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OBJECTIVE To describe the relationships between the cumulative incidences of long-term complications in individuals with type 1 diabetes (T1D) and assess whether observed associations are independent of age, duration of diabetes, and glycemic levels. METHODS Proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), reduced estimated glomerular filtration rate (eGFR), amputations, cardiovascular disease (CVD), and mortality were assessed in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study over ∼30 years. RESEARCH DESIGN AND RESULTS The cumulative incidence of complications ranged from 3% (amputations) to 37% (CSME). There were large differences in the cumulative incidence of PDR between participants with versus without prior CSME (66% vs. 15%), reduced eGFR (59% vs. 29%), and amputation (68% vs. 32%); reduced eGFR with or without prior PDR (25% vs. 9%), amputation (48% vs. 13%), and CVD (30% vs. 11%); CVD with or without prior reduced eGFR (37% vs. 14%) and amputation (50% vs. 16%); and mortality with or without prior reduced eGFR (22% vs. 9%), amputation (35% vs. 8%), and CVD (25% vs. 8%). Adjusted for age, duration of T1D, and mean updated HbA1c, the complications and associations with higher risk included PDR with CSME (hazard ratio [HR] 1.88; 95% CI 1.42, 2.50), reduced eGFR (HR 1.41; 95% CI 1.01, 1.97), and CVD (HR 1.43; 95% CI 1.06, 1.92); CSME with higher risk of PDR (HR 3.94; 95% CI 3.18 4.89), reduced eGFR (HR 1.49; 95% CI 1.10, 2.01), and CVD (HR 1.35; 95% CI 1.03, 1.78); reduced eGFR with higher risk of CVD (HR 2.09; 95% CI 1.44, 3.03), and death (HR 3.40; 95% CI 2.35, 4.92); amputation(s) with death (HR 2.97; 95% CI 1.70, 2.90); and CVD with reduced eGFR (HR 1.59; 95% CI 1.08, 2.34) and death (HR 1.95; 95% CI 1.32, 2.90). CONCLUSIONS Long-term micro- and macrovascular complications and mortality are highly correlated. Age, diabetes duration, and glycemic levels do not completely explain these associations.

Objective To describe the relationships between the cumulative incidences of long-term complications in individuals with type 1 diabetes (T1D), and assess whether observed associations are independent of age, duration of diabetes, and glycemic levels. Methods Proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), reduced eGFR, amputations, cardiovascular disease (CVD) and mortality were assessed in DCCT/EDIC over ~30 years. Results The cumulative incidence of complications ranged from 3% (amputations) to 37% (CSME). There were large differences in the cumulative incidence of: PDR between participants with versus without prior CSME (66% vs. 15%), reduced eGFR (59% vs. 29%) and amputation (68% vs. 32%); reduced eGFR with/without prior PDR (25% vs. 9%), amputation (48% vs. 13%), and CVD (30% vs. 11%); CVD with/without prior reduced eGFR (37% vs. 14%) and amputation (50% vs. 16%); and mortality with/without prior reduced eGFR (22% vs. 9%), amputation (35% vs. 8%) and CVD (25% vs. 8%). Adjusted for age, duration of T1D, and mean updated HbA1c, the complications and associations with higher risk included: PDR with CSME (HR=1.88, 95%CI:[1.42,2.50]), reduced eGFR (HR=1.41, [1.01,1.97]), and CVD (HR=1.43, [1.06,1.92]); CSME with higher risk of PDR (HR=3.94, [3.18,4.89]), reduced eGFR (HR=1.49, [1.10,2.01]), and CVD (HR=1.35, [1.03,1.78]); reduced eGFR with higher risk of CVD (HR=2.09, [1.44,3.03]) and death (HR=3.40, [2.35,4.92]); amputation(s) with death (HR=2.97, [1.70,2.90]); and CVD with reduced eGFR (HR=1.59, [1.08,2.34]) and death (HR=1.95, [1.32,2.90]). Conclusions Long term micro- and macrovascular complications and mortality are highly correlated. Age, diabetes duration, and glycemic levels do not completely explain these associations.

Objective This study was designed to determine whether intensive lifestyle intervention (ILI) aimed at weight loss lowers cancer incidence and mortality. Methods Data from the Look AHEAD trial were examined to investigate whether participants randomized to ILI designed for weight loss would have reduced overall cancer incidence, obesity-related cancer incidence, and cancer mortality, as compared with the diabetes support and education (DSE) comparison group. This analysis included 4,859 participants without a cancer diagnosis at baseline except for nonmelanoma skin cancer. Results After a median follow-up of 11 years, 684 participants (332 in ILI and 352 in DSE) were diagnosed with cancer. The incidence rates of obesity-related cancers were 6.1 and 7.3 per 1,000 person-years in ILI and DSE, respectively, with a hazard ratio (HR) of 0.84 (95% CI: 0.68-1.04). There was no significant difference between the two groups in total cancer incidence (HR, 0.93; 95% CI: 0.80-1.08), incidence of nonobesity-related cancers (HR, 1.02; 95% CI: 0.83-1.27), or total cancer mortality (HR, 0.92; 95% CI: 0.68-1.25). Conclusions An ILI aimed at weight loss lowered incidence of obesity-related cancers by 16% in adults with overweight or obesity and type 2 diabetes. The study sample size likely lacked power to determine effect sizes of this magnitude and smaller.

Objective To examine the effects of an intensive lifestyle intervention (ILI) on cardiovascular disease (CVD), the Action for Health in Diabetes (Look AHEAD) trial randomized 5,145 participants with type 2 diabetes and overweight/obesity to a ILI or diabetes support and education. Although the primary outcome did not differ between the groups, there was suggestive evidence of heterogeneity for prespecified baseline CVD history subgroups (interaction P = 0.063). Event rates were higher in the ILI group among those with a CVD history (hazard ratio 1.13 [95% CI: 0.90-1.41]) and lower among those without CVD (hazard ratio 0.86 [95% CI: 0.72-1.02]). Methods This study conducted post hoc analyses of the rates of the primary composite outcome and components, adjudicated cardiovascular death, nonfatal myocardial infarction (MI), stroke, and hospitalization for angina, as well as three secondary composite cardiovascular outcomes. Results Interaction P values for the primary and two secondary composites were similar (0.060-0.064). Of components, the interaction was significant for nonfatal MI (P = 0.035). This interaction was not due to confounding by baseline variables, different intervention responses for weight loss and physical fitness, or hypoglycemic events. In those with a CVD history, statin use was high and similar by group. In those without a CVD history, low-density lipoprotein cholesterol levels were higher (P = 0.003) and statin use was lower (P ≤ 0.001) in the ILI group. Conclusions Intervention response heterogeneity was significant for nonfatal MI. Response heterogeneity may need consideration in a CVD-outcome trial design.

OBJECTIVE Patients with type 2 diabetes are encouraged to lose weight, but excessive weight loss in older adults may be a marker of poor health and subsequent mortality. We examined weight change during the postintervention period of Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) with diabetes support and education (DSE) (control) in overweight/obese individuals with type 2 diabetes and sought to identify predictors of excessive postintervention weight loss and its association with mortality. RESEARCH DESIGN AND METHODS These secondary analyses compared postintervention weight change (year 8 to final visit; median 16 years) in ILI and DSE in 3,999 Look AHEAD participants. Using empirically derived trajectory categories, we compared four subgroups: weight gainers (n = 307), weight stable (n = 1,561), steady losers (n = 1,731), and steep losers (n = 380), on postintervention mortality, demographic variables, and health status at randomization and year 8. RESULTS Postintervention weight change averaged −3.7 ± 9.5%, with greater weight loss in the DSE than the ILI group. The steep weight loss trajectory subgroup lost on average 17.7 ± 6.6%; 30% of steep losers died during postintervention follow-up versus 10–18% in other trajectories (P < 0001). The following variables distinguished steep losers from weight stable: baseline, older, longer diabetes duration, higher BMI, and greater multimorbidity; intervention, randomization to control group and less weight loss in years 1–8; and year 8, higher prevalence of frailty, multimorbidity, and depressive symptoms and lower use of weight control strategies. CONCLUSIONS Steep weight loss postintervention was associated with increased risk of mortality. Older individuals with longer duration of diabetes and multimorbidity should be monitored for excessive unintentional weight loss.

OBJECTIVE: To reanalyze the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial using a new composite cardiovascular disease (CVD) outcome to determine how best to treat patients with type 2 diabetes mellitus (T2DM) and stable coronary artery disease (CAD). METHODS: From January 1, 2001 to November 30, 2008, 2,368 T2DM patients with angiographically defined CAD were randomly assigned to insulin sensitizing (IS) or insulin providing (IP) therapy and simultaneously to coronary revascularization (REV) versus no or delayed revascularization (MED) with all patients receiving intensive medical treatment. The outcome for this analysis was a composite of eight CVD events. RESULTS: Four-year composite CVD outcome Kaplan-Meier rates were 35.8% (95% CI: 33.1–38.5%) with IS versus 41.6% (38.7–44.5%) with IP (P=.004). Most of this difference was associated with lower in-trial levels of fibrinogen, c-reactive protein, and hemoglobin A1c (HbA1c) with IS. Four-year composite CVD rates were 32.7% (30.0–35.4%) with REV versus 44.7% (41.8–47.6%) with MED (P

OBJECTIVE: This study examined end-of-trial health outcomes in participants in the Look AHEAD (Action for Health in Diabetes) trial who had bariatric surgery during the approximately 10-year randomized intervention. METHODS: Data were obtained from the Look AHEAD public access database of 4901 individuals with type 2 diabetes and overweight/obesity who were assigned to intensive lifestyle intervention (ILI) or a diabetes support and education (DSE) control group. Changes in outcomes in participants who had bariatric surgery were compared with those in participants with a body mass index (BMI) ≥ 30 kg/m(2) who remained in the ILI and DSE groups. RESULTS: A total of 99 DSE and 97 ILI participants had bariatric surgery. At randomization, these 196 participants were significantly younger and more likely to be female and to have higher BMIs than the remaining ILI (N=1972) and DSE (N=2009) participants. At trial’s end, surgically-treated participants lost 19.3% of baseline weight, compared with 5.6% and 3.3% for the ILI and DSE groups, respectively, and were more likely to achieve partial or full remission of their diabetes. CONCLUSIONS: The large, sustained improvements in weight and diabetes observed in this self-selected sample of surgically-treated participants are consistent with results of multiple randomized trials.

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

OBJECTIVE Intensive treatment (INT) of type 1 diabetes reduces the incidence of cardiovascular disease (CVD) events compared with conventional treatment (CONV), but it also results in more weight gain. Our objective was to examine whether excessive weight gain from INT of type 1 diabetes is independently associated with subsequent CVD events. RESEARCH DESIGN AND METHODS Quartiles (Q) of weight gain in 1,213 participants aged 18 years and older at enrollment in the Diabetes Control and Complications Trial (DCCT) were determined within randomized treatment groups (INT vs. CONV) using change in BMI from baseline to the closeout DCCT visits. Effects of this weight gain on CVD risk factors and outcomes during an additional 20 years of observational follow-up were then determined. RESULTS The Q4 INT group experienced greater proportional weight gain (median change in BMI, 6.08 kg/m2), increases in CVD risk factors, and need for medications for hypertension and lipids compared with the Q1–3 INT and comparable CONV groups. Over a mean of 26 years of follow-up, the numbers of major and total CVD events were not statistically different in Q4 compared with Q1–3 of either the INT or CONV group. By year 14, however, the incident CVD event curve became significantly higher in the Q4 INT group than in the Q1–3 INT groups (P = 0.024) and was similar to that for the CONV group. CONCLUSIONS For the first 13 years after DCCT, INT for type 1 diabetes reduced macrovascular events compared with CONV, even when excessive weight gain occurred. After this, total CVD events significantly increased in the Q4 INT group, becoming equivalent to those in the CONV group. Longer follow-up is needed to determine whether this trend continues and results in more major CVD events.

Partial ileal bypass (PIB) in the National Institutes of Health-sponsored Program on the Surgical Control of the Hyperlipidemias (POSCH) randomized controlled trial was found to reduce plasma cholesterol, in particular low density lipoprotein cholesterol, with concomitant retardation of atherosclerotic cardiovascular disease and increased life expectancy. Glucagon-like peptide-1, related to amelioration of type 2 diabetes, is increased over 5-fold after PIB. We hypothesized that PIB, in addition to its action on cholesterol metabolism, may also prevent type 2 diabetes.We surveyed by telephone inquiry of former POSCH patients the 30+year posttrial incidence of type 2 diabetes or prediabetes, the presence of which was a trial exclusion criteria. We were able to contact 17.4% (n = 838) of the original POSCH population.Of 66 control responders, 17 contracted type 2 diabetes (25.8%); of 80 PIB responders, 8 contracted type 2 diabetes (10%). The difference between groups was significant (P = .015 by Fisher exact test) with an odds ratio of .320 for the PIB group and an over 2-fold (2.6) increase in the incidence of type 2 diabetes in the controls. Including borderline type 2 diabetes (prediabetic) patients, these values were 22 of 66 controls (33.3%) and 10 of 80 PIB patients (12.5%), with an odds ratio of .286 and a P.004, and again an over 2-fold (2.7) increase in the incidence of type 2 diabetes in the control patients.PIB appears to afford partial protection from the onset of type 2 diabetes for over 30 years.

Improvement in type 2 diabetes after Roux-en-Y gastric bypass (RYGB) has been attributed partly to weight loss, but mechanisms beyond weight loss remain unclear. We performed an ancillary study to the Diabetes Surgery Study to assess changes in incretins, insulin sensitivity, and secretion 1 year after randomization to lifestyle modification and intensive medical management (LS/IMM) alone (n = 34) or in conjunction with RYGB (n = 34). The RYGB group lost more weight and had greater improvement in HbA1c. Fasting glucose was lower after RYGB than after LS/IMM, although the glucose area under the curve decreased comparably for both groups. Insulin sensitivity increased in both groups. Insulin secretion was unchanged after LS/IMM but decreased after RYGB, except for a rapid increase during the first 30 min after meal ingestion. Glucagon-like peptide 1 (GLP-1) was substantially increased after RYGB, while gastric inhibitory polypeptide and glucagon decreased. Lower HbA1c was most strongly correlated with the percentage of weight loss for both groups. At baseline, a greater C-peptide index and 90-min postprandial C-peptide level were predictive of lower HbA1c at 1 year after RYGB. β-Cell glucose sensitivity, which improved only after RYGB, and improved disposition index were associated with lower HbA1c in both groups, independent of weight loss. Weight loss and preserved β-cell function both predominantly determine the greatest glycemic benefit after RYGB.

BACKGROUND: Lifestyle interventions have been shown to improve physical function over the short term; however, whether these benefits are sustainable is unknown. The long-term effects of an intensive lifestyle intervention (ILI) on physical function were assessed using a randomized post-test design in the Look AHEAD trial. METHODS: Overweight and obese (body mass index ≥ 25 kg/m(2)) middle-aged and older adults (aged 45–76 years at enrollment) with type 2 diabetes enrolled in Look AHEAD, a trial evaluating an ILI designed to achieve weight loss through caloric restriction and increased physical activity compared to diabetes support and education (DSE), underwent standardized assessments of performance-based physical function including a 4- and 400-m walk, lower extremity physical performance (expanded Short Physical Performance Battery, SPPB(exp)), and grip strength approximately 11 years postrandomization and 1.5 years after the intervention was stopped (n = 3,783). RESULTS: Individuals randomized to ILI had lower odds of slow gait speed (

Background The purpose of this study is to compare effects of different nations on Roux-en-Y gastric bypass (RYGB) vs. intensive medical management (IMM) in achieving remission of type 2 diabetes mellitus (T2DM). Materials and Methods Between April 2008 and December 2011, this randomized, controlled clinical trial was conducted at four teaching hospitals in the United States and Taiwan involving 71 participants with mild obesity (BMI 30–35 kg/m2). Thirty-six of 71 participants were randomly assigned to the RYGB group, and the others were in IMM group. Partial or complete remission of T2DM was defined as blood HbA1c

Fructose consumption predicts increased hepatic fibrosis in those with nonalcoholic fatty liver disease (NAFLD). Because of its ability to lower hepatic adenosine triphosphate (ATP) levels, habitual fructose consumption could result in more hepatic ATP depletion and impaired ATP recovery. The degree of ATP depletion after an intravenous (IV) fructose challenge test in low- versus high-fructose consumers was assessed. We evaluated diabetic adults enrolled in the Action for Health in Diabetes Fatty Liver Ancillary Study (n = 244) for whom dietary fructose consumption estimated by a 130-item food frequency questionnaire and hepatic ATP measured by phosphorus magnetic resonance spectroscopy and uric acid (UA) levels were performed (n = 105). In a subset of participants (n = 25), an IV fructose challenge was utilized to assess change in hepatic ATP content. The relationships between dietary fructose, UA, and hepatic ATP depletion at baseline and after IV fructose challenge were evaluated in low- (

To compare the relative efficacy of medical management, the duodenal switch (DS), and the laparoscopic adjustable gastric band (LAGB) to the Roux-en-Y gastric bypass (RYGB) for treatment of type 2 diabetes mellitus (T2DM).The RYGB resolves T2DM in a high proportion of patients and is considered the standard operation for T2DM resolution in morbidly obese patients. However, no data exist comparing the efficacy of medical management and other bariatric operations to the RYGB for treatment of T2DM in comparable patient populations.We performed a retrospective case-matched study of morbidly obese patients with T2DM who had undergone medical management (nonsurgical controls [NSC]; N = 29), LAGB (N = 30), or DS (N = 27) and were compared with matched T2DM patients who had undergone RYGB. Matching was performed with respect to age, sex, body mass index, and hemoglobin A1C (HbA1C). Outcomes assessed were changes in body mass index, HbA1C, and diabetes medication scores at 1 year.The Roux-en-Y gastric bypass produced greater weight loss, HbA1C normalization, and medication score reduction compared to both NSC and LAGB-matched cohorts. Duodenal switch produced greater reductions in HbA1C and medication score than RYGB, despite no greater weight loss at 1 year. Surgical complications were rarely life threatening.This study provides an important perspective about the comparative efficacy of LAGB, DS, and NSC to the RYGB for treatment of T2DM among obese patients. After 1 year of follow-up, RYGB is superior to NSC and LAGB with respect to weight loss and improvement in diabetes whereas DS is superior to RYGB in reducing HbA1C and medication score.

Importance The Roux-en-Y gastric bypass is effective in achieving established diabetes treatment targets, but durability is unknown. Objective To compare durability of Roux-en-Y gastric bypass added to intensive lifestyle and medical management in achieving diabetes control targets. Design, Setting, and Participants Observational follow-up of a randomized clinical trial at 4 sites in the United States and Taiwan, involving 120 participants who had a hemoglobin A1c(HbA1c) level of 8.0% or higher and a body mass index between 30.0 and 39.9 (enrolled between April 2008 and December 2011) were followed up for 5 years, ending in November 2016. Interventions Lifestyle-intensive medical management intervention based on the Diabetes Prevention Program and LookAHEAD trials for 2 years, with and without (60 participants each) Roux-en-Y gastric bypass surgery followed by observation to year 5. Main Outcomes and Measures The American Diabetes Association composite triple end point of hemoglobin A1cless than 7.0%, low-density lipoprotein cholesterol less than 100 mg/dL, and systolic blood pressure less than 130 mm Hg at 5 years. Results Of 120 participants who were initially randomized (mean age, 49 years [SD, 8 years], 72 women [60%]), 98 (82%) completed 5 years of follow-up. Baseline characteristics were similar between groups: mean (SD) body mass index 34.4 (3.2) for the lifestyle–medical management group and 34.9 (3.0) for the gastric bypass group and had hemoglobin A1clevels of 9.6% (1.2) and 9.6% (1.0), respectively. At 5 years, 13 participants (23%) in the gastric bypass group and 2 (4%) in the lifestyle-intensive medical management group had achieved the composite triple end point (difference, 19%; 95% CI, 4%-34%;P = .01). In the fifth year, 31 patients (55%) in the gastric bypass group vs 8 (14%) in the lifestyle–medical management group achieved an HbA1clevel of less than 7.0% (difference, 41%; 95% CI, 19%-63%;P = .002). Gastric bypass had more serious adverse events than did the lifestyle–medical management intervention, 66 events vs 38 events, most frequently gastrointestinal events and surgical complications such as strictures, small bowel obstructions, and leaks. Gastric bypass had more parathyroid hormone elevation but no difference in B12deficiency. Conclusions and Relevance In extended follow-up of obese adults with type 2 diabetes randomized to adding gastric bypass compared with lifestyle and intensive medical management alone, there remained a significantly better composite triple end point in the surgical group at 5 years. However, because the effect size diminished over 5 years, further follow-up is needed to understand the durability of the improvement. Trial Registration clinicaltrials.gov Identifier:NCT00641251

Studies in both healthy and diabetic subjects demonstrated that fructose produced a smaller postprandial rise in plasma glucose and serum insulin than other common carbohydrates. Substitution of dietary fructose for other carbohydrates produced a 13% reduction in mean plasma glucose in a study of type 1 and type 2 diabetic subjects. However, there is concern that fructose may aggravate lipemia. In 1 study, day-long plasma triglycerides in healthy men were 32% greater while they consumed a high-fructose diet than while they consumed a high-glucose diet. There is also concern that fructose may be a factor contributing to the growing worldwide prevalence of obesity. Fructose stimulates insulin secretion less than does glucose and glucose-containing carbohydrates. Because insulin increases leptin release, lower circulating insulin and leptin after fructose ingestion might inhibit appetite less than consumption of other carbohydrates and lead to increased energy intake. However, there is no convincing experimental evidence that dietary fructose actually does increase energy intake. There is also no evidence that fructose accelerates protein glycation. High fructose intake has been associated with increased risk of gout in men and increased risk of kidney stones. Dietary fructose appears to have adverse effects on postprandial serum triglycerides, so adding fructose in large amounts to the diet is undesirable. Glucose may be a suitable replacement sugar. The fructose that occurs naturally in fruits and vegetables provides only a modest amount of dietary fructose and should not be of concern.

Abstract Many protocols have been used in clinical and research settings for collecting systolic blood pressure (SBP) measurements to calculate the ankle–brachial index (ABI); however, it is not known how useful it is to replicate measurements and which measures best reflect cardiovascular risk. Standardized measurements of ankle and arm SBP from 5140 overweight or obese individuals with type 2 diabetes were used to estimate sources of variation. Measurement characteristics of leg-specific ABI, as calculated using a standard algorithm based on the highest SBP of the dorsalis pedis or posterior tibial arteries, were projected using simulations. Coefficients of variability ranged from 2% to 3% when single SBP measurements were used and ABI was overestimated by 2–3%. Taking two SBP measurements at each site reduced standard errors and bias each by 30–40%. The sensitivity of detecting low ABI ranges exceeded 90% for ABI within 0.05 of the 0.90 clinical cut-point. The average and the minimum of the two (i.e. right and left) leg-specific ABI values had similar U-shaped relationships with Framingham risk scores; however, the average leg ABI had slightly greater precision. Replicating SBP measurements reduces the error and bias of ABI. Averaging leg-specific values may increase power for characterizing cardiovascular disease risk.

Medical nutrition therapy (MNT) is important in preventing diabetes, managing existing diabetes, and preventing, or at least slowing, the rate of development of diabetes complications. It is, therefore, important at all levels of diabetes prevention. MNT is also an integral component of diabetes self-management education (or training). This position statement provides evidence-based recommendations and interventions for diabetes MNT. The previous position statement with accompanying technical review was published in 2002 and modified slightly in 2004. This statement updates previous position statements, focuses on key references published since the year 2000, and uses grading according to the level of evidence available...

OBJECTIVE We compared 3-year achievement of an American Diabetes Association composite treatment goal (HbA1c RESEARCH DESIGN AND METHODS A total of 120 adult participants, with BMI 30.0–39.9 kg/m2 and HbA1c ≥8.0%, were randomized 1:1 to two treatment arms at three clinical sites in the U.S. and one in Taiwan. All patients received the lifestyle-medical management intervention for 24 months; half were randomized to also receive gastric bypass. RESULTS At 36 months, the triple end point goal was met in 9% of lifestyle-medical management patients and 28% of gastric bypass patients (P = 0.01): 10% and 19% lower than at 12 months. Mean (SD) HbA1c values at 3 years were 8.6% (3.5) and 6.7% (2.0) (P < 0.001). No lifestyle-medical management patient had remission of diabetes at 36 months, whereas 17% of gastric bypass patients had full remission and 19% had partial remission. Lifestyle-medical management patients used more medications than gastric bypass patients: mean (SD) 3.8 (3.3) vs. 1.8 (2.4). Percent weight loss was mean (SD) 6.3% (16.1) in lifestyle-medical management vs. 21.0% (14.5) in gastric bypass (P < 0.001). Over 3 years, 24 serious or clinically significant adverse events were observed in lifestyle-medical management vs. 51 with gastric bypass. CONCLUSIONS Gastric bypass is more effective than lifestyle-medical management intervention in achieving diabetes treatment goals, mainly by improved glycemic control. However, the effect of surgery diminishes with time and is associated with more adverse events.

Postprandial hypoglycemia after gastric bypass surgery is a serious problem. Available treatments are often ineffective.The objective was to test the hypotheses that injection of rapid-acting insulin before a high-carbohydrate meal or replacement of other carbohydrates with fructose in the meal would prevent hypoglycemia.This was a randomized, crossover trial comparing a high-carbohydrate meal with premeal saline injection (control), a high-carbohydrate meal with premeal insulin injection, and a high-fructose meal with total carbohydrate content similar to the control meal.The setting was an academic medical center.Ten patients with post-gastric bypass hyperinsulinemic hypoglycemia participated.Interventions included lispro insulin injected before test meals and replacement of other carbohydrates with fructose in test meals.The main outcome measure was plasma glucose60 mg/dL after test meals.After the control meal, mean peak glucose and insulin were 173 ± 47 mg/dL and 134 ± 55 mU/L, respectively; mean glucose nadir was 44 ± 15 mg/dL; and eight of 10 subjects demonstrated glucose60 mg/dL. Five subjects demonstrated a glucose nadir40 mg/dL. There were no significant differences in the corresponding values after premeal insulin treatment, except that the mean glucose nadir of 34 ± 10 mg/dL was lower (P.05). After the fructose meal, mean peak postprandial glucose and insulin were 117 ± 20 mg/dL and 45 ± 31 mU/L, respectively (both P.001 for comparison with control), mean glucose nadir was 67 ± 10 mg/dL (P.001), and two of 10 subjects demonstrated glucose60 mg/dL (P.05).People with post-gastric bypass hypoglycemia can consume a meal sweetened with fructose with little risk of hypoglycemia. Treatment with rapid-acting insulin before a carbohydrate-containing meal did not prevent hypoglycemia.

Both obesity and genetics contribute to cardiovascular disease (CVD). We examined whether a genetic risk score (GRS) prospectively predicted cardiovascular morbidity and mortality among overweight/obese individuals with type 2 diabetes and whether behavioural weight loss could diminish this association.Look AHEAD (Action for Health in Diabetes) is a randomised controlled trial to determine the effects of intensive lifestyle intervention (ILI), including weight loss and physical activity, relative to diabetes support and education, on cardiovascular outcomes among overweight/obese individuals with type 2 diabetes. Of the participants, 4,016 provided consent for genetic analyses and had DNA samples passing quality control procedures. These secondary data analyses focused on whether a GRS derived from 153 single nucleotide polymorphisms (SNPs) associated with coronary artery disease in the most recent genome-wide association study predicted cardiovascular morbidity and mortality over a median of 9.6 years of follow-up, and whether ILI would diminish this association.The GRS significantly predicted the primary composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for angina in the full sample (HR, 95% CI per 1 SD increase in GRS: 1.19 [1.10, 1.28]) and among individuals with no known history of CVD at baseline (HR 1.18 [95% CI 1.07, 1.30]). In no case did ILI significantly alter this association.A GRS comprised of SNPs significantly predicts cardiovascular morbidity and mortality over 9.6 years of follow-up in Look AHEAD. Lifestyle intervention did not alter the genetic association.NCT00017953; NCT01270763.

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.

Background.Research has shown less aggressive treatment and poorer control of cardiovascular disease (CVD) risk factors in women than men.Methods.We analyzed sex differences in pharmacotherapy strategies and attainment of goals for hemoglobin A1c (HbA1c), blood pressure (BP), and low density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes and established coronary artery disease enrolled into the BARI 2D trial.Results.Similar numbers of drugs were prescribed in both women and men. Women were less frequent on metformin or sulfonylurea and more likely to take insulin and to be on higher doses of hydroxymethylglutaryl-CoA reductase inhibitors (statins) than men. After adjusting for baseline differences and treatment prescribed, women were less likely to achieve goals for HbA1c (OR = 0.71, 95% CI 0.57, 0.88) and LDL-C (OR = 0.64, 95% CI 0.53, 0.78). More antihypertensives were prescribed to women, and yet BP ≤ 130/80 mmHg did not differ by sex.Conclusions.Women entering the BARI 2D trial were as aggressively treated with drugs as men. Despite equivalent treatment, women less frequently met targets for HbA1c and LDL-C. Our findings suggest that there may be sex differences in response to drug therapies used to treat diabetes, hypertension, and hyperlipidemia.

OBJECTIVE—To investigate whether blood pressure is different in type 2 diabetic patients on a diet rich in carbohydrates versus a diet rich in cis-monounsaturated fatty acids. Data on the dietary effects on these diets’ glucose and lipid metabolism have been previously published. RESEARCH DESIGN AND METHODS—The study compared the effect of feeding 42 type 2 diabetic patients a carefully controlled isoenergic high-carbohydrate (high-carb; 55% energy as carbohydrate, 30% as fat, and 10% as monounsaturated fat) and high−monounsaturated fat (high-mono; 45% energy as fat, 25% as monounsaturated fat, and 40% as carbohydrate) diet for 6 weeks each in a four-center, randomized, cross-over study on blood pressure. Twenty-one patients continued the diet they received during the second phase for an additional 8 weeks. RESULTS—According to repeated-measures ANOVA, blood pressure during the last 3 days of each phase was similar after 6 weeks of the high-carb and high-mono diets (systolic blood pressure: 128 ± 16 vs. 127 ± 15 mmHg, P = 0.9; diastolic blood pressure: 75 ± 7 vs. 75 ± 8 mmHg, P = 0.7). However, after 14 weeks of the high-carb diet (n = 13), there was a significant increase in blood pressure compared with 6 weeks of the high-mono diet (systolic blood pressure: 132 ± 13 vs. 126 ± 11 mmHg, P = 0.04; diastolic blood pressure: 83 ± 6 vs. 76 ± 7 mmHg, P = 0.002). After 14 weeks of the high-mono diet (n = 8), the reduction in blood pressure was not significant compared with 6 weeks of the high-carb diet (systolic blood pressure: 118 ± 14 vs. 121 ± 16 mmHg, P = 0.4; diastolic blood pressure: 71 ± 8 vs. 75 ± 10 mmHg, P = 0.3). CONCLUSION—Although the exchange of carbohydrates with monounsaturated fats may not affect blood pressure in the short term, long-term consumption of a high-carbohydrate diet may modestly raise blood pressure in type 2 diabetic patients.

Reducing the dietary glycemic load and the glycemic index was proposed as a novel approach to weight reduction. A parallel-design, randomized 12-wk controlled feeding trial with a 24-wk follow-up phase was conducted to test the hypothesis that a hypocaloric diet designed to reduce the glycemic load and the glycemic index would result in greater sustained weight loss than other hypocaloric diets. Obese subjects (n = 29) were randomly assigned to 1 of 3 diets providing 3138 kJ less than estimated energy needs: high glycemic index (HGI), low glycemic index (LGI), or high fat (HF). For the first 12 wk, all food was provided to subjects (feeding phase). Subjects (n = 22) were instructed to follow the assigned diet for 24 additional weeks (free-living phase). Total body weight was obtained and body composition was assessed by skinfold measurements. Insulin sensitivity was assessed by the homeostasis model (HOMA). At 12 wk, weight changes from baseline were significant in all groups but not different among groups (-9.3 +/- 1.3 kg for the HGI diet, -9.9 +/- 1.4 kg for the LGI diet, and -8.4 +/- 1.5 kg for the HF diet). All groups improved in insulin sensitivity at the end of the feeding phase of the study. During the free-living phase, all groups maintained their initial weight loss and their improved insulin sensitivity. Weight loss and improved insulin sensitivity scores were independent of diet composition. In summary, lowering the glycemic load and glycemic index of weight reduction diets does not provide any added benefit to energy restriction in promoting weight loss in obese subjects.

OBJECTIVE—The purpose of this study was to evaluate the effects of a combination weight loss program using intermittent low-calorie diets, energy-controlled meal replacement products, and sibutramine on weight loss, diabetes control, and cardiovascular risk factors in overweight or obese subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS—Overweight or obese individuals with type 2 diabetes treated with diet or oral medication were randomly assigned to either a standard therapy or combination therapy group. Both groups received a standardized program to facilitate weight loss. The combination therapy group also received 10–15 mg sibutramine daily, low-calorie diets using meal replacement products for 1 week every 2 months, and between low-calorie diet weeks, once daily use of meal replacement product and snack bars to replace one usual meal and snack. Primary outcome measures were changes in body weight, glycemic control, plasma lipids, blood pressure, pulse, and body composition at 1 year. RESULTS—At 1 year, combination therapy, compared with standard therapy, resulted in significantly more weight loss (−7.3 ± 1.3 kg vs. −0.8 ± 0.9 kg, P < 0.001) and reduction in HbA1c (−0.6 ± 0.3 vs. 0.0 ± 0.2%, P = 0.05). Combination therapy resulted in reduced requirement for diabetes medications and decreased fat mass and lean body mass. A 5-kg decrease in weight at 1 year was associated with a decrease of 0.4% in HbA1c (P = 0.006). Changes in fasting glucose, lipids, pulse, and blood pressure did not differ between groups. CONCLUSIONS—This combination weight loss program resulted in greater weight loss and improved diabetes control compared with a standard weight loss program in overweight or obese subjects with type 2 diabetes.

Medical nutrition therapy for people with diabetes should be individualized, with consideration given to the individual's usual food and eating habits, metabolic profile, treatment goals and desired outcomes. Monitoring of metabolic parameters, including glucose, HbA1c, lipids, blood pressure, body weight, and renal function, when appropriate, as well as quality of life is essential to assess the need for changes in therapy and ensure successful outcomes. Ongoing nutrition self-management education and care needs to be available for individuals with diabetes. Additionally many areas of nutrition and diabetes require additional research.

Summary Background Conventional treatments for patients with type 2 diabetes are often inadequate. We aimed to assess outcomes of diabetes control and treatment risks 2 years after adding Roux-en-Y gastric bypass to intensive lifestyle and medical management. Methods We report 2-year outcomes of a 5-year randomised trial (the Diabetes Surgery Study) at four teaching hospitals (three in the USA and one in Taiwan). At baseline, eligible participants had to have HbA 1c of at least 8·0% (64 mmol/mol), BMI between 30·0 and 39·9 kg/m 2 , and type 2 diabetes for at least 6 months, and be aged 30–67 years. We randomly assigned participants to receive either intensive lifestyle and medical management alone (lifestyle and medical management), or lifestyle and medical management plus standard Roux-en-Y gastric bypass surgery (gastric bypass). Staff from the clinical centres had access to data from individual patients, but were masked to other patients' data and aggregated data until the 2-year follow-up. Drugs for hyperglycaemia, hypertension, and dyslipidaemia were prescribed by protocol. The primary endpoint was achievement of the composite treatment goal of HbA 1c less than 7·0% (53 mmol/mol), LDL cholesterol less than 2·59 mmol/L, and systolic blood pressure less than 130 mm Hg at 12 months; here we report the composite outcome and other pre-planned secondary outcomes at 24 months. Analyses were done on an intention-to-treat basis, with multiple imputations for missing data. This study is registered with ClinicalTrials.gov, number NCT00641251, and is still ongoing. Findings Between April 21, 2008, and Nov 21, 2011, we randomly assigned 120 eligible patients to either lifestyle and medical management alone (n=60) or with the addition of gastric bypass (n=60). One patient in the lifestyle and medical management group died (from pancreatic cancer), thus 119 were included in the primary analysis. Significantly more participants in the gastric bypass group achieved the composite triple endpoint at 24 months than in the lifestyle and medical management group (26 [43%] vs eight [14%]; odds ratio 5·1 [95% CI 2·0–12·6], p=0·0004), mainly through improved glycaemic control (HbA 1c vs 14 [24%]; treatment difference −1·9% (−2·5 to −1·4); p=0·0001). 46 clinically important adverse events occurred in the gastric bypass group and 25 in the lifestyle and medical management group (mainly infections in both groups [four in the lifestyle and medical management group, eight in the gastric bypass group]). With a negative binomial model adjusted for site, the event rate for the gastric bypass group was non-significantly higher than the lifestyle and medical management group by a factor of 1·67 (95% CI 0·98–2·87, p=0·06). Across both years of the study, the gastric bypass group had seven serious falls with five fractures, compared with three serious falls and one fracture in the lifestyle and medical management group. All fractures happened in women. Many more nutritional deficiencies occurred in the gastric bypass group (mainly deficiencies in iron, albumin, calcium, and vitamin D), despite protocol use of nutritional supplements. Interpretation The addition of gastric bypass to lifestyle and medical management in patients with type 2 diabetes improved diabetes control, but adverse events and nutritional deficiencies were more frequent. Larger and longer studies are needed to investigate whether the benefits and risk of gastric bypass for type 2 diabetes can be balanced. Funding Covidien, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Nutrition Obesity Research Centers, and the National Center for Advancing Translational Sciences.

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10-8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10-11) and 8q12 (minimum p value 1.82×10-11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

Long-term effects of behavioural weight loss interventions on diabetes complications are unknown. In a secondary analysis of the Look AHEAD (Action for Health in Diabetes) multicentre randomised clinical trial, we assessed whether an intensive lifestyle intervention (ILI) affects the development of nephropathy in people with type 2 diabetes.Overweight or obese people aged 45-76 years with type 2 diabetes were randomly assigned (1:1) to ILI or to a diabetes support and education (DSE) group by a central web-based data management system, stratified by clinical centre and blocked with random block sizes. The ILI was designed to achieve and maintain weight loss through reduced caloric consumption and increased physical activity. The interventions were terminated early because of absence of effect on the primary outcome of cardiovascular disease events in the main Look AHEAD trial. Albuminuria and estimated glomerular filtration rate were prespecified as two of many other outcomes and were assessed from baseline until the interventions ended. They were combined post hoc to define the main outcome for this report, very-high-risk chronic kidney disease (CKD), based on the 2013 Kidney Disease Improving Global Outcomes (KDIGO) classification. Outcomes assessors and laboratory staff were masked to treatment, but participants and interventionists were not masked. Time-to-event data were analysed by intention to treat by the Kaplan-Meier method and proportional hazards models. The Look AHEAD trial is registered with ClinicalTrials.gov, NCT00017953.Of the 5145 participants randomly assigned in the Look AHEAD trial (2570 to ILI and 2575 to DSE), analyses for very-high-risk CKD were done in 2423 (94%) of patients in the ILI group and 2408 (94%) of those in the DSE group. After a median of 8·0 years (IQR 7·9-9·9) of follow-up, the incidence of very-high-risk CKD was lower in the ILI group than in the DSE group, with incidence rates of 0·91 cases per 100 person-years in the DSE group and 0·63 per 100 person-years in the ILI group (difference 0·27 cases per 100 person-years, hazard ratio 0·69, 95% CI 0·55-0·87; p=0·0016). This effect was partly attributable to reductions in bodyweight, HbA1c, and systolic blood pressure. There were no safety concerns regarding kidney-related adverse events.Weight loss should be considered as an adjunct to medical treatments to prevent or delay progression of CKD in overweight or obese people with type 2 diabetes.National Institute of Diabetes and Digestive and Kidney Diseases.

Background Little is known about diet quality with a reduced-energy, low-fat, partial meal replacement plan, especially in individuals with type 2 diabetes. The Action for Health in Diabetes (Look AHEAD) trial implemented a partial meal replacement plan in the Intensive Lifestyle Intervention. Objective To compare dietary intake and percent meeting fat-related and food group dietary recommendations in Intensive Lifestyle Intervention and Diabetes Support and Education groups at 12 months. Design A randomized controlled trial comparing Intensive Lifestyle Intervention with Diabetes Support and Education at 0 and 12 months. Participants/setting From 16 US sites, the first 50% of participants (aged 45 to 76 years, overweight or obese, with type 2 diabetes) were invited to complete dietary assessments. Complete 0- and 12-month dietary assessments (collected between 2001 and 2004) were available for 2,397 participants (46.6% of total participants), with 1,186 randomized to Diabetes Support and Education group and 1,211 randomized to Intensive Lifestyle Intervention group. Main outcome measures A food frequency questionnaire assessed intake: energy; percent energy from protein, fat, carbohydrate, polyunsaturated fatty acids, and saturated fats; trans -fatty acids; cholesterol; fiber; weekly meal replacements; and daily servings from food groups from the Food Guide Pyramid. Statistical analyses performed Mixed-factor analyses of covariance, using Proc MIXED with a repeated statement, with age, sex, race/ethnicity, education, and income controlled. Unadjusted χ 2 tests compared percent meeting fat-related and food group recommendations at 12 months. Results At 12 months, Intensive Lifestyle Intervention participants had a significantly lower fat and cholesterol intake and greater fiber intake than Diabetes Support and Education participants. Intensive Lifestyle Intervention participants consumed more servings per day of fruits; vegetables; and milk, yogurt, and cheese; and fewer servings per day of fats, oils, and sweets than Diabetes Support and Education participants. A greater percentage of Intensive Lifestyle Intervention participants than Diabetes Support and Education participants met fat-related and most food group recommendations. Within Intensive Lifestyle Intervention, a greater percentage of participants consuming two or more meal replacements per day than participants consuming less than one meal replacement per day met most fat-related and food group recommendations. Conclusions The partial meal replacement plan consumed by Intensive Lifestyle Intervention participants was related to superior diet quality.

Look AHEAD (Action for Health in Diabetes) was a randomized clinical trial designed to examine the long-term health effects of weight loss in overweight and obese individuals with type 2 diabetes. The primary result was that the incidence of cardiovascular events over a median follow-up of 9.6 years was not reduced in the Intensive Lifestyle Group relative to the control group. This finding is discussed, with emphasis on its implications for design of trials and clinical treatment of obese persons with type 2 diabetes.

Background: About 9% of average dietary energy intake in the United States comes from fructose. Such a high consumption raises concern about the metabolic effects of this sugar. Objective: The objective of this study was to determine the effect of dietary fructose on plasma lipids. Design: The study was conducted in the General Clinical Research Center at Fairview-University of Minnesota Medical Center. The participants were 24 healthy adult volunteers (12 men and 12 women; 6 of each sex were aged

Post-gastric bypass hyperinsulinemic hypoglycemia causing confusion and loss of consciousness was recently described, and appears to be an important late complication of gastric bypass surgery.We report 3 additional patients with this disorder, and describe their responses to high and low carbohydrate test meals. The patients were 1 woman and 2 men ranging in age from 50 to 65 years who underwent Roux-en-Y gastric bypass (RYGBP) for morbid obesity. 15 to 37 months after surgery, they started to have episodes of postprandial confusion and loss of consciousness. When given high carbohydrate mixed meals, all 3 demonstrated peak plasma glucose >200 mg/dl (11.1 mmol/l) and peak serum insulin >300 μU/l (1800 pmol/l). Although serum insulin declined rapidly, all 3 developed hypoglycemia with plasma glucose

Background. Involvement of the thyroid gland is an important morbidity of therapy for Hodgkin's disease, which should be well recognized by caretakers of these patients. However, the roles of age at the time of therapy for Hodgkin's disease, chemotherapy, treatment with reduced dose of radiation and lymphangiography in causing thyroid abnormalities have not been defined. Materials and Methods. Eighty-nine pediatric and young adult patients (less than 21 years old at diagnosis) with Hodgkin's disease who were treated with either radiation alone (57 patients), radiation and chemotherapy (20 patients), or chemotherapy alone (12 patients) at the University of Minnesota between 1971 and 1986 were periodically evaluated. Results. The median age at diagnosis was 14 years, and the median duration of follow up was 11 years. Of 89 patients evaluable for thyroid abnormalities, 51 patients developed biochemical hypothyroidism. The median time to development of hypothyroidism was six years. The estimated actuarial risk of developing hypothyroidism was 60% at 11 years. Radiation to the thyroid region was associated with an elevated risk of development of hypothyroidism (relative risk = 9.9), with patients receiving mantle irradiation alone developing hypothyroidism earlier (median time 2.5 years) than patients receiving combined modality treatment (median time 6 years; p = 0.001). Dose of radiation was the chief correlate for the development of hypothyroidism (relative risk increasing by 1.02/Gy; p < 0.001). Age, gender, chemotherapy and prior lymphangiography were not shown to be significant risk factors for the development of hypothyroidism. Four patients were diagnosed with thyroid nodules, (diagnosed 7.6 to 14.3 years after treatment of Hodgkin's disease), with histology showing multinodular goiter (2), single colloid nodule (1) and papillary carcinoma (1). Transient hyperthyroidism developed in two patients 8 and 13 months after treatment for Hodgkin's disease. Conclusions. There is a high risk for development of thyroid disease after patients have received radiation therapy for Hodgkin's disease, reinforcing the need for continued clinical and biochemical evaluation of such patients.

Cite this article as: John E. Connett, Sayeed Ikramuddin, Avis J. Thomas, John P. Bantle, Charles J. Billington, Keong Chong, Lee-Ming Chuang, William B. Inabnet III, Robert W. Jeffery, Judith Korner, Patricia S. Laqua, Wei-Jei Lee, Daniel B. Leslie, WITHDRAWN: A Randomized Trial Comparing Roux-en-Y Gastric Bypass to Intensive Medical Management in Obese Patients with Type 2 Diabetes Mellitus, Surgery for Obesity and Related Diseases, http://dx.doi.org/10.1016/j.soard.2012.08.011

The treatment goals recommended by the American Diabetes Association (ADA) for patients with type 2 diabetes mellitus include hemoglobin A1c (HbA1C)

OBJECTIVE Subcutaneous insulin is absorbed at different rates from different anatomical regions, but it is not clear how much the varying rates of absorption affect plasma glucose concentrations in diabetic subjects. To address this issue, subcutaneous injections of insulin in the abdomen were compared with subcutaneous injections of insulin in the thigh. RESEARCH DESIGN AND METHODS In a crossover trial, 22 type I diabetic subjects received, in random order, a test dose of regular insulin injected subcutaneously in the abdomen on one morning and in a thigh on another morning. The subjects also received, in random order, usual morning doses of NPH and regular insulins injected subcutaneously in the abdomen on one morning and in a thigh on another morning. The study was performed in the University of Minnesota General Clinical Research Center. Main outcome measures were plasma glucose and serum free insulin. RESULTS After injections of regular insulin in the abdomen, the peak postprandial increment in plasma glucose was 3.1 mM or 29% lower (P < 0.001), the peak increment in serum free insulin was 54 pM or 38% higher (P = 0.017), and the length of time required to achieve peak serum free insulin was significantly shorter than after injections of regular insulin in the thigh. After injections of NPH and regular insulins in the abdomen, the morning peak increment in plasma glucose was 2.5 mM or 18% lower (P = 0.008) than after injections of NPH and regular insulins in a thigh. However, no significant difference was observed in the afternoon peak increment in plasma glucose. CONCLUSIONS A subcutaneous injection of regular insulin in the abdomen produced a substantially greater reduction in plasma glucose than an injection of regular insulin in the thigh. Changing the injection site of regular insulin from the abdomen to the thigh had an effect equivalent to reducing the dose administered. With injections of NPH and regular insulin in combination, the influence of the region used for injection was less but still potentially important.

Objective— To assess in diabetic subjects the effects of dietary sucrose on glycemia and lipemia. Research Design and Methods— Twelve type II diabetic subjects consumed, in random order, two isocaloric, 55% carbohydrate study diets for 28 days. In one diet, 19% of energy was derived from sucrose. In the other diet, Results— No significant differences were noted between the study diets at any time point in mean plasma glucose. At day 28, mean plasma glucose values for the sucrose diet were 9.6 ± 0.5 mM and for the starch diet were 9.4 ± 0.6 mM (P = 0.63). Also, no significant differences were observed between the study diets in urine glucose, fasting serum total, HDL, or LDL cholesterol; fasting serum TG; or peak postprandial serum TG. Conclusions— A high sucrose diet did not adversely affect glycemia or lipemia in type II diabetic subjects.

OBJECTIVE To examine the persistence of the original treatment effects 10 years after the Diabetes Control and Complications Trial (DCCT) in the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. In the DCCT, intensive therapy aimed at near-normal glycemia reduced the risk of microvascular complications of type 1 diabetes mellitus compared with conventional therapy. METHODS Retinopathy was evaluated by fundus photography in 1211 subjects at EDIC year 10. Further 3-step progression on the Early Treatment Diabetic Retinopathy Study scale from DCCT closeout was the primary outcome. RESULTS After 10 years of EDIC follow-up, there was no significant difference in mean glycated hemoglobin levels (8.07% vs 7.98%) between the original treatment groups. Nevertheless, compared with the former conventional treatment group, the former intensive group had significantly lower incidences from DCCT close of further retinopathy progression and proliferative retinopathy or worse (hazard reductions, 53%-56%; P < .001). The risk (hazard) reductions at 10 years of EDIC were attenuated compared with the 70% to 71% over the first 4 years of EDIC (P < .001). The persistent beneficial effects of former intensive therapy were largely explained by the difference in glycated hemoglobin levels during DCCT. CONCLUSION The persistent difference in diabetic retinopathy between former intensive and conventional therapy ("metabolic memory") continues for at least 10 years but may be waning. TRIAL REGISTRATION (clinicaltrials.gov) Identifiers: NCT00360815 and NCT00360893.

Moderate alcohol consumption is associated with reduced cardiovascular disease rates in nondiabetic populations. However, the effects of alcohol in people with diabetes are not well defined. Accordingly, we tested the hypothesis that alcohol would raise plasma high-density lipoprotein (HDL) cholesterol or have other beneficial metabolic effects in persons with type 2 diabetes mellitus. To assess the acute effects of alcohol on plasma glucose and serum insulin, subjects were inpatients for 2 days during which they received, in random order, 240 mL wine or grape juice with their evening meal. To assess the chronic effects of alcohol on fasting plasma lipids, subjects consumed, in random order, 120 to 240 mL wine daily for 30 days and abstained from alcohol for 30 days. Participants were 18 non-insulin-treated volunteers with type 2 diabetes mellitus. Acutely, 240 mL wine containing 24 g alcohol had no effect on plasma glucose or serum insulin. Chronically, wine consumption for 30 days (mean consumption, 18 g alcohol per day) compared with abstinence for 30 days resulted, respectively, in mean +/- SEM fasting plasma cholesterol of 160 +/- 6 and 160 +/- 8 mg/dL (P = .98), HDL cholesterol of 47 +/- 3 and 46 +/- 3 mg/dL (P = .87), low-density lipoprotein cholesterol of 82 +/- 5 and 82 +/- 6 mg/dL (P = .98), triglycerides of 157 +/- 19 and 159 +/- 19 mg/dL (P = .88), glucose of 128 +/- 6 and 128 +/- 7 mg/dL (P = .84), and serum insulin of 14 +/- 2 and 17 +/- 3 microU/mL (P = .03). Moderate consumption of alcohol in the form of wine did not raise plasma HDL cholesterol. However, alcohol did not have any harmful metabolic effect; and chronic consumption lowered fasting serum insulin. People with type 2 diabetes mellitus should not be discouraged from using alcohol in moderation.

Background The prevalence of obesity-induced type 2 diabetes mellitus is increasing worldwide. The objective of this review and meta-analysis is to determine the impact of bariatric surgery on type 2 diabetes in association with the procedure performed and the weight reduction achieved. Methods The review includes all articles published in English from January 1, 1990, to April 30, 2006. Results The dataset includes 621 studies with 888 treatment arms and 135,246 patients; 103 treatment arms with 3188 patients reported on resolution of diabetes, that is, the resolution of the clinical and laboratory manifestations of type 2 diabetes. Nineteen studies with 43 treatment arms and 11,175 patients reported both weight loss and diabetes resolution separately for the 4070 diabetic patients in these studies. At baseline, the mean age was 40.2 years, body mass index was 47.9 kg/m 2 , 80% were female, and 10.5% had previous bariatric procedures. Meta-analysis of weight loss overall was 38.5 kg or 55.9% excess body weight loss. Overall, 78.1% of diabetic patients had complete resolution, and diabetes was improved or resolved in 86.6% of patients. Weight loss and diabetes resolution were greatest for patients undergoing biliopancreatic diversion/duodenal switch, followed by gastric bypass, and least for banding procedures. Insulin levels declined significantly postoperatively, as did hemoglobin A1c and fasting glucose values. Weight and diabetes parameters showed little difference at less than 2 years and at 2 years or more. Conclusion The clinical and laboratory manifestations of type 2 diabetes are resolved or improved in the greater majority of patients after bariatric surgery; these responses are more pronounced in procedures associated with a greater percentage of excess body weight loss and is maintained for 2 years or more.

Background Some alarming cases of hypoglycemic episodes in patients who have undergone Roux-en-Y gastric bypass have been reported. The syndrome of hyperinsulinemic hypoglycemia with nesidioblastosis after Roux-en-Y gastric bypass has been previously reported and is controversial. It has been suggested that subtotal or total pancreatectomy might be needed to control the symptoms in these patients. We have identified a similar cohort of patients with hyperinsulinemic hypoglycemia for whom we have reviewed patient characteristics and measured the glucose and insulin response to mixed meals. Methods We reviewed the charts of 14 patients identified by clinic follow-up who reported episodes consistent with hyperinsulinemic hypoglycemia (lightheadedness or loss of consciousness after a high-carbohydrate meal). All patients were given a mixed meal consisting of high carbohydrates on day 1 and a low-carbohydrate meal on day 2. The plasma glucose and serum insulin levels were measured before (fasting) and 30, 60, 90, 120, 150, and 180 minutes after the meal. Results After a high-carbohydrate meal, 12 of 14 patients demonstrated hyperglycemia associated with hyperinsulinemia at 30 minutes. These patients subsequently became hypoglycemic while the serum insulin was rapidly declining. After reaching a nadir at 120 minutes, the plasma glucose level corrected spontaneously. After a low-carbohydrate mixed meal, the patients demonstrated very little change in plasma glucose and only a modest increase in serum insulin. Of the 12 patients treated with a low-carbohydrate diet, 6 had substantive symptom improvement, and 10 exhibited at least some improvement. Conclusion The hyperinsulinemic hypoglycemia noted in some patients after Roux-en-Y gastric bypass has many similarities to the dumping syndrome. A low-carbohydrate diet successfully improved symptoms in most of our patients. Approaches to treatment should involve a low-carbohydrate diet and alpha-glucosidase inhibitors rather than pancreatectomy.