In Caucasians with type 2 diabetes, circulating TNF receptors 1 (TNFR1) and 2 (TNFR2) predict end... more In Caucasians with type 2 diabetes, circulating TNF receptors 1 (TNFR1) and 2 (TNFR2) predict end-stage renal disease (ESRD). Here we examined this relationship in a longitudinal cohort study of American Indians with type 2 diabetes with measured glomerular filtration rate (mGFR, iothalamate) and urinary albumin-to-creatinine ratio (ACR). ESRD was defined as dialysis, kidney transplant, or death attributed to diabetic kidney disease. Age-gender-adjusted incidence rates and incidence rate ratios of ESRD were computed by Mantel-Haenszel stratification. The hazard ratio of ESRD was assessed per interquartile range increase in the distribution of each TNFR after adjusting for baseline age, gender, mean blood pressure, HbA1c, ACR, and mGFR. Among the 193 participants, 62 developed ESRD and 25 died without ESRD during a median follow-up of 9.5 years. The age-gender-adjusted incidence rate ratio of ESRD was higher among participants in the highest versus lowest quartile for TNFR1 (6.6, 95%...
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, Jan 3, 2015
Urinary monocyte chemoattractant protein-1 (MCP-1) and hepcidin are potential biomarkers of renal... more Urinary monocyte chemoattractant protein-1 (MCP-1) and hepcidin are potential biomarkers of renal inflammation. We examined their association with development of diabetic nephropathy (DN) lesions in normotensive normoalbuminuric subjects with type 1 diabetes (T1D) from the Renin-Angiotensin System Study. Biomarker concentrations were measured in baseline urine samples from 224 subjects who underwent kidney biopsies at baseline and after 5 years. Fifty-eight urine samples below the limit of quantitation (LOQ, 28.8 pg/mL) of the MCP-1 assay were assigned concentrations of LOQ/√2 for analysis. Relationships between ln(MCP-1/Cr) or ln(hepcidin/Cr) and morphometric variables were assessed by sex using multiple linear regression after adjustment for age, T1D duration, HbA1c, mean arterial pressure, albumin excretion rate (AER) and glomerular filtration rate (GFR). In models that examined changes in morphometric variables, the baseline morphometric value was also included. Baseline mean ag...
During the first 7 years of the Diabetes Prevention Program Outcomes Study (DPPOS), diabetes inci... more During the first 7 years of the Diabetes Prevention Program Outcomes Study (DPPOS), diabetes incidence rates, when compared with the Diabetes Prevention Program (DPP), decreased in the placebo (-42%) and metformin (-25%), groups compared with the rates in the intensive lifestyle intervention (+31%) group. Participants in the placebo and metformin groups were offered group intensive lifestyle intervention prior to entering the DPPOS. The following two hypotheses were explored to explain the rate differences: "effective intervention" (changes in weight and other factors due to intensive lifestyle intervention) and "exhaustion of susceptible" (changes in mean genetic and diabetes risk scores). No combination of behavioral risk factors (weight, physical activity, diet, smoking, and antidepressant or statin use) explained the lower DPPOS rates of diabetes progression in the placebo and metformin groups, whereas weight gain was the factor associated with higher rates o...
The relative effectiveness of 3 approaches to blood pressure control-(i) an intensive lifestyle i... more The relative effectiveness of 3 approaches to blood pressure control-(i) an intensive lifestyle intervention (ILI) focused on weight loss, (ii) frequent goal-based monitoring of blood pressure with pharmacological management, and (iii) education and support-has not been established among overweight and obese adults with type 2 diabetes who are appropriate for each intervention. Participants from the Action for Health in Diabetes (Look AHEAD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) cohorts who met criteria for both clinical trials were identified. The proportions of these individuals with systolic blood pressure (SBP) <140mm Hg from annual standardized assessments over time were compared with generalized estimating equations. Across 4 years among 480 Look AHEAD and 1,129 ACCORD participants with baseline SBPs between 130 and 159mm Hg, ILI (OR = 1.46; 95% CI = [1.18-1.81]) and frequent goal-based monitoring with pharmacotherapy (OR = 1.51; 95% CI = [1.16-...
A prior genome-wide association study (GWAS) in Pima Indians identified a variant within PFKFB2 (... more A prior genome-wide association study (GWAS) in Pima Indians identified a variant within PFKFB2 (rs17258746) associated with body mass index (BMI). PFKFB2 encodes 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase isoform 2, which plays a role in glucose metabolism. To follow-up on the GWAS, tag SNPs across PFKFB2 were genotyped in American Indians who had longitudinal data on BMI (n = 6839), type 2 diabetes (T2D; n = 7710), diabetic nephropathy (DN; n = 2452), % body fat (n = 555) and insulin secretion (n = 298). Two SNPs were further genotyped in urban American Indians to assess replication for DN (n = 864). PFKFB2 expression was measured in 201 adipose biopsies using real-time RT-PCR and 61 kidney biopsies using the Affymetrix U133 array. Two SNPs (rs17258746 and rs11120137), which capture the same signal, were associated with maximum BMI in adulthood (β = 1.02 per risk allele, P = 7.3 × 10(-4)), maximum BMI z-score in childhood (β = 0.079, P = 0.03) and % body fat in adulthood...
To assess the relative impact of an intensive lifestyle intervention (ILI) on use and costs of he... more To assess the relative impact of an intensive lifestyle intervention (ILI) on use and costs of health care within the Look AHEAD trial. A total of 5,121 overweight or obese adults with type 2 diabetes were randomly assigned to an ILI that promoted weight loss or to a comparison condition of diabetes support and education (DSE). Use and costs of health-care services were recorded across an average of 10 years. ILI led to reductions in annual hospitalizations (11%, P = 0.004), hospital days (15%, P = 0.01), and number of medications (6%, P < 0.001), resulting in cost savings for hospitalization (10%, P = 0.04) and medication (7%, P…
Non-insulin-dependent diabetes mellitus (NIDDM) is a major cause of end-stage renal disease. Howe... more Non-insulin-dependent diabetes mellitus (NIDDM) is a major cause of end-stage renal disease. However, the course and determinants of renal failure in this type of diabetes have not been clearly defined. We studied glomerular function at intervals of 6 to 12 months for 4 years in 194 Pima Indians selected to represent different stages in the development and progression of diabetic renal disease. Initially, 31 subjects had normal glucose tolerance, 29 had impaired glucose tolerance, 30 had newly diagnosed diabetes, and 104 had had diabetes for five years or more; of these 104, 20 had normal albumin excretion, 50 had microalbuminuria, and 34 had macroalbuminuria. The glomerular filtration rate, renal plasma flow, urinary albumin excretion, and blood pressure were measured at each examination. Initially, the mean (+/-SE) glomerular filtration rate was 143+/-7 ml per minute in subjects with newly diagnosed diabetes, 155+/-7 ml per minute in those with microalbuminuria, and 124+/-7 ml per minute in those with macroalbuminuria; these values were 16 percent, 26 percent, and 1 percent higher, respectively, than in the subjects with normal glucose tolerance (123+/-4 ml per minute). During four years of follow-up, the glomerular filtration rate increased by 18 percent in the subjects who initially had newly diagnosed diabetes (P=0.008); the rate declined by 3 percent in those with microalbuminuria at base line (P=0.29) and by 35 percent in those with macroalbuminuria (P&lt;0.001). Higher base-line blood pressure predicted increasing urinary albumin excretion (P=0.006), and higher base-line urinary albumin excretion predicted a decline in the glomerular filtration rate (P&lt;0.001). The initial glomerular filtration rate did not predict worsening albuminuria. The glomerular filtration rate is elevated at the onset of NIDDM and remains so while normal albumin excretion or microalbuminuria persists. It declines progressively after the development of macroalbuminuria.
Common polymorphisms of the transcription factor 7-like 2 gene (TCF7L2) have recently been associ... more Common polymorphisms of the transcription factor 7-like 2 gene (TCF7L2) have recently been associated with type 2 diabetes. We examined whether the two most strongly associated variants (rs12255372 and rs7903146) predict the progression to diabetes in persons with impaired glucose tolerance who were enrolled in the Diabetes Prevention Program, in which lifestyle intervention or treatment with metformin was compared with placebo. We genotyped these variants in 3548 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors. We assessed the effect of genotype on measures of insulin secretion and insulin sensitivity at baseline and at one year. Over an average period of three years, participants with the risk-conferring TT genotype at rs7903146 were more likely to have progression from impaired glucose tolerance to diabetes than were CC homozygotes (hazard ratio, 1.55; 95 percent confidence interval, 1.20 to 2.01; P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). The effect of genotype was stronger in the placebo group (hazard ratio, 1.81; 95 percent confidence interval, 1.21 to 2.70; P=0.004) than in the metformin and lifestyle-intervention groups (hazard ratios, 1.62 and 1.15, respectively; P for the interaction between genotype and intervention not significant). The TT genotype was associated with decreased insulin secretion but not increased insulin resistance at baseline. Similar results were obtained for rs12255372. Common variants in TCF7L2 seem to be associated with an increased risk of diabetes among persons with impaired glucose tolerance. The risk-conferring genotypes in TCF7L2 are associated with impaired beta-cell function but not with insulin resistance. (ClinicalTrials.gov number, NCT00004992. [ClinicalTrials.gov]).
Among 384 Pima Indians with impaired glucose tolerance according to World Health Organization cri... more Among 384 Pima Indians with impaired glucose tolerance according to World Health Organization criteria who were followed for 1.6 to 11.5 years (median, 3.3), non-insulin-dependent diabetes mellitus (NIDDM) developed in 118 (31 percent), glucose tolerance remained impaired in 100 (26 percent), and glucose tolerance returned to normal in 166 (43 percent). The cumulative incidence of NIDDM was 25 and 61 percent at 5 and 10 years, respectively. The risk of development of diabetes was 6.3 times (95 percent confidence interval, 3.8 to 10.6) as high as in a normoglycemic control group (n = 752). Variables predicting deterioration to NIDDM were age up to the age of 40, after which increasing age had a beneficial effect; higher plasma glucose levels during fasting and after carbohydrate loading; and higher serum insulin levels after fasting and lower levels after carbohydrate loading, suggesting that insulin resistance and decreased beta-cell responsiveness are important determinants of the clinical outcome of impaired glucose tolerance. Obese subjects had 2.9 times (95 percent confidence interval, 2.0 to 10.9) the incidence of NIDDM as the nonobese. Obesity was not, however, predictive of progression to NIDDM after an adjustment for plasma glucose and serum insulin levels. We conclude that in this population approximately one fourth of subjects with impaired glucose tolerance have NIDDM at five years and two thirds at 10 years (approximately one third revert to normal) and that age and plasma glucose and insulin levels are the best predictors of clinical outcome.
CNDP1 is located on 18q22.3, where linkage with diabetic nephropathy has been observed in several... more CNDP1 is located on 18q22.3, where linkage with diabetic nephropathy has been observed in several populations, including Pima Indians. However, evidence for association between CNDP1 alleles and diabetic nephropathy is equivocal and population-dependent. This study investigated CNDP1 as a candidate for diabetic kidney disease in Pima Indians. Nineteen tag single nucleotide polymorphisms spanning the CNDP1 locus were selected using genotype data from Chinese individuals in the HapMap resource along with 2 variants previously associated with diabetic nephropathy. All variants were genotyped in 3 different samples including a diabetic end-stage renal disease (ESRD) case-control study, a family-based study of diabetic individuals who participated in the linkage study for nephropathy, and a cohort of diabetic individuals in whom longitudinal measures of glomerular filtration rates (GFR) were performed. There was no statistically significant evidence for association with diabetic ESRD. However, nominal evidence for association was found in the family study, where markers rs12957330 (Odds ratio [OR]=0.29 per copy of G allele; p=0.04) and rs17817077 (OR=0.46 per copy of G allele; p=0.05) were associated with diabetic nephropathy. In addition, markers rs12964454, rs7244647, and rs7229005 were associated with changes in GFR (-8.5ml/min per copy of the G allele; p=0.04; 18.8ml/min per copy of the C allele; p=0.03; and -13.4ml/min per copy of the C allele; p=0.001, respectively). These findings provide nominal evidence supporting a role between CNDP1 variants and diabetic kidney disease.
Both a low estimated glomerular filtration rate (eGFR) and albuminuria are known risk factors for... more Both a low estimated glomerular filtration rate (eGFR) and albuminuria are known risk factors for end-stage renal disease (ESRD). To determine their joint contribution to ESRD and other kidney outcomes, we performed a meta-analysis of nine general population cohorts with 845,125 participants and an additional eight cohorts with 173,892 patients, the latter selected because of their high risk for chronic kidney disease (CKD). In the general population, the risk for ESRD was unrelated to eGFR at values between 75 and 105 ml/min per 1.73 m(2) but increased exponentially at lower levels. Hazard ratios for eGFRs averaging 60, 45, and 15 were 4, 29, and 454, respectively, compared with an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log ESRD risk without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 30, 300, and 1000 mg/g were 5, 13, and 28, respectively, compared with an albumin-to-creatinine ratio of 5. Albuminuria and eGFR were associated with ESRD, without evidence for multiplicative interaction. Similar associations were found for acute kidney injury and progressive CKD. In high-risk cohorts, the findings were generally comparable. Thus, lower eGFR and higher albuminuria are risk factors for ESRD, acute kidney injury and progressive CKD in both general and high-risk populations, independent of each other and of cardiovascular risk factors.
Journal of the American Dietetic Association, 1996
A dietary survey was conducted in the Gila River Indian Community in Arizona using two methods of... more 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. 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. An age- and sex-stratified sample of 575 Pima Indians (273 men, 302 women) aged 18 to 74 years participated in the study. 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. 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. 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.
An insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene is assoc... more 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.
Screening for chronic kidney disease is recommended in people at high risk, but data on the indep... more Screening for chronic kidney disease is recommended in people at high risk, but data on the independent and combined associations of estimated glomerular filtration rate (eGFR) and albuminuria with all-cause and cardiovascular mortality are limited. To clarify this, we performed a collaborative meta-analysis of 10 cohorts with 266,975 patients selected because of increased risk for chronic kidney disease, defined as a history of hypertension, diabetes, or cardiovascular disease. Risk for all-cause mortality was not associated with eGFR between 60-105 ml/min per 1.73 m², but increased at lower levels. Hazard ratios at eGFRs of 60, 45, and 15 ml/min per 1.73 m² were 1.03, 1.38 and 3.11, respectively, compared to an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log risk for all-cause mortality without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 10, 30 and 300 mg/g were 1.08, 1.38, and...
In Caucasians with type 2 diabetes, circulating TNF receptors 1 (TNFR1) and 2 (TNFR2) predict end... more In Caucasians with type 2 diabetes, circulating TNF receptors 1 (TNFR1) and 2 (TNFR2) predict end-stage renal disease (ESRD). Here we examined this relationship in a longitudinal cohort study of American Indians with type 2 diabetes with measured glomerular filtration rate (mGFR, iothalamate) and urinary albumin-to-creatinine ratio (ACR). ESRD was defined as dialysis, kidney transplant, or death attributed to diabetic kidney disease. Age-gender-adjusted incidence rates and incidence rate ratios of ESRD were computed by Mantel-Haenszel stratification. The hazard ratio of ESRD was assessed per interquartile range increase in the distribution of each TNFR after adjusting for baseline age, gender, mean blood pressure, HbA1c, ACR, and mGFR. Among the 193 participants, 62 developed ESRD and 25 died without ESRD during a median follow-up of 9.5 years. The age-gender-adjusted incidence rate ratio of ESRD was higher among participants in the highest versus lowest quartile for TNFR1 (6.6, 95%...
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, Jan 3, 2015
Urinary monocyte chemoattractant protein-1 (MCP-1) and hepcidin are potential biomarkers of renal... more Urinary monocyte chemoattractant protein-1 (MCP-1) and hepcidin are potential biomarkers of renal inflammation. We examined their association with development of diabetic nephropathy (DN) lesions in normotensive normoalbuminuric subjects with type 1 diabetes (T1D) from the Renin-Angiotensin System Study. Biomarker concentrations were measured in baseline urine samples from 224 subjects who underwent kidney biopsies at baseline and after 5 years. Fifty-eight urine samples below the limit of quantitation (LOQ, 28.8 pg/mL) of the MCP-1 assay were assigned concentrations of LOQ/√2 for analysis. Relationships between ln(MCP-1/Cr) or ln(hepcidin/Cr) and morphometric variables were assessed by sex using multiple linear regression after adjustment for age, T1D duration, HbA1c, mean arterial pressure, albumin excretion rate (AER) and glomerular filtration rate (GFR). In models that examined changes in morphometric variables, the baseline morphometric value was also included. Baseline mean ag...
During the first 7 years of the Diabetes Prevention Program Outcomes Study (DPPOS), diabetes inci... more During the first 7 years of the Diabetes Prevention Program Outcomes Study (DPPOS), diabetes incidence rates, when compared with the Diabetes Prevention Program (DPP), decreased in the placebo (-42%) and metformin (-25%), groups compared with the rates in the intensive lifestyle intervention (+31%) group. Participants in the placebo and metformin groups were offered group intensive lifestyle intervention prior to entering the DPPOS. The following two hypotheses were explored to explain the rate differences: "effective intervention" (changes in weight and other factors due to intensive lifestyle intervention) and "exhaustion of susceptible" (changes in mean genetic and diabetes risk scores). No combination of behavioral risk factors (weight, physical activity, diet, smoking, and antidepressant or statin use) explained the lower DPPOS rates of diabetes progression in the placebo and metformin groups, whereas weight gain was the factor associated with higher rates o...
The relative effectiveness of 3 approaches to blood pressure control-(i) an intensive lifestyle i... more The relative effectiveness of 3 approaches to blood pressure control-(i) an intensive lifestyle intervention (ILI) focused on weight loss, (ii) frequent goal-based monitoring of blood pressure with pharmacological management, and (iii) education and support-has not been established among overweight and obese adults with type 2 diabetes who are appropriate for each intervention. Participants from the Action for Health in Diabetes (Look AHEAD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) cohorts who met criteria for both clinical trials were identified. The proportions of these individuals with systolic blood pressure (SBP) <140mm Hg from annual standardized assessments over time were compared with generalized estimating equations. Across 4 years among 480 Look AHEAD and 1,129 ACCORD participants with baseline SBPs between 130 and 159mm Hg, ILI (OR = 1.46; 95% CI = [1.18-1.81]) and frequent goal-based monitoring with pharmacotherapy (OR = 1.51; 95% CI = [1.16-...
A prior genome-wide association study (GWAS) in Pima Indians identified a variant within PFKFB2 (... more A prior genome-wide association study (GWAS) in Pima Indians identified a variant within PFKFB2 (rs17258746) associated with body mass index (BMI). PFKFB2 encodes 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase isoform 2, which plays a role in glucose metabolism. To follow-up on the GWAS, tag SNPs across PFKFB2 were genotyped in American Indians who had longitudinal data on BMI (n = 6839), type 2 diabetes (T2D; n = 7710), diabetic nephropathy (DN; n = 2452), % body fat (n = 555) and insulin secretion (n = 298). Two SNPs were further genotyped in urban American Indians to assess replication for DN (n = 864). PFKFB2 expression was measured in 201 adipose biopsies using real-time RT-PCR and 61 kidney biopsies using the Affymetrix U133 array. Two SNPs (rs17258746 and rs11120137), which capture the same signal, were associated with maximum BMI in adulthood (β = 1.02 per risk allele, P = 7.3 × 10(-4)), maximum BMI z-score in childhood (β = 0.079, P = 0.03) and % body fat in adulthood...
To assess the relative impact of an intensive lifestyle intervention (ILI) on use and costs of he... more To assess the relative impact of an intensive lifestyle intervention (ILI) on use and costs of health care within the Look AHEAD trial. A total of 5,121 overweight or obese adults with type 2 diabetes were randomly assigned to an ILI that promoted weight loss or to a comparison condition of diabetes support and education (DSE). Use and costs of health-care services were recorded across an average of 10 years. ILI led to reductions in annual hospitalizations (11%, P = 0.004), hospital days (15%, P = 0.01), and number of medications (6%, P < 0.001), resulting in cost savings for hospitalization (10%, P = 0.04) and medication (7%, P…
Non-insulin-dependent diabetes mellitus (NIDDM) is a major cause of end-stage renal disease. Howe... more Non-insulin-dependent diabetes mellitus (NIDDM) is a major cause of end-stage renal disease. However, the course and determinants of renal failure in this type of diabetes have not been clearly defined. We studied glomerular function at intervals of 6 to 12 months for 4 years in 194 Pima Indians selected to represent different stages in the development and progression of diabetic renal disease. Initially, 31 subjects had normal glucose tolerance, 29 had impaired glucose tolerance, 30 had newly diagnosed diabetes, and 104 had had diabetes for five years or more; of these 104, 20 had normal albumin excretion, 50 had microalbuminuria, and 34 had macroalbuminuria. The glomerular filtration rate, renal plasma flow, urinary albumin excretion, and blood pressure were measured at each examination. Initially, the mean (+/-SE) glomerular filtration rate was 143+/-7 ml per minute in subjects with newly diagnosed diabetes, 155+/-7 ml per minute in those with microalbuminuria, and 124+/-7 ml per minute in those with macroalbuminuria; these values were 16 percent, 26 percent, and 1 percent higher, respectively, than in the subjects with normal glucose tolerance (123+/-4 ml per minute). During four years of follow-up, the glomerular filtration rate increased by 18 percent in the subjects who initially had newly diagnosed diabetes (P=0.008); the rate declined by 3 percent in those with microalbuminuria at base line (P=0.29) and by 35 percent in those with macroalbuminuria (P&lt;0.001). Higher base-line blood pressure predicted increasing urinary albumin excretion (P=0.006), and higher base-line urinary albumin excretion predicted a decline in the glomerular filtration rate (P&lt;0.001). The initial glomerular filtration rate did not predict worsening albuminuria. The glomerular filtration rate is elevated at the onset of NIDDM and remains so while normal albumin excretion or microalbuminuria persists. It declines progressively after the development of macroalbuminuria.
Common polymorphisms of the transcription factor 7-like 2 gene (TCF7L2) have recently been associ... more Common polymorphisms of the transcription factor 7-like 2 gene (TCF7L2) have recently been associated with type 2 diabetes. We examined whether the two most strongly associated variants (rs12255372 and rs7903146) predict the progression to diabetes in persons with impaired glucose tolerance who were enrolled in the Diabetes Prevention Program, in which lifestyle intervention or treatment with metformin was compared with placebo. We genotyped these variants in 3548 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors. We assessed the effect of genotype on measures of insulin secretion and insulin sensitivity at baseline and at one year. Over an average period of three years, participants with the risk-conferring TT genotype at rs7903146 were more likely to have progression from impaired glucose tolerance to diabetes than were CC homozygotes (hazard ratio, 1.55; 95 percent confidence interval, 1.20 to 2.01; P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001). The effect of genotype was stronger in the placebo group (hazard ratio, 1.81; 95 percent confidence interval, 1.21 to 2.70; P=0.004) than in the metformin and lifestyle-intervention groups (hazard ratios, 1.62 and 1.15, respectively; P for the interaction between genotype and intervention not significant). The TT genotype was associated with decreased insulin secretion but not increased insulin resistance at baseline. Similar results were obtained for rs12255372. Common variants in TCF7L2 seem to be associated with an increased risk of diabetes among persons with impaired glucose tolerance. The risk-conferring genotypes in TCF7L2 are associated with impaired beta-cell function but not with insulin resistance. (ClinicalTrials.gov number, NCT00004992. [ClinicalTrials.gov]).
Among 384 Pima Indians with impaired glucose tolerance according to World Health Organization cri... more Among 384 Pima Indians with impaired glucose tolerance according to World Health Organization criteria who were followed for 1.6 to 11.5 years (median, 3.3), non-insulin-dependent diabetes mellitus (NIDDM) developed in 118 (31 percent), glucose tolerance remained impaired in 100 (26 percent), and glucose tolerance returned to normal in 166 (43 percent). The cumulative incidence of NIDDM was 25 and 61 percent at 5 and 10 years, respectively. The risk of development of diabetes was 6.3 times (95 percent confidence interval, 3.8 to 10.6) as high as in a normoglycemic control group (n = 752). Variables predicting deterioration to NIDDM were age up to the age of 40, after which increasing age had a beneficial effect; higher plasma glucose levels during fasting and after carbohydrate loading; and higher serum insulin levels after fasting and lower levels after carbohydrate loading, suggesting that insulin resistance and decreased beta-cell responsiveness are important determinants of the clinical outcome of impaired glucose tolerance. Obese subjects had 2.9 times (95 percent confidence interval, 2.0 to 10.9) the incidence of NIDDM as the nonobese. Obesity was not, however, predictive of progression to NIDDM after an adjustment for plasma glucose and serum insulin levels. We conclude that in this population approximately one fourth of subjects with impaired glucose tolerance have NIDDM at five years and two thirds at 10 years (approximately one third revert to normal) and that age and plasma glucose and insulin levels are the best predictors of clinical outcome.
CNDP1 is located on 18q22.3, where linkage with diabetic nephropathy has been observed in several... more CNDP1 is located on 18q22.3, where linkage with diabetic nephropathy has been observed in several populations, including Pima Indians. However, evidence for association between CNDP1 alleles and diabetic nephropathy is equivocal and population-dependent. This study investigated CNDP1 as a candidate for diabetic kidney disease in Pima Indians. Nineteen tag single nucleotide polymorphisms spanning the CNDP1 locus were selected using genotype data from Chinese individuals in the HapMap resource along with 2 variants previously associated with diabetic nephropathy. All variants were genotyped in 3 different samples including a diabetic end-stage renal disease (ESRD) case-control study, a family-based study of diabetic individuals who participated in the linkage study for nephropathy, and a cohort of diabetic individuals in whom longitudinal measures of glomerular filtration rates (GFR) were performed. There was no statistically significant evidence for association with diabetic ESRD. However, nominal evidence for association was found in the family study, where markers rs12957330 (Odds ratio [OR]=0.29 per copy of G allele; p=0.04) and rs17817077 (OR=0.46 per copy of G allele; p=0.05) were associated with diabetic nephropathy. In addition, markers rs12964454, rs7244647, and rs7229005 were associated with changes in GFR (-8.5ml/min per copy of the G allele; p=0.04; 18.8ml/min per copy of the C allele; p=0.03; and -13.4ml/min per copy of the C allele; p=0.001, respectively). These findings provide nominal evidence supporting a role between CNDP1 variants and diabetic kidney disease.
Both a low estimated glomerular filtration rate (eGFR) and albuminuria are known risk factors for... more Both a low estimated glomerular filtration rate (eGFR) and albuminuria are known risk factors for end-stage renal disease (ESRD). To determine their joint contribution to ESRD and other kidney outcomes, we performed a meta-analysis of nine general population cohorts with 845,125 participants and an additional eight cohorts with 173,892 patients, the latter selected because of their high risk for chronic kidney disease (CKD). In the general population, the risk for ESRD was unrelated to eGFR at values between 75 and 105 ml/min per 1.73 m(2) but increased exponentially at lower levels. Hazard ratios for eGFRs averaging 60, 45, and 15 were 4, 29, and 454, respectively, compared with an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log ESRD risk without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 30, 300, and 1000 mg/g were 5, 13, and 28, respectively, compared with an albumin-to-creatinine ratio of 5. Albuminuria and eGFR were associated with ESRD, without evidence for multiplicative interaction. Similar associations were found for acute kidney injury and progressive CKD. In high-risk cohorts, the findings were generally comparable. Thus, lower eGFR and higher albuminuria are risk factors for ESRD, acute kidney injury and progressive CKD in both general and high-risk populations, independent of each other and of cardiovascular risk factors.
Journal of the American Dietetic Association, 1996
A dietary survey was conducted in the Gila River Indian Community in Arizona using two methods of... more 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. 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. An age- and sex-stratified sample of 575 Pima Indians (273 men, 302 women) aged 18 to 74 years participated in the study. 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. 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. 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.
An insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene is assoc... more 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.
Screening for chronic kidney disease is recommended in people at high risk, but data on the indep... more Screening for chronic kidney disease is recommended in people at high risk, but data on the independent and combined associations of estimated glomerular filtration rate (eGFR) and albuminuria with all-cause and cardiovascular mortality are limited. To clarify this, we performed a collaborative meta-analysis of 10 cohorts with 266,975 patients selected because of increased risk for chronic kidney disease, defined as a history of hypertension, diabetes, or cardiovascular disease. Risk for all-cause mortality was not associated with eGFR between 60-105 ml/min per 1.73 m², but increased at lower levels. Hazard ratios at eGFRs of 60, 45, and 15 ml/min per 1.73 m² were 1.03, 1.38 and 3.11, respectively, compared to an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log risk for all-cause mortality without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 10, 30 and 300 mg/g were 1.08, 1.38, and...
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