Search PubMed⌕ Search

Biomedical subjects

W C Knowler

Publications and source records attributed to W C Knowler.

At least 109 records · Page 6Linked to original sources
PubMed1995

Screening for mtDNA diabetes mutations in Pima Indians with NIDDM.

More than half of the Pima Indians over age 35 years have non-insulin-dependent (type II) diabetes mellitus (NIDDM). Extensive data indicate the importance of maternal diabetes in determining their risk for diabetes. Generally, the risk of having NIDDM is higher in patients with affected mothers than affected fathers. This has been attributed to intrauterine factors, but recently mitochondrial inheritance has been raised as an alternative hypothesis. In other populations, several families and individuals with diabetes due to a mitochondrial DNA point mutation at nucleotide 3243 in the tRNA(leu(UUR)) gene have been described, as has one family with a 10.4 kb mitochondrial DNA duplication/deletion. We tested whether these specific mitochondrial gene mutations could explain a portion of the excess maternal transmission seen in the Pima Indians. Mitochondrial DNA obtained from blood lymphocytes of 148 Pima Indians with NIDDM was screened both for the point mutation at nt 3243, and the 10.4 kb duplication/deletion. Neither of these mutations was detected, and although a small proportion of the excess maternal transmission in Pima Indians could still be due to yet undescribed mitochondrial mutations or imprinted nuclear genes, our data support the role of the intrauterine environment in this population.

Adolescent↗
PubMed1995

Early and late insulin response as predictors of NIDDM in Pima Indians with impaired glucose tolerance.

Risk factors predicting deterioration to diabetes mellitus were examined in 181 subjects with impaired glucose tolerance. Fifty-seven subjects had impaired glucose tolerance on one occasion followed by normal glucose tolerance at a repeat oral glucose tolerance test, and 124 subjects had impaired glucose tolerance on two successive oral glucose tolerance tests. Subjects were followed for a median period of 5.0 years (range 1.0-17.2). The age- and sex-adjusted cumulative incidence of diabetes at 10 years of follow-up was higher in subjects who had impaired glucose tolerance on both tests (70%) than in those whose glucose tolerance was normal at the repeat test (53%), [rate ratio (RR) = 1.6, 95% confidence intervals (CI) = 1.0-2.5]. Proportional hazards analyses were used to identify baseline risk factors (measured at the repeat oral glucose tolerance test) for subsequent diabetes, and incidence rate ratios were calculated for the 90th percentile compared with the 10th percentile of each continuous variable for the whole group. In all subjects, in separate models, higher body mass index [RR = 2.0, 95% CI = 2.2-9.9], high fasting serum insulin concentrations [RR = 2.4, 95% CI = 1.4-4.2], and low early insulin response [RR = 0.5, 95% CI = 0.3-0.8] 30 min after a glucose load were significant predictors for deterioration to diabetes. In a multivariate analysis which controlled for age and sex, 120-min post-load glucose, fasting insulin and late insulin response predicted diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Diabetic nephropathy: a risk factor for diabetes mellitus in offspring.

Both non-insulin-dependent diabetes mellitus and diabetic nephropathy show familial aggregation. If diabetes and renal disease have independent determinants (genetic or otherwise), offspring of parents with diabetic renal disease should have a similar risk of diabetes to those offspring of parents with diabetes alone. To test this hypothesis, the prevalence of diabetes was examined in a population-based pedigree study in Pima Indian offspring of three mutually exclusive parental types: 1) diabetic with renal disease, 2) diabetic, but without renal disease and 3) non-diabetic. Among offspring of one diabetic parent and one non-diabetic parent (n = 320) the prevalence of diabetes at ages 15-24 years and 25-34 years was 0% and 11%, respectively if the diabetic parent did not have renal disease compared with 6% and 28% respectively if the diabetic parent did have renal disease. Corresponding rates for offspring of two diabetic parents (n = 121) were 10% and 17%, respectively if neither parent had renal disease compared with 30% and 50%, respectively if one parent did have renal disease. The presence of renal disease in a parent with diabetes relative to diabetes alone was associated with 2.5 times the odds of diabetes (95% confidence interval 1.4-4.3) in the offspring controlled for age, age at onset of parental diabetes and diabetes in the other parent using logistic regression. These findings provide support for parental diabetic renal disease, independent of age at onset of parental diabetes, conferring an increased risk for diabetes in the offspring.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Meta-analysis reveals association between most common class II haplotype in full-heritage Native Americans and rheumatoid arthritis.

The association of RA with the alleles at the HLA system was tested among Pima and Tohono O'odham Indians (Pimans) of the Gila River Indian Community of Arizona. Serologic class I (HLA-A, -B, and -C) alleles were typed in 51 individuals with RA and in 302 without RA. Serologic class II (HLA-DR, DQ; DR52 DR53) alleles were typed in a subset of 47 with RA and 147 without RA. Molecular subtypes of DR3X6, DRB1*1402, and *1406 were determined in 29 individuals, 16 with RA and 13 without RA. Among the cases with RA, 46 of 47 had the serologic antigen HLA-DR3X6, as did 140 of 147 of those without the disease. However, this association was not statistically significant because of the high prevalence of the antigen in the controls. Data from Pimans were analyzed with similar results from the Tlingit and Yakima Indians. A meta-analysis employing the Mantel-Haenszel procedure, stratified by tribe, revealed a statistically significant association between the most common haplotype, DRB1*1402 DQA1*0501 DQB1*0301 DRB3*0101, and RA (summary odds ratio = 2.63, 95% confidence interval = 1.08, 6.46). There was also a statistically significant difference in the genotype distributions of one class I locus, HLA-C, between those with and without RA (chi 2 = 12.4, 5 df; p = 0.03). It is concluded that the association with the most common class II haplotype in full-heritage Native Americans might help explain their high prevalence of RA.

Adolescent↗
PubMed1995

The U-shaped association between body mass index and mortality: relationship with weight gain in a Native American population.

In order to determine whether weight loss explains high mortality rates in those with a low body mass index (BMI), the relationships between BMI, rate of weight gain and mortality were examined in Pima Indians. Subjects were 814 diabetic and 1814 nondiabetic participants in a longitudinal survey who had at least two examinations after age 20. Median duration of follow-up was 8.1 (range 0.03-25.1) years. BMI showed a U-shaped relationship with mortality rates in men with the lowest rates in the 30-35 kg/m2 category; an inverse relationship was seen in women. Subjects who were losing weight had higher mortality rates than those who were gaining. However, excess mortality among the lightest subjects was present among those who were gaining weight. Among nondiabetic subjects, the mortality ratio (MR) for BMI < 25 kg/m2 compared with 30-35 kg/m2 was 1.5 [95% confidence interval (CI) 1.0-2.2] unadjusted for weight gain, while the adjusted MR was 1.3 [95% CI 0.9-1.9]. Weight loss, which may reflect underlying illness, is associated with high mortality rates in Pima Indians but does not fully account for the high mortality in the lightest individuals.

Adult↗
PubMed1995

Progression of overt nephropathy in non-insulin-dependent diabetes.

The detection of overt albuminuria (> 300 mg/g creatinine) in the absence of azotemia was used to diagnose early nephropathy in 34 Pima Indians with NIDDM of 16 +/- 1 years duration. Differential solute clearances were performed serially to define the course of the glomerular injury over 48 months. At baseline, the GFR (107 +/- 5 ml/min), filtration fraction and sieving coefficients of relatively permeant dextrans (< 52 A) were all depressed below corresponding values in 20 normoalbuminuric Pima Indians with a similar duration of NIDDM. Over the ensuing 48 months the GFR (-34%) and filtration fraction (-13%) in the nephropathic patients declined further. The sieving coefficients of large, nearly impermeant dextrans (> 56 A radius) increased selectively and fractional clearances of albumin and IgG increased correspondingly by > 10-fold. Analysis of the findings with pore theory revealed: (1) a progressive decline in pore density and the ultrafiltration coefficient (Kf); and (2) broadening of glomerular pore-size distribution that resulted in greater prominence of large pores (> 70 A radius). We conclude that increasing loss of intrinsic ultrafiltration capacity is the predominant cause of the early and progressive decline in GFR that follows the development of nephropathy in NIDDM. We speculate that progressive impairment of barrier size-selectivity contributes to but does not fully account for the increasingly heavy proteinuria that is observed early in the course of this disorder.

Adolescent↗
PubMed1995

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.

Adult↗
PubMed1995

Lack of IRS-1 codon 513 and 972 polymorphism in Pima Indians.

Insulin receptor substrate-1 (IRS-1), an endogenous substrate for the insulin receptor tyrosine kinase, mediates many or all of the metabolic actions of insulin. Recently, polymorphism at codons 513 and 972 of the IRS-1 gene resulting in 2 amino acid substitutions that were associated with type II diabetes were found in a Caucasian population. Using allele specific oligonucleotide (ASO) hybridization, we screened 242 diabetic and 190 nondiabetic Pima Indians, a population with a very high prevalence of type II diabetes. Neither of the two mutations was present in either diabetic or nondiabetic subjects. We conclude that polymorphism at codons 513 and 972 of the IRS-1 gene observed in certain Caucasian populations is very rare or absent in Pima Indians.

Adult↗
PubMed1995

Rate of weight gain, weight fluctuation, and incidence of NIDDM.

The relationships of rate of weight gain and weight fluctuation to incidence of non-insulin-dependent diabetes mellitus (NIDDM) were examined in Pima Indians. The 1,458 subjects were participants in a prospective study with examinations approximately every 2 years. Rate of weight gain was defined as the slope of the regression line of weight with time for two or more consecutive examinations > or = 2 years apart and weight fluctuation as the root-mean-square departure from this line for four examinations. Among men, incidence of NIDDM was strongly and significantly related to rate of weight gain (e.g., age-adjusted incidence = 56.7/1,000 person-years in those with weight gain > or = 3 kg/year and 16.9/1,000 person-years for those losing weight [Ptrend < 0.01]). In women, weight gain was significantly related to diabetes incidence only in those who were not initially overweight (body mass index < 27.3 kg/m2). In contrast to the relationship with weight gain, weight fluctuation was not associated with incidence of diabetes in either sex. These findings suggest that weight control in overweight individuals may be a more effective strategy for prevention of NIDDM in men than in women, whereas prevention of obesity may prevent diabetes in both sexes. Concern about a diabetogenic effect of weight fluctuation should not deter weight-control efforts.

Adult↗
PubMed1995

Familial relationships between obesity and NIDDM.

Obesity and family history of diabetes are both risk factors for non-insulin-dependent diabetes mellitus (NIDDM), but it has been proposed that lean individuals with NIDDM have a greater load of diabetes susceptibility genes. If this is the case, one might expect a high prevalence of NIDDM in relatives of diabetic individuals with a low body mass index (BMI). Among Pima Indians participating in an epidemiological study, prevalence of NIDDM was evaluated in relation to BMI of a diabetic parent or to the average parental BMI when both parents had diabetes in 1,535 offspring from 547 families. Prevalence of NIDDM was also evaluated in relation to BMI of a randomly selected index diabetic sibling in 1,722 siblings from 721 families. NIDDM was diagnosed by an oral glucose tolerance test. Compared with offspring of diabetic parent(s) at the 25th percentile of BMI, the odds ratio (OR) for diabetes in offspring of diabetic parents at the 75th percentile was 0.6 (95% confidence interval [CI] 0.5-0.7), adjusted for age, sex, BMI in offspring, number of diabetic parents, and age at onset of diabetes and sex of the diabetic parent(s). In the analysis according to BMI in a diabetic sibling, the corresponding OR was 0.8 (95% CI 0.6-0.9). Risk ratios were only modestly higher when the analysis was restricted to relatives of subjects whose BMI had been determined before the onset of diabetes. NIDDM in the presence of a low BMI is more strongly familial than that at a higher BMI.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Evidence for linkage between a region on chromosome 1p and the acute insulin response in Pima Indians.

A low acute insulin response (AIR) is a predictor of non-insulin-dependent diabetes mellitus (NIDDM) in insulin-resistant Pima Indians. We have initiated a search for regions of the genome linked with the AIR using sib-pair linkage analysis as a first step in identifying genes that are determinants of this phenotype. Eighteen short tandem-repeat polymorphisms from chromosome 1 were genotyped in over 900 Pima Indians and tested for linkage with NIDDM and in a subset of Pima Indians for linkage with AIR. The anonymous DNA marker D1S198 on chromosome 1p was linked with AIR (P = 0.000056) in 175 sib pairs from 60 families, all with normal glucose tolerance, but no linkage was observed between D1S198 and NIDDM (P = 0.44, 996 sib pairs). Additional markers genotyped on chromosome 1 did not show linkage with AIR or NIDDM. This study indicates that a locus on chromosome 1p may be a determinant of the phenotypic variation seen in the AIR.

Chromosomes, Human, Pair 1↗
PubMed1995

Preventing non-insulin-dependent diabetes.

Many risk factors for non-insulin-dependent diabetes mellitus (NIDDM), such as obesity, physical inactivity, and high-fat diet, can potentially be modified. Furthermore, some of the metabolic abnormalities, such as insulin resistance and impaired glucose tolerance, that predict diabetes can be improved by behavior modification and drug treatment. Thus, at least to some extent, NIDDM may be preventable. Several small clinical trials have addressed the hypothesis that NIDDM can be prevented by dietary modification, physical activity, or drug treatment. Some studies suggest a preventive effect, but the conclusions are limited by considerations of sample size, randomization, or intensity of the interventions. Consequently, the hypothesis that NIDDM is preventable requires further testing.

Behavior Therapy↗
PubMed1995

Incidence and determinants of elevated urinary albumin excretion in Pima Indians with NIDDM.

OBJECTIVE: To examine the incidence and determinants of elevated urinary albumin excretion in Pima Indians with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: The incidence of elevated urinary albumin excretion (> or = 30 mg albumin/g creatinine) and its relationship with baseline characteristics was determined in 456 Pima Indians > or = 15 years old with NIDDM who were followed for up to 11.6 years (median 4.7 years). RESULTS: Of these 456 subjects, 192 (42%; 58 men, 134 women) developed elevated urinary albumin excretion, 172 of whom (90%) were within the microalbuminuric range (30-299 mg/g). The incidence of elevated urinary albumin excretion was related to retinopathy, type, of diabetes treatment, longer duration of diabetes, lower body mass index, and higher values of mean arterial pressure, HbA1, and fasting and 2-h postload plasma glucose concentration at the baseline examination, but not to sex. A relationship with cholesterol was found in durations of diabetes of > or = 10 years. The cumulative incidence of elevated albumin excretion was 17% after 5 years of NIDDM. CONCLUSIONS: The incidence of elevated urinary albumin excretion in Pima Indians with NIDDM is at least as high as that reported previously in insulin-dependent diabetes mellitus, and its major determinants are the same as those shown previously to predict the development of more advanced renal disease in this population.

Adolescent↗
PubMed1995

Comparison of body size measurements as predictors of NIDDM in Pima Indians.

OBJECTIVE--To determine and compare the abilities of various anthropometric measurements to predict the development of non-insulin-dependent diabetes mellitus (NIDDM) in Pima Indian men and women. RESEARCH DESIGN AND METHODS--A total of 290 male and 443 female Pima Indians were followed for up to 6 years for the development of NIDDM. A proportional hazards analysis was used to assess the ability of anthropometric measurements evaluated at baseline to predict NIDDM. Receiver operating characteristic (ROC) curves were used to compare individual variables in predicting NIDDM. RESULTS--In separate models controlled for age and sex, body mass index (BMI), waist circumference, thigh circumference, waist-to-thigh ratio (WTR), weight, and percentage body fat (PBF) estimated by bioelectric resistance each predicted NIDDM, which developed in 30 men and 52 women. The highest incidence rate ratios (IRRs; for 1 SD of a variable) were for WTR in men and for PBF in women, although the confidence interval (CI) for PBF was wide. In stepwise analyses, WTR was the most significant predictor in men (IRR for 1 SD = 1.58, 95% CI = 1.20-2.07), and BMI was the most significant predictor in women (IRR for 1 SD = 1.65, 95% CI = 1.29-2.11). However, by ROC analyses, thigh circumference was the only variable significantly worse than WTR in men or BMI in women at predicting NIDDM. CONCLUSIONS-- Measurements such as waist circumference, WTR, weight, and BMI may be useful as more complicated measurements, such as PBF by bioelectrical resistance, for identifying groups of individuals whose body habitus places them at high risk of developing NIDDM.

Adolescent↗
PubMed1995

Segregation analysis of non-insulin-dependent diabetes mellitus in Pima Indians: evidence for a major-gene effect.

Non-insulin-dependent diabetes mellitus (NIDDM) has a high prevalence in Pima Indians. The disorder is familial, but the extent to which genetic factors are involved in its etiology is largely unknown. Segregation analysis was used to determine whether familial aggregation of NIDDM in this population could reflect the action of a single major gene. The analysis included 2,697 subjects from 653 nuclear families in which both parents and at least one offspring had been examined in the course of a longitudinal epidemiological study. The REGTL program of the SAGE package was used to fit models in which age at onset of NIDDM is transmitted from parent to offspring under the unified model for segregation analysis. Likelihood-ratio tests were used to test hypotheses related to genetic transmission. The hypothesis of no major effect was strongly rejected (P < .01), as was that of no transmission of the major effect (P < .01). Mendelian transmission was not rejected (P = .91). Similar results were obtained when covariates for obesity and birth cohort were added to the models and when a power transformation of age at onset was estimated. A strong effect of birth cohort with earlier age at onset in the later born cohorts was observed (P < .01). The findings are consistent with the hypothesis that a major gene influences the risk for NIDDM in Pima Indians by affecting age at onset. The expression of this gene may depend on environmental factors that have become more prevalent in recent-birth cohorts.

Adolescent↗