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1.  Clinical and genetic determinants of progression of type 2 diabetes: A DIRECT Study 
Diabetes care  2013;37(3):718-724.
Objective
The rate at which diabetes progresses following diagnosis of type 2 diabetes is highly variable between individuals.
Research Design and Methods
We studied 5250 patients with type 2 diabetes using comprehensive electronic medical records on all patients in Tayside, Scotland from 1992 onwards. We investigated the association of clinical, biochemical and genetic factors with the risk of progression of type 2 diabetes from diagnosis to requirement for insulin treatment (defined as insulin treatment or HbA1c ≥8.5%/69 mmol/mol treated with two or more non-insulin diabetes therapies).
Results
Risk of progression was associated with both low and high BMI. In an analysis stratified by BMI and HbA1c at diagnosis, faster progression was independently associated with younger age at diagnosis, higher log triacylglyceride concentrations (Hazard Ratio (HR) 1.28 per mmol/L (95% CI 1.15-1.42)) and lower HDL concentrations (HR 0.70 per mmol/L (95% CI 0.55-0.87)). A high genetic risk score derived from 61 diabetes risk variants was associated with a younger age of diagnosis, a younger age at starting insulin, but was not associated with the progression rate from diabetes to requirement for insulin treatment.
Conclusions
Increased triacylglyceride and low HDL are independently associated with increased rate of progression of diabetes. The genetic factors that predispose to diabetes are different from those that cause rapid progression of diabetes suggesting a difference in biological process that needs further investigation.
doi:10.2337/dc13-1995
PMCID: PMC4038744  PMID: 24186880
2.  DIETARY ENERGY INTAKE IS ASSOCIATED WITH TYPE 2 DIABETES RISK MARKERS IN CHILDREN 
Diabetes care  2013;37(1):116-123.
Objective
Energy intake, energy density and nutrient intakes are implicated in type 2 diabetes risk in adults, but little is known about their influence on emerging type 2 diabetes risk in childhood. We examined these associations in a multi-ethnic population of children.
Research Design and Methods
Cross-sectional study of 2017 children predominantly of white European, South Asian and black African-Caribbean origin aged 9-10 years who had a detailed 24 hour dietary recall, measurements of body composition and provided a fasting blood sample for measurements of plasma glucose, HbA1c and serum insulin; HOMA insulin resistance was also derived.
Results
Energy intake was positively associated with insulin resistance. After the removal of 176 participants with implausible energy intakes (unlikely to be representative of habitual intake), energy intake was more strongly associated with insulin resistance, and was also associated with glucose and fat mass index. Energy density was also positively associated with insulin resistance and fat mass index. However, in mutually adjusted analyses, the associations for energy intake remained while those for energy density became non-significant. Individual nutrient intakes showed no associations with type 2 diabetes risk markers.
Conclusions
Higher total energy intake was strongly associated with high levels of insulin resistance and may help to explain emerging type 2 diabetes risk in childhood. Studies are needed to establish whether reducing energy intake produces sustained favourable changes in insulin resistance and circulating glucose levels.
doi:10.2337/dc13-1263
PMCID: PMC3966263  PMID: 23939542
3.  Pesticide Exposure and Self-Reported Gestational Diabetes Mellitus in the Agricultural Health Study 
Diabetes care  2007;30(3):529-534.
OBJECTIVE
To examine the association between pesticide use during pregnancy and gestational diabetes mellitus (GDM) among wives of licensed pesticide applicators.
RESEARCH DESIGN AND METHODS
Using data from the Agricultural Health Study (AHS), we estimated the association between self-reported pesticide-related activities during the first trimester of the most recent pregnancy and GDM among 11,273 women whose pregnancy occurred within 25 years of enrollment.
RESULTS
A total of 506 (4.5%) women reported having had GDM. Women who reported agricultural pesticide exposure (mixing or applying pesticides to crops or repairing pesticide application equipment) during pregnancy were more likely to report GDM (odds ratio [OR] 2.2 [95% CI 1.5–3.3]). We saw no association between residential pesticide exposure (applying pesticides in the home and garden during pregnancy) and GDM (1.0 [0.8–1.3]). Among women who reported agricultural exposure during pregnancy, risk of GDM was associated with ever-use of four herbicides (2,4,5-T; 2,4,5-TP; atrazine; or butylate) and three insecticides (diazinon, phorate, or carbofuran).
CONCLUSIONS
These findings suggest that activities involving exposure to agricultural pesticides during the first trimester of pregnancy may increase the risk of GDM.
doi:10.2337/dc06-1832
PMCID: PMC3902103  PMID: 17327316
5.  Quality of Diabetes Care in U.S. Academic Medical Centers 
Diabetes care  2005;28(2):337-442.
Objective
To assess both standard and novel diabetes quality measures in a national sample of U.S. academic medical centers.
Research Design and Methods
This retrospective cohort study was conducted from 10 January 2000 to 10 January 2002. It involved 30 U.S. academic medical centers, which contributed data from 44 clinics (27 primary care clinics and 17 diabetes/endocrinology clinics). For 1,765 eligible adult patients with type 1 or type 2 diabetes with at least two clinic visits in the 24 months before 10 January 2002, including one visit in the 6 months before 10 January 2002, we assessed measurement and control of HbA1c, blood pressure, and cholesterol and corresponding medical regimen changes at the most recent clinic visit.
Results
In this ethnically and economically diverse cohort, annual testing rates were very high (97.4% for HbA1c, 96.6% for blood pressure, and 87.6% for total cholesterol). Fewer patients were at HbA1c goal (34.0% <7.0%) or blood pressure goal (33.0% <130/80 mmHg) than lipid goals (65.1% total cholesterol <200 mg/dl, 46.1% with LDL cholesterol <100 mg/dl). Only 10.0% of the cohort met recommended goals for all three risk factors. At the most recent clinic visit, 40.4% of patients with HbA1c concentrations above goal underwent adjustment of their corresponding regimens. Among untreated patients, few with elevated blood pressure (10.1% with blood pressure >130/80 mmHg) or elevated LDL cholesterol (5.6% with LDL >100 mg/dl) were started on corresponding therapy. Patients with type 2 diabetes were no less likely to be intensified than patients with type 1 diabetes.
Conclusions
High rates of risk factor testing do not necessarily translate to effective metabolic control. Low rates of medication adjustment among patients with levels above goal suggest a specific and novel target for quality improvement measurement.
PMCID: PMC3829636  PMID: 15677789
6.  Clinical Predictors of Disease Progression and Medication Initiation in Untreated Patients with Type 2 Diabetes and A1C Less Than 7% 
Diabetes care  2007;31(3):10.2337/dc07-1934.
Objective
Many patients with early diabetes remain untreated. Our objectives were to identify clinical predictors of 1) worsening glycemic control and 2) medical treatment initiation in response to worsening glycemic control among patients with type 2 diabetes.
Research Design and Methods
We identified 5,804 type 2 diabetic patients seen at least twice between June 2005 and June 2006 within our 12-clinic primary care network. We examined predictors of diabetes progression (A1C ≥7% or initiation of hypoglycemic agent) over a 1-year follow-up period in 705 patients who had A1C <7% and were not on glucose-lowering medications at baseline. In the 200 patients in this group who progressed, we examined predictors of medical therapy initiation.
Results
In multivariate analyses, baseline A1C (P < 0.0001), younger age (P = 0.04), and weight gain (P = 0.03) were independent predictors of progression after adjusting for race, sex, and baseline HDL levels. Each decade of increasing age reduced the risk of progression by 15%. Each 1-lb increase in weight was associated with a 2% increased odds of progression. Likelihood of medication initiation among progressors decreased by 40% (P = 0.02) with every decade of age and decreased by 2.3% (P = 0.02) with each 1-mg/dl decrease in LDL level from baseline after adjusting for race, sex, and weight change.
Conclusions
Among untreated primary care patients with type 2 diabetes and A1C < 7%, younger patients and those with weight gain were more likely to have diabetes progression and should be the focus of aggressive diabetes management.
doi:10.2337/dc07-1934
PMCID: PMC3829640  PMID: 18083790
7.  How Doctors Choose Medications to Treat Type 2 Diabetes 
Diabetes care  2007;30(6):10.2337/dc06-2499.
OBJECTIVE
Glycemic control remains suboptimal despite the wide range of available medications. More effective medication prescription might result in better control. However, the process by which physicians choose glucose-lowering medicines is poorly understood. We sought to study the means by which physicians choose medications for type 2 diabetic patients.
RESEARCH DESIGN AND METHODS
We surveyed 886 physician members of either the Society of General Internal Medicine (academic generalists, response rate 30%) or the American Diabetes Association (specialists, response rate 23%) currently managing patients with type 2 diabetes. Respondents weighed the importance of 15 patient, physician, and nonclinical factors when deciding which medications to prescribe for type 2 diabetic subjects at each of three management stages (initiation, use of second-line oral agents, and insulin).
RESULTS
Respondents reported using a median of five major considerations (interquartile range 4–6) at each stage. Frequently cited major considerations included overall assessment of the patient’s health/comorbidity, A1C level, and patient’s adherence behavior but not expert guidelines/hospital algorithms or patient age. For insulin initiation, academic generalists placed greater emphasis on patient adherence (76 vs. 60% of specialists, P < 0.001). These generalists also identified patient fear of injections (68%) and patient desire to prolong noninsulin therapy (68%) as major insulin barriers. Overall, qualitative factors (e.g., adherence, motivation, overall health assessment) were somewhat more highly considered than quantitative factors (e.g., A1C, age, weight) with mean aggregate scores of 7.3 vs. 6.9 on a scale of 0–10, P < 0.001.
CONCLUSIONS
The physicians in our survey considered a wide range of qualitative and quantitative factors when making medication choices for hyperglycemia management. The apparent complexity of the medication choice process contrasts with current evidence-based treatment guidelines.
doi:10.2337/dc06-2499
PMCID: PMC3829641  PMID: 17337497
8.  Long-Term Effects on Medical Costs of Improving Depression Outcomes in Patients With Depression and Diabetes 
Diabetes care  2008;31(6):10.2337/dc08-0032.
OBJECTIVE
The purpose of this study was to examine the 5-year effects on total health care costs of the Pathways depression intervention program for patients with diabetes and comorbid depression compared with usual primary care.
RESEARCH DESIGN AND METHODS
The Pathways Study was conducted in nine primary care practices of a large HMO and enrolled 329 patients with diabetes and comorbid major depression. The current study analyzed the differences in long-term medical costs between intervention and usual care patients. Participants were randomly assigned to a nurse depression intervention (n = 164) or to usual primary care (n = 165). The intervention included education about depression, behavioral activation, and a choice of either starting with support of antidepressant medication treatment by the primary care doctor or problem-solving therapy in primary care. Interventions were provided for up to 12 months, and the main outcome measures are health costs over a 5-year period.
RESULTS
Patients in the intervention arm of the study had improved depression outcomes and trends for reduced 5-year mean total medical costs of –$3,907 (95% CI –$15,454 less to $7,640 more) compared with usual care patients. A sensitivity analysis found that these cost differences were largely explained by the patients with depression and the most severe medical comorbidity.
CONCLUSIONS
The Pathways depression collaborative care program improved depression outcomes compared with usual care with no evidence of greater long-term costs and with trends for reduced costs among the more severely medically ill patients with diabetes.
doi:10.2337/dc08-0032
PMCID: PMC3810023  PMID: 18332158
9.  Long-Term Mortality in Nationwide Cohorts of Childhood-Onset Type 1 Diabetes in Japan and Finland 
Diabetes care  2003;26(7):2037-2042.
Objective
This study compares mortality from type 1 diabetes in Japan and Finland and examines the effects of sex, age at diagnosis, and calendar time period of diagnosis on mortality.
Research Design and Methods
Patients with type 1 diabetes from Japan (n = 1,408) and Finland (n = 5,126), diagnosed from 1965 through 1979, at age <18 years, were followed until 1994. Mortality was estimated with and without adjustment for that of the general population to assess absolute and relative mortality using Cox proportional hazard models.
Results
Overall mortality rates in Japan and Finland were 607 (95% CI 510–718) and 352 (315–393), respectively, per 100,000 person-years; standardized mortality ratios were 12.9 (10.8–15.3) and 3.7 (3.3–4.1), respectively. Absolute mortality was higher for men than for women in Finland, but relative mortality was higher for women than for men in both cohorts. Absolute mortality was higher in both cohorts among those whose diabetes was diagnosed during puberty, but relative mortality did not show any significant difference by age at diagnosis in either cohort. In Japan, both absolute and relative mortality were higher among those whose diagnosis was in the 1960s rather than the 1970s.
Conclusions
Mortality from type 1 diabetes was higher in Japan compared with Finland. The increased risk of death from type 1 diabetes seems to vary by sex, age at diagnosis, and calendar time period of diagnosis. Further investigation, especially on cause-specific mortality, is warranted in the two countries.
PMCID: PMC3752687  PMID: 12832309
10.  Age, BMI, and Race Are Less Important Than Random Plasma Glucose in Identifying Risk of Glucose Intolerance 
Diabetes care  2008;31(5):884-886.
OBJECTIVE
Age, BMI, and race/ethnicity are used in National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and American Diabetes Association (ADA) guidelines to prompt screening for pre-diabetes and diabetes, but cutoffs have not been evaluated rigorously.
RESEARCH DESIGN AND METHODS
Random plasma glucose (RPG) was measured and 75-g oral glucose tolerance tests were performed in 1,139 individuals without known diabetes. Screening performance was assessed by logistic regression and area under the receiver operating characteristic curve (AROC).
RESULTS
NIDDK/ADA indicators age >45 years and BMI >25 kg/m2 provided significant detection of both diabetes and dysglycemia (both AROCs 0.63), but screening was better with continuous-variable models of age, BMI, and race and better still with models of age, BMI, race, sex, and family history (AROC 0.78 and 0.72). However, screening was even better with RPG alone (AROCs 0.81 and 0.72). RPG >125 mg/dl could be used to prompt further evaluation with an OGTT.
CONCLUSIONS
Use of age, BMI, and race/ethnicity in guidelines for screening to detect diabetes and pre-diabetes may be less important than evaluation of RPG. RPG should be investigated further as a convenient, inexpensive screen with good predictive utility.
doi:10.2337/dc07-2282
PMCID: PMC3685424  PMID: 18310308
11.  A Prospective Study of the Association Between Quantity and Variety of Fruit and Vegetable Intake and Incident Type 2 Diabetes 
Diabetes Care  2012;35(6):1293-1300.
OBJECTIVE
The association between quantity of fruit and vegetable (F&V) intake and risk of type 2 diabetes (T2D) is not clear, and the relationship with variety of intake is unknown. The current study examined the association of both quantity and variety of F&V intake and risk of T2D.
RESEARCH DESIGN AND METHODS
We examined the 11-year incidence of T2D in relation to quantity and variety of fruit, vegetables, and combined F&V intake in a case-cohort study of 3,704 participants (n = 653 diabetes cases) nested within the European Prospective Investigation into Cancer and Nutrition-Norfolk study, who completed 7-day prospective food diaries. Variety of intake was derived from the total number of different items consumed in a 1-week period. Multivariable, Prentice-weighted Cox regression was used to estimate hazard ratios (HRs) and 95% CIs.
RESULTS
A greater quantity of combined F&V intake was associated with 21% lower hazard of T2D (HR 0.79 [95% CI 0.62–1.00]) comparing extreme tertiles, in adjusted analyses including variety. Separately, quantity of vegetable intake (0.76 [0.60–0.97]), but not fruit, was inversely associated with T2D in adjusted analysis. Greater variety in fruit (0.70 [0.53–0.91]), vegetable (0.77 [0.61–0.98]), and combined F&V (0.61 [0.48–0.78]) intake was associated with a lower hazard of T2D, independent of known confounders and quantity of intake comparing extreme tertiles.
CONCLUSIONS
These findings suggest that a diet characterized by a greater quantity of vegetables and a greater variety of both F&V intake is associated with a reduced risk of T2D.
doi:10.2337/dc11-2388
PMCID: PMC3357245  PMID: 22474042
13.  Disparities in HbA1c Levels Between African-American and Non-Hispanic White Adults With Diabetes 
Diabetes care  2006;29(9):2130-2136.
OBJECTIVE
Among individuals with diabetes, a comparison of HbA1c (A1C) levels between African Americans and non-Hispanic whites was evaluated. Data sources included PubMed, Web of Science, the Cumulative Index to Nursing and Allied Health, the Cochrane Library, the Combined Health Information Database, and the Education Resources Information Center.
RESEARCH DESIGN AND METHODS
We executed a search for articles published between 1993 and 2005. Data on sample size, age, sex, A1C, geographical location, and study design were extracted. Cross-sectional data and baseline data from clinical trials and cohort studies for African Americans and non-Hispanic whites with diabetes were included. Diabetic subjects aged <18 years and those with pre-diabetes or gestational diabetes were excluded. We conducted a meta-analysis to estimate the difference in the mean values of A1C for African Americans and non-Hispanic whites.
RESULTS
A total of 391 studies were reviewed, of which 78 contained A1C data. Eleven had data on A1C for African Americans and non-Hispanic whites and met selection criteria. A meta-analysis revealed the standard effect to be 0.31 (95% CI 0.39–0.25). This standard effect correlates to an A1C difference between groups of ~0.65%, indicating a higher A1C across studies for African Americans. Grouping studies by study type (cross-sectional or cohort), method of data collection for A1C (chart review or blood draw), and insurance status (managed care or nonmanaged care) showed similar results.
CONCLUSIONS
The higher A1C observed in this meta-analysis among African Americans compared with non-Hispanic whites may contribute to disparity in diabetes morbidity and mortality in this population.
doi:10.2337/dc05-1973
PMCID: PMC3557948  PMID: 16936167
14.  Youth Type 2 Diabetes 
Diabetes care  2005;28(3):638-644.
OBJECTIVE
This study evaluates insulin sensitivity, pancreatic β-cell function (BCF), and the balance between the two in youth with type 2 diabetes and assesses the relationship of diabetes duration and HbA1c to insulin sensitivity and BCF.
RESEARCH DESIGN AND METHODS
The subjects were 14 adolescents with type 2 diabetes and 20 obese control subjects of comparable age, BMI, body composition, and puberty. Insulin sensitivity was evaluated with a 3-h hyperinsulinemic (80 mU · m−2 · min−1) euglycemic clamp. First-phase insulin secretion (FPIS) and second-phase insulin secretion (SPIS) were evaluated with a 2-h hyperglycemic (12.5 mmol/l) clamp. Fasting glucose rate of appearance was determined with the use of [6,6-2H2]glucose.
RESULTS
Fasting glucose rate of appearance was higher in type 2 diabetic patients than in obese control subjects (16.5 ± 1.1 vs. 12.3 ± 0.5 µmol · kg−1 · min−1; P = 0.002). Insulin sensitivity was lower in type 2 diabetic patients than in obese control subjects (1.0 ± 0.1 vs. 2.0 ± 0.2 µmol · kg−1 · min−1 per pmol/l; P = 0.001). Fasting insulin was higher in type 2 diabetic patients than in obese control subjects (289.8 ± 24.6 vs. 220.2 ± 18.0 pmol/l; P = 0.007), and FPIS and SPIS were lower (FPIS: 357.6 ± 42.0 vs. 1,365.0 ± 111.0 pmol/l; SPIS: 652.2 ± 88.8 vs. 1,376.4 ± 88.8 pmol/l; P < 0.001 for both). The glucose disposition index (GDI = insulin sensitivity × FPIS) was ~86% lower in type 2 diabetic patients than in obese control subjects. HbA1c correlated with FPIS (r = −0.61, P = 0.025) with no relationship to insulin sensitivity.
CONCLUSIONS
Despite the impairment in both insulin sensitivity and BCF in youth with type 2 diabetes, the magnitude of the derangement is greater in BCF than insulin sensitivity when compared with that in obese control subjects. The inverse relationship between BCF and HbA1c may either reflect the impact of deteriorating BCF on glycemic control or be a manifestation of a glucotoxic phenomenon on BCF. Future studies in youth type 2 diabetes should target the natural course of β-cell failure and means of retarding and/or preventing it.
PMCID: PMC3428068  PMID: 15735201
16.  A Prospective Study of Cardiorespiratory Fitness and Risk of Type 2 Diabetes in Women 
Diabetes care  2007;31(3):550-555.
OBJECTIVE
The purpose of this study was to determine the independent and joint associations of cardiorespiratory fitness (CRF) and BMI with the incidence of type 2 diabetes in women.
RESEARCH DESIGN AND METHODS
An observational cohort of 6,249 women aged 20–79 years was free of baseline cardiovascular disease, cancer, and diabetes. CRF was measured using a maximal treadmill exercise test. BMI was computed from measured height and weight. The incidence of type 2 diabetes was identified primarily by 1997 American Diabetes Association criteria.
RESULTS
During a 17-year follow-up, 143 cases of type 2 diabetes occurred. Compared with the least fit third, the multivariate (including BMI)-adjusted hazard ratio (HR) (95% CI) was 0.86 (0.59–1.25) for the middle third and 0.61 (0.38–0.96) for the upper third of CRF. For BMI, the multivariate (including CRF)-adjusted HR (95% CI) was 2.34 (1.55–3.54) for overweight individuals and 3.70 (2.12–6.44) for obese individuals, compared with normal-weight patients. In the combined analyses, overweight/obese unfit (the lowest one-third of CRF) women had significantly higher risks compared with normal-weight fit (the upper two-thirds of CRF) women.
CONCLUSIONS
Low CRF and higher BMI were independently associated with incident type 2 diabetes. The protective effect of CRF was observed in individuals who were overweight or obese, but CRF did not eliminate the increased risk in these groups. These findings underscore the critical importance of promoting regular physical activity and maintaining normal weight for diabetes prevention.
doi:10.2337/dc07-1870
PMCID: PMC3410433  PMID: 18070999
17.  A prospective study of the association between quantity and variety of fruit and vegetable intake and incident type 2 diabetes 
Diabetes care  2012;35(6):1293-1300.
Objective
The association between quantity of fruit and vegetable intake and risk of type 2 diabetes (T2D) is not clear, and the relationship with variety of intake is unknown. The current study examined the association of both quantity and variety of fruit and vegetable intake and risk of T2D.
Research Design and Methods
We examined the 11-year incidence of T2D in relation to quantity and variety of fruit, vegetables and combined fruit and vegetable intake in a case-cohort study of 3,704 participants (n=653 T2D cases) nested within the European Prospective Investigation into Cancer and Nutrition-Norfolk Study, who completed 7-day prospective food diaries. Variety of intake was derived from the total number of different items consumed in a one week period. Multivariable Prentice-weighted Cox regression was used to estimate hazard ratios (HR) and 95% CI.
Results
Greater quantity of combined fruit and vegetable intake was associated with 21% lower hazard of T2D (HR 0.79; 0.62-1.00) comparing extreme tertiles, in adjusted analyses including variety. Separately, quantity of vegetable intake (HR 0.76; 0.60-0.97), but not fruit, was inversely associated with T2D in adjusted analysis. Greater variety in fruit (HR 0.70; 0.53-0.91), vegetable (HR 0.77; 0.61-0.98), and combined fruit and vegetable (HR 0.61; 0.48-0.78) intake was associated with a lower hazard of T2D, independent of known confounders and quantity of intake comparing extreme tertiles.
Conclusions
These findings suggest that a diet characterised by greater quantity of vegetable and greater variety of both fruit and vegetable intake is associated with a reduced risk of T2D.
doi:10.2337/dc11-2388
PMCID: PMC3357245  PMID: 22474042
19.  Metabolic Syndrome and Onset of Depressive Symptoms in the Elderly 
Diabetes Care  2011;34(4):904-909.
OBJECTIVE
Given the increasing prevalence of both metabolic syndrome (MetS) and depressive symptoms during old age, we aimed to examine prospectively the association between MetS and the onset of depressive symptoms according to different age-groups in a large, general elderly population.
RESEARCH DESIGN AND METHODS
This was a prospective cohort study of 4,446 men and women aged 65–91 years who were free of depression or depressive symptoms at baseline (the Three-City Study, France). MetS was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. New onset of depressive symptoms (the Center for Epidemiologic Studies Depression Scale score ≥16 and use of antidepressant treatment) was assessed at 2- and 4-year follow-ups.
RESULTS
After adjusting for a large range of potential confounders, we observed MetS to be associated with 1.73-fold (95% CI 1.02–2.95) odds for new-onset depressive symptoms in the youngest age-group (65–70 years at baseline), independently of cardiovascular diseases. No such association was seen in older age-groups.
CONCLUSIONS
Our findings suggest that the link between MetS and depressive symptoms evidenced until now in middle-aged people can be extended to older adults but not to the oldest ones. Additional research is needed to examine if a better management of MetS prevents depressive symptoms in people aged 65–70 years.
doi:10.2337/dc10-1644
PMCID: PMC3064049  PMID: 21346185
20.  Overall diet history and reversibility of the metabolic syndrome over 5 years: the Whitehall II prospective cohort study 
Diabetes Care  2010;33(11):2339-2341.
Objective
We examined the impact of adherence to the Alternative Healthy Eating Index (AHEI), a set of dietary guidelines targeting major chronic diseases, on metabolic syndrome (MetS) reversion in a middle-aged population.
Research Design and Methods
Analyses were carried on the 339 participants (28% women, mean age 56.4 years) from the Whitehall II study with MetS defined by the National Cholesterol Education Program Adult treatment Panel III criteria. Reversion was defined as not having MetS after 5-years of follow-up (158 cases).
Results
After controlling for potential confounders, adherence to AHEI was associated with MetS reversion (odds ratio 1.88, 95% CI:1.04–3.41), predominantly in participants with central obesity and in those with high triglyceride.
Conclusions
Our findings support the benefit of adherence to AHEI dietary guidelines for individuals with MetS, especially those with central obesity or high triglyceride levels.
doi:10.2337/dc09-2200
PMCID: PMC2963491  PMID: 20671094
Diet; Female; Humans; Logistic Models; Male; Metabolic Syndrome X; metabolism; pathology; Middle Aged; Prospective Studies; Metabolic syndrome; Prospective study; the Alternative Healthy Eating Index
21.  Educational Disparities in Mortality Among Adults With Diabetes in the U.S. 
Diabetes Care  2010;33(6):1200-1205.
OBJECTIVE
To measure relative and absolute educational disparities in mortality among U.S. adults with diabetes and to compare their magnitude with disparities observed within the nondiabetic population.
RESEARCH DESIGN AND METHODS
A total of 85,867 individuals (5,007 with diabetes), aged 35–84 years, who participated in the National Health Interview Survey from 1986 to 1996 were followed for mortality through 31 December 2002. Relative and absolute educational disparities in all-cause, cardiovascular disease (CVD), and non-CVD mortality were measured.
RESULTS
In relative terms, the risk of all-cause mortality was 28% higher in diabetic adults with the lowest versus the highest position on the educational scale (relative index of inequality 1.28 [95% CI 1.08–1.53]). This inverse relationship reflected marked disparities in CVD mortality and was found in all age, sex, and race/ethnicity groups except Hispanics. Although substantial, this relative educational gradient in mortality among adults with diabetes was smaller than in the nondiabetic population. In absolute terms, diabetic adults with the lowest position on the educational scale suffered 503 excess deaths per 10,000 person-years of follow-up compared with those with the highest position. These absolute disparities were stronger than in the nondiabetic population. The results were even more striking for CVD mortality.
CONCLUSIONS
The risk of mortality differs substantially according to educational level among individuals with diabetes in the U.S. Although relative educational disparities in mortality are weaker in adults with versus without diabetes, their absolute impact is greater and translates into a major mortality burden.
doi:10.2337/dc09-2094
PMCID: PMC2875423  PMID: 20200302
22.  Metabolic syndrome and onset of depressive symptoms in the elderly: findings from the three-city study 
Diabetes Care  2011;34(4):904-909.
Objective
Given the increasing prevalence of both metabolic syndrome (MetS) and depressive symptoms during old age, we aimed to examine prospectively the association between MetS and onset of depressive symptoms according to different age-groups in a large general elderly population.
Research Design and Methods
Prospective cohort study of 4446 men and women aged 65 to 91 and free of depression or depressive symptoms at baseline (the Three-City study, France). MetS was defined using the NCEP-ATP III criteria. New onset of depressive symptoms (the Center for Epidemiologic Studies Depression Scale (CES-D) score≥16 and use of antidepressant treatment) was assessed at 2- and 4-year follow-ups.
Results
After adjusting for a large range of potential confounders, we observed MetS to be associated with a 1.73-fold (95% CI: 1.02–2.95) odds for new-onset depressive symptoms in the youngest age group (65 to 70 at baseline), independently of cardiovascular diseases. No such association was seen in older age groups.
Conclusion
Our findings suggest that the link between MetS and depressive symptoms evidenced until now in middle-aged can be extended to older adults but not to the oldest ones. Further research is needed to examine if a better management of MetS prevents depressive symptoms in people aged 65 to 70.
doi:10.2337/dc10-1644
PMCID: PMC3064049  PMID: 21346185
Depressive symptoms; metabolic syndrome; elderly; prospective study
23.  Insulin Reduces Plasma Arginase Activity in Type 2 Diabetes Patients 
Diabetes care  2007;31(1):134-139.
Objective
We sought to determine whether dysregulation of arginine metabolism is related to insulin resistance and underlies impaired nitric oxide generation in type 2 diabetic (T2DM) patients.
Research Design and Methods
We measured plasma arginase activity, arginine metabolites and skeletal muscle NOS activity in 12 T2DM and 10 age/BMI matched non-diabetic subjects before and following 4 hour euglycemic hyperinsulinemic clamp with muscle biopsies. Arginine metabolites were determined by tandem mass spectroscopy. Arginase activity was determined by conversion of [14C] guanidoinoarginine to [14 C] urea.
Results
Glucose disposal (Rd) was reduced by 50% in diabetic vs. control subjects. NOS activity was 4 fold reduced in the diabetic group (107 ± 45 vs. 459 ± 100 pmol/min•mg protein, P<0.05) and failed to increase with insulin. Plasma arginase activity was increased by 50% in diabetic vs. control group (0.48 ± 0.11 vs.0.32 ± 0.12 umol/ml•hr, P < 0.05) and markedly declined in diabetic subjects with 4-h insulin infusion (to 0.13 ± 0.04 vs. basal, P <0.05). In both groups collectively, plasma arginase activity correlated positively with fasting plasma glucose (R = 0.46, P < 0.05) and HbA1c levels (R = 0.51, P < 0.02), but not with Rd.
Conclusions
Plasma arginase activity is increased in T2DM subjects with impaired NOS activity, correlates with the degree of hyperglycemia, and is reduced by physiologic hyperinsulinemia. Elevated arginase activity may contribute to impaired nitric oxide generation in type 2 diabetes and insulin may ameliorate this defect via reducing arginase activity.
doi:10.2337/dc07-1198
PMCID: PMC3101496  PMID: 17928367
type 2 diabetes; insulin; arginase; nitric oxide; hyperglycemia; insulin resistance
24.  High Baseline Insulin Levels Associated With 6-Year Incident Observed Sleep Apnea 
Diabetes Care  2010;33(5):1044-1049.
OBJECTIVE
Obstructive sleep apnea is common in patients with type 2 diabetes, and its association with insulin and insulin resistance has been examined in cross-sectional studies. We evaluate risk factors for incident observed sleep apnea in a general population not selected for sleep disturbances.
RESEARCH DESIGN AND METHODS
A total of 1,780 men and 1,785 women, aged 33 to 68 years, from the cohort Data from an Epidemiologic Study on the Insulin Resistance Syndrome (D.E.S.I.R.) responded to the question, “Has someone said to you that you stop breathing during your sleep?” at baseline and 6 years. Anthropometric, clinical, and biological factors were recorded at both time points.
RESULTS
At baseline, 14% of men and 7% of women reported having observed sleep apnea (positive response to question); 6-year incidences were 14 and 6%, respectively. Age, anthropometric parameters, blood pressure, and sleep characteristics were all associated with prevalent, observed apnea episodes, in both sexes. Baseline waist circumference was the strongest predictor of incident apnea: standardized odds ratio (OR), adjusted for age and sex, 1.34 (95% CI 1.19–1.52). After adjustment for age, sex, and waist circumference, the standardized ORs for incident observed apnea were identical for fasting insulin and the homeostasis model assessment of insulin resistance: 1.31 (1.13–1.51) and 1.24 (1.09–1.41) for triglycerides and 1.52 (1.12–2.05) for smoking. Observed apnea at baseline was not associated with changes in anthropometric or biological parameters over the 6-year follow-up.
CONCLUSIONS
The most important baseline risk factor for incident apnea was adiposity. After accounting for adiposity, other risk factors were high insulin, insulin resistance, high triglycerides, and smoking, factors amenable to lifestyle intervention.
doi:10.2337/dc09-1901
PMCID: PMC2858172  PMID: 20185739
25.  Calcium Plus Vitamin D Supplementation and the Risk of Incident Diabetes in the Women's Health Initiative 
Diabetes care  2008;31(4):701-707.
Objective
Experimental and epidemiologic studies suggest that calcium and vitamin D may reduce the risk of developing diabetes. We examined the effect of calcium plus vitamin D supplementation on the incidence of drug-treated diabetes in postmenopausal women.
Research Design and Methods
The Women's Health Initiative Calcium/Vitamin D Trial randomly assigned postmenopausal women to receive 1,000 mg elemental calcium plus 400 IU of vitamin D3 daily, or placebo, in a double-blind fashion. Among 33,951 participants without self-reported diabetes at baseline, we ascertained by treatment assignment new diagnoses of diabetes treated with oral hypoglycemic agents or insulin. Effects of the intervention on fasting measurements of glucose, insulin, and insulin resistance were examined among a subset of participants.
Results
Over a median follow-up time of 7 years, 2,291 women were newly diagnosed with diabetes. The hazard ratio for incident diabetes associated with calcium/vitamin D treatment was 1.01 (95% CI 0.94 –1.10) based on intention to treat. This null result was robust in subgroup analyses, efficacy analyses accounting for nonadherence, and analyses examining change in laboratory measurements.
Conclusions
Calcium plus vitamin D3 supplementation did not reduce the risk of developing diabetes over 7 years of follow-up in this randomized placebo-controlled trial. Higher doses of vitamin D may be required to affect diabetes risk, and/or associations of calcium and vitamin D intake with improved glucose metabolism observed in nonrandomized studies may be the result of confounding or of other components of foods containing these nutrients.
doi:10.2337/dc07-1829
PMCID: PMC3046029  PMID: 18235052

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