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M Angelyn Bethel,
Antonio R Chacra,
Prakash Deedwania,
Gregory R Fulcher,
Rury R Holman,
Trond Jenssen, Steven E Kahn,
Naomi S Levitt,
John J V McMurray,
Robert M Califf,
Sotirios A Raptis,
Laine Thomas,
Jie-Lena Sun,
Steven M Haffner
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ABSTRACT: We used baseline data from the NAVIGATOR trial to (1) identify risk factors for diabetes progression in those with impaired glucose tolerance and high cardiovascular risk, (2) create models predicting 5-year incident diabetes, and (3) provide risk classification tools to guide clinical interventions. Multivariate Cox proportional hazards models estimated 5-year incident diabetes risk and simplified models examined the relative importance of measures of glycemia in assessing diabetes risk. The C-statistic was used to compare models; reclassification analyses compare the models' ability to identify risk groups defined by potential therapies (routine or intensive lifestyle advice or pharmacologic therapy). Diabetes developed in 3,254 (35%) participants over 5 years median follow-up. The full prediction model included fasting and 2-hour glucose and hemoglobin A1c (HbA1c) values but demonstrated only moderate discrimination for diabetes (C = 0.70). Simplified models with only fasting glucose (C = 0.67) or oral glucose tolerance test values (C = 0.68) had higher C statistics than models with HbA1c alone (C = 0.63). The models were unlikely to inappropriately reclassify participants to risk groups that might receive pharmacologic therapy. Our results confirm that in a population with dysglycemia and high cardiovascular risk, traditional risk factors are appropriate predictors and glucose values are better predictors than HbA1c, but discrimination is moderate at best, illustrating the challenges of predicting diabetes in a high-risk population. In conclusion, our novel risk classification paradigm based on potential treatment could be used to guide clinical practice based on cost and availability of screening tests.
The American journal of cardiology 04/2013; · 3.58 Impact Factor
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Mark M Smits,
Pier Woudstra,
Kristina M Utzschneider,
Jenny Tong,
Fernando Gerchman,
Mirjam Faulenbach,
Darcy B Carr,
Kathryn Aston-Mourney,
Alan Chait,
Robert H Knopp,
James B Meigs,
Edward J Boyko, Steven E Kahn
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ABSTRACT: PURPOSE: Confirmatory factor analysis (CFA) was used to test the hypothesis whether adipocytokines are associated with the risk factor cluster that characterizes the metabolic syndrome (MetS). METHODS: Data from 134 nondiabetic subjects were analyzed using CFA. Insulin sensitivity (SI) was quantified using intravenous glucose tolerance tests, visceral fat area by computed tomography and fasting high-density lipoprotein, triglycerides, monocyte chemoattractant protein-1 (MCP-1), serum amyloid A (SAA), tumor necrosis factor (TNF)-α, adiponectin, resistin, leptin, interleukin (IL)-6, C-reactive protein (CRP), and plasminogen activator inhibitor (PAI)-1 were measured. RESULTS: The basic model representing the MetS included six indicators comprising obesity, SI, lipids, and hypertension, and demonstrated excellent goodness of fit. Using multivariate analysis, MCP-1, SAA, and TNF-α were not independently associated with any of the MetS variables. Adiponectin, resistin, leptin, CRP, and IL-6 were associated with at least one of the risk factors, but when added to the basic model decreased all goodness-of-fit parameters. PAI-1 was associated with all cardiometabolic factors and improved goodness-of-fit compared with the basic model. CONCLUSIONS: Addition of PAI-1 increased the CFA model goodness of fit compared with the basic model, suggesting that this protein may represent an added feature of the MetS.
Annals of epidemiology 03/2013; · 2.95 Impact Factor
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ABSTRACT: 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.
Obesity 03/2013; · 4.28 Impact Factor
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ABSTRACT: Neprilysin contributes to free fatty acid (FFA)-induced cellular dysfunction in nonislet tissues in type 2 diabetes. Here, we show for the first time that with prolonged FFA exposure, islet neprilysin is upregulated and this is associated with reduced insulin pre-mRNA and ATP levels, oxidative/nitrative stress, impaired potassium and calcium channel activities, and decreased glucose-stimulated insulin secretion (GSIS). Genetic ablation of neprilysin specifically protects against FFA-induced impairment of calcium influx and GSIS in vitro and in vivo but does not ameliorate other FFA-induced defects. Importantly, adenoviral overexpression of neprilysin in islets cultured without FFA reproduces the defects in both calcium influx and GSIS, suggesting that upregulation of neprilysin per se mediates insulin secretory dysfunction and that the mechanism for protection conferred by neprilysin deletion involves prevention of reduced calcium influx. Our findings highlight the critical nature of calcium signaling for normal insulin secretion and suggest that interventions to inhibit neprilysin may improve β-cell function in obese humans with type 2 diabetes.
Diabetes 01/2013; · 8.29 Impact Factor
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ABSTRACT: OBJECTIVE
To examine whether the patterns of insulin concentration during the oral glucose tolerance test (OGTT) predict type 2 diabetes.RESEARCH DESIGN AND METHODS
We followed 400 nondiabetic Japanese Americans for 10-11 years. Insulin concentrations at 30, 60, and 120 min during a 2-h 75-g OGTT at baseline were used to derive the following possible patterns of insulin: pattern 1 (30-min peak, higher insulin level at 60 than at 120 min), pattern 2 (30-min peak, lower or equal level at 60 vs. 120 min), pattern 3 (60-min peak); pattern 4 (120-min peak, lower level at 30 than at 60 min), and pattern 5 (120-min peak, equal or higher level at 30 vs. 60 min). Insulin sensitivity was estimated by homeostasis model assessment of insulin resistance (HOMA-IR) and Matsuda index. Insulin secretion was estimated by the insulinogenic index (IGI) [Δinsulin/Δglucose (30-0 min)] and disposition index (IGI/HOMA-IR).RESULTSThere were 86 incident cases of type 2 diabetes. The cumulative incidence was 3.2, 9.8, 15.4, 47.8, and 37.5% for patterns 1, 2, 3, 4, and 5, respectively. Compared with pattern 1, patterns 4 and 5, characterized by a lasting late insulin response, were associated with significantly less insulin sensitivity as measured by the Matsuda index and lower early insulin response by the disposition index. The multiple-adjusted odds ratios of type 2 diabetes were 12.55 (95% CI 4.79-32.89) for pattern 4 and 8.34 (2.38-29.27) for pattern 5 compared with patterns 1 and 2. This association was independent of insulin secretion and sensitivity.CONCLUSION
The patterns of insulin concentration during an OGTT strongly predict the development of type 2 diabetes.
Diabetes care 12/2012; · 8.09 Impact Factor
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ABSTRACT: Deposition of islet amyloid polypeptide (IAPP) as amyloid is a pathological hallmark of the islet in type 2 diabetes, which is toxic to β cells. We previously showed that the enzyme neprilysin reduces islet amyloid deposition, and thereby reduces β-cell apoptosis, by inhibiting fibril formation. Two other enzymes, matrix metalloproteinase (MMP)-2 and MMP-9, are extracellular gelatinases capable of degrading another amyloidogenic peptide, Aβ, the constituent of amyloid deposits in Alzheimers disease. We therefore investigated whether MMP-2 and MMP-9 play a role in reducing islet amyloid deposition. MMP-2 and MMP-9 mRNA were present in mouse islets but only MMP-9 activity was detectable. In an islet culture model where human IAPP (hIAPP) transgenic mouse islets develop amyloid but non-transgenic islets do not, a broad-spectrum MMP inhibitor (GM6001) and an MMP-2/9 inhibitor increased amyloid formation and the resultant β-cell apoptosis. In contrast, a specific MMP-2 inhibitor had no effect on either amyloid deposition or β-cell apoptosis. Mass spectrometry demonstrated that MMP-9 degraded amyloidogenic hIAPP but not non-amyloidogenic mouse IAPP. Thus, MMP-9 constitutes an endogenous islet protease that limits islet amyloid deposition and its toxic effects via degradation of hIAPP. As islet MMP-9 mRNA levels are decreased in type 2 diabetic subjects, islet MMP-9 activity may also be decreased in human type 2 diabetes, thereby contributing to increased islet amyloid deposition and β-cell loss. Approaches to increase islet MMP-9 activity could reduce or prevent amyloid deposition and its toxic effects in type 2 diabetes.
Journal of Biological Chemistry 12/2012; · 4.77 Impact Factor
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Mirjam V Faulenbach,
Lorena A Wright,
Carlos Lorenzo,
Kristina M Utzschneider,
Julia H Goedecke,
Wilfred Y Fujimoto,
Edward J Boyko,
Marguerite J McNeely,
Donna L Leonetti,
Steven M Haffner, Steven E Kahn
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ABSTRACT: OBJECTIVE: To determine the prevalence of a negative insulinogenic index (change in plasma insulin/change in plasma glucose from 0 to 30min) from an oral glucose tolerance test according to glucose tolerance category. MATERIALS AND METHODS: Data from the San Antonio Heart Study (n=2494), Japanese American Community Diabetes Study (JACDS; n=594) and Genetics of NIDDM Study (n=1519) were examined. Glucose tolerance was defined by ADA criteria. RESULTS: In the combined cohort, the prevalence of a negative insulinogenic index was significantly higher in diabetes 20/616 (3.2%) compared to normal glucose tolerance 43/2667 (1.6%) (p<0.05). Longitudinally, in the JACDS cohort, the prevalence did not change from baseline (3/594; 0.5%) to 5 (4/505; 0.7%) and 10years (8/426; 1.9%) (p=0.9) and no subject had a repeat negative insulinogenic index. CONCLUSIONS: A negative insulinogenic index occurs at a low prevalence across glucose tolerance categories although more often in diabetes, but without recurrence over time.
Journal of diabetes and its complications 11/2012; · 2.11 Impact Factor
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ABSTRACT: OBJECTIVES-Visceral adiposity is an important risk factor for cardiovascular disease and type 2 diabetes. We sought to determine whether change in intraabdominal fat area (IAF) over time predicts subsequent development of diabetes.RESEARCH DESIGN AND METHODS-We followed up 436 nondiabetic Japanese-American subjects (mean age 51.9 years, mean BMI 24.2 kg/m(2), 54% male) for development of diabetes. We fit a logistic regression model to examine the association over a 10-year follow-up between change in IAF at 5-year follow-up and other fat areas (measured by computed tomography) and development of incident diabetes, adjusted for age, sex, family history of diabetes in a first-degree relative, second-generation versus third-generation Japanese American (Nisei vs. Sansei), baseline IAF, BMI, weight change over time, smoking status, physical activity level, and subcutaneous fat (SCF) depot areas.RESULTS-Cumulative incidence of diabetes was 20.4% at 10 years. Mean change in IAF was 10.9 cm(2). An increase of 1SD, in IAF was associated with a 1.65-fold increase in the odds of diabetes over 10 years (OR = 1.65, 95% CI 1.21-2.25) after adjusting for the above covariates. This association was also independent of changes in thoracic, thigh, and abdominal SCF, as well as change in weight.CONCLUSIONS-We conclude that baseline IAF and accumulation of fat in this area over time are independent predictors of the development of type 2 diabetes in Japanese Americans.
Diabetes care 09/2012; · 8.09 Impact Factor
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ABSTRACT: OBJECTIVE
We sought to assess the association between maternal gestational physical activity and insulin action and body composition in early infancy.RESEARCH DESIGN AND METHODS
At 28-32 weeks, gestation, pregnant women participating in an observational study in Sweden underwent assessments of height, weight, and body composition, an oral glucose tolerance test, and 10 days of objective physical activity assessment. Thirty mothers and infants returned at 11-19 weeks, postpartum. Infants underwent assessments of weight, length, and body composition.RESULTSEarly insulin response was correlated with total physical activity (r = -0.47; P = 0.007). Early insulin response (r = -0.36; P = 0.045) and total physical activity (r = 0.52; P = 0.037) were also correlated with infant fat-free mass. No maternal variable was significantly correlated with infant adiposity.CONCLUSIONS
The relationships between maternal physical activity, insulin response, and infant fat-free mass suggest that physical activity during pregnancy may affect metabolic outcomes in the mother and her offspring.
Diabetes care 09/2012; · 8.09 Impact Factor
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ABSTRACT: Patients with chronic kidney disease are often insulin resistant and glucose intolerant-abnormalities that promote cardiovascular disease. Administration of 1,25-dihydroxyvitamin D (calcitriol) has improved glucose metabolism in patients with end-stage renal disease. We conducted a randomized, placebo-controlled clinical trial to test whether paricalcitol, a 1,25-dihydroxyvitamin D analog, changes glucose tolerance in earlier stages of chronic kidney disease. In a crossover design, 22 nondiabetic patients with estimated glomerular filtration rates of stage 3-4 chronic kidney disease and fasting plasma glucose of 100-125 mg/dl were given daily oral paricalcitol for 8 weeks and matching placebo for 8 weeks, separated by an 8-week washout period. The order of interventions was random and blinded to both participants and investigators. Paricalcitol significantly reduced serum concentrations of parathyroid hormone, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D while significantly increasing serum concentrations of fibroblast growth factor-23 and 24,25-dihydroxyvitamin D. Paricalcitol, however, had no significant effect on glucose tolerance (the primary outcome measure), insulin sensitivity, beta-cell insulin response, plasma free fatty acid suppression, or urinary F2-isoprostane excretion. Thus, despite substantial effects on vitamin D metabolism, paricalcitol did not improve glucose metabolism in nondiabetic patients with stage 3-4 chronic kidney disease.Kidney International advance online publication, 22 August 2012; doi:10.1038/ki.2012.311.
Kidney International 08/2012; · 6.61 Impact Factor
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ABSTRACT: Our objective was to quantify and predict diabetes risk reduction during the Diabetes Prevention Program Outcomes Study (DPPOS) in participants who returned to normal glucose regulation at least once during the Diabetes Prevention Program (DPP) compared with those who consistently met criteria for prediabetes.
DPPOS is an ongoing observational study of participants from the DPP randomised trial. For this analysis, diabetes cumulative incidence in DPPOS was calculated for participants with normal glucose regulation or prediabetes status during DPP with and without stratification by previous randomised treatment group. Cox proportional hazards modelling and generalised linear mixed models were used to quantify the effect of previous (DPP) glycaemic status on risk of later (DPPOS) diabetes and normal glucose regulation status, respectively, per SD in change. Included in this analysis were 1990 participants of DPPOS who had been randomly assigned to treatment groups during DPP (736 intensive lifestyle intervention, 647 metformin, 607 placebo). These studies are registered at ClinicalTrials.gov, NCT00004992 (DPP) and NCT00038727 (DPPOS).
Diabetes risk during DPPOS was 56% lower for participants who had returned to normal glucose regulation versus those who consistently had prediabetes (hazard ratio [HR] 0·44, 95% CI 0·37-0·55, p<0·0001) and was unaffected by previous group assignment (interaction test for normal glucose regulation and lifestyle intervention, p=0·1722; normal glucose regulation and metformin, p=0·3304). Many, but not all, of the variables that increased diabetes risk were inversely associated with the chance of a participant reaching normal glucose regulation status in DPPOS. Specifically, previous achievement of normal glucose regulation (odds ratio [OR] 3·18, 95% CI 2·71-3·72, p<0·0001), increased β-cell function (OR 1·28; 95% CI 1·18-1·39, p<0·0001), and insulin sensitivity (OR 1·16, 95% CI 1·08-1·25, p<0·0001) were associated with normal glucose regulation in DPPOS, whereas the opposite was true for prediction of diabetes, with increased β-cell function (HR 0·80, 95% CI 0·71-0·89, p<0·0001) and insulin sensitivity (HR 0·83, 95% CI 0·74-0·94, p=0·0001) having a protective effect. Among participants who did not return to normal glucose regulation in DPP, those assigned to the intensive lifestyle intervention had a higher diabetes risk (HR 1·31, 95% CI 1·03-1·68, p=0·0304) and lower chance of normal glucose regulation (OR 0·59, 95% CI 0·42-0·82, p=0·0014) than did the placebo group in DPPOS.
We conclude that prediabetes is a high-risk state for diabetes, especially in patients who remain with prediabetes despite intensive lifestyle intervention. Reversion to normal glucose regulation, even if transient, is associated with a significantly reduced risk of future diabetes independent of previous treatment group.
US National Institutes of Health.
The Lancet 06/2012; 379(9833):2243-51. · 38.28 Impact Factor
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ABSTRACT: Migrant Japanese populations in both the United States and Brazil have for a long time shown a higher prevalence of type 2 diabetes than in native Japanese, suggesting an interaction of lifestyle and genetic predisposition in the etiology of type 2 diabetes. The overall objective of the Seattle Japanese American Community Diabetes Study was to learn more about the etiology and pathogenesis of type 2 diabetes in Japanese Americans. This metabolically based epidemiologic study included extensive assessments of insulin sensitivity, insulin response, and adiposity with the latter including measurements of body fat distribution by both anthropometry and computed tomography. Because of this, the importance of visceral adiposity as a risk factor for abnormal glucose tolerance, hypertension, coronary heart disease, and the metabolic syndrome was demonstrated. In conjunction with an examination of diet and physical activity patterns, the result was a clearer understanding of the etiology and pathogenesis of type 2 diabetes in Japanese Americans. Wepropose that a lifestyle that fosters increased weight gain, especially in the visceral adipose depot, promotes the development of insulin resistance which in turn exposes an underlying reduced beta-cell reserve in susceptible individuals, resulting in glucose intolerance and eventually in many the development of diabetes. We have shown that it may be possible to delay or prevent the development of diabetes through dietary and exercise interventions in individuals identified as having impaired glucose tolerance. The lessons learned from studying migrant Japanese in Seattle may in many ways be applicable to other populations of Asian origin.
Journal of diabetes investigation. 06/2012; 3(3):212-224.
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ABSTRACT: To determine the mechanism by which the bile acid sequestrant colesevelam improves glycemic control.
We performed a frequently sampled intravenous glucose tolerance test (FSIGT) with minimal model analysis and a meal tolerance test (MTT) in 20 subjects with impaired fasting glucose (11 men, 9 women; mean age 60.7 ± 1.9 years, BMI 29.4 ± 0.9 kg/m(2)) in a single-blind study after 2 weeks of placebo treatment and 8 weeks of colesevelam 3.75 g daily. From these tests, insulin sensitivity, β-cell function, and glucose tolerance were determined, along with gastrointestinal peptide levels during the MTT.
Fasting plasma glucose and HbA(1c) decreased with colesevelam (from 5.9 ± 0.1 to 5.7 ± 0.1 mmol/L, P < 0.05, and from 5.86 ± 0.06 to 5.76 ± 0.06%, P = 0.01, respectively), but fasting insulin did not change. Colesevelam had no effect on any FSIGT measures. In contrast, the MTT incremental area under the curve (iAUC) for both glucose (from 249.3 ± 28.5 to 198.8 ± 23.6 mmol/L · min, P < 0.01) and insulin (from 20,130 [13,542-35,292] to 13,086 [9,804-21,138] pmol/L · min, P < 0.05) decreased with colesevelam. However, the ratio of iAUC insulin to iAUC glucose was not changed. iAUC for cholecystokinin (CCK) increased (from 43.2 [0-130.1] to 127.1 [47.2-295.2] pmol/L · min, P < 0.01), while iAUC for fibroblast growth factor 19 decreased (from 11,185 [1,346-17,661] to 2,093 [673-6,707] pg/mL · min, P < 0.01) with colesevelam. However, iAUC for glucagon, glucose-dependent insulinotropic peptide, and glucagon-like peptide 1 did not change.
Colesevelam improves oral but not intravenous glucose tolerance without changing insulin sensitivity, β-cell function, or incretins. This effect may be at least partially explained by the colesevelam-induced increase in CCK.
Diabetes care 03/2012; 35(5):1119-25. · 8.09 Impact Factor
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ABSTRACT: Intentional weight loss is an important component of treatment for overweight patients with type 2 diabetes, but the effects on bone density are not known. We used data from the Look AHEAD trial to determine the impact of an intensive lifestyle weight loss intervention (ILI) compared with diabetes support and education (DSE) on changes in bone mineral density (BMD) over 12 months. Overweight and obese adults with type 2 diabetes were randomly assigned to ILI or DSE. In a substudy of BMD conducted at 5 of 16 clinical centers, hip, spine, and whole body dual X-ray absorptiometry scans were obtained at baseline and 1-year later on 642 of 739 ILI and 632 of 740 DSE participants. At baseline, mean age was 58.4 years, and average body mass index was 35.2 kg/m(2). Total hip BMD T-score was <-2.5 in 1% and <-1.0 in 8%. At 1 year, weight loss was greater in ILI than DSE (-8.6% versus -0.7%), and glycemic control and fitness were also improved. Bone loss over 1 year was greater in ILI at the total hip (-1.4% versus -0.4%; p < 0.001) and femoral neck (-1.5% versus -0.8%; p = 0.009), but change in BMD for the lumbar spine and whole body did not differ between groups. In ILI, bone loss at the total hip was independently associated with weight loss in men and women and with poorer glycemic control in men, but was not associated with changes in fitness. One year of an intensive lifestyle intervention in adults with type 2 diabetes, resulting in weight loss, was associated with a modest increase in hip bone loss despite improved fitness and glycemic control.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2012; 27(3):619-27. · 6.04 Impact Factor
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Jose C Florez,
Kathleen A Jablonski,
Jarred B McAteer,
Paul W Franks,
Clinton C Mason,
Kieren Mather,
Edward Horton,
Ronald Goldberg,
Dana Dabelea, Steven E Kahn,
Richard F Arakaki,
Alan R Shuldiner,
William C Knowler
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ABSTRACT: Common genetic variants have been recently associated with fasting glucose and insulin levels in white populations. Whether these associations replicate in pre-diabetes is not known. We extended these findings to the Diabetes Prevention Program, a clinical trial in which participants at high risk for diabetes were randomized to placebo, lifestyle modification or metformin for diabetes prevention. We genotyped previously reported polymorphisms (or their proxies) in/near G6PC2, MTNR1B, GCK, DGKB, GCKR, ADCY5, MADD, CRY2, ADRA2A, FADS1, PROX1, SLC2A2, GLIS3, C2CD4B, IGF1, and IRS1 in 3,548 Diabetes Prevention Program participants. We analyzed variants for association with baseline glycemic traits, incident diabetes and their interaction with response to metformin or lifestyle intervention. We replicated associations with fasting glucose at MTNR1B (P<0.001), G6PC2 (P = 0.002) and GCKR (P = 0.001). We noted impaired β-cell function in carriers of glucose-raising alleles at MTNR1B (P<0.001), and an increase in the insulinogenic index for the glucose-raising allele at G6PC2 (P<0.001). The association of MTNR1B with fasting glucose and impaired β-cell function persisted at 1 year despite adjustment for the baseline trait, indicating a sustained deleterious effect at this locus. We also replicated the association of MADD with fasting proinsulin levels (P<0.001). We detected no significant impact of these variants on diabetes incidence or interaction with preventive interventions. The association of several polymorphisms with quantitative glycemic traits is replicated in a cohort of high-risk persons. These variants do not have a detectable impact on diabetes incidence or response to metformin or lifestyle modification in the Diabetes Prevention Program.
PLoS ONE 01/2012; 7(9):e44424. · 4.09 Impact Factor
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Frederick L Brancati,
Mary Evans,
Curt D Furberg,
Nancy Geller,
Steven Haffner, Steven E Kahn,
Peter G Kaufmann,
Cora E Lewis,
David M Nathan,
Bertram Pitt,
Monika M Safford
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ABSTRACT: The Look AHEAD (Action for Health in Diabetes) Study is a long-term clinical trial that aims to determine the cardiovascular disease (CVD) benefits of an intensive lifestyle intervention (ILI) in obese adults with type 2 diabetes. The study was designed to have 90% statistical power to detect an 18% reduction in the CVD event rate in the ILI Group compared to the Diabetes Support and Education (DSE) Group over 10.5 years of follow-up. The original power calculations were based on an expected CVD rate of 3.125% per year in the DSE group; however, a much lower-than-expected rate in the first 2 years of follow-up prompted the Data and Safety Monitoring Board (DSMB) to recommend that the Steering Committee undertake a formal blinded evaluation of these design considerations. The Steering Committee created an Endpoint Working Group (EPWG) that consisted of individuals masked to study data to examine relevant issues. The EPWG considered two primary options: (1) expanding the definition of the primary endpoint and (2) extending follow-up of participants. Ultimately, the EPWG recommended that the Look AHEAD Steering Committee approve both strategies. The DSMB accepted these modifications, rather than recommending that the trial continue with inadequate statistical power. Trialists sometimes need to modify endpoints after launch. This decision should be well justified and should be made by individuals who are fully masked to interim results that could introduce bias. This article describes this process in the Look AHEAD study and places it in the context of recent articles on endpoint modification and recent trials that reported endpoint modification.
Clinical Trials 01/2012; 9(1):113-24. · 1.92 Impact Factor
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ABSTRACT: 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.
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).
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, P(lifestyle*SNP) = 0.032; GNPDA2 rs10938397, P(lifestyle*SNP) = 0.016; MTCH2 rs10838738, P(lifestyle*SNP) = 0.022) and long-term (NEGR1 rs2815752, P(metformin*SNP) = 0.028; FTO rs9939609, P(lifestyle*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 (P(lifestyle*SNP) < 0.05).
Genetic information may help identify people who require additional support to maintain reduced weight after clinical intervention.
Diabetes care 12/2011; 35(2):363-6. · 8.09 Impact Factor
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ABSTRACT: Intentional weight loss is an important component of treatment for overweight patients with type 2 diabetes, but the effects on bone density are not known. We used data from the Look AHEAD trial to determine the impact of an intensive lifestyle weight loss intervention (ILI) compared to diabetes support and education (DSE) on changes in bone mineral density (BMD) over 12 months. Overweight and obese adults with type 2 diabetes were randomly assigned to ILI or DSE. In a sub-study of BMD conducted at 5 of 16 clinical centers, hip, spine and whole body dual x-ray absorptiometry scans were obtained at baseline and one year later on 642 of 739 ILI and 632 of 740 DSE participants. At baseline, mean age was 58.4 years, and average body mass index was 35.2 kg/m(2) . Total hip BMD T-score was <-2.5 in 1% and <-1.0 in 8%. At one year, weight loss was greater in ILI than DSE (-8.6% versus -0.7%), and glycemic control and fitness were also improved. Bone loss over one year was greater in ILI at the total hip (-1.4% versus -0.4%; p<0.001) and femoral neck (-1.5% versus -0.8%; p=0.009) , but change in BMD for the lumbar spine and whole body did not differ between groups. In ILI, bone loss at the total hip was independently associated with weight loss in men and women and with poorer glycemic control in men, but was not associated with changes in fitness. One year of an intensive lifestyle intervention in adults with type 2 diabetes, resulting in weight loss, was associated with a modest increase in hip bone loss despite improved fitness and glycemic control. © 2011 American Society for Bone and Mineral Research.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 12/2011; · 6.04 Impact Factor
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Julia H Goedecke,
Juliet Evans,
Dheshnie Keswell,
Roland H Stimson,
Dawn E W Livingstone,
Philip Hayes,
Kevin Adams,
Joel A Dave,
Hendriena Victor,
Naomi S Levitt,
Estelle V Lambert,
Brian R Walker,
Jonathan R Seckl,
Tommy Olsson, Steven E Kahn
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ABSTRACT: Black South African women are less insulin sensitive than their White counterparts, despite less central and greater peripheral fat deposition. We hypothesized that this paradox may be explained, in part, by differences in the adipogenic capacity of sc adipose tissue (SAT).
Our objective was to measure adipogenic and lipogenic gene expression in abdominal and gluteal SAT depots and determine their relationships with insulin sensitivity (S(I)) in South African women.
Fourteen normal-weight [body mass index (BMI) <25 kg/m(2)] Black, 13 normal-weight White, 14 obese (BMI >30 kg/m(2)) Black, and 13 obese White premenopausal South African women participated in this cross-sectional study. Main outcomes: S(I) (frequently sampled i.v. glucose tolerance test) in relation to expression of adipogenic and lipogenic genes in abdominal and gluteal SAT depots.
With increasing BMI, Black women had less visceral fat (P = 0.03) and more abdominal (P = 0.017) and gynoid (P = 0.041) SAT but had lower S(I) (P < 0.01) than White women. The expression of adipogenic and lipogenic genes was proportionately lower with obesity in Black but not White women in the gluteal and deep SAT depots (P < 0.05 for ethnicity × BMI effect). In Black women only, the expression of these genes correlated positively with S(I) (all P < 0.05), independently of age and fat mass.
Obese Black women have reduced SAT expression of adipogenic and lipogenic genes compared with White women, which associates with reduced S(I). These findings suggest that obesity in Black women impairs SAT adipogenesis and storage, potentially leading to insulin resistance and increased risk of type 2 diabetes.
The Journal of clinical endocrinology and metabolism 09/2011; 96(12):E2029-33. · 6.50 Impact Factor
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ABSTRACT: The rise in LDL with egg feeding in lean insulin-sensitive (LIS) participants is 2- and 3-fold greater than in lean insulin-resistant (LIR) and obese insulin-resistant (OIR) participants, respectively.
We determined whether differences in cholesterol absorption, synthesis, or both could be responsible for these differences by measuring plasma sterols as indexes of cholesterol absorption and endogenous synthesis.
Plasma sterols were measured by gas chromatography-mass spectrometry in a random subset of 34 LIS, 37 LIR, and 37 OIR participants defined by the insulin sensitivity index (S(I)) and by BMI criteria selected from a parent group of 197 participants. Cholestanol and plant sterols provide a measure of cholesterol absorption, and lathosterol provides a measure of cholesterol synthesis.
The mean (±SD) ratio of plasma total absorption biomarker sterols to cholesterol was 4.48 ± 1.74 in LIS, 3.25 ± 1.06 in LIR, and 2.82 ± 1.08 in OIR participants. After adjustment for age and sex, the relations of the absorption sterol-cholesterol ratios were as follows: LIS > OIR (P < 0.001), LIS > LIR (P < 0.001), and LIR > OIR (P = 0.11). Lathosterol-cholesterol ratios were 0.71 ± 0.32 in the LIS participants, 0.95 ± 0.47 in the LIR participants, and 1.29 ± 0.55 in the OIR participants. After adjustment for age and sex, the relations of lathosterol-cholesterol ratios were as follows: LIS < OIR (P < 0.001), LIS < LIR (P = 0.03), and LIR < OIR (P = 0.002). Total sterol concentrations were positively associated with S(I) and negatively associated with obesity, whereas lathosterol correlations were the opposite.
Cholesterol absorption was highest in the LIS participants, whereas cholesterol synthesis was highest in the LIR and OIR participants. Therapeutic diets for hyperlipidemia should emphasize low-cholesterol diets in LIS persons and weight loss to improve S(I) and to decrease cholesterol overproduction in LIR and OIR persons.
American Journal of Clinical Nutrition 09/2011; 94(5):1182-8. · 6.67 Impact Factor
