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Objective To compare glycemic efficacy of Technosphere insulin (TI) versus that of insulin aspart (IA), each added to basal insulin, in type 2 diabetes. Methods This randomized, 24-week trial included subjects aged from 18 to 80 years who were treated with subcutaneous insulin for 3 months and had glycated hemoglobin (HbA1C) levels of 7.0% to 11.5%. After receiving stabilized insulin glargine doses during a 4-week lead in, the subjects were randomized to TI or IA. The primary end point was an HbA1C change from baseline, with the differences analyzed by equivalence analyses. Results In the overall cohort (N = 309; males, 23.3%), mean (SD) age was 58.5 (8.4) years, body mass index was 30.8 (4.7) kg/m2, weight was 82.2 (13.6) kg, and duration of diabetes was 12.2 (7.1) years. An intention-to-treat cohort had 150 subjects randomized to TI (mean [SD] HbA1C: 8.9% [1.1%]) and 154 randomized to IA (mean [SD] HbA1C: 9.0% [1.3%]). At 24 weeks, mean (SD) HbA1C value declined to 7.9% (1.3%) and 7.7% (1.1%) in the TI and IA cohorts, respectively. A treatment difference of 0.26% was not statistically significant, but the predefined equivalency margin was not met. Subjects receiving TI lost 0.78 kg compared to baseline; subjects receiving IA gained 0.23 kg (P =.0007). The incidence of mild/moderate hypoglycemia was lower for the TI cohort, though not statistically significant. Conclusion Both TI and IA resulted in significant and clinically meaningful HbA1C reductions. TI also resulted in significant and clinically meaningful weight reductions. These data support the use of inhaled insulin as a treatment option for individuals with type 2 diabetes.

Technosphere Insulin (TI) is an inhaled insulin. Studies comparing TI with short-acting insulin analogues provide important insights on efficacy, dosing, and time course of action.Planned enrollment of 230 subjects was limited to 138 due to premature study discontinuation. The primary efficacy endpoint was a noninferiority of glycosylated hemoglobin (HbA1c) of 0.4% for TI compared with insulin lispro (LIS) in a 16-week phase 3 randomized clinical trial in type 1 diabetes mellitus.HbA1c values were similar in the TI and LIS groups at the beginning of the trial (7.8% and 7.6%, respectively) and at trial endpoint (7.7% and 7.6%, respectively). Least squares mean changes from baseline were similar between study groups. Glucose values after a standard meal were significantly lower with TI in the first 90 minutes post meal compared with LIS. Mild or moderate hypoglycemia event rates were also significantly lower with TI compared with LIS (5.97 vs 8.01, respectively; P = .0269). Cough was the most commonly reported adverse event with TI. Pulmonary function as measured by forced expiratory volume in 1 second was not different between groups at baseline, 16 weeks, or 4 weeks off study drug.HbA1c was unchanged and overall glucose control was comparable between groups. Treatment with TI resulted in improved post-meal glucose and a lower risk of hypoglycemia compared with LIS.背景: Technosphere胰岛素(TI)是一种吸入型胰岛素。该研究将TI与短效胰岛素类似物进行比较，并对有关疗效、剂量和作用时间的关系进行分析。 方法: 由于研究提前终止，计划招募的230名受试者最后限于138名。在1型糖尿病患者为期16周的3期随机临床试验中，主要研究终点是TI的糖化血红蛋白(HbA1c)与赖脯胰岛素(LIS)相比的非劣效性为0.4%。 结果: TI和LIS组的HbA1c值在试验开始和终点时相似，在试验开始时分别为7.8%和7.6%，试验终点时分别为7.7%和7.6%。研究组之间最小二乘均值相对于基线的变化相似。与LIS相比，TI在标准餐后前90分钟内的血糖显著降低。与LIS相比，TI的轻度或中度低血糖事件发生率也显著降低(分别为5.97和8.01； P = 0.0269)。咳嗽是最常见的TI不良反应。用1秒用力呼气量测量的肺功能在基线、停药16周或停药4周组之间没有差异。 结论: 各组间的HbA1c没有变化，总体血糖控制水平相当。与LIS相比，TI治疗可改善餐后血糖，降低低血糖风险。.

Background and Objective Technosphere® Insulin (TI), a human insulin powder for inhalation (Afrezza®; MannKind Corporation, Westlake Village, CA, USA), is an ultra-rapid-acting inhaled insulin indicated to improve postprandial glycemic control in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM). Because TI is absorbed across the alveolar membrane, the objective of this analysis was to characterize its pulmonary safety. Methods Pooled data from 13 phase 2/3 clinical studies in 5505 patients with T1DM or T2DM treated with TI, Technosphere inhalation powder without insulin (TP; placebo), or active-comparator treatment were analyzed for incidences of respiratory treatment-emergent adverse events (TEAEs), changes in pulmonary function, and lung malignancies. Radiographic changes in the lungs were monitored in a subset of 229 patients. Results Among 3017 patients receiving TI, the median duration of TI exposure was 168 days; median active-comparator and TP exposure durations were 363 and 149 days for 2198 and 290 patients, respectively. Respiratory TEAEs were comparable across treatments, except for a higher incidence of mild cough with TI in active-comparator studies (28.0% vs. 5.2%). Slight reversible declines in pulmonary function from baseline were observed for TI versus TP and active-comparator treatments, including in a subpopulation of patients with retrospectively identified lung dysfunction. Lung malignancies were reported in two patients on active TI therapy with a smoking history. No clinically significant changes from baseline were observed in radiographic images. Conclusions Pulmonary safety assessment of the TI inhalation system did not identify any safety issues in individuals with either T1DM or T2DM. Electronic supplementary material The online version of this article (10.1007/s40261-020-00958-8) contains supplementary material, which is available to authorized users.

BACKGROUND Severe hypoglycemic episodes are life-threatening events demanding rapid administration of glucagon by a caregiver or bystander. The glucagon analog dasiglucagon is stable in aqueous formulation and therefore suitable for delivery in a ready-to-use autoinjector, potentially increasing speed and ease of use compared with standard glucagon emergency kits (GEKs). METHODS In an open-label, randomized, crossover, comparative device handling study, trained caregivers and untrained bystanders administered the dasiglucagon autoinjector or Eli Lilly GEK to manikins in a simulated emergency hypoglycemia situation. RESULTS In total, 54 participants were randomized (18 patient-caregiver pairs and 18 bystanders). Overall, 94% of trained caregivers were able to administer the dasiglucagon autoinjector successfully within 15 minutes, compared with 56% for the GEK (P

AIM To evaluate the effect of final HbA1c levels on the incidences of hypoglycaemia in participants with type 1 diabetes treated with inhaled Technosphere® Insulin or subcutaneous insulin aspart, reported in alignment with the International Hypoglycaemia Study Group recommendations. METHODS In the randomized, phase 3, multicentre AFFINITY-1 study, adults (N = 375) who had type 1 diabetes for ≥ 12 months and an HbA1c level of 58-86 mmol/mol (7.5-10.0%) were randomized to receive basal insulin plus either inhaled Technosphere Insulin or subcutaneous insulin aspart. This was a post-hoc regression analysis on a subset (N = 279) of the randomized AFFINITY-1 cohort for whom baseline and end-of-treatment HbA1c values were reported. Primary outcome measures were incidence and event rates for levels 1, 2 and 3 hypoglycaemia, respectively defined as blood glucose levels of ≤ 3.9 mmol/l

Dasiglucagon is a novel glucagon analog, stable in aqueous solution and suitable for delivery in a ready-to-use autoinjector (HypoPal®) for the treatment of severe hypoglycemia. This study was performed to assess HypoPal device handling vs. GEK during simulated episodes of severe hypoglycemia. Participants included persons with diabetes (PWD) and their caregivers and untrained bystanders (UB) with no experience with diabetes. Participants had no experience with either device. PWD were trained by staff and subsequently trained caregivers (TC) on the use of devices; UB received no instruction on use prior to simulations. Primary outcome was success of TC to correctly use HypoPal vs. GEK. Secondary outcomes included success of UB, time to successful administration, and assessment of confidence in, ease of use of and preference for each device. The success rate was significantly greater for HypoPal vs. GEK in TC (p These data support that dasiglucagon HypoPal use is easier, more reliable, and faster than the use of GEK and offers the potential to improve the time to recovery from a severe hypoglycemic event. Disclosure N. Bailey: Research Support; Spouse/Partner; Zealand Pharma A/S. J. Dimsits: Employee; Self; Zealand Pharma A/S. R. Tehranchi: Employee; Self; Zealand Pharma A/S. D. M. Kendall: Employee; Self; Zealand Pharma A/S, Employee; Spouse/Partner; Amgen Inc., Stock/Shareholder; Self; Eli Lilly and Company, MannKind Corporation. T. S. Bailey: Consultant; Self; Abbott Diabetes, LifeScan, Novo Nordisk, Sanofi, Research Support; Self; Abbott, Abbott Diabetes, Biolinq, Capillary Biomedical, Inc., Dexcom, Inc., Eli Lilly and Company, Kowa Research Institute, Inc., Lexicon Pharmaceuticals, Inc., Livongo, Medtronic, Medtrum Technologies, Novo Nordisk, REMD Biotherapeutics, Sanofi, Sanvita, Viacyte, Inc., vTv Therapeutics, Zealand Pharma A/S, Speaker’s Bureau; Self; BD, Medtronic, Sanofi. Funding Zealand Pharma A/S

Technosphere Insulin (TI) is a dry-powder formulation of recombinant human insulin adsorbed onto Technosphere microparticles for oral inhalation. Data from two 52-wk randomized phase 3 trials in type 2 DM were combined to analyze the effects of TI on body weight. In one trial, patients on basal insulin were randomized to prandial TI or insulin aspart. In the other trial, basal insulin plus prandial TI was compared to 70/30 insulin analog mixture. Primary efficacy end point in each trial was change in A1C. Weight data were captured in each study. Weight and A1C data were analyzed based on modified Intention to Treat Analyses and LS mean changes from baseline. In these analyses, the TI arms were combined and comparisons were made between TI and each of the comparator arms. Aspart and 70/30 arms were not compared to each other. Data for 26 and 52 wk time points are reported. Results At both 26 and 52 weeks, TI was associated with less weight gain than either aspart or premixed insulin. Differences were significant for TI vs. each comparator. A1C differences among treatment arms were small and only statistically significant for TI vs. aspart at 52 weeks. Conclusion: In insulin treated T2DM persons, TI is associated with less weight gain than Insulin aspart or premixed 70/30 analog insulin. These weight differences appear to be independent of changes in A1C. Disclosure J. Manoukian: Employee; Self; MannKind Corporation. D.M. Kendall: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company. P.M. Morey: Employee; Self; MannKind Corporation. B.J. Hoogwerf: Consultant; Self; MannKind Corporation. Employee; Spouse/Partner; MannKind Corporation. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.

The impact of inhaled Technosphere Insulin (TI) on measures of pulmonary function remain an important component of clinical use. TI is an ultra rapid-acting prandial insulin delivered via deep pulmonary inhalation allowing for prompt absorption in the alveoli. Prior studies have demonstrated that, on average, changes in pulmonary function testing (PFT) are limited to small changes (∼1%) in forced expiratory volume in 1 second (FEV1). This comprehensive post-hoc analysis examined the incidence of significant decline in FEV1 over two years in subjects with type 1 and type 2 diabetes treated with TI. Subjects were included if they had at least five FEV1 measurements (including baseline and month 24). FEV1 must have been ≥70% of predicted at baseline. At each time point, subjects were classified as having a significant change in FEV1 if there was a ≥15% decline from baseline. Of the 377 subjects, 331 (87.8%) had no measure with ≥15% decline in FEV1 at any time point. Of subjects who had at least one measure with a decline of ≥15%, the majority (n=38) experienced this decline on a transient basis (defined as occurring at two or fewer time points). Eight individuals (2.1%) demonstrated a persistent decline in FEV1 (occurring at three or more time points). Four subjects in the comparator arm (0.7%, n=586) had persistent decline. In conclusion, persistent significant decline in FEV1 during the use of TI was uncommon. Disclosure M.C. Jones: Employee; Self; MannKind Corporation. T.S. Tran: Employee; Self; MannKind Corporation. J.A. Krueger: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company, MannKind Corporation. P.M. Morey: Employee; Self; MannKind Corporation. B.J. Hoogwerf: Consultant; Self; MannKind Corporation. Employee; Spouse/Partner; MannKind Corporation. Stock/Shareholder; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. D.M. Kendall: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company.

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.

In a recent study (STAT, NCT03143816), patients with type 1 diabetes mellitus (T1DM) treated with Technosphere Insulin (TI) demonstrated better early postprandial glucose (PPG) control than those on subcutaneous (SC) insulin aspart. The average daily dose of TI in patients who took TI as directed in the protocol was twice that of aspart (40.5 vs. 20.6 units). Despite the higher dose, the TI group experienced less time in hypoglycemia than the aspart group. These results prompted a retrospective analysis of mixed-meal tolerance tests (MMTTs) conducted in T1DM to further evaluate the 2:1 dosing ratio. In study MKC-TI-009 (NCT00308308), patients with T1DM underwent 1 to 3 MMTTs. A total of 1326 PPG profiles were evaluable: 674 MMTTs from 261 patients on SC aspart and 652 MMTTs from 264 patients on TI. On average, the area under the PPG excursion curve (PPGE AUC) decreased with increasing dose, and the mean (SE) ratio of the aspart slope to the TI slope was 2.1 (0.3), consistent with the results of STAT. This was confirmed when doses of TI 8, 16, and 24 units were compared with mean (SE) aspart doses of 4 (1), 8 (1), and 12 (1) units, respectively (Figure). The PPGE curves confirm the earlier onset and shorter duration of TI, while the tendency to drop below baseline in the late postprandial period reflects the longer duration of action of SC aspart. The timing of hypoglycemia (levels 1 and 2) follows the pattern of PPGEs. Disclosure M.L. Grant: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; MannKind Corporation. F. Pompilio: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Amgen Inc., MannKind Corporation. G. Sharma: Employee; Self; MannKind Corporation. J.A. Krueger: Employee; Self; Eli Lilly and Company, MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company. D.M. Kendall: Employee; Spouse/Partner; Amgen Inc. Employee; Self; MannKind Corporation. Stock/Shareholder; Self; MannKind Corporation. N. Zaveri: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Becton, Dickinson and Company. Funding MannKind Corporation

Technosphere Insulin (TI) is an ultra-rapid, short-acting inhaled insulin that provides glycemic control in patients with diabetes. This ongoing, 2-part, open-label, interventional study aims to assess the efficacy and safety of TI in children aged 4 to 17 years with type 1 diabetes mellitus (T1DM) who are on a stable regimen of basal-bolus insulin therapy. Part 1 is a single-arm study that includes evaluation of insulin pharmacokinetics (PK) after a single prandial dose of TI (4, 8, or 12 units), followed by a 4-week titration period. Approximately 46 patients will be enrolled across 3 age cohorts: cohort 1 (13-17 years), cohort 2 (8-12 years), and cohort 3 (4-7 years). As of August 16, 2018, 15 patients had enrolled in cohort 1, 14 had received at least 1 dose, and 8 completed the titration period. Overall, 50% of the safety population (n=14) was female, mean duration of T1DM was 6.2 years, mean age was 15 years, and mean body mass index was 22.4 kg/m2. Initial PK results from cohort 1 demonstrated insulin metabolism similar to that in adult patients receiving TI. Insulin concentrations rapidly increased in the first 30 minutes after TI treatment and returned to baseline by 120 minutes for the 4-, 8-, and 12-unit doses. Mean postprandial glucose levels decreased within 1-hour postdose for the 8- and 12-unit dose groups. Seven patients developed treatment-related cough of mild (6 events) or moderate (1 event) severity. Seven patients experienced a total of 41 hypoglycemic events, but no patient required the assistance of another person to administer corrective carbohydrates. No clinically relevant declines in pulmonary function were reported. Two patients discontinued the study due to adverse events (cough, diabetic ketoacidosis). These data will help determine the appropriate age range for inclusion and recommended dosing for part 2, which will be a 1-year efficacy and safety study. Disclosure M.L. Grant: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; MannKind Corporation. J.A. Krueger: Employee; Self; Eli Lilly and Company, MannKind Corporation. Stock/Shareholder; Self; Eli Lilly and Company. M. Fineman: Consultant; Self; MannKind Corporation. Employee; Self; Elcelyx Therapeutics, Inc. Stock/Shareholder; Self; Elcelyx Therapeutics, Inc. G. Sharma: Employee; Self; MannKind Corporation. F. Pompilio: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; Amgen Inc., MannKind Corporation. D.M. Kendall: Employee; Spouse/Partner; Amgen Inc. Employee; Self; MannKind Corporation. Stock/Shareholder; Self; MannKind Corporation. Funding MannKind Corporation

AIMS: To describe global patterns of insulin treatment and to assess the impact of patient, provider, health system and economic influences on treatment decisions for patients with insulin-treated type 2 diabetes (T2D). METHODS: This prospective cohort study of insulin-treated patients with T2D was conducted across 18 countries categorized as high, upper-middle or lower-middle income regions. Information collected from patients included knowledge of diabetes, experiences and interactions with their healthcare provider. Physician information included specialty, practice size, availability of diabetes support services, volume of diabetes patients treated and time spent per patient. Physicians determined an individualized haemoglobin A1c (HbA1c) target for each patient by the start of the study. Changes in T2D therapies and HbA1c were recorded for 2 years. RESULTS: Complete treatment data were available for 2528 patients. Median age was 61 years and median duration of diabetes was 11.4 years. Changes to treatment regimen occurred in 90.0% of patients, but changes were less common in countries with a higher economic status (P

Hypoglycemia (HG) and fear of HG limit effective insulin therapy and contribute to suboptimal glycemic control. Ultra-short acting insulins reduce HG risk by providing their glucose-lowering effect early and reducing the risk of late postprandial HG. AFFINITY-1, a treat-to-target study in T1D on multiple daily injection therapy, demonstrated one such ultra-short acting insulin, TI (Afrezza®), was non-inferior to SC aspart in A1C reduction (Bode et al, Diabetes Care 2015). Consistent with its action profile, a lower rate of HG was observed in TI users overall, particularly in the 2-5 h post-meal interval and in those achieving target A1C In this post-hoc analysis of patients with reported A1C values at end of treatment, mean rates for all HG and severe HG obtained from combined SMBG and AE reporting were significantly lower with TI than with aspart (Figure). A negative binomial regression including treatment, region, type of basal insulin, and A1C at end of treatment yielded an LS-mean HG rate for patients on TI 26% lower than comparable patients on aspart across the entire A1C range (mean ratio:0.74, 95% CI: 0.68-0.81). TI’s rapid onset and ultra-short action provide insulin when needed at meals and between meals. This profile improves overall and prandial glucose control and, as demonstrated in AFFINITY-1, has the potential to reduce the risk of late post-meal HG. Disclosure L. Blonde: Other Relationship; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Other Relationship; Self; Lexicon Pharmaceuticals, Inc.. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Janssen Scientific Affairs, LLC.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Merck & Co., Inc., Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Other Relationship; Self; Novo Nordisk Inc., Sanofi. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Sanofi US. F. Pompilio: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; MannKind Corporation, Amgen Inc. S.R. Bruce: Consultant; Self; MannKind Corporation, Oramed Pharmaceuticals, Inc. M.L. Grant: Employee; Self; MannKind Corporation. Stock/Shareholder; Self; MannKind Corporation. D.M. Kendall: Employee; Self; MannKind Corporation. Employee; Spouse/Partner; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.

Introduction Although depression is often associated with poor glycemic control in patients with type 2 diabetes mellitus (T2DM), this observation has been inconsistent. This exploratory, post hoc analysis investigated associations between depression parameters and glycemic control using data from a 24-month, prospective, observational, non-interventional study evaluating glycemic response following insulin initiation for T2DM. Methods We analyzed data from a 24-month, prospective, observational study that evaluated glycemic response in patients with T2DM who initiated insulin therapy (N = 985) in 5 European countries. Secondary measures included patient-reported diagnosis of depression at baseline, severity of depressed/anxious mood (EuroQol (EQ)-5D item) and diabetes-related distress (Psychological Distress domain of the Diabetes Health Profile, DHP-18). The latter two measures were assessed at baseline and 5 time points throughout the study. Glycemic control was measured by glycated hemoglobin (HbA1c) at these same time points. Analyses employed t tests to assess the unadjusted baseline difference in HbA1c between patients with and without the respective depression parameter. The potential effect of demographic and clinical confounding variables was controlled through a linear model structure. Patient HbA1c levels were analyzed by presence/absence of a history of diagnosed depression, depressed mood, and diabetes-related distress. Results Patients with higher depression parameters or distress at baseline had significantly higher rates of microvascular complications at baseline. Patients with a history of diagnosed depression or high diabetes-related distress had higher HbA1c than patients without. HbA1c of patients with or without depressed mood was not significantly different at baseline. The proportion of patients with depressed mood declined after insulin initiation, whereas the proportion of patients with high diabetes-related distress did not significantly change. HbA1c improved following insulin initiation, regardless of presence/absence of studied depression/distress parameters at baseline. Conclusion History of diagnosed depression, diabetes-related distress, and depressed mood were associated with a higher rate of microvascular complications. Diagnosed depression and diabetes-related distress also showed higher HbA1c at baseline when insulin was initiated. Insulin therapy improved glycemic control, while preexisting depressed mood declined and diabetes-related distress remained unchanged. Electronic supplementary material The online version of this article (doi:10.1007/s13300-015-0118-y) contains supplementary material, which is available to authorized users.

Purpose Although diabetes is recognized as a risk factor for the development of cognitive impairment and for accelerated progression to Alzheimer disease (AD), it is unclear whether patients with diabetes who have already progressed to AD have a different rate of cognitive and functional decline compared with that in those without diabetes. This post hoc exploratory analysis compared cognitive and functional decline over an 18-month period in patients with mild AD dementia with and without comorbid diabetes. Decline in quality of life was assessed as a secondary objective. Methods In a post hoc exploratory analysis, we analyzed data from the placebo groups of three 18-month, randomized, placebo-controlled trials of solanezumab and semagacestat in patients with AD. Data from patients with mild AD dementia (Mini-Mental State Examination [MMSE] score, 20–26) and comorbid diabetes at baseline were compared with data from patients with mild AD dementia without diabetes at baseline. Cognition was assessed using the 14-item AD Assessment Scale–Cognitive Subscale (ADAS-Cog 14 ) and the MMSE. Functioning was assessed with the AD Cooperative Study–Activities of Daily Living Inventory (instrumental subset) (ADCS-iADL). Quality of life was assessed using the European Quality of Life–5 Dimensions scale, proxy version (proxy utility score and visual analog scale score), and the Quality of Life in AD scale, self-report and proxy (caregiver) versions. Group comparisons of changes from baseline to 18 months in cognitive, functional, and quality-of-life measures employed a repeated-measures model adjusted for propensity score, study, baseline cognition score (functional or quality of life), age, sex, level of education, genotype of the apolipoprotein E gene, and concurrent use of an acetylcholinesterase inhibitor or memantine. Findings At baseline, patients with mild AD dementia with and without diabetes did not significantly differ on the cognitive measures, but those without diabetes were functioning at a significantly higher level. At 18 months, compared with patients without diabetes, those with diabetes showed a numerically but statistically nonsignificantly lesser cognitive decline (least squares mean between-group differences: ADAS-Cog 14 score, 1.61 [ P = 0.21]; MMSE score, –0.40 [ P = 0.49]) and a statistically significantly lesser functional decline (least squares mean between-group difference in ADCS-iADL score, –3.07; P = 0.01). The 2 groups did not differ on declines in the quality-of-life measures. Implications The present findings suggest that diabetes may influence the rate of functional decline among patients with mild AD dementia. These results require replication in studies that address the limitations of the present post hoc exploratory analysis and that explore the potential causes of the observed differences.

Many insulin-treated patients with type 2 diabetes (T2D) do not reach hemoglobin A1c (HbA1c) 7%, but have clinically relevant HbA1c reductions. Using an integrated database (IDB) of 53 insulin lispro clinical trials and a real-world evidence (RWE) database of T2D patients initiating insulin therapy, an expanded HbA1c measure was used to identify responders to insulin therapy.Analysis included 4,908 patients (IDB) and 1,134 patients (RWE) with T2D treated with any insulin regimen with a baseline and ≥1 post-baseline HbA1c. Responders were defined as patients with endpoint HbA1c 7% (cut point [CP]) and/or either ≥1% absolute (ABS) decrease, and/or ≥10% relative (REL) decrease in HbA1c from baseline. The percentage of responders with CP vs ABS and concordance between ABS and REL were calculated. As the ABS and REL measures were highly correlated (94%), the ABS measure was used to compare characteristics of responders and non-responders by age, diabetes duration, race/ethnicity, baseline HbA1c, and insulin regimen at 24 weeks.In both databases, more responders were identified with ABS or REL (62%) than CP (41%). More ABS responders had a baseline HbA1c ≥ 9% and a shorter diabetes duration than non-responders. Basal insulin-treated patients in the IDB had 78.2% responders at 24 weeks, compared to 69.7% with basal/bolus or pre-mixed insulin (75.4%). Results were similar in the IDB and RWE.Composite HbA1c measures identified more patients with clinically meaningful responses to therapy than the broadly accepted HbA1c 7% and may be useful in assessing clinical trials, clinical care, and quality measures.

The American Diabetes Association consensus statement on the treatment of type 2 diabetes mellitus (T2DM) in older patients highlights the need for treatment pattern and effectiveness data from real-world settings and populations. This retrospective cohort study assessed the relative frequency of use of four commonly prescribed antihyperglycemia treatments for T2DM and quantified their effectiveness up to 2 years post-initiation.Within a large, U.S.-based, electronic health record database, we investigated usage of insulin, sulfonylureas, glucagon-like peptide-1(GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with T2DM, focusing on those ≥65 years old, although younger patients were included for comparative purposes.Inclusion criteria were met by 77,440 patients. Mean baseline glycosylated hemoglobin (HbA1c) levels for patients ≥65 years old varied among treatments: insulin (7.7% [61 mmol/mol]; n=3,311), sulfonylureas (7.0% [53 mmol/mol]; n=5,706), GLP-1 receptor agonists (7.1% [54 mmol/mol]; n=260), and DPP-4 inhibitors (7.1% [54 mmol/mol]; n=1,096). Older patients demonstrated good glycemic control at therapy initiation and were prescribed glucose-lowering agents at lower HbA1c values compared with younger patients. A large proportion of older patients were prescribed sulfonylureas (56%) and insulin (34%) compared with GLP-1 receptor agonists (3.4%) and DPP-4 inhibitors (12%), despite the associated risk of hypoglycemia.Patients initiating insulin and sulfonylureas demonstrated more sustained glycemic control compared with GLP-1 receptor agonists and DPP-4 inhibitors. A majority of older patients with T2DM was initiated on sulfonylureas and insulin at relatively low levels of HbA1c, a practice not entirely consistent with the recommendations of published guidelines.

There is a link between Oliver Wendell Holmes' poem “The One-Hoss Shay” (1) and every patient with diabetes who has ever received a kidney or pancreas transplant. Yet, most of the 4,128 diabetes patients in the U.S. who received renal transplants in 2011 (2) and the 1,051 diabetes patients who received a pancreas transplant in 2011 (3) do not know how Dr. Frederick C. Goetz (1922–2012) used this delightful poem as parallel to how the medical profession viewed patients with diabetes. Dr. Goetz, who always preferred to be addressed as “Fred” by any who knew him, played a seminal role in assuring that both renal and pancreas transplantation were available to suitable patients with diabetes. While today this is considered a standard of clinical care, Fred maintained his equanimity in the face of much skepticism and criticism—often from friends and colleagues. This profile outlines Fred’s role in the history of renal and pancreas transplantation, but also strives to capture some of the “essence” of Frederick C. Goetz—as a caregiver, physician, scientist, and teacher. This profile is written from the perspective of three physicians, each of whom first met Fred while they were medical students at the University of Minnesota and whose collective observations and collaboration with Fred spanned more than three decades of his academic career. Fred was born and raised in Fond du Lac, WI. He graduated from Harvard College (1943) and Harvard Medical School (1946). He served in the U.S. Army as a physician in Korea where he met his future wife, Mary Rose Riordan. After a residency, chief residency, and fellowship (with Dr. George Thorn) at Massachusetts General Hospital, he joined the University of Minnesota as the Director of Diabetes Research. His career was focused on diabetes and its complications. His personal life was filled with interests …

Background The burden on caregivers of patients with Alzheimer’s disease (AD) is associated with the patient’s functional status and may also be influenced by chronic comorbid medical conditions, such as diabetes. This post-hoc exploratory analysis assessed whether comorbid diabetes in patients with AD affects caregiver burden, and whether caregivers with diabetes experience greater burden than caregivers without diabetes. Caregiver and patient healthcare resource use (HCRU) were also assessed. Methods Baseline data from the GERAS observational study of patients with AD and their caregivers (both n = 1495) in France, Germany and the UK were analyzed. Caregiver burden was assessed using the Zarit Burden Interview (ZBI). Caregiver time on activities of daily living (ADL: basic ADL; instrumental ADL, iADL) and supervision (hours/month), and caregiver and patient HCRU (outpatient visits, emergency room visits, nights hospitalized) were assessed using the Resource Utilization in Dementia instrument for the month before the baseline visit. Regression analyses were adjusted for relevant covariates. Time on supervision and basic ADL was analyzed using zero-inflated negative binomial regression. Results Caregivers of patients with diabetes (n = 188) were younger and more likely to be female (both p

Since our last publication about diabetes and fasting during Ramadan (1), we have received many inquires and comments concerning important issues that were not discussed in the previous document, including the voluntary 1- to 2-day fasts per week that many Muslims practice throughout the year, as well as the effect of prolonged fasting (more than 18 h a day) in regions far from the equator during Ramadan when it occurs in summer—a phenomenon expected to affect millions worldwide for the next 10–15 years. Since 2005, there have been substantial additions to the literature, including two studies examining the effect of structured education and support for safe fasting, both of which had promising results (2,3). In addition, new medications, such as the incretin-based therapies, have been introduced with less risk for hypoglycemia. According to a 2009 demographic study, Islam has 1.57 billion adherents, making up 23% of the world population of 6.8 billion, and is growing by ∼3% per year (4). Fasting during Ramadan, a holy month of Islam, is a duty for all healthy adult Muslims. The high global prevalence of type 2 diabetes—6.6% among adults age 20–79 years (5)—coupled with the results of the population-based Epidemiology of Diabetes and Ramadan 1422/2001 (EPIDIAR) study, which demonstrated among 12,243 people with diabetes from 13 Islamic countries that ∼43% of patients with type 1 diabetes and ∼79% of patients with type 2 diabetes fast during Ramadan (6), lead to the estimate that worldwide more than 50 million people with diabetes fast during Ramadan. Ramadan is a lunar-based month, and its duration varies between 29 and 30 days. Muslims who fast during Ramadan must abstain from eating, drinking, use of oral medications, and smoking from predawn to after sunset; however, there are no restrictions on food or fluid intake between sunset …

Exenatide is the first glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus (T2DM). Exenatide lowers blood glucose through multiple mechanisms, including enhancement of glucose-dependent insulin secretion, suppression of excess glucagon secretion, reduction of food intake and slowing of gastric emptying. The current formulation of exenatide requires twice-daily dosing (exenatide BID), and an extended-release formulation of exenatide is now in development for use as a once-weekly injection (exenatide QW). The purpose of this report is to review the most current clinical data on the development of exenatide QW for the treatment of T2DM. In clinical trials, exenatide QW significantly improved glycemic control, resulted in patient weight loss, and was well tolerated in patients with T2DM. In a head-to-head clinical trial, exenatide QW caused greater improvements in glycemic control and was better tolerated than exenatide BID. Given the rapidly increasing prevalence of diabetes and obesity worldwide, exenatide QW is a promising development candidate for the treatment of T2DM.

OBJECTIVE Traditional blood glucose–lowering agents do not sustain adequate glycemic control in most type 2 diabetic patients. Preclinical studies with exenatide have suggested sustained improvements in β-cell function. We investigated the effects of 52 weeks of treatment with exenatide or insulin glargine followed by an off-drug period on hyperglycemic clamp–derived measures of β-cell function, glycemic control, and body weight. RESEARCH DESIGN AND METHODS Sixty-nine metformin-treated patients with type 2 diabetes were randomly assigned to exenatide (n = 36) or insulin glargine (n = 33). β-Cell function was measured during an arginine-stimulated hyperglycemic clamp at week 0, at week 52, and after a 4-week off-drug period. Additional end points included effects on glycemic control, body weight, and safety. RESULTS Treatment-induced change in combined glucose- and arginine-stimulated C-peptide secretion was 2.46-fold (95% CI 2.09–2.90, P < 0.0001) greater after a 52-week exenatide treatment compared with insulin glargine treatment. Both exenatide and insulin glargine reduced A1C similarly: −0.8 ± 0.1 and −0.7 ± 0.2%, respectively (P = 0.55). Exenatide reduced body weight compared with insulin glargine (difference −4.6 kg, P < 0.0001). β-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy. CONCLUSIONS Exenatide significantly improves β-cell function during 1 year of treatment compared with titrated insulin glargine. After cessation of both exenatide and insulin glargine therapy, β-cell function and glycemic control returned to pretreatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therapy.

In Brief The medical risks associated with eating disorders in diabetes are significant. Clinicians working with patients who are at risk for eating disorders should be cognizant of patterns that might indicate the presence of disturbed eating behaviors in their patients. This article discusses the warning signs, screening tools, and diagnostic criteria associated with eating disorders in type 1 diabetes.

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.

Metabolic syndrome represents a cluster of risk factors commonly associated with obesity and diabetes that in turn are associated with an increased risk of cardiovascular disease. The worldwide prevalence of metabolic syndrome, obesity, and diabetes is on the rise, leading to serious public health concerns surrounding the downstream consequences in the form of premature cardiovascular disease. In this review, we examine the debate surrounding the characterization and diagnosis of metabolic syndrome and discuss potential treatment options.

Purpose The purpose of this study was to evaluate the impact of a tobacco cessation intervention using motivational interviewing on smoking cessation rates during diabetes self-management training (DSMT). Methods A randomized controlled trial was conducted with subjects recruited from an ongoing type 2 diabetes adult education program at a large diabetes center. A total of 114 subjects were randomized to intervention (n = 57; face-to-face motivational interviewing plus telephone counseling and offering of medication) or standard care (n = 57). Outcome measures included tobacco cessation rates, mean number of cigarettes smoked, A1C, weight, blood pressure, and lipids. Results Intensive intervention using motivational interviewing integrated into a standard DSMT program resulted in a trend toward greater abstinence at 3 months of follow-up in those receiving the intervention. However, this same trend was not observed at 6 months. The addition of this structured smoking cessation intervention did not negatively affect either diabetes education or other measures of diabetes management, including A1C values.

OBJECTIVE—We sought to evaluate the effects of muraglitazar, a dual (α/γ) peroxisome proliferator–activated receptor (PPAR) activator within the new glitazar class, on hyperglycemia and lipid abnormalities. RESEARCH DESIGN AND METHODS—A double-blind, randomized, controlled trial was performed in 1,159 patients with type 2 diabetes inadequately controlled with metformin. Patients received once-daily doses of either 5 mg muraglitazar or 30 mg pioglitazone for a total of 24 weeks in addition to open-label metformin. Patients were continued in a double-blind fashion for an additional 26 weeks. RESULTS—Analyses were conducted at week 24 for HbA1c (A1C) and at week 12 for lipid parameters. Mean A1C at baseline was 8.12 and 8.13% in muraglitazar and pioglitazone groups, respectively. At week 24, muraglitazar reduced mean A1C to 6.98% (−1.14% from baseline), and pioglitazone reduced mean A1C to 7.28% (−0.85% from baseline; P < 0.0001, muraglitazar vs. pioglitazone). At week 12, muraglitazar and pioglitazone reduced mean plasma triglyceride (−28 vs. −14%), apolipoprotein B (−12 vs. −6%), and non-HDL cholesterol (−6 vs. −1%) and increased HDL cholesterol (19 vs. 14%), respectively (P < 0.0001 vs. pioglitazone for all comparisons). At week 24, weight gain (1.4 and 0.6 kg, respectively) and edema (9.2 and 7.2%, respectively) were observed in the muraglitazar and pioglitazone groups; at week 50, weight gain and edema were 2.5 and 1.5 kg, respectively, and 11.8 and 8.9%, respectively. At week 50, heart failure was reported in seven patients (five with muraglitazar and two with pioglitazone), and seven deaths occurred: three from sudden death, two from cerebrovascular accident, and one from pancreatic cancer in the muraglitazar group and one from perforated duodenal ulcer in the pioglitazone group. CONCLUSIONS—We found that 5 mg muraglitazar resulted in greater improvements in A1C and lipid parameters than a submaximal dose of 30 mg pioglitazone when added to metformin. Weight gain and edema were more common when muraglitazar was compared with a submaximal dose of pioglitazone.

Current strategies for the treatment of type 2 diabetes target deficient insulin secretion and insulin resistance, but have not been shown to correct the progressive β-cell dysfunction characteristic of the disease. Traditionally, type 2 diabetes is treated in a stepwise manner with medical nutrition therapy, oral anti-diabetes therapies, and ultimately exogenous insulin. These therapies improve glycemic control, but are unable to prevent or delay either deterioration in glucose control or the decline of β-cell function. Despite the use of current anti-diabetes therapies, patients with type 2 diabetes are likely to experience deteriorating glycemic control and substantial weight gain. In addition to these issues, patients treated with insulin secretogogues such as sulfonylureas and exogenous insulin are subject to an increased risk of hypoglycemia. Moreover, insulin-based therapies do not fully address the complex hormonal irregularities, such as glucagon hypersecretion, that characterize type 2 diabetes. In view of the drawbacks associated with current treatment strategies, new therapies are being developed that may provide more durable glycemic control with associated reductions in body weight. These new therapies include the incretin mimetics, agents that share many of the glucoregulatory effects of the incretin hormones such as glucagon-like peptide-1 (GLP-1). Leveraging the physiological functions of incretin hormones such as GLP-1 may potentially benefit the ever growing number of patients with type 2 diabetes.

Editor’s note: This commentary was originally solicited as part of a Point-Counterpoint feature, but the author of the Counterpoint failed to provide the promised manuscript. Thiazolidinediones (TZDs), or “glitazones,” were first introduced for the treatment of type 2 diabetes in 1996, when troglitazone (Rezulin; Parke-Davis/Warner-Lambert) was approved by the Food and Drug Administration. Since the introduction of this unique class of compounds, many clinicians have embraced their use, whereas others have debated the role of insulin-sensitizing therapy for the management of type 2 diabetes. While troglitazone was withdrawn from the market in 2000 due to idiosyncratic hepatoxicity, two other glitazones, pioglitazone (Actos; Takeda Chemical Industries) and rosiglitazone (Avandia; GlaxoSmithKline), continue to be widely used by clinicians. Before the introduction of glitazones, conventional management of type 2 diabetes involved stepwise addition of medical nutrition therapy, sulfonylureas, and metformin. Despite broader use of early drug therapy, many patients do not achieve adequate blood glucose control (1). Even in those who do achieve treatment targets, a gradual deterioration in blood glucose control is often seen (2). These observations have prompted clinicians to use newer therapies, such as the glitazones, and have increased the use of early combination therapy to achieve glycemic targets Glitazones uniquely target insulin resistance—a core physiologic defect in those with type 2 diabetes—and by so doing significantly improve glucose control. Glitazones improve insulin action in muscle, adipose, and hepatic tissue by acting as agonists of peroxisome proliferator–activated receptor-γ (PPAR-γ) nuclear receptors. Activation of PPAR-γ results in a myriad of both metabolic and vascular effects by upregulating and downregulating expression of numerous genes, including genes known to regulate lipid and glucose metabolism, vascular function, thrombotic function, and the inflammatory response. Glitazones increase nonoxidative glucose disposal, increase triglyceride synthesis, and improve free fatty acid (FFA) metabolism (3). Glitazones also lower blood pressure, …

CVD is the primary cause of morbidity and mortality in patients who have diabetes mellitus. Most such patients have at least one lipid abnormality. Managing these complex lipid disorders is a crucial component of comprehensive diabetes mellitus care and limits the risk for cardiovascular morbidity and mortality. With the high prevalence of mixed lipid disorders, management must focus on all components of the lipid profile. Lowering LDL-C levels remains the first priority, but abnormalities in HDL-C and TG levels also should be treated aggressively. Statins, fibrates, and niacin, along with newer therapies such as ezetimibe, can improve significantly components of the lipid profile. Alone or in combination, these agents can treat the dyslipidemia of diabetes mellitus effectively and safely.

We evaluated the clinical accuracy, precision, and ease-of-use of a whole blood referenced glucose meter system that uses a 10-test disk (Ascensia Confirm Blood Glucose Monitoring System, Bayer Healthcare LLC). The meter system was tested by 100 subjects and eight health care professionals at two separate diabetes centers. Meter blood glucose test results, obtained by the subjects and health care professionals, were accurate and correlated well when compared with laboratory results. The means of the subject and healthcare professional blood glucose results were within 4.8% of the laboratory mean glucose result. When compared with laboratory results, the correlation coefficient was 0.96 for subject meter results and 0.97 for health care professional meter results. Error grid analyses demonstrated that all subject and health care professional blood glucose measurements fell within zones A and B ('no effect on clinical action' and 'altered clinical action with little or no effect on clinical outcome,' respectively). Ninety-three percent (93%) of subjects rated the meter system favorably on an 'ease-of-use' questionnaire. A majority of subjects correctly performed blood glucose self-monitoring tasks simply by reviewing the user guide. In summary, this unique meter that uses a 10-test disk was shown to be both accurate and precise, and subjects with diabetes were able to use the system properly with minimal instructions.

To construct a novel and clinically relevant means of representing self-monitored blood pressure (SMBP).Patients treated to an office blood pressure (BP)130/80 mmHg measured their BP at home for 14 days using an Omron IC semi-automatic portable monitor with memory. SMBP data were transferred from the monitor to a computer to produce graphic profiles (SMBPp) that depict the hourly variation in BP throughout a "typical" or modal day.Office BP and SMBP data from 66 subjects with type 2 diabetes and hypertension (HTN), who completed a previous study of intensified management, were analyzed based on European Society of Hypertension-European Society of Cardiology (ESH-ESC) classifications. Patients were classified as Optimal (6), Normal (12), High Normal (15), Isolated systolic HTN (29) and Grades 1, 2 or 3 HTN (4). SMBP disagreed in 32 cases, placing 29 patients in higher risk categories. Analysis by SMBPp of the 33 patients originally classified as Optimal, Normal or High Normal showed that on average 50 +/- 31% of their systolic SMBP values exceeded ESH-ESC thresholds for HTN (135 mmHg). It also revealed that 74 +/- 21% of their SMBP values exceeded the treatment goal (25 mmHg) for high-risk patients with type 2 diabetes.SMBPp allowed for a definitive measurement of the dynamic daily BP changes. It produced compelling evidence of persistent patterns of BP fluctuations among patients with normal office BP whose uncontrolled HTN would have remained undetected.

OBJECTIVES After participating in the CME activity, primary care physicians should be able to: 1. Know the clinical features of the insulin resistance syndrome 2. Understand the role of insulin resistance in the pathogenesis of type 2 diabetes 3. Be familiar with the agents used in the management of patients with type 2 diabetes 4. Know the mechanisms known or postulated to contribute to the accelerated development of cardiovascular disease in the insulin resistance syndrome 5. Identify the pharmacologic agents used in the treatment of insulin resistance

OBJECTIVE—To determine whether clinically significant differences exist in fasting blood glucose (BG) at the forearm, palm, and thigh relative to the fingertip; to assess the impact of prandial status by comparing BG between alternative sites and the fingertip at several time intervals after carbohydrate intake; to assess the effects of moderate brief exercise on site-to-site differences in BG; to evaluate the impact of site preparation by local rubbing on alternative-site testing (AST) equivalence; and to determine levels of perceived pain and satisfaction associated with AST. RESEARCH DESIGN AND METHODS—Fasting BG was measured using the One Touch Ultra (LifeScan, Milpitas, CA) at the fingertip, palm, thigh, and each forearm (with local rubbing) in 86 patients with type 2 diabetes. A 40-g carbohydrate meal was consumed and BG was again measured from each site at 60, 90, and 120 min postmeal, with an additional forearm test at 90 min without local rubbing. Patients then exercised for 15 min with repeat BG at each site. Differences in BG between sites were assessed using repeated-measures ANOVA and regression analyses. RESULTS—Significant differences in BG at alternative sites were found 60 min postmeal (P = 0.0003) and postexercise (P = 0.037). Specifically, clinically significant differences (expressed as percent difference from the fingertip) at 60 min include −8.8 ± 10.8% at the forearm and −13.7 ± 10.7% at the thigh, and postexercise +19.1 ± 19.1% at the forearm and +15.6 ± 22.6% at the thigh. However, no significant differences were observed between sites in either the fasting state or at 90 and 120 min postmeal. The dynamic results suggest a time lag in equilibration of forearm and thigh BG during periods of rapid glucose change. Palm and fingertip BG test results were similar at all time points. CONCLUSIONS—AST results are consistent with fingertip BG results in both the fasting state and 2 h postmeal; no benefit from site preparation by local rubbing was noted. However, testing at sites other than the hand cannot be recommended 1 h postmeal or immediately after exercise. AST is equivalent and appropriate for use at testing times commonly used in clinical practice.

We report a case of severe hypoglycemia occurring in a 35-yr-old woman, 6 yr after pancreas transplantation for type 1 diabetes mellitus. Extensive preoperative and intraoperative exploration failed to disclose the presence of a focal adenomatous lesion. Partial allograft pancreatectomy was performed initially, but it failed to control the hypoglycemic symptoms, leading to complete removal of the pancreas allograft. Histopathological examination of the resected pancreas allograft showed the presence of nesidioblastosis, characterized by foci of islet cells budding off ducts, accompanied by an increase in the number of islets, numerous small intralobular islet cell aggregates, and nesidiodysplasia (large, hyperchromatic islet cell nuclei). Islet neogenesis-associated protein-positive islets and ducts were seen by immunofluorescence. Insulin-positive islets ranged from very small to large, with isolated insulin-positive cells diffusely scattered, consistent with islet neogenesis. Very little glucagon staining was identified. Reported cases of adult nesidioblastosis are reviewed. The significance of nesidioblastosis in the context of pancreas transplantation and possible mechanisms of posttransplant hypoglycemia are discussed.

OBJECTIVES— The current study was conducted to compare the effectiveness of delivering diabetes education in either a group or individual setting using a consistent, evidence-based curriculum. RESEARCH DESIGN AND METHODS— A total of 170 subjects with type 2 diabetes were randomly assigned to either group (n = 87) or individual (n = 83) educational settings. Subjects received education in four sequential sessions delivered at consistent time intervals over a 6-month period. Outcomes included changes in knowledge, self-management behaviors, weight, BMI, HbA1c, health-related quality of life, patient attitudes, and medication regimen. Changes were assessed at baseline and after the 2-week, 3-month, and 6-month education sessions. RESULTS— Both educational settings had similar improvements in knowledge, BMI, health-related quality of life, attitudes, and all other measured indicators. HbA1c decreased from 8.5 ± 1.8% at baseline to 6.5 ± 0.8% at 6 months (P < 0.01) in the study population as a whole. Subjects assigned to the individual setting had a 1.7 ± 1.9% reduction in HbA1c (P < 0.01), whereas subjects assigned to the group setting had a 2.5 ± 1.8% reduction in HbA1c (P < 0.01). The difference in HbA1c improvement was marginally greater in subjects assigned to group education versus individualized education (P = 0.05). CONCLUSIONS— This study demonstrates that diabetes education delivered in a group setting, when compared with an individual setting, was equally effective at providing equivalent or slightly greater improvements in glycemic control. Group diabetes education was similarly effective in delivering key educational components and may allow for more efficient and cost-effective methods in the delivery of diabetes education programs.

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.