Characteristics of adult- compared to childhood-onset type 1 diabetes.

AIMS: To compare diagnosis characteristics, diabetes management and comorbidities in a population diagnosed with type 1 diabetes in childhood with those in a similar population diagnosed in adulthood to identify disease differences related to the age of diabetes onset. METHODS: This analysis was performed using the T1D Exchange Clinic Registry, a cross-sectional survivor cohort. Retrospectively collected characteristics were compared across the following age-at-diagnosis groups: <10, 10-17, 18-24, 25-39 and ≥40 years. RESULTS: The entire cohort included 20 660 participants [51% female, median (interquartile range) age 18 (14-36) years, 82% non-Hispanic white]. Diabetic ketoacidosis at diagnosis was more common among those with onset in childhood. Participants diagnosed as adults were more likely to be overweight/obese at diagnosis and to have used oral agents preceding type 1 diabetes diagnosis (57%). Current insulin pump use was less frequent in participants diagnosed at older ages. Current glycaemic control, measured by HbA1c , insulin requirements and use of a continuous glucose monitor were not different by age at diagnosis. Coeliac disease was the only comorbidity that was observed to have a different frequency by age at diagnosis, being more common in the participants diagnosed at a younger age. CONCLUSIONS: These results show differences and similarities between type 1 diabetes diagnosed in childhood vs adulthood; notably, there was a tendency for there was a higher frequency of diabetic ketoacidosis at onset in children and a higher frequency of use of oral antidiabetes agents in adults. The data indicate that there is little distinction between the clinical characteristics and outcomes of type 1 diabetes diagnosed in childhood vs adulthood. Optimizing glycaemic control remains a challenge in all age groups, with lower use of insulin pumps impacting those diagnosed as adults.

Novelty Improves the Formation and Persistence of Memory in a Naturalistic School Scenario.

One of the top challenges in education and neuroscience consists in translating laboratory results into strategies to improve learning and memory in teaching environments. In that sense, during the last two decades, researchers have discovered specific temporal windows around learning, during which the intervention with some experiences induces modulatory effects on the formation and/or persistence of memory. Based on these results, the aim of the present study was to design a specific strategy to improve the memory of students in a high-school scenario, by assessing the effect of a novel situation experienced close to learning. We found that the long-term memory about a geometrical figure was more precise in the group of students that faced a novel situation 1 h before or after learning the figure than the control group of students who did not face the novelty. This enhancement was probably triggered by processes acting on memory formation mechanisms that remained evident 45 days after learning, indicating that the improvement was sustained over time. In addition, our results showed that novelty no longer improved the memory if it was experienced 4 h before or after learning. However, far beyond this window of efficacy, when it was faced around 10 h after learning, the novel experience improved the memory persistence tested 7 days later. In summary, our findings characterized different temporal windows of the effectiveness of novelty acting on memory processing, providing a simple and inexpensive strategy that could be used to improve memory formation and persistence in high-school students.

Associations between HbA1c and continuous glucose monitoring-derived glycaemic variables.

AIMS: To identify clinically useful associations between HbA1c levels and various continuous glucose monitoring-derived metrics. METHODS: We retrospectively analysed end-of-study HbA1c levels and >2 weeks of continuous glucose monitoring data collected from 530 adults with Type 1 diabetes or insulin-requiring Type 2 diabetes during four randomized trials. Each trial lasted ≥24 weeks and provided central laboratory end-of-study HbA1c levels and continuous glucose monitoring data from the preceding 3 months. Participants were assigned to groups based on either HbA1c levels or continuous glucose monitoring-derived glucose values. RESULTS: HbA1c was strongly correlated with mean glucose value (r=0.80), time spent with glucose values in the 3.9-10.0 mmol/l range (time in range; r=-0.75) and percentage of glucose values >13.9 mmol/l (r=0.72), but was weakly correlated with the percentage of glucose values <3.9 mmol/l (r=-0.39) or <3.0 mmol/l (r=-0.21). The median percentage of glucose values <3.0 mmol/l was <1.2% (<20 min/day) for all HbA1c -based groups, but the median percentage of values >13.9 mmol/l varied from 2.5% (0.6 h/day) to 27.8% (6.7 h/day) in the lowest and highest HbA1c groups, respectively. More than 90% of participants with either <2% of glucose values >13.9 mmol/l, mean glucose <7.8 mmol/l, or time in range >80% had HbA1c levels ≤53 mmol/mol (≤7.0%). For participants with HbA1c ≥64 mmol/mol (≥8.0%), the median time in range was 44%, with 90% of participants having a time in range of <59%. CONCLUSIONS: The associations shown in the present study suggest that continuous glucose monitoring-derived metrics may help guide diabetes therapy intensification efforts in an HbA1c -independent manner.

Effect of liraglutide on anthropometric measurements, sagittal abdominal diameter and adiponectin levels in people with type 2 diabetes treated with multiple daily insulin injections: evaluations from a randomized trial (MDI-liraglutide study 5).

AIM: Use of the glucagon-like peptide 1 receptor agonist liraglutide has been shown to reduce weight. Different types of anthropometric measurements can be used to measure adiposity. This study evaluated the effect of liraglutide on sagittal abdominal diameter, waist circumference, waist-to-hip ratio and adiponectin levels in people with type 2 diabetes (T2D) treated with multiple daily insulin injections (MDI). MATERIALS AND METHODS: In the multicentre, double-blind, placebo-controlled MDI-liraglutide trial, 124 individuals with T2D treated with MDI were randomized to either liraglutide or placebo. Basal values of weight, waist circumference, waist-to-hip ratio, sagittal abdominal diameter and adiponectin were compared with measurements at 12 and 24 weeks after randomization. RESULTS: Baseline-adjusted mean weight loss was 3.8 ± 2.9 kg greater in liraglutide than placebo-treated individuals (p < 0.0001). Waist circumference was reduced by 2.9 ± 4.3 cm and 0.2 ± 3.6 cm in the liraglutide and placebo groups, respectively, after 24 weeks (baseline-adjusted mean difference: 2.6 ± 4.0 cm, p = 0.0005). Corresponding reductions in sagittal abdominal diameter were 1.1 ± 1.7 cm and 0.0 ± 1.8 cm (baseline-adjusted mean difference: 1.1 ± 1.7 cm, p = 0.0008). Hip circumference was reduced in patients randomized to liraglutide (baseline-adjusted mean difference between treatment groups: 2.8 ± 3.8 cm, p = 0.0001), but there was no significant difference between the groups in either waist-to-hip ratio (baseline-adjusted mean difference: 0.0 ± 0.04 cm, p = 0.51) or adiponectin levels (baseline-adjusted mean difference: 0.8 ± 3.3 mg L-1, p = 0.17). Lower HbA1c and mean glucose levels measured by masked continuous glucose monitoring at baseline were associated with greater effects of liraglutide on reductions in waist circumference and sagittal abdominal diameter. CONCLUSIONS: In patients with T2D, adding liraglutide to MDI may reduce abdominal and hip obesity to a similar extent, suggesting an effect on both visceral and subcutaneous fat. Liraglutide had greater effects on reducing abdominal obesity in patients with less pronounced long-term hyperglycaemia but did not affect adiponectin levels.

Non-insulin treatments for Type 1 diabetes: critical appraisal of the available evidence and insight into future directions.

Intensive insulin therapy is the mainstay of treatment for people with Type 1 diabetes, but hypoglycaemia and weight gain are often limiting factors in achieving glycaemic targets and decreasing the risk of diabetes-related complications. The inclusion of pharmacological agents used traditionally in Type 2 diabetes as adjuncts to insulin therapy in Type 1 diabetes has been explored, with the goal of mitigating such drawbacks. Pramlintide and metformin result in modest HbA1c and weight reductions, but their use is limited by poor tolerability and, in the case of pramlintide, by frequency of injections and cost. The addition of glucagon-like peptide-1 receptor agonists to insulin results in improved glycaemic control, reduced insulin doses and weight loss, but this is at the expense of higher rates of hypoglycaemia and hyperglycaemia with ketosis. Sodium-glucose co-transporter-2 and dual sodium-glucose co-transporter-2 and -1 inhibitors also improve glucose control, but with reductions in weight and insulin requirements potentiating the risk of acidosis-related events and hypoglycaemia. The high proportion of people with Type 1 diabetes not achieving glycaemic targets, the negative clinical impact of intensive insulin therapy and the rise in obesity and cardiovascular disease and mortality, underline the need for individualized clinical care. The evaluation of new therapies, effective in Type 2 diabetes, as adjuncts to insulin therapy represents a promising strategy, particularly given the beneficial effects on cardiovascular and renal outcomes in people with Type 2 diabetes with or at high risk of complications that are also observed in patients with Type 1 diabetes. As the population with Type 1 diabetes ages, our mission is to evolve and provide better tools and improved therapies to excel, not only in glycaemic control but also in risk reduction and reduction of complications.

Safety and efficacy of insulin degludec/insulin aspart with bolus mealtime insulin aspart compared with standard basal-bolus treatment in people with Type 1 diabetes: 1-year results from a randomized clinical trial (BOOST® T1).

AIMS: To evaluate the long-term safety and efficacy of a simplified basal-bolus regimen of once-daily insulin degludec/insulin aspart (IDegAsp) with additional IAsp vs. a standard basal-bolus insulin regimen of insulin detemir (IDet) with IAsp in adults with Type 1 diabetes. METHODS: This was an open-label trial comprising a 26-week core phase followed by a 26-week extension phase. Participants were randomized to IDegAsp once daily at the main meal and IAsp at remaining meals (IDegAsp+IAsp), or IDet (once or twice daily) and IAsp at all meals (IDet+IAsp). Insulins were titrated to target plasma glucose of < 5 mmol/l (< 90 mg/dl) at pre-breakfast (IDegAsp and IDet) and at pre-meal (IAsp). RESULTS: After 52 weeks, the overall confirmed hypoglycaemia rate was 31.8 episodes/patient-years of exposure (PYE) with IDegAsp+Asp and 36.7 episodes/PYE with IDet+IAsp, and the rate of nocturnal confirmed hypoglycaemia was significantly lower with IDegAsp+Asp than with IDet+IAsp (3.1 vs. 5.4 episodes/PYE, respectively; P < 0.05). Adverse event rates were comparable between groups. Mean HbA1c decreased from baseline by 0.7% (IDegAsp+IAsp) and 0.6% (IDet+IAsp), achieving 60 or 61 mmol/mol (7.6% or 7.7%, respectively), at Week 52. The mean total daily insulin dose was lower with IDegAsp+IAsp than with IDet+IAsp (ratio: 0.87; 95% CI 0.79-0.95; P = 0.0026). CONCLUSIONS: Once-daily treatment with IDegAsp and IAsp as bolus insulin for remaining meals was associated with significantly lower risk of nocturnal confirmed hypoglycaemia, improved glycaemic control and showed non-inferiority compared with IDet+IAsp, the standard of care in Type 1 diabetes.

Blood glucose control using a computer-guided glucose management system in allogeneic hematopoietic cell transplant recipients.

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for patients with hematological malignancies. However, is associated with substantial rates of morbidity and mortality. We and others have shown that malglycemia is associated with adverse transplant outcome. Therefore, improving glycemic control may improve transplant outcome. In this prospective study we evaluated the feasibility of using Glucommander (a Computer-Guided Glucose Management System; CGGM) in order to achieve improved glucose control in hospitalized HCT patients. Nineteen adult patients contributed 21 separate instances on CGGM. Patients were on CGGM for a median of 43 h. Median initial blood glucose (BG) on CGGM was 244 mg/dL, and patients on 20 study instances reached the study BG target of 100-140 mg/dL after a median of 6 h. After BG reached the target range, the median average BG level per patient was 124 mg/dL. Six patients had a total of 10 events of BG <70 mg/dL (0.9% of BG measurements), and no patients experienced BG level <40 mg/dL. The total estimated duration of BG <70 mg/dL was 3 h (0.2% of the total CGGM time). In conclusion, our study demonstrates that stringent BG control in HCT patients using CGGM is feasible.

Options for prandial glucose management in type 2 diabetes patients using basal insulin: addition of a short-acting GLP-1 analogue versus progression to basal-bolus therapy.

Integrating patient-centered diabetes care and algorithmic medicine poses particular challenges when optimized basal insulin fails to maintain glycaemic control in patients with type 2 diabetes. Multiple entwined physiological, psychosocial and systems barriers to insulin adherence are not easily studied and are not adequately considered in most treatment algorithms. Moreover, the limited number of alternatives to add-on prandial insulin therapy has hindered shared decision-making, a central feature of patient-centered care. This article considers how the addition of a glucagon-like peptide 1 (GLP-1) analogue to basal insulin may provide new opportunities at this stage of treatment, especially for patients concerned about weight gain and risk of hypoglycaemia. A flexible framework for patient-clinician discussions is presented to encourage development of decision-support tools applicable to both specialty and primary care practice.

Self-monitoring of blood glucose.

Many would argue that the introduction of modern-day diabetes management started 30 years ago with the introduction of self-monitoring of blood glucose (SMBG) at home. While that may be true, it is interesting that many of today's fundamental questions have yet to be answered. Furthermore, the technology itself continues to change, to improve and to better exist with our non-diabetes technology. For example, the first SMBG 'apps' are available now for smart-phones (iPhone), and we can expect the phones themselves to participate more directly with SMBG and diabetes management. Still, both researchers (and payors) continue to ask some fundamental questions. 1. What is the efficacy of SMBG for patients not requiring insulin therapy? 2. What is the optimum frequency of SMBG for patients who do require insulin therapy? 3. What is the role of software to assist in data management for SMBG (for both patients and clinicians)? 4. What is the cost effectiveness of SMBG for all of the different patient populations with diabetes? 5. What is the ideal chemistry which results in the least amount of interfering substances with SMBG? 6. What is an acceptable accuracy for SMBG both at home and in the hospital? The accuracy question is more important than ever since all continuous glucose monitoring (CGM) for now are calibrated with SMBG results. 7 What is the best strategy for teaching patients how best to use their SMBG data? 8. What is the best way to integrate SMBG with insulin pump therapy? 9. What is the role of SMBG with today's CGM devices? 10. What will the role of SMBG be 5-10 years from now with future CGM devices? These are just some of the questions which need more thought and study as we move into 2011. In this chapter we have selected papers that appeared in the PubMed on this topic and chose those we thought were most influential in this area. We have then addressed many of these topics although answers are far from clear for many of them. Although SMBG is not 'new' technology, much research needs to be completed before we fully understand this tool's full impact, particularly as CGM becomes more popular.

Sulphonylurea-metformin combination therapy, cardiovascular disease and all-cause mortality: the Fremantle Diabetes Study.

AIM: To determine whether combination of metformin-sulphonylurea is associated with an increased risk of cardiovascular disease (CVD) and mortality in an urban community-based cohort of type 2 patients. METHODS: We studied 1271 (98.2%) of 1294 type 2 participants in the observational Fremantle Diabetes Study (mean age 64.2 years, 48.8% males) who had detailed diabetes-specific therapy recorded at baseline and complete follow-up data. Mortality and hospital discharge data were collected over 13 174 patient-years (mean +/- SD: 10.4 +/- 3.9 years). Cox proportional hazards modelling was used to determine whether baseline diabetes treatments were independently associated with cardiovascular mortality, hospitalization for/death from CVD or all-cause mortality after adjustment for other explanatory variables. RESULTS: During follow-up, 523 deaths occurred (41.1%) of which 269 (51.4%) were attributed to CVD. Hospitalization for CVD as principal diagnosis occurred at least once for 481 (37.8%) participants. In Kaplan-Meier analyses, there were significant differences in cardiovascular mortality, hospitalization for/death from CVD and all-cause mortality between diabetes therapy groups (p < 0.001). Compared with diet and metformin monotherapy, those treated with metformin-sulphonylurea had higher cardiovascular and all-cause mortality (p < or = 0.024). Insulin users had significantly higher cardiovascular mortality, hospitalization for/death from CVD and all-cause mortality than those on combination therapy (p < or = 0.016). After adjustment for significant variables in the most parsimonious models, diabetes treatment was not independently associated with any of the three study endpoints (p > or = 0.49). CONCLUSIONS: Combination metformin-sulphonylurea appears as safe as other blood glucose-lowering therapies used for type 2 diabetes.

Self-monitoring of blood glucose.

Studies have shown that reducing A1c levels can delay and/or reduce the overall risk of microvascular and macrovascular complications associated with both type 1 and type 2 diabetes (1-5). Implementation of intensive diabetes management [using insulin pumps or multiple daily injections along with increased frequency of self-monitoring of blood glucose (SMBG)] is expensive although there is a significant reduction in risk of long-term complications and cost (6,7). Although the benefits of optimal glucose control seem clear, the risk of severe hypoglycaemia can be a barrier to achieving this goal (1,4,5). In fact, there is nearly a threefold increase in hypoglycaemia with intensification of treatment in type 1 diabetes (1). This is further complicated by the results of recent clinical trials in type 2 diabetes [ACCORD (8), ADVANCE (9) and VADT (10)]. The results of these trials have shown conflicting outcomes in the intensively treated arm. This paradox has created a need for new technology that will facilitate optimal glucose control by recommending appropriate insulin doses while decreasing the risk of hypoglycaemia. There is no doubt of the role of SMBG in insulin-requiring patients with diabetes as it helps guide patients and the providers to adjust their insulin dose on a daily basis. There is enough data documenting the beneficial effects of increased SMBG in such individuals. However, the story for patients with type 2 diabetes not on insulin therapy is different. There is no consensus on frequency and timing of SMBG and its exact impact on glucose control in non-insulin-requiring individuals with type 2 diabetes is debatable. Part of the reason for this controversy may be related to increasing healthcare cost and thus payers finding ways not to reimburse SMBG, since there is conflicting data and the evidence of SMBG improving long-term outcomes in such individuals is not fully evaluated. The prevalence of diabetes is rising worldwide and there are more than 24 million people, with both type 1 and 2 diabetes (diagnosed and undiagnosed), in the USA (11-15). With a limited number of endocrinologists or diabetes specialists available in the USA, most clinical diabetes care is provided by primary care physicians (16). Tools to help patients adjust their insulin dose at home should help in improving their glucose control. Several technologies such as continuous glucose monitors (sensors) and glucometers (SMBG) are on the market and have been shown to help patients improve glucose excursions, reduce glucose variability, decrease time spent in hypoglycaemia and hyperglycaemia and improve A1c levels (17-19). Other software available on insulin pumps can also guide patients with adjustment of insulin dose, especially meal-time boluses (20). We hope that the future might see many such technologies being used on a regular basis to guide providers and patients for better long-term outcomes.

High frequency of unrecognized hypoglycaemias in patients with Type 2 diabetes is discovered by continuous glucose monitoring.

AIMS: To evaluate the use of a CGMS in the detection of hypoglycaemia in people with type 2 diabetes as an outpatient procedure. METHODS: 31 type 2 diabetic patients underwent glucose monitoring by means of CGMS (Medtronic MiniMed) for up to three days. Patients took part in at least four SMBG (self monitoring blood glucose) tests per day. After three days of monitoring, the CGMS data was downloaded and analysed by a physician to identify the frequency of hypoglycaemias (< or =50 mg/dl) and borderline values (51-70 mg/dl), their duration and distribution. Findings were discussed with the patient and if necessary treatment was adjusted. Eight weeks later, monitoring was repeated to asses the effects of the adjusted treatment. RESULTS: Average duration of sensor wear was 4.19 days. Correlation between the sensor and the SMBG readings was high. A high number of hypoglycaemias and borderline values were detected by the CGMS, most of them unrecognized by the patient. The frequency of hypoglycaemias and borderline values just as the duration could be significantly reduced from first to second monitoring. CONCLUSION: Using the CGMS in type 2 diabetic patients achieved the detection of numerous hypoglycaemias and borderline values both nocturnal and/or unnoticed. The CGMS provides accurate data, which cannot be achieved by conventional SMBG tests. That opens the possibility for treatment adjustment and improvement in metabolic control. For patients it provides a better understanding of the effects of insulin or oral agents, nutrition and exercises to their glucose level.

[Morphology of drug induced liver damage]. / Morphologische Veränderungen der medikamenteninduzierten Leberschädigung.

Hepatotoxicity is a significant complication of therapeutic drug use. As ist can imitate nearly all hepatopathies, the diagnosis of drug-induced liver disease is difficult. Most often, it is a diagnosis of exclusion. The following morphological changes are known, dependent on the target cell type: acute and chronic hepatitis, granuloma formation, and fatty liver disease, cholestatic type acute and chronic liver damage with or without inflammation,or mixed forms of liver injury. Portal or perisinusoidal fibrosis can occur following each type of liver damage. Vascular changes or neoplasms are rare. Drug induced liver injuries are more likely induced by type B damage, which is not expected and cannot be reproduced in animal testing. Type A damage, which is known from toxicity assays, is less likely. A specific therapeutic regime is not available. Therefore, early recognition and cessation of the use of the drug is necessary.

Prediction of relapse by day 100 BCR-ABL quantification after allogeneic stem cell transplantation for chronic myeloid leukemia.

Chronic myeloid leukemia (CML) relapse after allogeneic stem cell transplantation (SCT) is a relatively frequent situation, which is correlated to disease status, time from diagnosis to transplant and T-cell depletion. We evaluated the potential for early minimal residual disease (MRD) BCR-ABL quantification to predict relapse of CML patients receiving allogeneic SCT. Minimal residual disease was analyzed by real-time quantitative reverse transcriptase-polymerase chain reaction (RQ-PCR) at day 100 (d100) in 38 patients with >1 year follow-up after conventional non-T-cell-depleted SCT. Normal ABL control values from 1724 follow-up blood samples were used to define an RQ-PCR amplifiability index and the limits of reliable use of BCR-ABL ratios. We then compared the 14 patients with a high-level d100 BCR-ABL/ABL ratio (> or = 10(-4)) to that of the 24 patients with a negative/low-level ratio (<10(-4)). Despite being comparable for all classical parameters, the incidence of relapse was significantly higher in the high MRD group (11/14 (79%)) compared to that of the low/negative MRD group (7/24 (29%)) (P = 0.009), with d100 MRD values representing an independent risk factor of relapse and disease-free survival, but not of overall survival, in multivariate analysis. These data should facilitate risk-adapted post-transplant immunosuppression and/or tyrosine kinase inhibitor therapy based on an early evaluation of MRD.

[Adenocarcinoid of the appendix vermiformis]. / Adenokarzinoid der Appendix vermiformis.

Adenocarcinoids are rare tumors with histological features of both carcinoid tumor and adenocarcinoma. They show a more aggressive biological behaviour than conventional carcinoids. We report a case of a 64-years-old female patient with a diffuse infiltration of the appendicular wall by an adenocarcinoid. Due to the positive surgical margin and the tumor expansion a hemicolectomy was performed. There are no precise criteria to direct the operative choice between appendectomy and hemicolectomy. It is thought that appendectomy is sufficient in case of small tumors in the tip of the appendix. Patients with diffuse appendicular involvement require a more aggressive surgical therapy.

Does haploidentical transplantation in children with primary immunodeficiencies have the potential to exploit donor NK cell alloreactivity?

Donor potential to exert NK cell alloreactivity has been shown to confer survival advantage in haploidentical hematopoietic cell transplantation for hematological malignancies. We investigated killer immunoglobulin receptor (KIR) ligand incompatibility in 40 children receiving haploidentical transplantation for primary immunodeficiencies. The conditioning regimen consisted of busulfan and cyclophosphamide. T-cell depletion of the graft used complement-dependent lysis or CD34+ selection. Two patients died in the first month. The remaining 38 patients were divided into those with (n=13) and those without (n=25) donor potential to exert NK cell alloreactivity. Engraftment was similar in the two groups (61.5 and 64%, respectively). The incidence of grade II-IV acute graft-versus-host disease (GVHD) tended to be lower in the group with donor potential to exert NK cell alloreactivity, but the difference was not significant. In conclusion, in this series of patients with primary immunodeficiencies, donor potential to exert NK cell alloreactivity was not associated with significant advantages in engraftment and prevention of acute GVHD.