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1.  Preventing Diabetes in American Indian Communities 
Diabetes Care  2013;36(7):1820-1822.
doi:10.2337/dc12-2635
PMCID: PMC3687329  PMID: 23801794
2.  Comparison of Serum Cystatin C, Serum Creatinine, Measured GFR, and Estimated GFR to Assess the Risk of Kidney Failure in American Indians With Diabetic Nephropathy 
Background
We compared values of baseline serum cystatin C (SCysC), serum creatinine (SCr), and measured GFR (mGFR) for predicting end-stage renal disease (ESRD) in patients with type 2 diabetes and elevated albuminuria.
Study Design
Observational longitudinal study.
Setting & Participants
Pima Indians with type 2 diabetes and elevated albumin/creatinine ratio (ACR ≥ 30 mg/g).
Predictors
Baseline SCysC, SCr, and mGFR.
Outcomes & Measurements
Individuals were followed from their first diabetic examination with ACR ≥ 30 mg/g until December 2010, onset of ESRD, or death, whichever came first. Incidence rates adjusted for age, and sex were computed by Mantel-Haenszel stratification. The abilities of SCysC, SCr, and mGFR to predict ESRD were compared with receiver operating characteristic curves.
Results
Of 234 Pima Indians with a mean age of 42.8 years who were followed for a median of 10.7 (range, 0.6–21.3) years, 68 (29%) developed ESRD. The incidence of ESRD was significantly higher among patients in the lowest vs. highest tertile of 1/SCysC (incidence rate ratio, 2.43; 95%CI, 1.31–4.50). By contrast, mGFR and 1/SCr had J-shaped associations with ESRD. In unadjusted analyses, 1/SCysC had the highest area under the receiver operating characteristic curve (AUROC; 0.719±0.035) and mGFR the lowest (0.585±0.042; P<0.001); the AUROC for 1/SCr was intermediate (0.672±0.040; P of 0.1 and 0.03 vs 1/SCysC and mGFR, respectively). In analyses adjusted for age, sex, diabetes duration, height, weight, hemoglobin A1c, and ACR, 1/SCysC had the highest AUROC (0.845±0.026). Models with mGFR or 1/SCr alone had similar AUROCs (0.815±0.028) and both were lower than the model with 1/SCysC alone (P=0.02 and P=0.03, respectively).
Limitations
The predictive values of the filtration markers are limited to the extent that their precision is based on a single measurement.
Conclusions
SCysC was a better predictor of ESRD than mGFR or SCr in Pima Indians with type 2 diabetes and elevated albuminuria.
doi:10.1053/j.ajkd.2012.11.044
PMCID: PMC3664248  PMID: 23347458
3.  Do Genetic Modifiers of HDL-C and Triglyceride Levels also Modify Their Response to a Lifestyle Intervention in the Setting of Obesity and Type-2 Diabetes Mellitus? The Look AHEAD Study 
Background
High-density lipoprotein cholesterol (HDL-C) and triglycerides are cardiovascular risk factors susceptible to lifestyle behavior modification and genetics. We hypothesized that genetic variants identified by genome-wide association studies (GWASs) as associated with HDL-C or triglyceride levels will modify 1-year treatment response to an intensive lifestyle intervention (ILI), relative to a usual care of diabetes support and education (DSE).
Methods and Results
We evaluated 82 SNPs, representing 31 loci demonstrated by GWAS to be associated with HDL-C and/or triglycerides, in 3,561 participants who consented for genetic studies and met eligibility criteria. Variants associated with higher baseline HDL-C levels, cholesterol ester transfer protein (CETP) rs3764261 and hepatic lipase (LIPC) rs8034802, were found to be associated with HDL-C increases with ILI (p=0.0038 and 0.013, respectively) and had nominally significant treatment interactions (p=0.047 and 0.046, respectively). The fatty acid desaturase-2 (FADS-2) rs1535 variant, associated with low baseline HDL-C (p=0.017), was associated with HDL-C increases with ILI (0.0037) and had a nominal treatment interaction (p= 0.035). ApoB (rs693) and LIPC (rs8034802) SNPs showed nominally significant associations with HDL-C and triglyceride changes with ILI and a treatment interaction (p<0.05). A PGS1 SNP (rs4082919) showed the most significant triglyceride treatment interaction in the full cohort (p=0.0009).
Conclusions
This is the first study to identify genetic variants modifying lipid responses to a randomized lifestyle behavior intervention in overweight/obese diabetic individuals. The effect of genetic factors on lipid changes may differ from the effects on baseline lipids and are modifiable by behavioral intervention.
doi:10.1161/CIRCGENETICS.113.000042
PMCID: PMC4077278  PMID: 23861364
genomics; physiological; cholesterylester transfer protein genetics; triglycerides; behavior modification; lipoprotein
4.  FTO predicts weight regain in the Look AHEAD Clinical Trial 
International journal of obesity (2005)  2013;37(12):10.1038/ijo.2013.54.
Background
Genome-wide association studies have provided new insights into the genetic factors that contribute to the development of obesity. We hypothesized that these genetic markers would also predict magnitude of weight loss and weight regain after initial weight loss.
Methods
Established obesity risk alleles available on the Illumina CARe iSelect (IBC) chip were characterized in 3,899 overweight or obese participants with type 2 diabetes from the Look AHEAD (Action for Health in Diabetes), a randomized trial to determine the effects of intensive lifestyle intervention (ILI) and Diabetes Support and Education (DSE) on cardiovascular morbidity and mortality. Primary analyses examined the interaction between 13 obesity-risk polymorphisms in 8 genes and randomized treatment arm in predicting weight change at year 1, and weight regain at year 4 among individuals who lost 3% or more of their baseline weight by year 1.
Results
No SNPs were significantly associated with magnitude of weight loss or interacted with treatment arm at year 1. However, FTO rs3751812 predicted weight regain within DSE (1.56 kg per risk allele, p = 0.005), but not ILI (p = 0.761), resulting in SNP×treatment arm interaction (p = 0.009). In a partial replication of prior research, the obesity risk (G) allele at BDNF rs6265 was associated with greater weight regain across treatment arms (0.773 kg per risk allele), although results were of borderline statistical significance (p=0.051).
Conclusions
Variations in the FTO and BDNF loci may contribute risk of weight regain after weight loss.
doi:10.1038/ijo.2013.54
PMCID: PMC3750057  PMID: 23628854
type 2 diabetes; obesity; weight loss, diet, genetics
5.  Variation at the Melanocortin 4 Receptor gene and response to weight-loss interventions in the Diabetes Prevention Program 
Obesity (Silver Spring, Md.)  2013;21(9):E520-E526.
Objective
To assess associations and genotype × treatment interactions for melanocortin 4 receptor (MC4R) locus variants and obesity-related traits.
Design and Methods
Diabetes Prevention Program (DPP) participants (N=3,819, of whom 3,356 were genotyped for baseline and 3,234 for longitudinal analyses) were randomized into intensive lifestyle modification (diet, exercise, weight loss), metformin or placebo control. Adiposity was assessed in a subgroup (n=909) using computed tomography. All analyses were adjusted for age, sex, ethnicity and treatment.
Results
The rs1943218 minor allele was nominally associated with short-term (6 month; P=0.032) and long-term (2 year; P=0.038) weight change. Eight SNPs modified response to treatment on short-term (rs17066856, rs9966412, rs17066859, rs8091237, rs17066866, rs7240064) or long-term (rs12970134, rs17066866) reduction in body weight, or diabetes incidence (rs17066829) (all Pinteraction <0.05).
Conclusion
This is the first study to comprehensively assess the role of MC4R variants and weight regulation in a weight loss intervention trial. One MC4R variant was directly associated with obesity-related traits or diabetes; numerous other variants appear to influence body weight and diabetes risk by modifying the protective effects of the DPP interventions.
doi:10.1002/oby.20459
PMCID: PMC4023472  PMID: 23512951
MC4R; Randomized Controlled Trial; Lifestyle; Metformin; Gene-Environment Interaction; Genetic; Obesity; Diabetes Prevention Program; Adiposity
6.  Four-Year Change in Cardiorespiratory Fitness and Influence on Glycemic Control in Adults With Type 2 Diabetes in a Randomized Trial 
Diabetes Care  2013;36(5):1297-1303.
OBJECTIVE
To examine an intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) on 4-year change in fitness and physical activity (PA), and to examine the effect of change in fitness and PA, adjusting for potential confounders, on glycemic control in the Look AHEAD Trial.
RESEARCH DESIGN AND METHODS
Subjects were overweight/obese adults with type 2 diabetes mellitus (T2DM) with available fitness data at 4 years (n = 3,942).This clinical trial randomized subjects to DSE or ILI. DSE subjects received standard care plus information related to diet, PA, and social support three times per year. ILI subjects received weekly intervention contact for 6 months, which was reduced over the 4-year period, and were prescribed diet and PA. Measures included weight, fitness, PA, and HbA1c.
RESULTS
The difference in percent fitness change between ILI and DSE at 4 years was significant after adjustment for baseline fitness and change in weight (3.70 vs. 0.94%; P < 0.01). At 4 years, PA increased by 348 (1,562) kcal/week in ILI vs. 105 (1,309) kcal/week in DSE (P < 0.01). Fitness change at 4 years was inversely related to change in HbA1c after adjustment for clinical site, treatment, baseline HbA1c, prescribed diabetes medication, baseline fitness, and weight change (P < 0.01). Change in PA was not related to change in HbA1c.
CONCLUSIONS
A 4-year ILI increased fitness and PA in overweight/obese individuals with T2DM. Change in fitness was associated with improvements in glycemic control, which provides support for interventions to improve fitness in adults with T2DM.
doi:10.2337/dc12-0712
PMCID: PMC3631819  PMID: 23223405
7.  Can New-Onset Diabetes After Kidney Transplant Be Prevented? 
Diabetes Care  2013;36(5):1406-1412.
Because the negative consequences of new-onset diabetes mellitus after transplantation (NODAT) diminish the significant gains of kidney transplantation, it is imperative to develop clinical interventions to reduce the incidence of NODAT. In this review, we discuss whether intensive lifestyle interventions that delay or prevent type 2 diabetes mellitus may decrease the incidence of NODAT. We examine the literature pertaining to incidence and timing of onset of NODAT, as well as the risk factors and pathophysiology that NODAT shares with type 2 diabetes mellitus, namely pathways related to increased insulin resistance and decreased insulin secretion. Our central hypothesis is that NODAT results from the same metabolic risk factors that underlie type 2 diabetes mellitus. These risk factors are altered and enhanced by transplantation, “tipping” some transplant recipients with seemingly normal glucose homeostasis before transplant toward the development of NODAT. We describe the diabetogenic properties of transplant immunosuppressive drugs. We describe novel methods of prevention that are being explored, including resting the pancreatic β-cells by administration of basal insulin during the period immediately after transplant. On the basis of the current evidence, we propose that intensive lifestyle modification, adapted for individuals with chronic kidney disease or end-stage renal disease, as well as resting pancreatic β-cells during the immediate postoperative period, may lower the incidence of NODAT.
doi:10.2337/dc12-2067
PMCID: PMC3631828  PMID: 23613600
8.  Arsenic Exposure and Incidence of Type 2 Diabetes in Southwestern American Indians 
American Journal of Epidemiology  2013;177(9):962-969.
Association of urinary arsenic concentration with incident diabetes was examined in American Indians from Arizona who have a high prevalence of type 2 diabetes and were screened for diabetes between 1982 and 2007. The population resides where drinking water contains arsenic at concentrations above federally recommended limits. A total of 150 nondiabetic subjects aged ≥25 years who subsequently developed type 2 diabetes were matched by year of examination and sex to 150 controls who remained nondiabetic for ≥10 years. Total urinary arsenic concentration, adjusted for urinary creatinine level, ranged from 6.6 µg/L to 123.1 µg/L, and inorganic arsenic concentration ranged from 0.1 µg/L to 36.0 µg/L. In logistic regression models adjusted for age, sex, body mass index, and urinary creatinine level, the odds ratios for incident diabetes were 1.11 (95% confidence interval (CI): 0.79, 1.57) and 1.16 (95% CI: 0.89, 1.53) for a 2-fold increase in total arsenic and inorganic arsenic, respectively. Categorical analyses suggested a positive relationship between quartiles of inorganic arsenic and incident diabetes (P = 0.056); post-hoc comparison of quartiles 2–4 with quartile 1 revealed 2-fold higher odds of diabetes in the upper quartiles (OR = 2.14, 95% CI: 1.19, 3.85). Modestly elevated exposure to inorganic arsenic may predict type 2 diabetes in American Indians. Larger studies that include measures of speciated arsenic are required for confirmation.
doi:10.1093/aje/kws329
PMCID: PMC4023294  PMID: 23504692
arsenic; diabetes mellitus, type 2; incidence; Indians, North American; nested case-control studies
9.  Common genetic variation in the glucokinase gene (GCK) is associated with type 2 diabetes and rates of carbohydrate oxidation and energy expenditure 
Diabetologia  2014;57:1382-1390.
Aims/hypothesis
Glucokinase (GCK) plays a role in glucose metabolism and glucose-stimulated insulin secretion. Rare mutations in GCK cause MODY. We investigated whether common variation (minor allele frequency ≥0.01) in GCK is associated with metabolic traits and type 2 diabetes.
Methods
Four exonic single-nucleotide polymorphisms (SNPs) and three SNPs predicted to cause loss of promoter function were identified in whole-genome sequence data from 234 Pima Indians. These seven tag SNPs and rs4607517, a type 2 diabetes variant established in other studies, were analysed in 415 full-heritage non-diabetic Pima Indians characterised for metabolic traits, and 7,667 American Indians who had data on type 2 diabetes and BMI.
Results
A novel 3′ untranslated region (3′UTR) SNP, chr7:44184184-G/A, was associated with the rate of carbohydrate oxidation post-absorptively (β = 0.22 mg [kg estimated metabolic body size (EMBS)]−1 min−1, p = 0.005) and during a hyperinsulinaemic–euglycaemic clamp (β = 0.24 mg [kg EMBS]−1 min−1, p = 0.0002), the rate of carbohydrate oxidation in a respiratory chamber (β = 311 kJ/day, p = 0.03) and 24 h energy expenditure, which was attributable to the thermic effect of food (β = 520 kJ/day, p = 3.39 × 10−6). This 3′UTR SNP was also associated with diabetes (OR 1.36, 95% CI 1.11, 1.65, p = 0.002), where the A allele (allele frequency 0.05) was associated with a lower rate of carbohydrate oxidation, lower 24 h energy expenditure and higher risk for diabetes. In a Cox proportional hazards model, a rate of insulin-stimulated carbohydrate oxidation lower than the mean rate at baseline predicted a higher risk for developing diabetes than for those above the mean (hazard rate ratio 2.2, 95% CI 1.3, 3.6, p = 0.002).
Conclusions/interpretation
Common variation in GCK influences the rate of carbohydrate oxidation, 24 h energy expenditure and diabetes risk in Pima Indians.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-014-3234-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-014-3234-8
PMCID: PMC4052004  PMID: 24728127
Carbohydrate oxidation; Energy expenditure; GCK; Thermic effect of food; Type 2 diabetes
10.  The long-term effectiveness of a lifestyle intervention in severely obese individuals 
The American journal of medicine  2013;126(3):236-242.e2.
Objective
Severe obesity (BMI≥40kg/m2) is a serious public health concern. Although bariatric surgery is an efficacious treatment approach, it is limited in reach; thus non-surgical treatment alternatives are needed. We examined the 4-year effects of an intensive lifestyle intervention on body weight and cardiovascular disease risk factors among severely obese, compared to overweight (25≤BMI<30), class I (30≤BMI<35), and class II obese (35≤BMI<40) participants.
Methods
5,145 individuals with type 2 diabetes (45–76 years, BMI≥25kg/m2) were randomized to an intensive lifestyle intervention or diabetes support and education. The lifestyle intervention received a behavioral weight loss program which included group and individuals meetings, a ≥10% weight loss goal, calorie restriction, and increased physical activity. Diabetes support and education received a less intense educational intervention. 4-year changes in body weight and cardiovascular disease risk factors were assessed.
Results
Across BMI categories, 4-year changes in body weight were significantly greater in lifestyle participants compared to diabetes support and education (p’s<0.05). At year 4, severely obese lifestyle participants lost 4.9±8.5% which was similar to class I (4.8±7.2%) and class II obese (4.4±7.6%) and significantly greater than overweight (3.4±7.0%; p<0.05). 4-year changes in LDL-cholesterol, triglycerides, diastolic blood pressure, HbA1c, and blood glucose were similar across BMI categories in lifestyle participants; however the severely obese had less favorable improvements in HDL-cholesterol (3.1±0.4mg/dL) and systolic blood pressure (−1.4±0.7mmHg) compared to the less obese (p’s<0.05).
Conclusion
Lifestyle interventions can result in important long-term weight losses and improvements in cardiovascular disease risk factors among a significant proportion of severely obese individuals.
doi:10.1016/j.amjmed.2012.10.010
PMCID: PMC3574274  PMID: 23410564
Severe obesity; weight loss; lifestyle intervention; diabetes; cardiovascular disease
11.  Simple Anthropometrics Are More Correlated with Health Variables than Are Estimates of Body Composition in Yup’ik People 
Obesity (Silver Spring, Md.)  2013;21(9):E435-E438.
We aimed to: 1) evaluate the relationships between several indices of obesity with obesity-related risk factors; 2) compare the accuracy of body composition estimates derived from anthropometry and bioimpedance analysis (BIA) to estimates of body composition assessed by doubly-labeled water (DLW); and 3) establish equations for estimating fat mass (FM), fat-free mass (FFM), and percent body fat (PBF) in Yup’ik Eskimo people. Participants included 1056 adult Yup’ik People from 11 communities in Southwestern Alaska. In a substudy of 30 participants, we developed population-specific linear regression models for estimating FM, FFM, and PBF from anthropometrics, age, sex, and BIA against criterion measures derived from total body water assessed with DLW. These models were then used with the population cohort and we analyzed the relationships between obesity indices and several health-related and disease status variables: 1. fasting plasma lipids, 2. glucose, 3. HbA1c, 4. adiponectin, 5. blood pressure, 6) diabetes (DM), and 7) cerebrocoronary vascular disease (CCVD) which includes stroke and heart disease. The best model for estimating FM in the substudy used only three variables – sex, waist circumference (WC), and hip circumference and had multiple R2=0.9730. FFM and PBF were calculated from FM and body weight. WC and other anthropometrics were more highly correlated with a number of obesity-related risk factors than were direct estimates of body composition. We conclude that body composition in Yup’ik People can be accurately estimated from simple anthropometrics.
doi:10.1002/oby.20125
PMCID: PMC3748182  PMID: 23666898
Doubly labeled water; fat mass; percent body fat; lipids; blood pressure; adiponectin; diabetes; stroke; cardiovascular disease; body mass index; waist circumference; Alaska Native people
12.  Depression as a Predictor of Weight Regain Among Successful Weight Losers in the Diabetes Prevention Program 
Diabetes Care  2013;36(2):216-221.
OBJECTIVE
To determine whether depression symptoms or antidepressant medication use predicts weight regain in overweight individuals with impaired glucose tolerance (IGT) who are successful with initial weight loss.
RESEARCH DESIGN AND METHODS
A total of 1,442 participants who successfully lost at least 3% of their baseline body weight after 12 months of participation in the randomized controlled Diabetes Prevention Program (DPP) continued in their assigned treatment group (metformin, intensive lifestyle, or placebo) and were followed into the Diabetes Prevention Program Outcome Study (DPPOS). Weight regain was defined as a return to baseline DPP body weight. Participant weight and antidepressant medication use were assessed every 6 months. Depression symptoms (Beck Depression Inventory [BDI] score ≥11) were assessed every 12 months.
RESULTS
Only 2.7% of the overall cohort had moderate to severe depression symptoms at baseline; most of the participants with BDI score ≥11 had only mild symptoms during the period of observation. In unadjusted analyses, both depression symptoms (hazard ratio 1.31 [95% CI 1.03–1.67], P = 0.03) and antidepressant medication use at either the previous visit (1.72 [1.37–2.15], P < 0.0001) or cumulatively as percent of visits (1.005 [1.002–1.008], P = 0.0003) were predictors of subsequent weight regain. After adjustment for multiple covariates, antidepressant use remained a significant predictor of weight regain (P < 0.0001 for the previous study visit; P = 0.0005 for the cumulative measure), while depression symptoms did not.
CONCLUSIONS
In individuals with IGT who do not have severe depression and who initially lose weight, antidepressant use may increase the risk of weight regain.
doi:10.2337/dc12-0293
PMCID: PMC3554307  PMID: 23002085
13.  The C Allele of ATM rs11212617 Does Not Associate With Metformin Response in the Diabetes Prevention Program 
Diabetes Care  2012;35(9):1864-1867.
OBJECTIVE
The C allele at the rs11212617 polymorphism in the ataxia-telangiectasia–mutated (ATM) gene has been associated with greater clinical response to metformin in people with type 2 diabetes. We tested whether this variant modified the effect of metformin in the Diabetes Prevention Program (DPP), in which metformin reduced diabetes incidence by 31% in volunteers with impaired glucose tolerance.
RESEARCH DESIGN AND METHODS
We genotyped rs11212617 in 2,994 DPP participants and analyzed its effects on diabetes incidence and related traits.
RESULTS
Contrary to expectations, C carriers enjoyed no preventive advantage on metformin; their hazard ratio, compared with A carriers, was 1.17 ([95% CI 0.96–1.42], P = 0.13) under metformin. There were no significant differences by genotype in metformin’s effects on insulin sensitivity, fasting glucose, glycated hemoglobin, or disposition index.
CONCLUSIONS
The reported association of rs11212617 with metformin response was not confirmed for diabetes prevention or for effects on relevant physiologic parameters in the DPP.
doi:10.2337/dc11-2301
PMCID: PMC3425006  PMID: 22751958
14.  MAP2K3 is associated with body mass index in American Indians and Caucasians and may mediate hypothalamic inflammation 
Human Molecular Genetics  2013;22(21):4438-4449.
To identify genes that affect body mass index (BMI) in American Indians who are predominately of Pima Indian heritage, we previously completed a genome-wide association study in 1120 American Indians. That study also included follow-up genotyping for 9 SNPs in 2133 additional subjects. A comprehensive follow-up study has subsequently been completed where 292 SNPs were genotyped in 3562 subjects, of which 128 SNPs were assessed for replication in 3238 additional subjects. In the combined subjects (n = 6800), BMI associations for two SNPs, rs12882548 and rs11652094, approached genome-wide significance (P = 6.7 × 10−7 and 8.1 × 10−7, respectively). Rs12882548 is located in a gene desert on chromosome 14 and rs11652094 maps near MAP2K3. Several SNPs in the MAP2K3 region including rs11652094 were also associated with BMI in Caucasians from the GIANT consortium (P = 10−2–10−5), and the combined P-values across both American Indians and Caucasian were P = 10−4–10−9. Follow-up sequencing across MAP2K3 identified several paralogous sequence variants indicating that the region may have been duplicated. MAP2K3 expression levels in adipose tissue biopsies were positively correlated with BMI, although it is unclear if this correlation is a cause or effect. In vitro studies with cloned MAP2K3 promoters suggest that MAP2K3 expression may be up-regulated during adipogenesis. Microarray analyses of mouse hypothalamus cells expressing constitutively active MAP2K3 identified several up-regulated genes involved in immune/inflammatory pathways and a gene, Hap1, thought to play a role in appetite regulation. We conclude that MAP2K3 is a reproducible obesity locus that may affect body weight via complex mechanisms involving appetite regulation and hypothalamic inflammation.
doi:10.1093/hmg/ddt291
PMCID: PMC3792696  PMID: 23825110
15.  Variants in the LEPR gene are nominally associated with higher BMI and lower 24 hour energy expenditure in Pima Indians 
Obesity (Silver Spring, Md.)  2012;20(12):2426-2430.
Genome-wide association studies (GWASs) have been used to search for susceptibility genes for type 2 diabetes and obesity in the Pima Indians, a population with high a prevalence of both diseases. In these studies, a variant (rs2025804) in the LEPR gene was nominally associated with BMI in 1082 subjects (P=0.03 adjusted for age, sex, birth year, and family membership). Therefore the LEPR and leptin overlapping transcript (LEPROT) genes were selected for further sequencing and genotyping in larger population-based samples for association analyses with obesity-related phenotypes. Selected variants (n=80) spanning these genes were genotyped in a sample of full-heritage Pima Indians (n=2842) and several common variants including rs2025804 were nominally associated with BMI (P=0.05-0.003 adjusted for age, sex, birth year, and family membership). Four common tag variants associated with BMI in the full-heritage Pima Indian sample were genotyped in a second sample of mixed-heritage Native Americans (n=2969) and 3 of the variants showed nominal replication (P=0.03-0.006 adjusted as above and additionally for Indian heritage). Combining both samples provided the strongest evidence for association (adjusted P=0.0003-0.0001). A subset of these individuals (n=403) had been metabolically characterized for predictors of obesity and the BMI risk alleles for the variants tagged by rs2025804 were also associated with lower 24 hour energy expenditure as assessed in a human respiratory chamber (P=0.0007 adjusted for age, sex, fat mass, fat free mass, activity, and family membership). We conclude that common non-coding variation in the LEPR gene is associated with higher BMI and lower energy expenditure in Native Americans.
doi:10.1038/oby.2012.159
PMCID: PMC3479320  PMID: 22810975
16.  Diabetes and oral disease: implications for health professionals 
“Diabetes and Oral Disease: Implications for Health Professionals” was a one-day conference convened by the Columbia University College of Dental Medicine, the Columbia University College of Physicians and Surgeons, and the New York Academy of Sciences on May 4, 2011in New York City. The program included an examination of the bidirectional relationship between oral disease and diabetes and the inter-professional working relationships for the care of people who have diabetes. The overall goal of the conference was to promote discussion among the healthcare professions who treat people with diabetes, encourage improved communication and collaboration among them and ultimately, improve patient management of the oral and overall effects of diabetes. Attracting over 150 members of the medical and dental professions from eight different countries, the conference included speakers from academia and government and was divided into four sessions. This report summarizes the scientific presentations of the event.
doi:10.1111/j.1749-6632.2011.06460.x
PMCID: PMC3429365  PMID: 22409777
diabetes; oral disease; meeting report
17.  Identification of genetic variation that determines human trehalase activity and its association with type 2 diabetes 
Human Genetics  2013;132(6):697-707.
A prior linkage scan in Pima Indians identified a putative locus for type two diabetes (T2D) and body mass index (BMI) on chromosome 11q23-25. Association mapping across this region identified single nucleotide polymorphisms (SNPs) in the trehalase gene (TREH) that were associated with T2D. To assess the putative connection between trehalase activity and T2D, we performed a linkage study for trehalase activity in 570 Pima Indians who had measures of trehalase activity. Strong evidence of linkage of plasma trehalase activity (LOD = 7.0) was observed in the TREH locus. Four tag SNPs in TREH were genotyped in these subjects and plasma trehalase activity was highly associated with three SNPs: rs2276064, rs117619140 and rs558907 (p = 2.2 × 10−11–1.4 × 10−23), and the fourth SNP, rs10790256, was associated conditionally on these three (p = 2.9 × 10−7). Together, the four tag SNPs explained 51 % of the variance in plasma trehalase activity and 79 % of the variance attributed to the linked locus. These four tag SNPs were further genotyped in 828 subjects used for association mapping of T2D, and rs558907 was associated with T2D (odds ratio (OR) 1.94, p = 0.002). To assess replication of the T2D association, all four tag SNPs were additionally genotyped in two non-overlapping samples of Native Americans. Rs558907 was reproducibly associated with T2D in 2,942 full-heritage Pima Indians (OR 1.27 p = 0.03) and 3,897 “mixed” heritage Native Americans (OR 1.21, p = 0.03), and the strongest evidence for association came from combining all samples (OR 1.27 p = 1.6 × 10−4, n = 7,667). However, among 320 longitudinally studied subjects, measures of trehalase activity from a non-diabetic exam did not predict those who would eventually develop diabetes versus those who would remain non-diabetic (hazard ratio 0.94 per SD of trehalase activity, p = 0.29). We conclude that variants in TREH control trehalase activity, and although one of these variants is also reproducibly associated with T2D, it is likely that the effect of the SNP on risk of T2D occurs by a mechanism different than affecting trehalase activity. Alternatively, TREH variants may be tagging a nearby T2D locus.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-013-1278-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-013-1278-3
PMCID: PMC3654185  PMID: 23468175
19.  Genetic Predictors of Weight Loss and Weight Regain After Intensive Lifestyle Modification, Metformin Treatment, or Standard Care in the Diabetes Prevention Program 
Diabetes Care  2012;35(2):363-366.
OBJECTIVE
We tested genetic associations with weight loss and weight regain in the Diabetes Prevention Program, a randomized controlled trial of weight loss–inducing interventions (lifestyle and metformin) versus placebo.
RESEARCH DESIGN AND METHODS
Sixteen obesity-predisposing single nucleotide polymorphisms (SNPs) were tested for association with short-term (baseline to 6 months) and long-term (baseline to 2 years) weight loss and weight regain (6 months to study end).
RESULTS
Irrespective of treatment, the Ala12 allele at PPARG associated with short- and long-term weight loss (−0.63 and −0.93 kg/allele, P ≤ 0.005, respectively). Gene–treatment interactions were observed for short-term (LYPLAL1 rs2605100, Plifestyle*SNP = 0.032; GNPDA2 rs10938397, Plifestyle*SNP = 0.016; MTCH2 rs10838738, Plifestyle*SNP = 0.022) and long-term (NEGR1 rs2815752, Pmetformin*SNP = 0.028; FTO rs9939609, Plifestyle*SNP = 0.044) weight loss. Three of 16 SNPs were associated with weight regain (NEGR1 rs2815752, BDNF rs6265, PPARG rs1801282), irrespective of treatment. TMEM18 rs6548238 and KTCD15 rs29941 showed treatment-specific effects (Plifestyle*SNP < 0.05).
CONCLUSIONS
Genetic information may help identify people who require additional support to maintain reduced weight after clinical intervention.
doi:10.2337/dc11-1328
PMCID: PMC3263869  PMID: 22179955
20.  Greater Impact of Melanocortin-4 Receptor Deficiency on Rates of Growth and Risk of Type 2 Diabetes During Childhood Compared With Adulthood in Pima Indians 
Diabetes  2011;61(1):250-257.
Features of melanocortin-4 receptor (MC4R) deficiency have been observed to be more pronounced in childhood. Longitudinal data from a population-based study were used to separate the phenotypic effects of MC4R deficiency during childhood and adulthood. The MC4R exon was sequenced in 6,760 individuals of predominantly Pima Indian heritage, and discovered mutations were functionally assessed in vitro. Effects on BMI, height, and slope of BMI change were assessed during childhood (ages 5–20 years) and adulthood (ages 20–45 years). Six mutations affecting MC4R function, including three that may be private to Pima Indians, were found in 159 individuals (2.4%). The slope of BMI increase was greater in individuals carrying an MC4R mutation compared with noncarriers during childhood but not during adulthood. The final adult height obtained was higher in individuals with MC4R deficiency. There was an increased risk for developing type 2 diabetes in individuals with a defective MC4R during childhood and adulthood, but this was only independent of BMI in childhood. The greater rates of body mass accumulation and risk of type 2 diabetes before the age of 20 years in individuals with MC4R deficiency indicate that the effects of these mutations are more apparent during the active growth of childhood.
doi:10.2337/db11-0708
PMCID: PMC3237672  PMID: 22106157
21.  SIRT1 is Associated with a Decrease in Acute Insulin Secretion and a Sex Specific Increase in Risk for Type 2 Diabetes in Pima Indians 
Molecular genetics and metabolism  2011;104(4):661-665.
Genetic variation in SIRT1 affects obesity-related phenotypes in several populations. The purpose of this study was to determine whether variation in SIRT1 affects susceptibility to obesity or type 2 diabetes in Pima Indians, a population with very high prevalence and incidence rates of these diseases. Genotypic data from single nucleotide polymorphisms (SNPs) identified by sequencing regions of SIRT1 combined with SNPs in/near SIRT1 from a prior genome-wide association study determined that 4 tag SNPs (rs7895833, rs10509291, rs7896005, and rs4746720) could capture information across this gene and its adjacent 5′ region. The tag SNPs were genotyped in a population-based sample of 3501 Pima Indians (44% had diabetes, 58% female) for association with type 2 diabetes and BMI. Metabolic trait data and adipose biopsies were available on a subset of these subjects. Two tag SNPs, rs10509291 and rs7896005, were nominally associated with type 2 diabetes (P = 0.01, OR = 1.25 95%CI 1.05-1.48, and P = 0.02, OR = 1.17 95%CI 1.02-1.34, respectively; additive P values adjusted for age, sex, birth year, and family membership), but not BMI (adjusted P values 0.52 and 0.45, respectively). Among metabolically characterized subjects with normal glucose tolerance (N = 243), those carrying the diabetes risk allele (T) for rs10509291 and (G) for rs7896005 had a reduced acute insulin response (AIR) to an intravenous glucose bolus (adjusted P = 0.045 and 0.035, respectively). SIRT1 expression in adipose biopsies was negatively correlated with BMI (adjusted P = 0.00001). We conclude that variation in SIRT1 is nominally associated with reduced AIR and increased risk for type 2 diabetes. SIRT1 expression in adipose is correlated with BMI, but it remains unknown whether this is a cause or consequence of obesity.
doi:10.1016/j.ymgme.2011.08.001
PMCID: PMC3224181  PMID: 21871827
SIRT1; type 2 diabetes; insulin secretion; genetic associations
22.  Lifestyle Intervention Improves Heart Rate Recovery from Exercise in Adults with Type 2 Diabetes: Results from the Look AHEAD Study 
Journal of Obesity  2012;2012:309196.
The primary aims of this paper were (1) to evaluate the influence of intensive lifestyle weight loss and exercise intervention (ILI) compared with diabetes support and education (DSE) upon Heart Rate Recovery (HRR) from graded exercise testing (GXT) and (2) to determine the independent and combined effects of weight loss and fitness changes upon HRR. In 4503 participants (45–76 years) who completed 1 year of intervention, HRR was measured after a submaximal GXT to compare the influence of (ILI) with (DSE) upon HRR. Participants assigned to ILI lost an average 8.6% of their initial weight versus 0.7% in DSE group (P < 0.001) while mean fitness increased in ILI by 20.9% versus 5.8% in DSE (P < 0.001). At Year 1, all exercise and HRR variables in ILI improved (P < 0.0001) versus DSE: heart rate (HR) at rest was lower (72.8 ± 11.4 versus 77.7 ± 11.7 b/min), HR range was greater (57.7 ± 12.1 versus 53.1 ± 12.4 b/min), HR at 2 minutes was lower (89.3 ± 21.8 versus 93.0 ± 12.1 b/min), and HRR was greater (41.25 ± 22.0 versus 37.8 ± 12.5 b/min). Weight loss and fitness gain produced significant separate and independent improvements in HRR.
doi:10.1155/2012/309196
PMCID: PMC3512322  PMID: 23227314
23.  Parental Longevity and Diabetes Risk in the Diabetes Prevention Program 
Background.
Longevity clusters in families, and parental longevity may be associated with lower risk of chronic diseases in their children. It is unknown if diabetes risk is associated with parental longevity.
Methods.
We evaluated participants in the Diabetes Prevention Program with a parental history questionnaire at study entry. We classified them into five groups: premature death (parental death at age < 50 years), parental longevity (living to at least 80 years), and three intermediate groups (alive by age 49 but dying at age 50–59, 60–69, or 70–79). Those with alive parents and younger than 80 years were excluded. We analyzed separately effects of paternal (n = 2,165) and maternal (n = 1,739) longevity on diabetes incidence and risk after an average follow-up of 3.2 years.
Results.
At baseline, more diabetes risk factors (parental history of diabetes, coronary heart disease, higher body mass index, homeostasis model assessment for insulin resistance, and corrected insulin response) were found in participants whose parents died prematurely. Diabetes incidence was 9.5 cases/100 person-years in the 229 whose fathers died prematurely. In the 618 with paternal longevity, the rate was 6.6 cases/100 person-years (hazard ratio [95% confidence interval] = 0.68 [0.49–0.94]). The rates were 10.7 cases/100 person-years (n = 156) and 7.3 cases/100 person-years (n = 699, hazard ratio = 0.67 [95% confidence interval 0.47–0.95]) for those with maternal premature death or longevity, respectively. Associations with demographic and diabetes risk factors had minimal influence on the reduced risk found in those with paternal (adjusted hazard ratio = 0.78, 95% confidence interval 0.52–1.16) and maternal (adjusted hazard ratio = 0.64, 95% confidence interval 0.41–1.01) longevity.
Conclusion.
Parental longevity is associated with lower diabetes incidence in adults at high risk of type 2 diabetes.
doi:10.1093/gerona/glr114
PMCID: PMC3193521  PMID: 21852284
Parental longevity; Diabetes risk; Diabetes Prevention Program
24.  Predictive value of albuminuria in American Indian youth with or without type 2 diabetes 
Pediatrics  2010;125(4):e844-e851.
Objective
We examined the prognostic significance of elevated albuminuria in youth with type 2 diabetes.
Patients and Methods
Cross-sectional and prospective studies were conducted in Pima Indian youth aged 5-19 years at baseline who were examined between July 1, 1982 and December 31, 2007. Prevalence and sequential changes in the level of microalbuminuria (30≤ albumin-to-creatinine ratio <300 mg/g) and macroalbuminuria (albumin-to-creatinine ratio ≥300 mg/g) and incidence of macroalbuminuria were computed according to the presence or absence of type 2 diabetes.
Results
The prevalence of micro- and macroalbuminuria was 6.5% and 0.6% in the 3,856 nondiabetic youth and 18.5% and 2.9% in the 103 youth with diabetes. One-hundred-forty-one (75.4%) of 187 nondiabetic youth, but only one (7.1%) of 14 diabetic youth with elevated albumin-to-creatinine ratio (≥30 mg/g) regressed to undetectable or normal albumin-to-creatinine ratio (<30 mg/g) on subsequent examination. In a subset of 2,666 youth with a median follow-up of 8.1 years, 36 nondiabetic and 30 diabetic youth with baseline albumin-to-creatinine ratio <300 mg/g developed macroalbuminuria. For a given albumin-to-creatinine ratio level, the incidence of macroalbuminuria was 15.9-fold (95% CI = 11.1 to 22.6) higher in the diabetic than in the nondiabetic youth.
Conclusions
Elevated albuminuria is infrequent and largely transient in nondiabetic youth, but is relatively frequent and largely persistent in those with diabetes. Microalbuminuria in youth with type 2 diabetes strongly predicts progression to macroalbuminuria, supporting annual screening for albuminuria.
doi:10.1542/peds.2009-1230
PMCID: PMC3481836  PMID: 20194283
diabetic nephropathy; epidemiology; incidence; longitudinal; prevalence; risk factors
25.  Diabetic Nephropathy in American Indians, with a Special Emphasis on the Pima Indians 
Current diabetes reports  2008;8(6):486-493.
Diabetes affects American Indians disproportionately compared with other racial/ethnic groups in the United States and is almost exclusively type 2 diabetes. Much of our knowledge about diabetes in American Indians comes from studies in a few tribes. The most extensively studied American Indians are the Pima Indians from the Gila River Indian Community in Arizona, who participated in a longitudinal study of diabetes and its complications between 1965 and 2007. They have one of the highest reported incidence and prevalence of type 2 diabetes in the world, and kidney disease attributable to diabetes is a major cause of morbidity and mortality. In this article, we examine the course, determinants, and trends of diabetic kidney disease in American Indians, with special emphasis on studies conducted in the Pima Indians. We also review therapeutic strategies for managing diabetic kidney disease.
PMCID: PMC3480511  PMID: 18990306

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