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2.  Impact of Islet Autoimmunity on the Progressive β-Cell Functional Decline in Type 2 Diabetes 
Diabetes Care  2014;37(12):3286-3293.
OBJECTIVE
Cross-sectional studies have suggested that islet autoimmunity may be more prevalent in type 2 diabetes (T2D) than previously appreciated and may contribute to the progressive decline in β-cell function. In this study, we longitudinally evaluated the effect of islet autoimmune development on the progressive β-cell dysfunction in T2D patients.
RESEARCH DESIGN AND METHODS
Twenty-three T2D patients negative for islet autoantibodies (GAD antibody and insulinoma-associated protein 2) and islet-specific T cells were evaluated prospectively for up to 36 months. We investigated the percentage of patients who developed islet autoantibodies (Ab+) and/or islet-reactive T cells (T+) and the effect of the islet autoimmunity on fasting and glucagon-stimulated C-peptide responses. We defined positive islet autoimmunity as Ab+ and/or T+ for at least two study visits.
RESULTS
Of the 23 patients, 6 (26%) remained negative for islet autoimmunity (Ab−T−), 14 (61%) developed Ab+ and/or T+, and 3 (13%) were unclassifiable because they developed islet autoimmunity at only one study visit. Islet Ab+ was observed to be less stable than islet-specific T-cell responses. Development of islet autoimmunity was significantly associated with a more rapid decline in fasting (P < 0.0001) and glucagon-stimulated (P < 0.05) C-peptide responses.
CONCLUSIONS
These pilot data suggest that the development of islet autoimmunity in T2D is associated with a significantly more rapid β-cell functional decline.
doi:10.2337/dc14-0961
PMCID: PMC4237971  PMID: 25239783
3.  Effect of Hypoglycemia on Brain Structure in People With Type 2 Diabetes: Epidemiological Analysis of the ACCORD-MIND MRI Trial 
Diabetes Care  2014;37(12):3279-3285.
OBJECTIVE
The effect of hypoglycemia related to treatment of type 2 diabetes mellitus (T2DM) on brain structure remains unclear. We aimed to assess whether symptomatic severe hypoglycemia is associated with brain atrophy and/or white matter abnormalities.
RESEARCH DESIGN AND METHODS
We included T2DM participants with brain MRI from the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) trial. Symptomatic severe hypoglycemia was defined as blood glucose <2.8 mmol/L or symptoms resolved with treatments that required the assistance of another person or medical assistance (hypoglycemia requiring assistance [HA]). Standardized brain MRI was performed at baseline and at 40 months. Total brain volume (TBV) and abnormal white matter (AWM) volume were calculated using an automated computer algorithm. Brain MRI scans of hypoglycemic participants were also reviewed for local disease.
RESULTS
Of the 503 T2DM participants (mean age, 62 years) with successful baseline and 40-month brain MRI, 28 had at least one HA episode during the 40-month follow-up. Compared with participants without HA, those with HA had marginally significant less atrophy (less decrease in TBV) from baseline to 40 months (−9.55 [95% CI −15.21, −3.90] vs. −15.38 [95% CI −16.64, −14.12], P = 0.051), and no significant increase of AWM volume (2.06 [95% CI 1.71, 2.49] vs. 1.84 [95% CI 1.76, 1.91], P = 0.247). In addition, no unexpected local signal changes or volume loss were seen on hypoglycemic participants’ brain MRI scans.
CONCLUSIONS
Our study suggests that hypoglycemia related to T2DM treatment may not accentuate brain pathology, specifically brain atrophy or white matter abnormalities.
doi:10.2337/dc14-0973
PMCID: PMC4237972  PMID: 25267796
4.  Rationale and Design of the Vitamin D and Type 2 Diabetes (D2d) Study: A Diabetes Prevention Trial 
Diabetes Care  2014;37(12):3227-3234.
OBJECTIVE
Observational studies suggest that vitamin D may lower the risk of type 2 diabetes. However, data from long-term trials are lacking. The Vitamin D and Type 2 Diabetes (D2d) study is a randomized clinical trial designed to examine whether a causal relationship exists between vitamin D supplementation and the development of diabetes in people at high risk for type 2 diabetes.
RESEARCH DESIGN AND METHODS
D2d was designed with support from a U34 planning grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The final protocol was approved by the D2d Research Group, the data and safety monitoring board, and NIDDK. Key eligibility criteria are age ≥30 years, BMI of 24 (22.5 for Asian Americans) to 42 kg/m2, increased risk for diabetes (defined as meeting two of three glycemic criteria for prediabetes established by the American Diabetes Association [fasting glucose 100–125 mg/dL (5.5–6.9 mmol/L), 2-h postload glucose after 75-g glucose load 140–199 mg/dL (7.7–11.0 mmol/L), hemoglobin A1c 5.7–6.4% (39–46 mmol/mol)]), and no hyperparathyroidism, nephrolithiasis, or hypercalcemia. D2d participants are randomized to once-daily vitamin D3 (cholecalciferol 4,000 IU) or placebo and followed for an average of 3 years. The primary end point is time to incident diabetes as assessed by laboratory criteria during the study or by adjudication if diagnosed outside of D2d. Recruitment was initiated at the end of 2013.
CONCLUSIONS
D2d will test whether vitamin D supplementation is safe and effective at lowering the risk of progression to diabetes in people at high risk for type 2 diabetes.
doi:10.2337/dc14-1005
PMCID: PMC4237973  PMID: 25205139
5.  Incidence of Remission in Adults With Type 2 Diabetes: The Diabetes & Aging Study 
Diabetes Care  2014;37(12):3188-3195.
OBJECTIVE
To estimate the incidence of remission in adults with type 2 diabetes not treated with bariatric surgery and to identify variables associated with remission.
RESEARCH DESIGN AND METHODS
We quantified the incidence of diabetes remission and examined its correlates among 122,781 adults with type 2 diabetes in an integrated healthcare delivery system. Remission required the absence of ongoing drug therapy and was defined as follows: 1) partial: at least 1 year of subdiabetic hyperglycemia (hemoglobin A1c [HbA1c] level 5.7–6.4% [39–46 mmol/mol]); 2) complete: at least 1 year of normoglycemia (HbA1c level <5.7% [<39 mmol/mol]); and 3) prolonged: complete remission for at least 5 years.
RESULTS
The incidence density (remissions per 1,000 person-years; 95% CI) of partial, complete, or prolonged remission was 2.8 (2.6–2.9), 0.24 (0.20–0.28), and 0.04 (0.01–0.06), respectively. The 7-year cumulative incidence of partial, complete, or prolonged remission was 1.47% (1.40–1.54%), 0.14% (0.12–0.16%), and 0.007% (0.003–0.020%), respectively. The 7-year cumulative incidence of achieving any remission was 1.60% in the whole cohort (1.53–1.68%) and 4.6% in the subgroup with new-onset diabetes (<2 years since diagnosis) (4.3–4.9%). After adjusting for demographic and clinical characteristics, correlates of remission included age >65 years, African American race, <2 years since diagnosis, baseline HbA1c level <5.7% (<39 mmol/mol), and no diabetes medication at baseline.
CONCLUSIONS
In community settings, remission of type 2 diabetes does occur without bariatric surgery, but it is very rare.
doi:10.2337/dc14-0874
PMCID: PMC4237974  PMID: 25231895
7.  High Calorie Intake Is Associated With Worsening Insulin Resistance and β-Cell Function in Hispanic Women After Gestational Diabetes Mellitus 
Diabetes Care  2014;37(12):3294-3300.
OBJECTIVE
To assess associations between dietary intake and rates of change in insulin resistance and β-cell function in Hispanic women with prior gestational diabetes mellitus (GDM).
RESEARCH DESIGN AND METHODS
Sixty-two nondiabetic Hispanic women with pregnancies complicated by GDM completed oral and intravenous glucose tolerance tests and bioelectrical impedance measurements of body fat every 12–15 months postpartum for up to 12 years. Self-reported dietary intake was collected at all visits by structured food frequency questionnaires developed for Hispanics. Mixed-effects models were used to assess the relationship between dietary intake and rates of change in metabolic outcomes during follow-up.
RESULTS
The median length of follow-up from the first postpartum evaluation was 8.0 years (interquartile range 4.5–10.8 years). At baseline, women were 32 ± 5.7 years old and had a median calorie intake of 2,091 kcal/day. Over the course of follow-up, dietary intake did not change significantly. Higher baseline calorie intake was associated with a faster decline in insulin sensitivity, measured by the insulin sensitivity index (SI) (P = 0.029), and β-cell compensation, measured by the disposition index (DI) (P = 0.027), over time. These associations remained after adjustment for baseline characteristics; changes in BMI, calorie intake, levels of physical activity; and additional pregnancies during the follow-up period. The median rates were −0.06 vs. −0.02 units/year for SI and −810 vs. −692 units/year for DI for women with baseline calorie intake above versus below the cohort median.
CONCLUSIONS
High calorie intake is associated with a faster decline in insulin sensitivity and β-cell compensation in Hispanic women who are at high risk for type 2 diabetes, independent of adiposity.
doi:10.2337/dc14-1433
PMCID: PMC4237976  PMID: 25404660
8.  Glycated Hemoglobin and All-Cause and Cause-Specific Mortality in Singaporean Chinese Without Diagnosed Diabetes: The Singapore Chinese Health Study 
Diabetes Care  2014;37(12):3180-3187.
OBJECTIVE
Glycated hemoglobin (HbA1c) is a robust biomarker of the preceding 2 to 3 months average blood glucose level. The aim of this study was to examine the association between HbA1c and mortality in a cohort of Southeast Asians.
RESEARCH DESIGN AND METHODS
Analysis of 7,388 men and women, mean age 62 years, from the Singapore Chinese Health Study who provided a blood sample at the follow-up I visit (1999–2004) and reported no history of diabetes, previous adverse cardiovascular events, or cancer. A total of 888 deaths were identified through 31 December 2011 via registry linkage. Participants represented a random study sample of potential control subjects for a nested case-control genome-wide association study of type 2 diabetes in the population. Hazard ratios (HRs) for all-cause and cause-specific mortality by six categories of HbA1c were estimated with Cox regression models.
RESULTS
Relative to participants with an HbA1c of 5.4–5.6% (36–38 mmol/mol), participants with HbA1c ≥6.5% (≥48 mmol/mol) had an increased risk of all-cause, cardiovascular, and cancer mortality during an average of 10.1 years of follow-up; HRs (95% CIs) were 1.96 (1.56–2.46), 2.63 (1.77–3.90), and 1.51 (1.04–2.18), respectively. No level of HbA1c was associated with increased risk of respiratory mortality. Levels <6.5% HbA1c were not associated with mortality during follow-up. The results did not materially change after excluding observation of first 3 years post–blood draw.
CONCLUSIONS
HbA1c levels consistent with undiagnosed type 2 diabetes (≥6.5%) are associated with an increased risk of all-cause and cause-specific mortality in Chinese men and women.
doi:10.2337/dc14-0390
PMCID: PMC4237977  PMID: 25216509
9.  HDL Cholesterol and Cancer Risk Among Patients With Type 2 Diabetes 
Diabetes Care  2014;37(12):3196-3203.
OBJECTIVE
To investigate the relationship between HDL cholesterol (HDL-C) and cancer risk among type 2 diabetic patients.
RESEARCH DESIGN AND METHODS
We performed a retrospective cohort study of 14,169 men and 23,176 women with type 2 diabetes. Cox proportional hazards regression models were used to estimate the association of various levels of HDL cholesterol (HDL-C) with cancer risk.
RESULTS
During a mean follow-up period of 6.4 years, 3,711 type 2 diabetic patients had a cancer diagnosis. A significant inverse association between HDL-C and the risk of cancer was found among men and women. The multivariable-adjusted hazard ratios (HRs) of cancer at various levels of HDL-C at baseline (<30, 30–39.9, 40–49.9, 50–59.9, 60–69.9, 70–79.9, and ≥80 mg/dL) were 1.00, 0.87, 0.95, 1.01, 0.61, 0.45, and 0.37, respectively, in men (Ptrend = 0.027) and 1.00, 0.98, 0.88, 0.85, 0.84, 0.86, and 0.84, respectively, in women (Ptrend = 0.025). When stratified by race, BMI, smoking status, or medication use, the inverse association was still present. With an updated mean of HDL-C used in the analysis, the inverse association of HDL-C with cancer risk did not change. The inverse association substantially attenuated after excluding patients who died of or were diagnosed with cancer during the first 2 years of follow-up.
CONCLUSIONS
The study suggests an inverse association of HDL-C with cancer risk among men and women with type 2 diabetes, whereas the effect of HDL-C was partially mediated by reverse causation.
doi:10.2337/dc14-0523
PMCID: PMC4237978  PMID: 25216507
10.  BMI and Coronary Heart Disease Risk Among Low-Income and Underinsured Diabetic Patients 
Diabetes Care  2014;37(12):3204-3212.
OBJECTIVE
The association between obesity and coronary heart disease (CHD) risk remains debatable, and no studies have assessed this association among diabetic patients. The aim of our study was to investigate the association between BMI and CHD risk among patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS
The sample included 30,434 diabetic patients (10,955 men and 19,479 women) 30–95 years of age without a history of CHD or stroke in the Louisiana State University Hospital-Based Longitudinal Study.
RESULTS
During a mean follow-up period of 7.3 years, 7,414 subjects developed CHD. The multivariable-adjusted hazard ratios for CHD across levels of BMI at baseline (18.5–24.9, 25–29.9, 30–34.9, 35–39.9, and ≥40 kg/m2) were 1.00, 1.14 (95% CI 1.00–1.29), 1.27 (1.12–1.45), 1.54 (1.34–1.78), and 1.42 (1.23–1.64) (Ptrend < 0.001) in men and 1.00, 0.95 (0.85–1.07), 0.95 (0.84–1.06), 1.06 (0.94–1.20), and 1.09 (1.00–1.22) (Ptrend < 0.001) in women, respectively. When we used an updated mean or last visit value of BMI, the positive association between BMI and CHD risk did not change in men. However, the positive association of BMI with CHD changed to a U-shaped association in women when we used the last visit value of BMI.
CONCLUSIONS
Our study suggests that there is a positive association between BMI at baseline and during follow-up with the risk of CHD among patients with type 2 diabetes. We indicate a U-shaped association between BMI at the last visit and the risk of CHD among women with type 2 diabetes.
doi:10.2337/dc14-1091
PMCID: PMC4237979  PMID: 25249653
11.  The Cross-sectional and Longitudinal Associations of Diabetic Retinopathy With Cognitive Function and Brain MRI Findings: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial 
Diabetes Care  2014;37(12):3244-3252.
OBJECTIVE
Longitudinal evidence linking diabetic retinopathy with changes in brain structure and cognition is sparse. We used data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to determine whether diabetic retinopathy at baseline predicted changes in brain structure or cognition 40 months later.
RESEARCH DESIGN AND METHODS
Participants from the ACCORD-MIND and ACCORD-Eye substudies were included in analyses of cognition (n = 1,862) and MRI-derived brain variables (n = 432). Retinopathy was categorized as none, mild nonproliferative, or moderate/severe. Tests of cognition included the Mini-Mental State Examination (MMSE), Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test, and Stroop test. Primary brain outcomes were gray matter and abnormal white matter volumes.
RESULTS
Baseline retinopathy was associated with lower gray matter volume (adjusted means of 470, 466, and 461 cm3 for none, mild, and moderate/severe retinopathy, respectively; P = 0.03). Baseline retinopathy also predicted a greater change in MMSE and DSST scores at 40 months in each retinopathy category (MMSE: −0.20, −0.57, and −0.42, respectively [P = 0.04]; DSST: −1.30, −1.84, and −2.89, respectively[P = 0.01]).
CONCLUSIONS
Diabetic retinopathy is associated with future cognitive decline in people with type 2 diabetes. Although diabetic retinopathy is not a perfect proxy for diabetes-related brain and cognitive decline, patients with type 2 diabetes and retinopathy represent a subgroup at higher risk for future cognitive decline.
doi:10.2337/dc14-0502
PMCID: PMC4237980  PMID: 25193529
12.  The SEARCH for Diabetes in Youth Study: Rationale, Findings, and Future Directions 
Diabetes Care  2014;37(12):3336-3344.
The SEARCH for Diabetes in Youth (SEARCH) study was initiated in 2000, with funding from the Centers for Disease Control and Prevention and support from the National Institute of Diabetes and Digestive and Kidney Diseases, to address major knowledge gaps in the understanding of childhood diabetes. SEARCH is being conducted at five sites across the U.S. and represents the largest, most diverse study of diabetes among U.S. youth. An active registry of youth diagnosed with diabetes at age <20 years allows the assessment of prevalence (in 2001 and 2009), annual incidence (since 2002), and trends by age, race/ethnicity, sex, and diabetes type. Prevalence increased significantly from 2001 to 2009 for both type 1 and type 2 diabetes in most age, sex, and race/ethnic groups. SEARCH has also established a longitudinal cohort to assess the natural history and risk factors for acute and chronic diabetes-related complications as well as the quality of care and quality of life of persons with diabetes from diagnosis into young adulthood. Many youth with diabetes, particularly those from low-resourced racial/ethnic minority populations, are not meeting recommended guidelines for diabetes care. Markers of micro- and macrovascular complications are evident in youth with either diabetes type, highlighting the seriousness of diabetes in this contemporary cohort. This review summarizes the study methods, describes key registry and cohort findings and their clinical and public health implications, and discusses future directions.
doi:10.2337/dc14-0574
PMCID: PMC4237981  PMID: 25414389
13.  Changes in Adipose Tissue Depots and Metabolic Markers Following a 1-Year Diet and Exercise Intervention in Overweight and Obese Patients With Type 2 Diabetes 
Diabetes Care  2014;37(12):3325-3332.
OBJECTIVE
We aim to characterize the effects on total body fat and distribution of a 1-year intensive lifestyle intervention (ILI) for weight loss in overweight and obese adults with type 2 diabetes and to examine whether changes in adipose tissue (AT) depots were associated with changes in metabolic biomarkers.
RESEARCH DESIGN AND METHODS
Participants were 54 females and 38 males (age 57.8 ± 6.7 years [mean ± SD]; BMI 31.7 ± 3.5 kg/m2) enrolled in the Look AHEAD (Action for Health in Diabetes) trial randomized to ILI or diabetes support and education (DSE) from whom baseline and 1-year MRI measures of total AT (TAT) and regional (arm, trunk, leg) AT, including subcutaneous AT (SAT), visceral AT (VAT), and intermuscular AT (IMAT), were acquired. We tested whether mean changes in ILI and DSE were equal and, within groups, whether changes were different from zero. Regression models tested whether changes in AT compartments were associated with metabolic variable changes.
RESULTS
Body weight changed −0.52 ± 3.62 kg (P = 0.31) in DSE and −7.24 ± 5.40 kg (P < 0.0001) in ILI. Mean ILI changes were different from DSE (P < 0.001 for TAT, SAT, and IMAT and P < 0.01 for VAT in females). Within ILI, SAT and VAT decreased in males and females (P < 0.0001), but IMAT was unchanged (0.00 ± 0.54 kg; P = 0.99). In DSE, SAT and VAT did not change, but IMAT increased by 0.46 ± 0.55 kg (P < 0.001). Controlling for weight loss, reduction of specific AT depots was associated with improvement in metabolic biomarkers.
CONCLUSIONS
Weight loss of 7–10% from an ILI over 1 year reduced SAT and VAT and prevented an increase in IMAT. Reductions in AT depots were associated with improvements in biomarkers.
doi:10.2337/dc14-1585
PMCID: PMC4237982  PMID: 25336745
14.  Adipose Tissue, Muscle, and Function: Potential Mediators of Associations Between Body Weight and Mortality in Older Adults With Type 2 Diabetes 
Diabetes Care  2014;37(12):3213-3219.
OBJECTIVE
Studies in type 2 diabetes report both increased mortality for normal weight and no evidence of an obesity paradox. We aimed to examine whether adipose tissue, muscle size, and physical function, which are known to vary by weight, mediate associations between BMI and mortality.
RESEARCH DESIGN AND METHODS
The AGES-Reykjavik cohort comprised participants aged 66–96 years with diabetes defined by fasting glucose, medications, or self-report. BMI was determined from measured height and weight and classified as normal (18.5–24.9 kg/m2, n = 117), overweight (25.0–29.9 kg/m2, n = 293, referent group) or obese (≥30.0 kg/m2, n = 227). Thigh muscle area and intermuscular, visceral, and subcutaneous adipose tissues were assessed with computed tomography. Function was assessed from gait speed and knee extensor strength. Hazard ratios (HRs) and 95% CIs were estimated by Cox proportional hazards regression adjusted for demographics and diabetes-related risk factors.
RESULTS
The median follow-up was 6.66 years, and there were 85, 59, and 44 deaths among normal weight, overweight, and obese participants, respectively. There was no mortality risk for obese participants and an increased risk among normal weight compared with overweight participants (HR 1.72 [95% CI 1.12–2.64]). Associations remained with adjustment for adipose tissues and knee extensor strength; however, mortality risk for normal weight was attenuated following adjustment for thigh muscle (HR 1.36 [95% CI 0.87–2.11]) and gait speed (HR 1.44 [95% CI 0.91–2.27]). Linear regression confirmed with bootstrapping indicated that thigh muscle size mediated 46% of the relationship between normal weight and mortality.
CONCLUSIONS
Normal weight participants had elevated mortality risk compared with overweight participants. This paradoxical association was mediated in part by muscle size.
doi:10.2337/dc14-0293
PMCID: PMC4237983  PMID: 25315206
15.  Randomized Trial of Telephone Outreach to Improve Medication Adherence and Metabolic Control in Adults With Diabetes 
Diabetes Care  2014;37(12):3317-3324.
OBJECTIVE
Medication nonadherence is a major obstacle to better control of glucose, blood pressure (BP), and LDL cholesterol in adults with diabetes. Inexpensive effective strategies to increase medication adherence are needed.
RESEARCH DESIGN AND METHODS
In a pragmatic randomized trial, we randomly assigned 2,378 adults with diabetes mellitus who had recently been prescribed a new class of medication for treating elevated levels of glycated hemoglobin (A1C) ≥8% (64 mmol/mol), BP ≥140/90 mmHg, or LDL cholesterol ≥100 mg/dL, to receive 1) one scripted telephone call from a diabetes educator or clinical pharmacist to identify and address nonadherence to the new medication or 2) usual care. Hierarchical linear and logistic regression models were used to assess the impact on 1) the first medication fill within 60 days of the prescription; 2) two or more medication fills within 180 days of the prescription; and 3) clinically significant improvement in levels of A1C, BP, or LDL cholesterol.
RESULTS
Of the 2,378 subjects, 89.3% in the intervention group and 87.4% in the usual-care group had sufficient data to analyze study outcomes. In intent-to-treat analyses, intervention was not associated with significant improvement in primary adherence, medication persistence, or intermediate outcomes of care. Results were similar across subgroups of patients defined by age, sex, race/ethnicity, and study site, and when limiting the analysis to those who completed the intended intervention.
CONCLUSIONS
This low-intensity intervention did not significantly improve medication adherence or control of glucose, BP, or LDL cholesterol. Wide use of this strategy does not appear to be warranted; alternative approaches to identify and improve medication adherence and persistence are needed.
doi:10.2337/dc14-0596
PMCID: PMC4751474  PMID: 25315207
16.  The Look AHEAD Trial: Bone Loss at 4-Year Follow-up in Type 2 Diabetes 
Diabetes Care  2014;37(10):2822-2829.
OBJECTIVE
To determine whether an intensive lifestyle intervention (ILI) designed to sustain weight loss and improve physical fitness in overweight or obese persons with type 2 diabetes was associated with bone loss after 4 years of follow-up.
RESEARCH DESIGN AND METHODS
This randomized controlled trial of intensive weight loss compared an ILI with a diabetes support and education (DSE) group among 1,309 overweight or obese subjects. Bone mineral density was assessed at baseline and after 1 year and 4 years of intervention.
RESULTS
ILI was effective in producing significant weight loss (5.3% vs. 1.8% in ILI and DSE, respectively; P < 0.01) and increased fitness (6.4% vs. −0.8%) at year 4. In men, ILI participants had a greater rate of bone loss during the first year (−1.66% vs. −0.09% per year in ILI and DSE, respectively). Differences between groups were diminished by one-half after 4 years (−0.88% vs. −0.05% per year in ILI and DSE, respectively) but remained significant (P < 0.01). The difference in rate of hip bone loss between groups over 4 years was related to increased weight loss in ILI. Among women, the rate of bone loss did not differ between ILI and DSE after 4 years.
CONCLUSIONS
A 4-year weight loss intervention was significantly associated with a modest increase in bone loss at the hip in men but not in women.
doi:10.2337/dc14-0762
PMCID: PMC4170123  PMID: 25048381
17.  Cultures of Diabetic Foot Ulcers Without Clinical Signs of Infection Do Not Predict Outcomes 
Diabetes Care  2014;37(10):2693-2701.
OBJECTIVE
We examined associations between ulcer bioburden and ulcer outcomes in neuropathic diabetic foot ulcers (DFUs) that lacked clinical signs of infection.
RESEARCH DESIGN AND METHODS
Three dimensions of bioburden (i.e., microbial load, microbial diversity, and the presence of likely pathogens) were measured at baseline using swab cultures obtained by Levine’s technique. Subjects were assessed every 2 weeks for 26 weeks to determine the rate of healing and development of infection-related complications. Foot ulcers were off-loaded using total-contact casts and routinely debrided. To establish associations between bioburden and rate of healing, Cox proportional hazards and least squares regression were used after adjusting for ulcer depth, surface area, and duration.
RESULTS
A total of 77 subjects completed the study. Sixty-five (84.4%) had ulcers that healed during follow-up; weeks-to-closure ranged from 2 to 26 (median 4.0). Mean (± SD) percent reduction in surface area/week was 25.0% (± 23.33). Five (6.5%) of the DFUs developed an infection-related complication. None of the bioburden dimensions (i.e., microbial load, microbial diversity, or presence of likely pathogens) was significantly associated with weeks-to-closure or percent reduction in surface area per week. Weeks-to-closure was best predicted by ulcer duration, depth, and surface area (c-statistic = 0.75).
CONCLUSIONS
Culturing DFUs that showed no clinical signs of infection had no predictive value for outcomes of DFUs managed with total-contact casts and routine debridement. These findings support recommendations of the Infectious Disease Society of America that culturing and antibiotics should be avoided in treating DFUs that show no clinical signs of infection.
doi:10.2337/dc14-0051
PMCID: PMC4170124  PMID: 25011945
18.  We Can Change the Natural History of Type 2 Diabetes 
Diabetes Care  2014;37(10):2668-2676.
As diabetes develops, we currently waste the first ∼10 years of the natural history. If we found prediabetes and early diabetes when they first presented and treated them more effectively, we could prevent or delay the progression of hyperglycemia and the development of complications. Evidence for this comes from trials where lifestyle change and/or glucose-lowering medications decreased progression from prediabetes to diabetes. After withdrawal of these interventions, there was no “catch-up”—cumulative development of diabetes in the previously treated groups remained less than in control subjects. Moreover, achieving normal glucose levels even transiently during the trials was associated with a substantial reduction in subsequent development of diabetes. These findings indicate that we can change the natural history through routine screening to find prediabetes and early diabetes, combined with management aimed to keep glucose levels as close to normal as possible, without hypoglycemia. We should also test the hypothesis with a randomized controlled trial.
doi:10.2337/dc14-0817
PMCID: PMC4170125  PMID: 25249668
19.  Effects of Weight Loss, Weight Cycling, and Weight Loss Maintenance on Diabetes Incidence and Change in Cardiometabolic Traits in the Diabetes Prevention Program 
Diabetes Care  2014;37(10):2738-2745.
OBJECTIVE
This study examined specific measures of weight loss in relation to incident diabetes and improvement in cardiometabolic risk factors.
RESEARCH DESIGN AND METHODS
This prospective, observational study analyzed nine weight measures, characterizing baseline weight, short- versus long-term weight loss, short- versus long-term weight regain, and weight cycling, within the Diabetes Prevention Program (DPP) lifestyle intervention arm (n = 1,000) for predictors of incident diabetes and improvement in cardiometabolic risk factors over 2 years.
RESULTS
Although weight loss in the first 6 months was protective of diabetes (hazard ratio [HR] 0.94 per kg, 95% CI 0.90, 0.98; P < 0.01) and cardiometabolic risk factors (P < 0.01), weight loss from 0 to 2 years was the strongest predictor of reduced diabetes incidence (HR 0.90 per kg, 95% CI 0.87, 0.93; P < 0.01) and cardiometabolic risk factor improvement (e.g., fasting glucose: β = −0.57 mg/dL per kg, 95% CI −0.66, −0.48; P < 0.01). Weight cycling (defined as number of 5-lb [2.25-kg] weight cycles) ranged 0–6 times per participant and was positively associated with incident diabetes (HR 1.33, 95% CI 1.12, 1.58; P < 0.01), fasting glucose (β = 0.91 mg/dL per cycle; P = 0.02), HOMA-IR (β = 0.25 units per cycle; P = 0.04), and systolic blood pressure (β = 0.94 mmHg per cycle; P = 0.01). After adjustment for baseline weight, the effect of weight cycling remained statistically significant for diabetes risk (HR 1.22, 95% CI 1.02, 1.47; P = 0.03) but not for cardiometabolic traits.
CONCLUSIONS
Two-year weight loss was the strongest predictor of reduced diabetes risk and improvements in cardiometabolic traits.
doi:10.2337/dc14-0018
PMCID: PMC4170126  PMID: 25024396
20.  Effect of 8 Weeks of Overfeeding on Ectopic Fat Deposition and Insulin Sensitivity: Testing the “Adipose Tissue Expandability” Hypothesis 
Diabetes Care  2014;37(10):2789-2797.
OBJECTIVE
The presence of large subcutaneous adipocytes in obesity has been proposed to be linked with insulin resistance and type 2 diabetes through the “adipose tissue expandability” hypothesis, which holds that large adipocytes have a limited capacity for expansion, forcing lipids to be stored in nonadipose ectopic depots (skeletal muscle, liver), where they interfere with insulin signaling. This hypothesis has, however, been largely formulated by cross-sectional findings and to date has not been prospectively demonstrated in the development of insulin resistance in humans.
RESEARCH DESIGN AND METHODS
Twenty-nine men (26.8 ± 5.4 years old; BMI 25.5 ± 2.3 kg/m2) were fed 40% more than their baseline requirement for 8 weeks. Before and after overfeeding, insulin sensitivity was determined using a two-step hyperinsulinemic-euglycemic clamp. Intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) were measured by 1H-MRS and abdominal fat by MRI. Subcutaneous abdominal adipose and skeletal muscle tissues were collected to measure adipocyte size and markers of tissue inflammation.
RESULTS
Subjects gained 7.6 ± 2.1 kg (55% fat) and insulin sensitivity decreased 18% (P < 0.001) after overfeeding. IHL increased 46% from 1.5% to 2.2% (P = 0.002); however, IMCL did not change. There was no association between adipocyte size and ectopic lipid accumulation. Despite similar weight gain, subjects with smaller fat cells at baseline had a greater decrease in insulin sensitivity, which was linked with upregulated skeletal muscle tissue inflammation.
CONCLUSIONS
In experimental substantial weight gain, the presence of larger adipocytes did not promote ectopic lipid accumulation. In contrast, smaller fat cells were associated with a worsened metabolic response to overfeeding.
doi:10.2337/dc14-0761
PMCID: PMC4170127  PMID: 25011943
22.  Blood Pressure and Pulse Pressure Effects on Renal Outcomes in the Veterans Affairs Diabetes Trial (VADT) 
Diabetes Care  2014;37(10):2782-2788.
OBJECTIVE
Blood pressure (BP) control for renal protection is essential for patients with type 2 diabetes. Our objective in this analysis of Veterans Affairs Diabetes Trial (VADT) data was to learn whether on-study systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) affected renal outcomes measured as albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR).
RESEARCH DESIGN AND METHODS
The VADT was a prospective, randomized study of 1,791 veterans with type 2 diabetes to determine whether intensive glucose control prevented major cardiovascular events. In this post hoc study, time-varying covariate survival analyses and hazard ratios (HR) were used to determine worsening of renal outcomes.
RESULTS
Compared with SBP 105–129 mmHg, the risk of ACR worsening increased significantly for SBP 130–139 mmHg (HR 1.88 [95% CI 1.28–2.77]; P = 0.001) and for SBP ≥140 mmHg (2.51 [1.66–3.78]; P < 0.0001). Compared with a PP range of 40–49 mmHg, PP <40 was associated with significantly lowered risk of worsening ACR (0.36 [0.15–0.87]; P = 0.022) and PP ≥60 with significantly increased risk (2.38 [1.58–3.59]; P < 0.0001). Analyses of BP ranges associated with eGFR worsening showed significantly increased risk with rising baseline SBP and an interaction effect between SBP ≥140 mmHg and on-study A1C. These patients were 15% more likely than those with SBP <140 mmHg to experience eGFR worsening (1.15 [1.00–1.32]; P = 0.045) for each 1% (10.9 mmol/mol) A1C increase.
CONCLUSIONS
SBP ≥130 mmHg and PP >60 mmHg were associated with worsening ACR. The results suggest that treatment of SBP to <130 mmHg may lessen ACR worsening. The interaction between SBP ≥140 mmHg and A1C suggests that the effect of glycemic control on reducing progression of renal disease may be greater in hypertensive patients.
doi:10.2337/dc14-0284
PMCID: PMC4170129  PMID: 25048382
24.  Diabetic Kidney Disease: A Report From an ADA Consensus Conference 
Diabetes Care  2014;37(10):2864-2883.
The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly $25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included 1) identification and monitoring, 2) cardiovascular disease and management of dyslipidemia, 3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, 4) glycemia measurement, hypoglycemia, and drug therapies, 5) nutrition and general care in advanced-stage chronic kidney disease, 6) children and adolescents, and 7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD.
doi:10.2337/dc14-1296
PMCID: PMC4170131  PMID: 25249672
25.  Real-Time Continuous Glucose Monitoring Among Participants in the T1D Exchange Clinic Registry 
Diabetes Care  2014;37(10):2702-2709.
OBJECTIVE
To assess the frequency of continuous glucose monitoring (CGM) device use, factors associated with its use, and the relationship of CGM with diabetes outcomes (HbA1c, severe hypoglycemia [SH], and diabetic ketoacidosis [DKA]).
RESEARCH DESIGN AND METHODS
Survey questions related to CGM device use 1 year after enrollment in the T1D Exchange clinic registry were completed by 17,317 participants. Participants were defined as CGM users if they indicated using real-time CGM during the prior 30 days.
RESULTS
Nine percent of participants used CGM (6% of children <13 years old, 4% of adolescents 13 to <18 years, 6% of young adults 18 to <26 years, and 21% of adults ≥26 years). CGM use was more likely with higher education, higher household income, private health insurance, longer duration of diabetes, and use of insulin pump (P < 0.01 all factors). CGM use was associated with lower HbA1c in children (8.3% vs. 8.6%, P < 0.001) and adults (7.7% vs. 7.9%, P < 0.001). In adults, more frequent use of CGM (≥6 days/week) was associated with lower mean HbA1c. Only 27% of users downloaded data from their device at least once per month, and ≤15% of users reported downloading their device at least weekly. Among participants who used CGM at baseline, 41% had discontinued within 1 year.
CONCLUSIONS
CGM use is uncommon but associated with lower HbA1c in some age-groups, especially when used more frequently. Factors associated with discontinuation and infrequent use of retrospective analysis of CGM data should be considered in developing next-generation devices and education on CGM use.
doi:10.2337/dc14-0303
PMCID: PMC4392936  PMID: 25011947

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