determining susceptibility to nephropathy in addition to those leading to diabetes. In the present study, complex segregation analysis was performed in diabetic members of Pima Indian families to determine whether familial aggregation of nephropathy in this population could reflect the action of a single major gene. Nephropathy, defined by a urinary protein-to-creatinine ratio (PCR) > or = 500 mg/g, was analyzed as a discrete trait in a class C regressive logistic model. Individuals with PCR <500 mg/g were considered unaffected. Segregation analysis was performed both for nephropathy at the last examination (prevalent cases) and for duration of diabetes at the onset of nephropathy (incident cases). The REGD program was used for the analysis of the prevalent cases and the REGTL program for the incident cases, both from the Statistical Analysis for Genetic Epidemiology package (Case Western University, Cleveland, OH). The analysis of prevalent cases included 2,107 Pima Indians from 715 nuclear families. A subset of 504 of these families containing 1,403 individuals was used in the analysis of incident cases. Analysis of prevalent cases supported the existence of a gene with a major role, in that hypotheses of no major effect and of no transmission of a major effect were rejected (P = 0.00001; P = 0.003), whereas Mendelian transmission was not rejected (P = 0.85). A dominant model provided the best fit, but a recessive model could not be rejected. The analysis of incident cases, however, did not support a major gene effect on duration of diabetes at the onset of nephropathy, and analyses of lifetime occurrence of nephropathy were inconclusive. The analysis of prevalent cases supports the hypothesis of a major genetic effect on susceptibility to diabetic nephropathy in Pima Indians, but the analysis of incident cases does not support a genetic effect on duration of diabetes at the onset of nephropathy. The discrepancy may reflect the difficulty in precisely dating onset of nephropathy. The parameters of the model derived from segregation analysis of prevalent cases may be useful in linkage studies to detect nephropathy susceptibility loci.