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Biomedical subjects

W C Knowler

Publications and source records attributed to W C Knowler.

At least 91 records · Page 5Linked to original sources
PubMed1996

Survey of the diet of Pima Indians using quantitative food frequency assessment and 24-hour recall. Diabetic Renal Disease Study.

OBJECTIVE: A dietary survey was conducted in the Gila River Indian Community in Arizona using two methods of dietary assessment--24-hour recall and quantitative food frequency (QFF) assessment--to determine the usual intake of the population. DESIGN: Interviews were conducted by Pima women who were trained and monitored by a research dietitian. Energy and nutrient intake were calculated using a computerized dietary database that included specific Pima foods. SUBJECTS: An age- and sex-stratified sample of 575 Pima Indians (273 men, 302 women) aged 18 to 74 years participated in the study. STATISTICAL ANALYSES: Spearman correlations were used to compare the results of the two survey methods for energy and each nutrient. Intraclass correlations were used to measure reproducibility. RESULTS: According to the 24-hour recall, mean reported energy intakes within decades of age were 95% to 112% of those in the US population for Pima women, and 76% to 94% of those in the US population for Pima men. Total energy intake assessed using QFF was 30% higher in men and 33% higher in women than the intake assessed using the 24-hour recall method. CONCLUSIONS: A large dietary survey conducted using lay interviewers in a Native-American community was as reproducible as studies conducted in the general US population. The Pima diet was distributed among the major nutrients in a proportion similar to the US diet.

Adolescent↗
PubMed1996

Regional differences in albuminuria among American Indians: an epidemic of renal disease.

Albuminuria is a risk factor for renal and cardiovascular disease. We conducted a cross sectional survey of 4549 older American Indians in Arizona, Oklahoma and North and South Dakota of (micro)albuminuria. A range of 20.1 to 48.3% of all participants had either micro- (> or = 30 to < 300 mg albumin/g creatinine) or macroalbuminuria (> or = 300 mg albumin/g creatinine). A total of 53% of the participants were diabetic, and the prevalence in Arizona (65 to 70%) was significantly greater than the other two sites. Prevalence of micro- and macroalbuminuria were significantly higher among those who were older, diabetic or hypertensive, and participants from Arizona. Even normotensive, nondiabetic Arizona Indians had higher prevalence rates than similar participants elsewhere. Higher prevalence rates of micro- and macroalbuminuria were also found among Arizona participants than participants with similar degrees of glucose intolerance from the other two sites. Indians reporting the greatest degree of Indian blood were more likely to have abnormal albuminuria (P < 0.0001). The duration of diabetes, fasting plasma glucose, systolic blood pressure, fibrinogen and Indian heritage were independently associated with micro- or macroalbuminuria. The association of albuminuria with subsequent ESRD, cardiovascular morbidity and overall mortality suggests that these American Indians will face a large disease burden. The correlation with reported Indian blood implies a strong component of genetic susceptibility, possibly independent of diabetes.

Aged↗
PubMed1996

HLA*A2 confers mortality risk for cardiovascular disease in Pimans.

A sample of 1465 full heritage Piman Indians from Arizona were typed for the serological antigens of the HLA class I loci and then incorporated into a survival study that ended December 31, 1991. The total follow-up time was 11,749 person-years with an average of 8.0 years per person. During the study 298 persons died, 54 from cardiovascular disease (CVD). Allele HLA*A2 conferred a 4.94 fold rate for death from CVD (95% C.I. 1.91-12.77). When controlled for the potential confounding variables, cholesterol, mean blood pressure, smoking, body mass index, rheumatoid factor titer, and nephropathy, the mortality rate ratio (MRR) was 5.42 (95% C.I. 1.98-14.82). There was no statistically significant association of mortality with other HLA-A or HLA-B alleles, or for causes of death not related to cardiovascular disease.

Adult↗
PubMed1996

DRD2 haplotypes containing the TaqI A1 allele: implications for alcoholism research.

In recent years, a possible role of the dopamine D2 receptor (DRD2) locus in the etiology of alcoholism has been the focus of considerable attention. The literature now contains a mix of association studies with positive and negative conclusions. Various methodological flaws undermine the claims in many of the studies that conclude a positive association exists between alcoholism and the DRD2*A1 allele at the Taql "A" site. Although the studies with negative findings have more often come from studies using better analytic methodology, satisfactory resolution of whether or not genetic variation at the DRD2 locus plays some role in the etiology of alcoholism is unlikely to come from additional studies of the kind conducted thus far; an approach enlightened by a more thorough understanding of the population genetics of DRD2 and the phylogenetic origins of the DRD2 alleles is one alternative. If genetic variation at the DRD2 locus affects susceptibility to alcoholism, then such variation has a mutational and evolutionary history that can be traced with the aid of the various genetic polymorphisms that have been identified at the DRD2 locus. In this study, a third Taql restriction fragment-length polymorphism at DRD2, the Taql "D" site, has been converted to polymerase chain reaction-based typing and its frequencies determined in 22 populations from around the world. Haplotypes defined by the polymorphisms at the Taql "B" and "A" sites, and the short tandem repeat polymorphism in intron 2 have been constructed and the diversity of haplotypes containing the DRD2*A1 allele examined for all 22 populations. The ancestral origins of the three Taql polymorphisms have also been determined by sequencing the homologous regions in other higher primates. Because A1-containing haplotypes in populations of European, Middle Eastern, and African origin show considerable diversity within and among populations, properly designed association studies in populations descended from those areas of the world need to use haplotypes, not a single allelic system, and need to use appropriate methods to compensate for the near impossibility of genetically matching unrelated control samples.

Alcoholism↗
PubMed1996

The angiotensin-I converting enzyme (ACE) gene I/D polymorphism and ACE levels in Pima Indians.

An insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene is associated with plasma ACE levels in white populations. The occurrence of the I/D polymorphism and relationship to ACE levels was examined in a Pima Indian group (n = 305). The frequency of the D allele was lower in Pimas than whites (0.29 v 0.52 respectively). ACE levels were significantly associated with genotype in both groups (p = 0.0001), which accounted for 6.5% of the variation in ACE levels in Pimas and 18% in whites. The association of the I/D polymorphism with ACE levels confirms the relationship across ethnic groups. The low frequency of the D allele in Pima Indians shows that ethnic differences should be accounted for when studying the ACE gene.

Adult↗
PubMed1996

Severe periodontitis and risk for poor glycemic control in patients with non-insulin-dependent diabetes mellitus.

This study tested the hypothesis that severe periodontitis in persons with non-insulin-dependent diabetes mellitus (NIDDM) increases the risk of poor glycemic control. Data from the longitudinal study of residents of the Gila River Indian Community were analyzed for dentate subjects aged 18 to 67, comprising all those: 1) diagnosed at baseline with NIDDM (at least 200 mg/dL plasma glucose after a 2-hour oral glucose tolerance test); 2) with baseline glycosylated hemoglobin (HbA1) less than 9%; and 3) who remained dentate during the 2-year follow-up period. Medical and dental examinations were conducted at 2-year intervals. Severe periodontitis was specified two ways for separate analyses: 1) as baseline periodontal attachment loss of 6 mm or more on at least one index tooth; and 2) baseline radiographic bone loss of 50% or more on at least one tooth. Clinical data for loss of periodontal attachment were available for 80 subjects who had at least one follow-up examination, 9 of whom had two follow-up examinations at 2-year intervals after baseline. Radiographic bone loss data were available for 88 subjects who had at least one follow-up examination, 17 of whom had two follow-up examinations. Poor glycemic control was specified as the presence of HbA, of 9% or more at follow-up. To increase the sample size, observations from baseline to second examination and from second to third examinations were combined. To control for non-independence of observations, generalized estimating equations (GEE) were used for regression modeling. Severe periodontitis at baseline was associated with increased risk of poor glycemic control at follow-up. Other statistically significant covariates in the GEE models were: 1) baseline age; 2) level of glycemic control at baseline; 3) having more severe NIDDM at baseline; 4) duration of NIDDM; and 5) smoking at baseline. These results support considering severe periodontitis as a risk factor for poor glycemic control and suggest that physicians treating patients with NIDDM should be alert to the signs of severe periodontitis in managing NIDDM.

Adolescent↗
PubMed1996

Absence of linkage of obesity and energy metabolism to markers flanking homologues of rodent obesity genes in Pima Indians.

The homologues of single genes that cause obesity in rodents are suggested as candidate genes for modulation of body composition in humans. Among these genes are the four mouse mutations-diabetes (db), obesity (ob), tubby (tub), and yellow agouti (Ay). Variation in the human counterparts to these genes (OB, DB, TUB, and ASP, respectively) may contribute to human obesity, which is thought to have a substantial genetic component. To initially assess the potential contribution of these genes to human obesity, we examined polymorphic DNA markers that, by virtue of syntenic relationships to appropriate regions of the mouse genome, should be closely linked to the human counterparts of these genes. Using combined data from 716 Pima Indians comprising 217 nuclear families, we have tested a number of polymorphic microsatellite markers (three at DB, two at OB, five at TUB, and three at ASP) for sib-pair linkage to BMI, percentage body fat, resting metabolic rate, 24-h energy expenditure, and 24-h respiratory quotient. No significant linkages were found in an analysis of all sibships or in an analysis restricted to discordant sib pairs.

Adipose Tissue↗
PubMed1996

Relationship of locus of control to physical activity among people with and without diabetes.

OBJECTIVE: To examine the relationship between locus of control (LOC) (internal and external) and physical activity in Pima Indians and to determine whether this relationship is affected by the presence of diabetes. RESEARCH DESIGN AND METHODS: A population-based sample of 580 Pima Indians was recruited from an ongoing research study. LOC was measured on a 1-40 modified Rotter scale, and past year total physical activity (leisure and work physical activity levels combined) was measured by interviewer-administered questionnaire. RESULTS: Among both men and women without diabetes, individuals with an internal LOC (score 1-16) were significantly (P < 0.01) more active than those with an external (score 17-40) LOC (70 vs. 30 median metabolic equivalent [MET] hours per week for men: 12 vs. 5 median MET hours per week for women). Controlled for age and BMI, an internal LOC was significantly associated with a higher level of physical activity among men (P = 0.04) and women (P = 0.001) without diabetes, but not among those with diabetes. CONCLUSIONS: Nondiabetic Pima Indians with an internal LOC are more physically active than those with an external LOC. Enhancing perceptions of internal control may influence physical activity and thus have implications for diabetes prevention.

Adolescent↗
PubMed1996

Survival during renal replacement therapy for diabetic end-stage renal disease in Pima Indians.

OBJECTIVE: To examine survival in Pima Indians receiving renal replacement therapy for end-stage renal disease attributed to NIDDM. RESEARCH DESIGN AND METHODS: Vital status through 1994 was determined for 136 diabetic Pima Indians from the Gila River Indian Community who began renal replacement therapy between 1973 and 1990. RESULTS: Median survival from the onset of renal replacement therapy was 39 months (95% Ci, 31-54), 31 months (95% Ci, 11-48) in those who began treatment between 1973 and 1981, and 44 months (95% Ci, 32-56) in those who began treatment between 1982 and 1990 (P = 0.020). During these periods, mean age at onset of treatment increased from 53.3 to 56.1 years (P = 0.166), and mean duration of diabetes at the onset of treatment increased from 16.5 to 20.2 years (P = 0.003). After adjustment for sex, duration of diabetes, initial dialysis type, and kidney transplantation by an age-stratified proportional-hazards analysis, the death rate after starting renal replacement therapy in the second half of the study was 0.54 times (95% CI, 0.33-0.88) that in the first half. If this analysis was restricted to those who survived at least 90 days of therapy, the difference between the time periods was diminished (death rate ratio = 0.76; 95% CI, 0.43-1.32). CONCLUSIONS: Survival in Pima Indians receiving renal replacement therapy improved significantly over the study despite an increase in the average age and diabetes duration of those beginning dialysis. Much of the improvement in survival is attributable to a reduction in the number of deaths within the first 90 days of therapy. The median survival of 47 months in Pima Indians < 65 years old at the initiation of therapy is substantially longer than the 30 months reported in blacks and 16 months reported in whites of similar age with NIDDM.

Adult↗
PubMed1996

Familial aggregation of medial arterial calcification in Pima Indians with and without diabetes.

OBJECTIVE: Little is known about medial arterial calcification (MAC) other than its association with age, sex, diabetes, and diabetes complications. Familial aggregation of this disorder was studied to determine the importance of potential genetic factors and to assess whether such familial aggregation was independent of that of diabetes. RESEARCH DESIGN AND METHODS: Members of 1,256 Pima Indian nuclear families with 3,339 offspring were examined radiologically for MAC of the feet. Multiple logistic regression analyses were used to compare the presence of the disorder in a parent with the presence of MAC in an offspring and to determine whether familial aggregation of MAC was independent of parental diabetes. RESULTS: Controlled for age, sex, diabetes, serum cholesterol, and blood pressure, offspring of one parent with MAC had 3.3 (95% CI 1.5-7.6) times the odds of MAC as did offspring of parents without MAC, and offspring with both parents affected had an even higher risk (odds ratio, 8.1; 95% CI 3.4-18.8). Controlled for offspring age and sex and for parental age and diabetes, parental MAC was associated with the disorder in offspring (P < 0.001), but the effect of parental diabetes on MAC in the offspring was not significant when controlled for parental MAC (P = 0.36). Furthermore, offspring of nondiabetic parents with MAC, controlled for age, sex, diabetes, and diabetes duration, had 1.7 (95% CI 0.9-3.1) times the odds of MAC than did offspring of diabetic parents with MAC. CONCLUSIONS: Independent of parental age and diabetes and offspring age, sex, diabetes, and diabetes complications, parental MAC confers an increased risk of MAC in offspring. These findings suggest that the factors responsible for the familial clustering of MAC may be different from those for diabetes.

Adult↗
PubMed1996

A two-step strategy for identification of high-risk subjects for a clinical trial of prevention of NIDDM.

OBJECTIVE: To evaluate 2-h plasma glucose (2HPG), fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1), a combination of FPG and HbA1 (FPG-HbA1), and other factors as screening tests for identifying high-risk subjects for a clinical trial of prevention of NIDDM and to identify strategies to minimize the total number of oral glucose tolerance tests (OGTTs) required to recruit eligible subjects to the trial. RESEARCH DESIGN AND METHODS: One thousand, one hundred and eight nondiabetic Pima Indians aged 25-64 years were followed for up to 5 years, and factors predicting NIDDM, defined by World Health Organization criteria (2HPG > or = 11.1 mmol/l), were assessed using Cox's proportional hazards analysis. Various threshold values of FPG, HbA1, and FPG-HbA1 were determined, which, when combined with an OGTT, identified subjects with impaired glucose tolerance (IGT) (2HPG > or = 7.8 and < 11.1 mmol/l) at a number of specified risks for developing NIDDM in 5 years. The value of each of the three tests was then assessed by calculating (for each threshold) the numbers to be screened, the numbers requiring an OGTT, and the sample size of IGT subjects needed to detect a 33% reduction in NIDDM by an experimental intervention at a power of 80%. RESULTS: During a median of 4.3 years of follow-up, 91 (8.2%) of the 1.108 nondiabetic subjects developed NIDDM. The estimated 5-year cumulative incidence rate was 13.5%. Each of the variables, 2HPG, FPG, HbA1, FPG-HbA1, BMI, IGT, and systolic (sBP), diastolic (dBP), and mean (MBP) blood pressures, predicted NIDDM (P < 0.05 for each) when controlled for age and sex. In a stepwise proportional hazards analysis model, 2HPG and FPG-HbA1 (P < 0.001 for each) were selected as the best set of predictors of NIDDM and of fasting hyperglycemia (FPG > or = 7.8 mmol/l). CONCLUSIONS: A two-step strategy, in which high-risk individuals are first identified by FPG or FPG-HbA1 and then the OGTT is used to select subjects with IGT, requires fewer OGTTs than when using 2HPG as the initial screening test without substantially increasing the numbers that would need to be screened. Such a strategy also offers the advantage of reducing the necessary sample size and is therefore an effective, efficient, and convenient method of identifying eligible subjects for a clinical trial of prevention of NIDDM.

Adult↗
PubMed1996

Weight fluctuation, mortality and vascular disease in Pima Indians.

OBJECTIVE: To examine the relationship of weight fluctuation to mortality rates and incidence of vascular disease. SUBJECTS: A cohort of Pima Indians, 572 of whom had non-insulin-dependent diabetes mellitus and 766 without diabetes. DESIGN: Individuals were invited biennially to research examinations. The root mean square error (RMSE) of the linear trend of weight with time for the first four examinations after age 20 years was used as an index of weight fluctuation. Subjects were followed from the fourth examination until death or until 31 December 1991. The mortality rate ratio (MRR) and its 95% confidence interval (CI) for those with a high weight fluctuation index relative to those with a lower value were determined. The median duration of follow up was 9.3 (range 0.1-22.6) years. MEASUREMENTS: All cause mortality (n = 356); incidence of diabetic retinopathy (n = 145), diabetic nephropathy (n = 132) and electrocardiographic abnormalities (n = 82). RESULTS: There was no significant relationship between weight fluctuation and mortality for diabetic subjects (MRR = 1.0, 95% CI 0.8-1.3, p = 0.91). Nondiabetic subjects with a high weight fluctuation index had a higher mortality rate than those with a lower index (MRR = 1.5, 95% CI 1.0-2.1, p = 0.03); the association was stronger among men than among women. The excess mortality in the high weight fluctuation group was not due to cardiovascular diseases, but to noncardiovascular causes and the risk for alcohol-related death was particularly increased. Weight fluctuation was not associated with the incidence of diabetic retinopathy, nephropathy or electrocardiographic abnormalities. CONCLUSIONS: A high weight fluctuation index was associated with higher mortality rates in nondiabetic, but not in diabetic, Pima Indians. The excess mortality is largely due to noncardiovascular causes of death and may reflect lifestyle factors associated with weight fluctuation, rather than its metabolic effects.

Adult↗
PubMed1996

Low prevalences of chronic widespread pain and shoulder disorders among the Pima Indians.

OBJECTIVE: To establish the prevalence of shoulder disease and chronic widespread pain in Pima Indians. METHODS: Cross sectional analyses of data from 4230 subjects for shoulder disease and 105 subjects for chronic widespread pain participating in population surveys RESULTS: The prevalence of shoulder disease was 4.4% (95% CI, 3.8-5.1), age-sex adjusted to the 1980 US census population. This is lower than in a study of Caucasians [prevalence ratio (PR) = 0.29, 95% CI, 0.20-0.42 for men and PR = 0.55, 95% CI, 0.41-0.73 for women]. Shoulder disease was associated with non-insulin-dependent diabetes mellitus (PR = 1.67, 95% CI, 1.19-2.36). No chronic widespread pain was identified (95% CI, 0-3.5%). CONCLUSION: Prevalence of these pain syndromes in Pima Indians is lower than in predominantly Caucasian populations. These findings suggest that these populations have different pain perception or different patterns of risk factors for these disorders.

Adult↗
PubMed1996

Plasminogen activator inhibitor (PAI-1) and non-insulin-dependent diabetes in Pima Indians, south Asians and Europeans. Populations at varying risk of NIDDM and coronary artery disease.

Activity of plasminogen activator inhibitor-1 (PAI-1), a potent inhibitor of fibrinolysis, is raised in non-insulin-dependent diabetes mellitus (NIDDM) and may contribute to excess macrovascular disease. We investigated the association of PAI-1 activity with NIDDM in Pima Indians, a racial group with low risk of coronary artery disease, but in whom the impact of NIDDM on the occurrence of coronary artery disease is similar to other racial groups. We studied 308 (136 non-diabetic, 172 diabetic) Pima Indians from Arizona, and 138 (98 non-diabetic, 40 diabetic) South Asians and 129 (80 non-diabetic, 49 diabetic) Europeans living in North London. PAI-1 activity was measured by a spectrophotometric assay, and insulin, intact proinsulin and des 31,32 proinsulin concentrations were measured employing highly specific monoclonal antibody-based assays. Compared with non-diabetic subjects, PAI-1 activity was significantly higher in subjects with NIDDM among South Asians (22.8 +/- 7.3 vs. 17.4 +/- 6.9 AU/ml, p < 0.001) and Europeans (23.1 +/- 6.6 vs. 16.5 +/- 6.1 AU/ml, p < 0.001) but not among Pima Indians (19.5 +/- 9.6 vs. 18.5 +/- 8.6 AU/ml, ns). The association of PAI-1 activity with diabetes remained statistically significant when controlled for age, sex, body mass index and waist-hip ratio, serum triglyceride and fasting insulin concentrations in South Asians (p < 0.001) and Europeans (p < 0.001). The relationships of PAI-1 activity with clinical and biochemical variables were similar in the three racial groups other than for fasting and 2 h plasma glucose concentrations which were significantly associated with PAI-1 activity in South Asians (partial r = 0.32 and 0.31) and Europeans (partial r = 0.44 and 0.50) but not in Pima Indians (partial r = 0.11 and 0.15). In Pima Indians with NIDDM, PAI-1 activity was similar in those treated with sulphonylureas, insulin, or no drugs for diabetes. In conclusion, the association of PAI-1 with diabetes differs in racial groups who are at different risk of NIDDM and ischaemic heart disease. Previously reported differences in the prevalence of ischaemic heart disease between diabetic and non-diabetic Pima Indians, and between non-diabetic subjects from the three racial groups, are unlikely to be due to differences in PAI-1 activity.

Adult↗
PubMed1996

Hypertension in Pima Indians: prevalence and predictors.

THE PIMA INDIANS HAVE THE WORLD'S HIGHEST reported incidence of diabetes. Since 1965, this population has participated in a longitudinal epidemiological study of diabetes and its complications. The examinations have included a medical history for diabetes and other major health problems. The focus of this study is the correlation between the prevalence of hypertension and glucose tolerance in this population. Of the 4315 adults ages 18 and older, 50% had normal glucose tolerance; 12%, impaired glucose tolerance (IGT); 8%, newly diagnosed diabetes; and 31%, previously diagnosed diabetes of a mean duration of 11 years. Age-sex adjusted prevalence of hypertension was 24% in those with normal glucose tolerance, 34% in those with IGT, and 40% in those with diabetes. Hypertension was more common in men than in women and was positively related to obesity. Of the 2667 children ages 6 to 17 years, 4% had IGT, and 1% had diabetes. Blood pressure was higher in boys than girls and was associated with older age and worse glucose tolerance. Longitudinal analyses of data from 188 children ages 5 to 9 years who had their follow-up exam at ages 18 to 24 revealed no relationship between insulin concentration and blood pressure in either sex. In this group mean blood pressure at followup was positively correlated with relative weight, mean blood pressure, and 2-hour post-load plasma glucose concentration at baseline. In a multiple regression model, relative weight was the strongest predictor of mean blood pressure at the follow-up exam.

Adolescent↗
PubMed1995

Linkage between stature and a region on chromosome 20 and analysis of a candidate gene, bone morphogenetic protein 2.

Sib-pair linkage analysis of the quantitative trait, structure, in over 500 Pima Indians indicates that a genetic determinant of governing stature is located on chromosome 20. Analysis of 10 short tandem repeat polymorphisms localized this linkage to a 3.2cM region that includes D20S98 and D20S66. Using all possible sib-pair combinations, linkage was detected to both stature (P = 0.0001) and to leg length (P = 0.001), but not to sitting height. Single-strand conformational polymorphism analysis of exon 3 of the bone morphogenetic protein 2 (BMP2) gene, a candidate gene in this region, in genomic DNA of 20 of the tallest and 20 of the shortest individuals did not show any consistent differences associated with leg length or height. Sequence analysis of the region encoding the mature protein revealed a single nucleotide substitution, a T to G transversion, not detected by single-strand conformational polymorphism (SSCP) analysis. This transversion results in a conservative amino acid substitution of glycine for valine at codon 80 of BMP2. The frequency of this allele was 0.23 in the sample. No significant differences in height were noted in persons carrying either allele. This indicates that this structural alteration is the mature BMP2 protein does not contribute to the differences in stature observed in the Pima Indians, nor is this structural change in the mature protein likely to be responsible for the linkage observed with stature on chromosome 20.

Alleles↗
PubMed1995

Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the beta 3-adrenergic-receptor gene.

BACKGROUND: The beta 3-adrenergic receptor is expressed in visceral adipose tissue and is thought to contribute to the regulation of the resting metabolic rate and lipolysis. METHODS: To investigate whether mutations in the gene for the beta 3-adrenergic receptor predispose patients to obesity and non-insulin-dependent diabetes mellitus (NIDDM), we studied this gene in 10 Pima Indians by analysis of single-stranded conformational polymorphisms and dideoxy sequence analysis. Association studies were performed in 642 Pima subjects (390 with NIDDM and 252 without NIDDM). RESULTS: A missense mutation was identified in the gene for the beta 3-adrenergic receptor that results in the replacement of tryptophan by arginine (Trp64Arg) in the first intracellular loop of the receptor. This mutation was detected with allelic frequencies of 0.31 in Pima Indians, 0.13 in 62 Mexican Americans, 0.12 in 49 blacks, and 0.08 in 48 whites in the United States. Among Pimas, the frequency of the Trp64Arg mutation was similar in nondiabetic and diabetic subjects. However, in subjects homozygous for the mutation the mean (+/- SD) age at the onset of NIDDM was significantly lower (36 +/- 10 years) than in Trp64Arg heterozygotes (40 +/- 10 years) or normal homozygotes (41 +/- 11 years; P = 0.02). Furthermore, subjects with the mutation tended to have a lower adjusted resting metabolic rate (P = 0.14 by analysis of covariance). CONCLUSIONS: Pima subjects homozygous for the Trp64Arg beta 3-adrenergic-receptor mutation have an earlier onset of NIDDM and tend to have a lower resting metabolic rate. This mutation may accelerate the onset of NIDDM by altering the balance of energy metabolism in visceral adipose tissue.

Adult↗