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1.  A Genome-Wide Association Study in American Indians Implicates DNER as a Susceptibility Locus for Type 2 Diabetes 
Diabetes  2013;63(1):369-376.
Most genetic variants associated with type 2 diabetes mellitus (T2DM) have been identified through genome-wide association studies (GWASs) in Europeans. The current study reports a GWAS for young-onset T2DM in American Indians. Participants were selected from a longitudinal study conducted in Pima Indians and included 278 cases with diabetes with onset before 25 years of age, 295 nondiabetic controls ≥45 years of age, and 267 siblings of cases or controls. Individuals were genotyped on a ∼1M single nucleotide polymorphism (SNP) array, resulting in 453,654 SNPs with minor allele frequency >0.05. SNPs were analyzed for association in cases and controls, and a family-based association test was conducted. Tag SNPs (n = 311) were selected for 499 SNPs associated with diabetes (P < 0.0005 in case-control analyses or P < 0.0003 in family-based analyses), and these SNPs were genotyped in up to 6,834 additional Pima Indians to assess replication. Rs1861612 in DNER was associated with T2DM (odds ratio = 1.29 per copy of the T allele; P = 6.6 × 10−8, which represents genome-wide significance accounting for the number of effectively independent SNPs analyzed). Transfection studies in murine pancreatic β-cells suggested that DNER regulates expression of notch signaling pathway genes. These studies implicate DNER as a susceptibility gene for T2DM in American Indians.
PMCID: PMC3868048  PMID: 24101674
2.  Human Cardiovascular Disease IBC Chip-Wide Association with Weight Loss and Weight Regain in the Look AHEAD Trial 
Human heredity  2013;75(0):160-174.
The present study identified genetic predictors of weight change during behavioral weight loss treatment.
Participants were 3,899 overweight/obese individuals with type 2 diabetes from Look AHEAD, a randomized controlled trial to determine the effects of intensive lifestyle intervention (ILI), including weight loss and physical activity, relative to diabetes support and education, on cardiovascular outcomes. Analyses focused on associations of single nucleotide polymorphisms (SNPs) on the Illumina CARe iSelect (IBC) chip (minor allele frequency >5%; n = 31,959) with weight change at year 1 and year 4, and weight regain at year 4, among individuals who lost ≥ 3% at year 1.
Two novel regions of significant chip-wide association with year-1 weight loss in ILI were identified (p < 2.96E-06). ABCB11 rs484066 was associated with 1.16 kg higher weight per minor allele at year 1, whereas TNFRSF11A, or RANK, rs17069904 was associated with 1.70 kg lower weight per allele at year 1.
This study, the largest to date on genetic predictors of weight loss and regain, indicates that SNPs within ABCB11, related to bile salt transfer, and TNFRSF11A, implicated in adipose tissue physiology, predict the magnitude of weight loss during behavioral intervention. These results provide new insights into potential biological mechanisms and may ultimately inform weight loss treatment.
PMCID: PMC4257841  PMID: 24081232
Type 2 diabetes; Obesity; Weight loss; Diet; Genetics
3.  Preventing Diabetes in American Indian Communities 
Diabetes Care  2013;36(7):1820-1822.
PMCID: PMC3687329  PMID: 23801794
5.  Impact of Weight Loss on Ankle-Brachial Index and Inter-Artery Blood Pressures in Overweight and Obese Adults with Diabetes 
Obesity (Silver Spring, Md.)  2014;22(4):1032-1041.
To assess whether weight loss improves markers of peripheral artery disease and vascular stenosis.
Design and Methods
The Action for Health in Diabetes randomized clinical trial compared intensive lifestyle intervention (ILI) for weight loss to a control condition of diabetes support and education (DSE) in overweight or obese adults with type 2 diabetes. Annual ankle and brachial blood pressures over four years were used compute ankle-brachial indices (ABIs) and to assess inter-artery blood pressure differences in 5018 participants.
ILI, compared to DSE, produced 7.8% (Year 1) to 3.6% (Year 4) greater weight losses. These did not affect prevalence of low (<0.90) ABI (3.60% in DSE versus 3.14% in ILI; p=0.20) or elevated (>1.40) ABI (7.52% in DSE versus 7.59% in ILI: p=0.90), but produced smaller mean (SE) maximum inter-artery systolic blood pressure differences among ankle sites [19.7 (0.2) mmHg for ILI versus 20.6 (0.2) mmHg for DSE (p<0.001)] and between arms [5.8 (0.1) mmHg for ILI versus 6.1 (0.1) mmHg for DSE (p=0.01)].
Four years of intensive behavioral weight loss intervention did not significantly alter prevalence of abnormal ABI, however it did reduce differences in systolic blood pressures among arterial sites.
PMCID: PMC3968218  PMID: 24174392
Peripheral artery disease; Weight loss; Diabetes
6.  Whole Exome Sequencing Identifies Variation in CYB5A and RNF10 Associated with Adiposity and Type 2 Diabetes 
Obesity (Silver Spring, Md.)  2013;22(4):984-988.
Few coding variants in genes associated with type 2 diabetes (T2D) have been identified, and the underlying physiologic mechanisms whereby susceptibility genes influence T2D risk are often unknown. The objective of this study was to identify coding variation that increases risk for T2D via an effect on a pre-diabetic trait.
Design and Methods
Whole exome sequencing was done in 177 Pima Indians. Selected variants (N=345) were genotyped in 555 subjects characterized for body fatness, glucose disposal rates during a clamp, acute insulin response to glucose, and 2-hour plasma glucose concentrations during an OGTT, and were also genotyped in up to 5,880 subjects with longitudinal measures of BMI. Variants associated with quantitative traits were assessed for association with T2D in 7,667 subjects.
rs7238987 in CYB5A associated with body fatness (p=7.0×10−6). This SNP and a novel SNP in RNF10 also associated with maximum recorded BMI (p=6.2×10−7 and p=7.2×10−4) and maximum childhood BMI z-score (p=5.9×10−4 and p=8.5×10−7). The BMI increasing alleles increased risk for T2D (p= 0.01; OR=1.13 [1.03–1.24] and 9.5×10−3, OR=1.49 [1.10–2.02]).
CYB5A, which has a role in stearyl-CoA-desaturase activity, and RNF10, with an unknown role in weight regulating pathways, associated with adiposity and nominally increased risk for T2D in American Indians.
PMCID: PMC3968243  PMID: 24151200
BMI; Exome sequencing; RNF10; CYB5A; SCD1
7.  Validation of a Pretransplant Risk Score for New-Onset Diabetes After Kidney Transplantation 
Diabetes Care  2013;36(10):2881-2886.
Identification of patients at high risk for new-onset diabetes after kidney transplantation (NODAT) will facilitate clinical trials for its prevention.
We previously described a pretransplant predictive risk model for NODAT using seven pretransplant variables (age, planned use of maintenance corticosteroids, prescription for gout medicine, BMI, fasting glucose, fasting triglycerides, and family history of diabetes). We have now applied the initial model to a cohort of 474 transplant recipients from another center for validation. We performed two analyses in the validation cohort. The first was a standard model with variables derived from the original study. The second was a summary score model, in which the sum of dichotomized variables (all the variables dichotomized at clinically relevant cut points) was used to categorize, individuals into low (0–1), intermediate (2, 3), or high (4–7) risk groups. We also conducted a combined database analyses, merging the initial and validation cohorts (n = 792) to obtain better estimates for a prediction equation.
Although the frequency of several risk factors differed significantly between the two cohorts, the models performed similarly in each cohort. Using the summary score model, incidences of NODAT in low-risk, medium-risk, and high-risk groups in the initial cohort were 12, 29, and 56%, and in the validation cohort incidences were 11, 29, and 51%.
A pretransplant model for NODAT, including many type 2 diabetes risk factors, predicted NODAT in the validation cohort.
PMCID: PMC3781551  PMID: 24009296
8.  Effect of Losartan on Prevention and Progression of Early Diabetic Nephropathy in American Indians With Type 2 Diabetes 
Diabetes  2013;62(9):3224-3231.
Angiotensin receptor blockers are renoprotective in hypertensive azotemic patients with type 2 diabetes, but their efficacy in early diabetic kidney disease is uncertain. We performed a 6-year randomized clinical trial in 169 American Indians with type 2 diabetes and normoalbuminuria (albumin/creatinine ratio [ACR] <30 mg/g; n = 91) or microalbuminuria (ACR 30–299 mg/g; n = 78) at baseline. The primary outcome was decline in glomerular filtration rate (GFR) to ≤60 mL/min or to half the baseline value in subjects who entered with GFR <120 mL/min. Another outcome was differences in glomerular structure at end of treatment. Subjects received 100 mg losartan or placebo daily. GFR was measured annually; 111 subjects underwent kidney biopsies. Only nine subjects reached the GFR outcome, and the unadjusted hazard ratio (losartan vs. placebo) was 0.50 (95% CI, 0.12–1.99). Differences in mesangial fractional volume were not estimated in the combined albuminuria groups because of an interaction with treatment assignment. In separate analyses, mesangial fractional volume was lower in subjects treated with losartan in the microalbuminuria group (18.8 vs. 25.6%; P = 0.02), but not in the normoalbuminuria group (19.6 vs. 17.8%; P = 0.86). Treatment with losartan may preserve some features of kidney structure in American Indians with type 2 diabetes and microalbuminuria.
PMCID: PMC3749332  PMID: 23545707
9.  Variants associated with type 2 diabetes identified by the transethnic meta-analysis study: assessment in American Indians and evidence for a new signal in LPP 
Diabetologia  2014;57(11):2334-2338.
A recent genome-wide trans-ancestry meta-analysis identified seven new loci associated with type 2 diabetes. We assessed the replication of the seven lead single nucleotide polymorphisms (SNPs) and evaluated these loci for additional signals in American Indians.
Seven SNPs were genotyped in 7,710 individuals from a longitudinally studied American Indian population, and associations with type 2 diabetes, BMI and related phenotypes were assessed. Previous genome-wide association study (GWAS) data from these individuals were used to screen for additional type 2 diabetes signals at these loci. A variant independent of the trans-ancestry meta-analysis was identified within LPP, and its replication was assessed in an additional 3,106 urban American Indians.
SNP rs6813195 near to TMEM154 was nominally associated with type 2 diabetes (p = 0.01, OR 1.12 [95% CI 1.03, 1.22]) and adiposity: the type 2 diabetes risk allele was associated with a lower percentage body fat (β = −1.451%, p = 4.8 × 10−4). Another SNP, rs3130501 near to POU5F1–TCF19, was associated with BMI (β = −0.012, p = 0.004), type 2 diabetes adjusted for BMI (p = 0.02, OR 1.11 [95% CI 1.02, 1.22]), 2 h glucose concentrations (β = 0.080 mmol/l, p = 0.02) and insulin resistance estimated by homeostatic model (β = 0.039, p = 0.009). The independent variant identified at the LPP locus in our American Indian GWAS for type 2 diabetes was replicated in the additional samples (all American Indian meta-analysis, p = 8.9 × 10−6, OR 1.29 [95% CI 1.15, 1.45]).
For two of the seven newly identified variants, there was nominal evidence for association with type 2 diabetes and related traits in American Indians. Identification of an independent variant at the LPP locus suggests the existence of more than one type 2 diabetes signal at this locus.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-014-3351-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC4180905  PMID: 25112377
American Indians; ARL15; FAF1; GWAS; LPP; MPHOSPH9; POU5F1–TCF19; SSR1–RREB1; Trans-ancestry meta-analysis; Type 2 diabetes
10.  Common genetic variation in and near the melanocortin 4 receptor gene (MC4R) is associated with body mass index in American Indian adults and children 
Human Genetics  2014;133(11):1431-1441.
Six rare functional coding mutations were previously identified in melanocortin 4 receptor (MC4R) in 6,760 American Indians. Individuals heterozygous for one of these mutations become obese while young. We now investigate whether common non-coding variation near MC4R also contributes to obesity. Fifty-six tag single-nucleotide polymorphisms (SNPs) were genotyped in 3,229 full-heritage Pima Indians, and nine of these SNPs which showed evidence for association were genotyped in additional 3,852 mixed-heritage American Indians. Associations of SNPs with maximum body mass index (BMI) in adulthood (n = 5,918), BMI z score in childhood (n = 5,350), percent body fat (n = 864), energy expenditure (n = 358) and ad libitum food intake (n = 178) were assessed. Conditional analyses demonstrated that SNPs, rs74861148 and rs483125, were independently associated with BMI in adulthood (β = 0.68 kg/m2 per risk allele, p = 5 × 10−5; β = 0.58 kg/m2, p = 0.002, respectively) and BMI z score in childhood (β = 0.05, p = 0.02; β = 0.07, p = 0.01, respectively). One haplotype (frequency = 0.35) of the G allele at rs74861148 and the A allele at rs483125 provided the strongest evidence for association with adult BMI (β = 0.89 kg/m2, p = 5.5 × 10−7), and was also associated with childhood BMI z score (β = 0.08, p = 0.001). In addition, a promoter SNP rs11872992 was nominally associated with adult BMI (β = 0.61 kg/m2, p = 0.05) and childhood BMI z score (β = 0.11, p = 0.01), where the risk allele also modestly decreased transcription in vitro by 12 % (p = 0.005). This risk allele was further associated with increased percent body fat (β = 2.2 %, p = 0.002), increased food intake (β = 676 kcal/day, p = 0.007) and decreased energy expenditure (β = −53.4 kcal/day, p = 0.054). Common and rare variation in MC4R contributes to obesity in American Indians.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-014-1477-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4185108  PMID: 25103139
11.  Strong Parent-of-Origin Effects in the Association of KCNQ1 Variants With Type 2 Diabetes in American Indians 
Diabetes  2013;62(8):2984-2991.
Parent-of-origin effects were observed in an Icelandic population for several genetic variants associated with type 2 diabetes, including those in KLF14 (rs4731702), MOB2 (rs2334499), and KCNQ1 (rs2237892, rs231362). We analyzed parent-of-origin effects for these variants, along with two others in KCNQ1 identified in previous genome-wide association studies (rs2237895, rs2299620), in 7,351 Pima Indians from 4,549 nuclear families; 34% of participants had diabetes. In a subset of 287 normoglycemic individuals, acute insulin secretion was measured by an intravenous glucose tolerance test. Statistically significant (P < 0.05) parent-of-origin effects were seen for association with type 2 diabetes for all variants. The strongest effect was seen at rs2299620 in KCNQ1; the C allele was associated with increased diabetes when maternally derived (odds ratio [OR], 1.92; P = 4.1 × 10−12), but not when paternally derived (OR, 0.93; P = 0.47; P = 9.9 × 10−6 for difference in maternal and paternal effects). A maternally derived C allele also was associated with a 28% decrease in insulin secretion (P = 0.002). This study confirms parent-of-origin effects in the association with type 2 diabetes for variants in KLF14, MOB2, and KCNQ1. In Pima Indians, the effect of maternally derived KCNQ1 variants appears to be mediated through decreased insulin secretion and is particularly strong, accounting for 4% of the variance in liability to diabetes.
PMCID: PMC3717865  PMID: 23630301
12.  Assessing Accuracy of Genotype Imputation in American Indians 
PLoS ONE  2014;9(7):e102544.
Genotype imputation is commonly used in genetic association studies to test untyped variants using information on linkage disequilibrium (LD) with typed markers. Imputing genotypes requires a suitable reference population in which the LD pattern is known, most often one selected from HapMap. However, some populations, such as American Indians, are not represented in HapMap. In the present study, we assessed accuracy of imputation using HapMap reference populations in a genome-wide association study in Pima Indians.
Data from six randomly selected chromosomes were used. Genotypes in the study population were masked (either 1% or 20% of SNPs available for a given chromosome). The masked genotypes were then imputed using the software Markov Chain Haplotyping Algorithm. Using four HapMap reference populations, average genotype error rates ranged from 7.86% for Mexican Americans to 22.30% for Yoruba. In contrast, use of the original Pima Indian data as a reference resulted in an average error rate of 1.73%.
Our results suggest that the use of HapMap reference populations results in substantial inaccuracy in the imputation of genotypes in American Indians. A possible solution would be to densely genotype or sequence a reference American Indian population.
PMCID: PMC4094523  PMID: 25014012
13.  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 
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).
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.
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).
The predictive values of the filtration markers are limited to the extent that their precision is based on a single measurement.
SCysC was a better predictor of ESRD than mGFR or SCr in Pima Indians with type 2 diabetes and elevated albuminuria.
PMCID: PMC3664248  PMID: 23347458
14.  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 
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).
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.
PMCID: PMC4077278  PMID: 23861364
genomics; physiological; cholesterylester transfer protein genetics; triglycerides; behavior modification; lipoprotein
15.  FTO predicts weight regain in the Look AHEAD Clinical Trial 
International journal of obesity (2005)  2013;37(12):10.1038/ijo.2013.54.
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.
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.
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).
Variations in the FTO and BDNF loci may contribute risk of weight regain after weight loss.
PMCID: PMC3750057  PMID: 23628854
type 2 diabetes; obesity; weight loss, diet, genetics
16.  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.
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.
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).
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.
PMCID: PMC4023472  PMID: 23512951
MC4R; Randomized Controlled Trial; Lifestyle; Metformin; Gene-Environment Interaction; Genetic; Obesity; Diabetes Prevention Program; Adiposity
17.  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.
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.
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.
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.
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.
PMCID: PMC3631819  PMID: 23223405
18.  Four-Year Analysis of Cardiovascular Disease Risk Factors, Depression Symptoms, and Antidepressant Medicine Use in the Look AHEAD (Action for Health in Diabetes) Clinical Trial of Weight Loss in Diabetes 
Diabetes Care  2013;36(5):1088-1094.
To study the association of depressive symptoms or antidepressant medicine (ADM) use with subsequent cardiovascular disease (CVD) risk factor status in the Look AHEAD (Action for Health in Diabetes) trial of weight loss in type 2 diabetes.
Participants (n = 5,145; age [mean ± SD] 58.7 ± 6.8 years; BMI 35.8 ± 5.8 kg/m2) in two study arms (intensive lifestyle [ILI], diabetes support and education [DSE]) completed the Beck Depression Inventory (BDI), reported ADM use, and were assessed for CVD risk factors at baseline and annually for 4 years. Risk factor–positive status was defined as current smoking, obesity, HbA1c >7.0% or insulin use, and blood pressure or cholesterol not at levels recommended by expert consensus panel or medicine to achieve recommended levels. Generalized estimating equations assessed within-study arm relationships of elevated BDI score (≥11) or ADM use with subsequent year CVD risk status, controlled for demographic variables, CVD history, diabetes duration, and prior CVD risk status.
Prior year elevated BDI was associated with subsequent CVD risk factor–positive status for the DSE arm (A1C [odds ratio 1.30 (95% CI 1.09–1.56)]; total cholesterol [0.80 (0.65–1.00)]; i.e., protective from high total cholesterol) and the ILI arm (HDL [1.40 (1.12–1.75)], triglyceride [1.28 (1.00–1.64)]). Prior year ADM use predicted subsequent elevated CVD risk status for the DSE arm (HDL [1.24 (1.03–1.50)], total cholesterol [1.28 (1.05–1.57)], current smoking [1.73 (1.04–2.88)]) and for the ILI arm (A1C [1.25 (1.08–1.46)], HDL [1.32 (1.11–1.58)], triglycerides [1.75 (1.43–2.14)], systolic blood pressure [1.39 (1.11–1.74)], and obesity [1.46 (1.22–2.18)]).
Aggressive monitoring of CVD risk in diabetic patients with depressive symptoms or who are treated with ADM may be warranted.
PMCID: PMC3631821  PMID: 23359362
19.  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.
PMCID: PMC3631828  PMID: 23613600
20.  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.
PMCID: PMC4023294  PMID: 23504692
arsenic; diabetes mellitus, type 2; incidence; Indians, North American; nested case-control studies
21.  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(7):1382-1390.
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.
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.
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).
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.
PMCID: PMC4052004  PMID: 24728127
Carbohydrate oxidation; Energy expenditure; GCK; Thermic effect of food; Type 2 diabetes
22.  The long-term effectiveness of a lifestyle intervention in severely obese individuals 
The American journal of medicine  2013;126(3):236-242.e2.
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.
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.
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).
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.
PMCID: PMC3574274  PMID: 23410564
Severe obesity; weight loss; lifestyle intervention; diabetes; cardiovascular disease
23.  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.
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
24.  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.
PMCID: PMC3429365  PMID: 22409777
diabetes; oral disease; meeting report
25.  Depression as a Predictor of Weight Regain Among Successful Weight Losers in the Diabetes Prevention Program 
Diabetes Care  2013;36(2):216-221.
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.
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.
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.
In individuals with IGT who do not have severe depression and who initially lose weight, antidepressant use may increase the risk of weight regain.
PMCID: PMC3554307  PMID: 23002085

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