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Background and Aim: Diabetic ketoacidosis (DKA) is a serious medical emergency once considered typical of type 1 diabetes (T1DM), but now reported to occur in type 2 and GDM patients as well. DKA can cause severe complications and even prove fatal. The aim of our study was to review recent international and national guidelines on diagnosis, clinical presentation and treatment of diabetic ketoacidosis, to provide practical clinical recommendations., Methods and Results: Electronic databases (MEDLINE (via PUB Med), Scopus, Cochrane library were searched for relevant literature. Most international and national guidelines indicate the same accurate flow chart to diagnose, to evaluate from clinical and laboratory point of view, and treat diabetic ketoacidosis., Conclusion: Prompt diagnosis, rapid execution of laboratory analysis and correct treatment are imperative to reduce the mortality related to diabetic ketoacidosis. These recommendations are designed to help healthcare professionals reduce the frequency and burden of DKA., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: In late February 2020, due to the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the Italian Government closed down all educational and sport activities. In March, it introduced further measures to stop the spread of coronavirus disease (COVID-19), placing the country in a state of almost complete lockdown. We report the impact of these restrictions on glucose control among people with type 1 diabetes (T1D)., Methods: Data were collected on 33 individuals with T1D who were monitoring their glucose levels using a flash glucose monitoring device and remotely connected to the diabetes clinic on a cloud platform. We retrieved information on average glucose, standard deviation and percentage time in hypoglycaemia (< 70 mg/dl), glucose range (70-180 mg/dl) and hyperglycaemia (> 180 mg/dl). We compared glycaemic measures collected during lockdown to those collected before the SARS-CoV-2 epidemic and to the periods immediately before lockdown., Results: In 20 patients who had stopped working and were at home as a result of the lockdown, overall glycaemic control improved during the first 7 days of the lockdown as compared to the weeks before the spread of SARS-CoV-2. Average glucose declined from 177 ± 45 mg/dl (week before lockdown) to 160 ± 40 mg/dl (lockdown; p  = 0.005) and the standard deviation improved significantly. Time in range increased from 54.4 to 65.2% ( p  = 0.010), and time in hyperglycaemia decreased from 42.3 to 31.6% ( p  = 0.016). The number of scans per day remained unchanged. In 13 patients who continued working, none of the measures of glycaemic control changed during lockdown., Conclusion: Despite the limited possibility to exercise and the incumbent psychologic stress, glycaemic control improved in patients with T1D who stopped working during the lockdown, suggesting that slowing down routine daily activities can have beneficial effects on T1D management, at least in the short term., (© The Author(s) 2020.)

Background: High-fiber diets (HFDs) are recommended in the diet of persons with diabetes, yet such diets can impair macronutrient digestion and/or absorption, modify insulin sensitivity, and reset metabolism., Objectives: We studied the effects of a HFD on the kinetics of whole-body protein, a macronutrient that could be affected by dietary fiber, in type 1 diabetes mellitus (T1DM), under both basal-low insulinemic and hyperinsulinemic conditions., Methods: Eight men with T1DM (body mass index range: 21.8-27.8 kg/m2) were studied twice - before and after the addition of guar gum (∼15 g/d) to their usual diet for ∼4 mo. Whole-body protein degradation (i.e., the rate of appearance [Ra] of endogenous leucine), leucine disposal to protein synthesis (PS), deamination, and reamination, were determined before and after the HFD, both in the postabsorptive state and following a euglycemic, hyperinsulinemic, hyperaminoacidemic clamp, using isotope dilution methods., Results: After the HFD, mean values (± SEs) for postabsorptive leucine Ra decreased by ∼20%: from 2.52 (0.15) to 2.03 (0.16) μmol x kg-1 x min-1, P < 0.049, after vs. before the HFD respectively. PS also decreased, by ∼25%: from 2.03 (0.15) to 1.57 (0.15), P < 0.045. Leucine concentration (P = 0.1) and reamination (P = 0.095) decreased moderately, whereas deamination was unchanged. Following the clamp, plasma amino acid concentrations (P < 0.001), leucine deamination (+ ∼50%, P < 0.00002), reamination (+ ∼30%, P < 0.0007), and PS (+ ∼35%, P < 0.00001) were all increased compared with postabsorptive state values, whereas endogenous leucine Ra was suppressed (by 15%, P < 0.00001, and by 25%, P < 0.001, with the primary or the reciprocal pool models, respectively). No significant differences in these insulin effects before compared with after the HFD were observed. Metabolic control (glycated hemoglobin), daily insulin requirement, and insulin-mediated glucose disposal were unchanged after the HFD., Conclusions: A HFD downregulates postabsorptive protein turnover in men with T1DM, by decreasing both protein degradation and synthesis, possibly due to a subtle decrease and/or delay in amino acid absorption. It does not significantly affect the insulin (and amino acid sensitivity) to protein turnover, glucose disposal, and metabolic control., (Copyright © American Society for Nutrition 2019.)

Background and Aim: The objective of this cross-sectional study was to evaluate the degree of glycaemic control and the frequency of diabetic complications in Italian people with diabetes who were treated with continuous subcutaneous insulin infusion (CSII)., Methods and Results: Questionnaires investigating the organisation of diabetes care centres, individuals' clinical and metabolic features and pump technology and its management were sent to adult and paediatric diabetes centres that use CSII for treatment in Italy. Information on standard clinical variables, demographic data and acute and chronic diabetic complications was derived from local clinical management systems. The sample consisted of 6623 people with diabetes, which was obtained from 93 centres. Of them, 98.8% had type 1 diabetes mellitus, 57.2% were female, 64% used a conventional insulin pump and 36% used a sensor-augmented insulin pump. The median glycated haemoglobin (HbA 1c ) level was 60 mmol/mol (7.6%). The HbA 1c target (i.e. <58 mmol/mol for age <18 years and <53 mmol/mol for age >18 years) was achieved in 43.4% of paediatric and 23% of adult participants. Factors such as advanced pump functions, higher rate of sensor use, pregnancy in the year before the study and longer duration of diabetes were associated with lower HbA 1c levels. The most common chronic complications occurring in diabetes were retinopathy, microalbuminuria and hypertension. In the year before the study, 5% of participants reported ≥1 episode of severe hypoglycaemic (SH) episodes (SH) and 2.6% reported ≥1 episode of ketoacidosis., Conclusions: Advanced personal skills and use of sensor-based pump are associated with better metabolic control outcomes in Italian people with diabetes who were treated with CSII. The reduction in SH episodes confirms the positive effect of CSII on hypoglycaemia., Clinical Trial Registration Number: NCT 02620917 (ClinicalTrials.gov)., (Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Context: Iatrogenic hypoglycemia is the most common acute diabetic complication, and it significantly increases morbidity. In people with diabetes, reduction in the levels of circulating stem and progenitor cells predicts adverse outcomes., Objective: To evaluate whether hypoglycemia in diabetes affects circulating stem cells and endothelial progenitor cells (EPCs)., Design: We performed an experimental hypoglycemia study (Study 1) and a case-control study (Study 2)., Setting: Tertiary referral inpatient clinic., Patients and Other Participants: Type 1 diabetic patients (Study 1, n = 19); diabetic patients hospitalized for severe iatrogenic hypoglycemia, matched inpatient and outpatient controls (Study 2, n = 22/group)., Interventions: Type 1 diabetic patients underwent two in-hospital sessions of glucose monitoring during a breakfast meal with or without induction of hypoglycemia in random order. In Study 2, patients hospitalized for hypoglycemia and matched controls were compared., Main Outcome Measure: Circulating stem cells and EPCs were measured by flow cytometry based on the expression of CD34 and kinase insert domain receptor (KDR)., Results: In Study 1, the physiologic decline of CD34+KDR+ EPCs from 8 am to 2 pm was abolished by insulin-induced hypoglycemia in type 1 diabetic patients. In Study 2, diabetic patients hospitalized for severe iatrogenic hypoglycemia had significantly lower levels of CD34+ stem cells and CD34+KDR+ EPCs compared with diabetic inpatients or outpatient controls., Conclusions: In diabetic patients, a single mild hypoglycemic episode can compromise the physiologic EPC fluctuation, whereas severe hypoglycemia is associated with a marked reduction in stem cells and EPCs. These data provide a possible link between hypoglycemia and adverse outcomes of diabetes.

Backgrounds: In non-critical hospitalized patients with diabetes mellitus, guidelines suggest subcutaneous insulin therapy with basal-bolus regimen, even in old and vulnerable inpatients., Aim: To evaluate safety, efficacy, and benefit on clinical management of the GesTIO protocol, a set of subcutaneous insulin administration rules, in old and vulnerable non-ICU inpatients., Methods: Retrospective, observational study. Patients admitted to Geriatric Clinic of Padua were studied. 88 patients matched the inclusion criteria: type 2 diabetes or hospital-related hyperglycemia, ≥65 years, regular measurements of capillary glycemia, and basal-bolus subcutaneous insulin regimen managed by "GesTIO protocol" for five consecutive days., Main Outcome Measures: ratio of patients with blood glucose (BG) <3.9 mmol/l; number of BG per patient in target range (5-11.1 mmol/l); daily mean BG; and calls to physicians for adjusting insulin therapy., Results: Mean age was 82 ± 7 years. 9.1% patients experienced mild hypoglycaemia, and no severe hypoglycaemia was reported. The median number of BG per patients in target range increased from 2.0 ± 2 to 3.0 ± 2 (p < 0.001). The daily mean BG decreased from 11.06 ± 3.03 to 9.64 ± 2.58 mmol/l (-12.8%, p < 0.005). The mean number of calls to physicians per patient decreased from 0.83 to 0.45 (p < 0.05)., Conclusions: Treatment with GesTIO protocol allows a safe and effective treatment even in very old and vulnerable inpatients with a faster management insulin therapy.

Background: Patients with diabetes, especially pediatric ones, sometimes use continuous glucose monitoring (CGM) sensor in different positions from the approved ones. Here we compare the accuracy of Dexcom® G5 CGM sensor in three different sites: abdomen, gluteus (both approved) and arm (off-label)., Method: Thirty youths, 5-9 years old, with type 1 diabetes (T1D) wore the sensor during a clinical trial where frequent self-monitoring of blood glucose (SMBG) measurements were obtained. Sensor was inserted in different sites according to the patient habit. Accuracy metrics include absolute relative difference (ARD) and absolute difference (AD) of CGM with respect to SMBG. The three sites were compared with ANOVA. If the test detected a difference, an additional pair-wise comparison was performed., Results: Overall, no accuracy difference was detected: the mean ARD was 13.3% (SD = 13.5%) for abdomen, 13.4% (12.9%) for arm and 12.9% (20.2%) for gluteus ( P value = .83); the mean AD was 17.0 mg/dl (17.2 mg/dl) for abdomen, 17.2 mg/dl (17.1 mg/dl) for arm and 18.3 mg/dl (18.5 mg/dl) for gluteus ( P value = .30). In hypo- and euglycemia ARD ( P value = .87 and .15, respectively), and AD ( P value = .68 and .37, respectively) were not statistically different. At variance, in hyperglycemia, a significant difference was detected between the two approved sites, abdomen and gluteus (ΔARD = -2.2% [CI = -4.2%, -0.1%], P value = .04), whereas the comparisons with the off-label location, arm-abdomen, and arm-gluteus were not significant., Conclusions: These results suggest that the accuracy of the sensor placed on the arm was not significantly different with respect to the two approved insertion sites (abdomen and gluteus). Larger, randomized trials are needed to draw final conclusions.

Context: Closed-loop control (CLC) for the management of type 1 diabetes (T1D) is a novel method for optimizing glucose control, and strategies for individualized implementation are being developed., Objective: To analyze glycemic control in an overnight CLC system designed to "reset" the patient to near-normal glycemic targets every morning., Design: Randomized, crossover, multicenter clinical trial., Participants: Forty-four subjects with T1D requiring insulin pump therapy., Intervention: Sensor-augmented pump therapy (SAP) at home vs 5 nights of CLC (active from 23:00 to 07:00) in a supervised outpatient setting (research house or hotel), with a substudy of 5 nights of CLC subsequently at home., Main Outcome Measure: The percentage of time spent in the target range (70 to 180 mg/dL measured using a continuous glucose monitor)., Results: Forty subjects (age, 45.5 ± 9.5 years; hemoglobin A1c, 7.4% ± 0.8%) completed the study. The time in the target range (70 to 180 mg/dL) significantly improved in CLC vs SAP over 24 hours (78.3% vs 71.4%; P = 0.003) and overnight (85.7% vs 67.6%; P < 0.001). The time spent in a hypoglycemic range (<70 mg/dL) decreased significantly in the CLC vs SAP group over 24 hours (2.5% vs 4.3%; P = 0.002) and overnight (0.9% vs 3.2%; P < 0.001). The mean glucose level at 07:00 was lower with CLC than with SAP (123.7 vs 145.3 mg/dL; P < 0.001). The substudy at home, involving 10 T1D subjects, showed similar trends with an increased time in target (70 to 180 mg/dL) overnight (75.2% vs 62.2%; P = 0.07) and decreased time spent in the hypoglycemic range (<70 mg/dL) overnight in CLC vs SAP (0.6% vs 3.7%; P = 0.03)., Conclusion: Overnight-only CLC increased the time in the target range over 24 hours and decreased the time in hypoglycemic range over 24 hours in a supervised outpatient setting. A pilot extension study at home showed a similar nonsignificant trend., (Copyright © 2017 Endocrine Society)

Currently we observe a gap between theory and practices of patient engagement. If both scholars and health practitioners do agree on the urgency to realize patient engagement, no shared guidelines exist so far to orient clinical practice. Despite a supportive policy context, progress to achieve greater patient engagement is patchy and slow and often concentrated at the level of policy regulation without dialoguing with practitioners from the clinical field as well as patients and families. Though individual clinicians, care teams and health organizations may be interested and deeply committed to engage patients and family members in the medical course, they may lack clarity about how to achieve this goal. This contributes to a wide "system" inertia-really difficult to be overcome-and put at risk any form of innovation in this filed. As a result, patient engagement risk today to be a buzz words, rather than a real guidance for practice. To make the field clearer, we promoted an Italian Consensus Conference on Patient Engagement (ICCPE) in order to set the ground for drafting recommendations for the provision of effective patient engagement interventions. The ICCPE will conclude in June 2017. This document reports on the preliminary phases of this process. In the paper, we advise the importance of "fertilizing a patient engagement ecosystem": an oversimplifying approach to patient engagement promotion appears the result of a common illusion. Patient "disengagement" is a symptom that needs a more holistic and complex approach to solve its underlined causes. Preliminary principles to promote a patient engagement ecosystem are provided in the paper.

Background: In the past few years, the artificial pancreas-the commonly accepted term for closed-loop control (CLC) of blood glucose in diabetes-has become a hot topic in research and technology development. In the summer of 2014, we initiated a 6-month trial evaluating the safety of 24/7 CLC during free-living conditions., Research Design and Methods: Following an initial 1-month Phase 1, 14 individuals (10 males/4 females) with type 1 diabetes at three clinical centers in the United States and one in Italy continued with a 5-month Phase 2, which included 24/7 CLC using the wireless portable Diabetes Assistant (DiAs) developed at the University of Virginia Center for Diabetes Technology. Median subject characteristics were age 45 years, duration of diabetes 27 years, total daily insulin 0.53 U/kg/day, and baseline HbA1c 7.2% (55 mmol/mol)., Results: Compared with the baseline observation period, the frequency of hypoglycemia below 3.9 mmol/L during the last 3 months of CLC was lower: 4.1% versus 1.3%, P < 0.001. This was accompanied by a downward trend in HbA1c from 7.2% (55 mmol/mol) to 7.0% (53 mmol/mol) at 6 months. HbA1c improvement was correlated with system use (Spearman r = 0.55). The user experience was favorable with identified benefit particularly at night and overall trust in the system. There were no serious adverse events, severe hypoglycemia, or diabetic ketoacidosis., Conclusion: We conclude that CLC technology has matured and is safe for prolonged use in patients' natural environment. Based on these promising results, a large randomized trial is warranted to assess long-term CLC efficacy and safety.

Objective: To explore the experiences of children with type 1 diabetes and their parents taking part in an artificial pancreas (AP) clinical trial during a 7-day summer camp., Research Design and Methods: A semistructured interview, composed of 14 questions based on the Technology Acceptance Model, was conducted at the end of the clinical trial. Participants also completed the Diabetes Treatment Satisfaction Questionnaire (DTSQ, parent version) and the AP Acceptance Questionnaire., Results: Thirty children, aged 5-9 years, and their parents completed the study. A content analysis of the interviews showed that parents were focused on understanding the mechanisms, risks, and benefits of the new device, whereas the children were focused on the novelty of the new system. The parents' main concerns about adopting the new system seemed related to the quality of glucose control. The mean scores of DTSQ subscales indicated general parents' satisfaction (44.24 ± 5.99, range 32-53) and trustful views of diabetes control provided by the new system (7.8 ± 2.2, range 3-12). The AP Acceptance Questionnaire revealed that most parents considered the AP easy to use (70.5%), intended to use it long term (94.0%), and felt that it was apt to improve glucose control (67.0%)., Conclusions: Participants manifested a positive attitude toward the AP. Further studies are required to explore participants' perceptions early in the AP development to individualize the new treatment as much as possible, and to tailor it to respond to their needs and values., (© 2016 by the American Diabetes Association.)

Objective: To evaluate the efficacy of a portable, wearable, wireless artificial pancreas system (the Diabetes Assistant [DiAs] running the Unified Safety System) on glucose control at home in overnight-only and 24/7 closed-loop control (CLC) modes in patients with type 1 diabetes., Research Design and Methods: At six clinical centers in four countries, 30 participants 18-66 years old with type 1 diabetes (43% female, 96% non-Hispanic white, median type 1 diabetes duration 19 years, median A1C 7.3%) completed the study. The protocol included a 2-week baseline sensor-augmented pump (SAP) period followed by 2 weeks of overnight-only CLC and 2 weeks of 24/7 CLC at home. Glucose control during CLC was compared with the baseline SAP., Results: Glycemic control parameters for overnight-only CLC were improved during the nighttime period compared with baseline for hypoglycemia (time <70 mg/dL, primary end point median 1.1% vs. 3.0%; P < 0.001), time in target (70-180 mg/dL: 75% vs. 61%; P < 0.001), and glucose variability (coefficient of variation: 30% vs. 36%; P < 0.001). Similar improvements for day/night combined were observed with 24/7 CLC compared with baseline: 1.7% vs. 4.1%, P < 0.001; 73% vs. 65%, P < 0.001; and 34% vs. 38%, P < 0.001, respectively., Conclusions: CLC running on a smartphone (DiAs) in the home environment was safe and effective. Overnight-only CLC reduced hypoglycemia and increased time in range overnight and increased time in range during the day; 24/7 CLC reduced hypoglycemia and increased time in range both overnight and during the day. Compared with overnight-only CLC, 24/7 CLC provided additional hypoglycemia protection during the day., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: The Pediatric Artificial Pancreas (PedArPan) project tested a children-specific version of the modular model predictive control (MMPC) algorithm in 5- to 9-year-old children during a camp., Research Design and Methods: A total of 30 children, 5- to 9-years old, with type 1 diabetes completed an outpatient, open-label, randomized, crossover trial. Three days with an artificial pancreas (AP) were compared with three days of parent-managed sensor-augmented pump (SAP)., Results: Overnight time-in-hypoglycemia was reduced with the AP versus SAP, median (25(th)-75(th) percentiles): 0.0% (0.0-2.2) vs. 2.2% (0.0-12.3) (P = 0.002), without a significant change of time-in-target, mean: 56.0% (SD 22.5) vs. 59.7% (21.2) (P = 0.430), but with increased mean glucose 173 mg/dL (36) vs. 150 mg/dL (39) (P = 0.002). Overall, the AP granted a threefold reduction of time-in-hypoglycemia (P < 0.001) at the cost of decreased time-in-target, 56.8% (13.5) vs. 63.1% (11.0) (P = 0.022) and increased mean glucose 169 mg/dL (23) vs. 147 mg/dL (23) (P < 0.001)., Conclusions: This trial, the first outpatient single-hormone AP trial in a population of this age, shows feasibility and safety of MMPC in young children. Algorithm retuning will be performed to improve efficacy., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: After testing of a wearable artificial pancreas (AP) during evening and night (E/N-AP) under free-living conditions in patients with type 1 diabetes (T1D), we investigated AP during day and night (D/N-AP) for 1 month., Research Design and Methods: Twenty adult patients with T1D who completed a previous randomized crossover study comparing 2-month E/N-AP versus 2-month sensor augmented pump (SAP) volunteered for 1-month D/N-AP nonrandomized extension. AP was executed by a model predictive control algorithm run by a modified smartphone wirelessly connected to a continuous glucose monitor (CGM) and insulin pump. CGM data were analyzed by intention-to-treat with percentage time-in-target (3.9-10 mmol/L) over 24 h as the primary end point., Results: Time-in-target (mean ± SD, %) was similar over 24 h with D/N-AP versus E/N-AP: 64.7 ± 7.6 vs. 63.6 ± 9.9 (P = 0.79), and both were higher than with SAP: 59.7 ± 9.6 (P = 0.01 and P = 0.06, respectively). Time below 3.9 mmol/L was similarly and significantly reduced by D/N-AP and E/N-AP versus SAP (both P < 0.001). SD of blood glucose concentration (mmol/L) was lower with D/N-AP versus E/N-AP during whole daytime: 3.2 ± 0.6 vs. 3.4 ± 0.7 (P = 0.003), morning: 2.7 ± 0.5 vs. 3.1 ± 0.5 (P = 0.02), and afternoon: 3.3 ± 0.6 vs. 3.5 ± 0.8 (P = 0.07), and was lower with D/N-AP versus SAP over 24 h: 3.1 ± 0.5 vs. 3.3 ± 0.6 (P = 0.049). Insulin delivery (IU) over 24 h was higher with D/N-AP and SAP than with E/N-AP: 40.6 ± 15.5 and 42.3 ± 15.5 vs. 36.6 ± 11.6 (P = 0.03 and P = 0.0004, respectively)., Conclusions: D/N-AP and E/N-AP both achieved better glucose control than SAP under free-living conditions. Although time in the different glycemic ranges was similar between D/N-AP and E/N-AP, D/N-AP further reduces glucose variability., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Background: An artificial pancreas (AP) that can be worn at home from dinner to waking up in the morning might be safe and efficient for first routine use in patients with type 1 diabetes. We assessed the effect on glucose control with use of an AP during the evening and night plus patient-managed sensor-augmented pump therapy (SAP) during the day, versus 24 h use of patient-managed SAP only, in free-living conditions., Methods: In a crossover study done in medical centres in France, Italy, and the Netherlands, patients aged 18-69 years with type 1 diabetes who used insulin pumps for continuous subcutaneous insulin infusion were randomly assigned to 2 months of AP use from dinner to waking up plus SAP use during the day versus 2 months of SAP use only under free-living conditions. Randomisation was achieved with a computer-generated allocation sequence with random block sizes of two, four, or six, masked to the investigator. Patients and investigators were not masked to the type of intervention. The AP consisted of a continuous glucose monitor (CGM) and insulin pump connected to a modified smartphone with a model predictive control algorithm. The primary endpoint was the percentage of time spent in the target glucose concentration range (3·9-10·0 mmol/L) from 2000 to 0800 h. CGM data for weeks 3-8 of the interventions were analysed on a modified intention-to-treat basis including patients who completed at least 6 weeks of each intervention period. The 2 month study period also allowed us to asses HbA1c as one of the secondary outcomes. This trial is registered with ClinicalTrials.gov, number NCT02153190., Findings: During 2000-0800 h, the mean time spent in the target range was higher with AP than with SAP use: 66·7% versus 58·1% (paired difference 8·6% [95% CI 5·8 to 11·4], p<0·0001), through a reduction in both mean time spent in hyperglycaemia (glucose concentration >10·0 mmol/L; 31·6% vs 38·5%; -6·9% [-9·8% to -3·9], p<0·0001) and in hypoglycaemia (glucose concentration <3·9 mmol/L; 1·7% vs 3·0%; -1·6% [-2·3 to -1·0], p<0·0001). Decrease in mean HbA1c during the AP period was significantly greater than during the control period (-0·3% vs -0·2%; paired difference -0·2 [95% CI -0·4 to -0·0], p=0·047), taking a period effect into account (p=0·0034). No serious adverse events occurred during this study, and none of the mild-to-moderate adverse events was related to the study intervention., Interpretation: Our results support the use of AP at home as a safe and beneficial option for patients with type 1 diabetes. The HbA1c results are encouraging but preliminary., Funding: European Commission., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Studies of closed-loop control (CLC) systems have improved glucose levels in patients with type 1 diabetes. In this study we test a new CLC concept aiming to "reset" the patient overnight to near-normoglycemia each morning, for several consecutive nights., Subjects and Methods: Ten insulin pump users with type 1 diabetes (mean age, 46.4±8.5 years) were enrolled in a two-center (in the United States and Italy) randomized crossover trial comparing 5 consecutive nights of CLC (23:00-07:00 h) in an outpatient setting versus sensor-augmented insulin pump therapy of the same duration at home. Primary end points included time spent in 80-140 mg/dL as measured by continuous glucose monitoring overnight and fasting blood glucose distribution at 7:00 h., Results: Compared with sensor-augmented pump therapy, CLC improved significantly time spent between 80 and 140 mg/dL (54.5% vs. 32.2%; P<0.001) and between 70 and 180 mg/dL (85.4% vs. 59.1%; P<0.001); CLC reduced the mean glucose level at 07:00 h (119.3 vs. 152.9 mg/dL; P<0.001) and overnight mean glucose level (139.0 vs. 170.3 mg/dL; P<0.001) using a marginally lower amount of insulin (6.1 vs. 6.8 units; P=0.1). Tighter overnight control led to improved daytime control on the next day: the overnight/next-day control correlation was r=0.52, P<0.01., Conclusions: Multinight CLC of insulin delivery (artificial pancreas) results in significant improvement in morning and overnight glucose levels and time in target range, with the potential to improve daytime control when glucose levels were "reset" to near-normoglycemia each morning.

Background: The Control to Range Study was a multinational artificial pancreas study designed to assess the time spent in the hypo- and hyperglycemic ranges in adults and adolescents with type 1 diabetes while under closed-loop control. The controller attempted to keep the glucose ranges between 70 and 180 mg/dL. A set of prespecified metrics was used to measure safety., Research Design and Methods: We studied 53 individuals for approximately 22 h each during clinical research center admissions. Plasma glucose level was measured every 15-30 min (YSI clinical laboratory analyzer instrument [YSI, Inc., Yellow Springs, OH]). During the admission, subjects received three mixed meals (1 g of carbohydrate/kg of body weight; 100 g maximum) with meal announcement and automated insulin dosing by the controller., Results: For adults, the mean of subjects' mean glucose levels was 159 mg/dL, and mean percentage of values 71-180 mg/dL was 66% overall (59% daytime and 82% overnight). For adolescents, the mean of subjects' mean glucose levels was 166 mg/dL, and mean percentage of values in range was 62% overall (53% daytime and 82% overnight). Whereas prespecified criteria for safety were satisfied by both groups, they were met at the individual level in adults only for combined daytime/nighttime and for isolated nighttime. Two adults and six adolescents failed to meet the daytime criterion, largely because of postmeal hyperglycemia, and another adolescent failed to meet the nighttime criterion., Conclusions: The control-to-range system performed as expected: faring better overnight than during the day and performing with variability between patients even after individualization based on patients' prior settings. The system had difficulty preventing postmeal excursions above target range.

Objective: We estimate the effect size of hypoglycemia risk reduction on closed-loop control (CLC) versus open-loop (OL) sensor-augmented insulin pump therapy in supervised outpatient setting., Research Design and Methods: Twenty patients with type 1 diabetes initiated the study at the Universities of Virginia, Padova, and Montpellier and Sansum Diabetes Research Institute; 18 completed the entire protocol. Each patient participated in two 40-h outpatient sessions, CLC versus OL, in randomized order. Sensor (Dexcom G4) and insulin pump (Tandem t:slim) were connected to Diabetes Assistant (DiAs)-a smartphone artificial pancreas platform. The patient operated the system through the DiAs user interface during both CLC and OL; study personnel supervised on site and monitored DiAs remotely. There were no dietary restrictions; 45-min walks in town and restaurant dinners were included in both CLC and OL; alcohol was permitted., Results: The primary outcome-reduction in risk for hypoglycemia as measured by the low blood glucose (BG) index (LGBI)-resulted in an effect size of 0.64, P = 0.003, with a twofold reduction of hypoglycemia requiring carbohydrate treatment: 1.2 vs. 2.4 episodes/session on CLC versus OL (P = 0.02). This was accompanied by a slight decrease in percentage of time in the target range of 3.9-10 mmol/L (66.1 vs. 70.7%) and increase in mean BG (8.9 vs. 8.4 mmol/L; P = 0.04) on CLC versus OL., Conclusions: CLC running on a smartphone (DiAs) in outpatient conditions reduced hypoglycemia and hypoglycemia treatments when compared with sensor-augmented pump therapy. This was accompanied by marginal increase in average glycemia resulting from a possible overemphasis on hypoglycemia safety., (© 2014 by the American Diabetes Association.)

Patients with chronic diseases as well as health care systems could benefit from telemedicine applications such as remote monitoring (RM). RM relies on a device that sends patients' health data to a remote server accessible by care teams. Recent smartphone-based artificial pancreas (AP) systems collect comprehensive set of information and could therefore support the development of RM applied to diabetes. To better understand how RM could be integrated in future AP systems, we wanted to get patients' opinion on this concept, as they are the final users of these systems. An online questionnaire with 11 items was sent to 20 experienced patients who tested AP and RM during our recent outpatient studies in France and Italy. We received 17 answers. All patients considered that during their participation in trials, RM was useful, reassuring, and essential. One-third wouldn't have participated without it. When AP is commercialized, 88% of respondents think that AP should go with a RM tool, but it should be activated only at certain times, at first use or in case of difficulties (82%). Participants ask for technical support when a device fails (88%) and for medical help in case of prolonged hyperglycemia (65%) or severe or repeated hypoglycemia (53%), but not after each case of hypoglycemia (6%). More than 75% think that RM could help them to improve their blood glucose control. This preliminary work indicates that patients expect RM to be part of future AP development. Larger studies remain to be performed to investigate its usefulness and potential economic effectiveness., (© 2014 Diabetes Technology Society.)

Objective: Inpatient studies suggest that model predictive control (MPC) is one of the most promising algorithms for artificial pancreas (AP). So far, outpatient trials have used hypo/hyperglycemia-mitigation or medical-expert systems. In this study, we report the first wearable AP outpatient study based on MPC and investigate specifically its ability to control postprandial glucose, one of the major challenges in glucose control., Research Design and Methods: A new modular MPC algorithm has been designed focusing on meal control. Six type 1 diabetes mellitus patients underwent 42-h experiments: sensor-augmented pump therapy in the first 14 h (open-loop) and closed-loop in the remaining 28 h., Results: MPC showed satisfactory dinner control versus open-loop: time-in-target (70-180 mg/dL) 94.83 vs. 68.2% and time-in-hypo 1.25 vs. 11.9%. Overnight control was also satisfactory: time-in-target 89.4 vs. 85.0% and time-in-hypo: 0.00 vs. 8.19%., Conclusions: This outpatient study confirms inpatient evidence of suitability of MPC-based strategies for AP. These encouraging results pave the way to randomized crossover outpatient studies.

Objective: To compare two validated closed-loop (CL) algorithms versus patient self-control with CSII in terms of glycemic control., Research Design and Methods: This study was a multicenter, randomized, three-way crossover, open-label trial in 48 patients with type 1 diabetes mellitus for at least 6 months, treated with continuous subcutaneous insulin infusion. Blood glucose was controlled for 23 h by the algorithm of the Universities of Pavia and Padova with a Safety Supervision Module developed at the Universities of Virginia and California at Santa Barbara (international artificial pancreas [iAP]), by the algorithm of University of Cambridge (CAM), or by patients themselves in open loop (OL) during three hospital admissions including meals and exercise. The main analysis was on an intention-to-treat basis. Main outcome measures included time spent in target (glucose levels between 3.9 and 8.0 mmol/L or between 3.9 and 10.0 mmol/L after meals)., Results: Time spent in the target range was similar in CL and OL: 62.6% for OL, 59.2% for iAP, and 58.3% for CAM. While mean glucose level was significantly lower in OL (7.19, 8.15, and 8.26 mmol/L, respectively) (overall P = 0.001), percentage of time spent in hypoglycemia (<3.9 mmol/L) was almost threefold reduced during CL (6.4%, 2.1%, and 2.0%) (overall P = 0.001) with less time ≤2.8 mmol/L (overall P = 0.038). There were no significant differences in outcomes between algorithms., Conclusions: Both CAM and iAP algorithms provide safe glycemic control.

Objective: This study assessed the accuracy and reliability of three continuous glucose monitoring (CGM) systems., Research Design and Methods: We studied the Animas® (West Chester, PA) Vibe™ with Dexcom® (San Diego, CA) G4™ version A sensor (G4A), the Abbott Diabetes Care (Alameda, CA) Freestyle® Navigator I (NAV), and the Medtronic (Northridge, CA) Paradigm® with Enlite™ sensor (ENL) in 20 patients with type 1 diabetes mellitus. All systems were investigated both in a clinical research center (CRC) and at home. In the CRC, patients received a meal with a delayed and increased insulin dose to induce a postprandial glucose peak and nadir. Hereafter, randomization determined which two of the three systems would be worn at home until the end of functioning, attempting use beyond manufacturer-specified lifetime. Patients performed at least five reference finger sticks per day. An analysis of variance was performed on all data points ≥15 min apart., Results: Overall average mean absolute relative difference (MARD) (SD) measured at the CRC was 16.5% (14.3%) for NAV and 16.4% (15.6%) for ENL, outperforming G4A at 20.5% (18.2%) (P<0.001). Overall MARD when assessed at home was 14.5% (16.7%) for NAV and 16.5 (18.8%) for G4A, outperforming ENL at 18.9% (23.6%) (P=0.006). Median time until end of functioning was similar: 10.0 (1.0) days for G4A, 8.0 (3.5) days for NAV, and 8.0 (1.5) days for ENL (P=0.119)., Conclusions: In the CRC, G4A was less accurate than NAV and ENL sensors, which seemed comparable. However, at home, ENL was less accurate than NAV and G4A. Moreover, CGM systems often show sufficient accuracy to be used beyond manufacturer-specified lifetime.

Objective: To evaluate the feasibility of a wearable artificial pancreas system, the Diabetes Assistant (DiAs), which uses a smart phone as a closed-loop control platform., Research Design and Methods: Twenty patients with type 1 diabetes were enrolled at the Universities of Padova, Montpellier, and Virginia and at Sansum Diabetes Research Institute. Each trial continued for 42 h. The United States studies were conducted entirely in outpatient setting (e.g., hotel or guest house); studies in Italy and France were hybrid hospital-hotel admissions. A continuous glucose monitoring/pump system (Dexcom Seven Plus/Omnipod) was placed on the subject and was connected to DiAs. The patient operated the system via the DiAs user interface in open-loop mode (first 14 h of study), switching to closed-loop for the remaining 28 h. Study personnel monitored remotely via 3G or WiFi connection to DiAs and were available on site for assistance., Results: The total duration of proper system communication functioning was 807.5 h (274 h in open-loop and 533.5 h in closed-loop), which represented 97.7% of the total possible time from admission to discharge. This exceeded the predetermined primary end point of 80% system functionality., Conclusions: This study demonstrated that a contemporary smart phone is capable of running outpatient closed-loop control and introduced a prototype system (DiAs) for further investigation. Following this proof of concept, future steps should include equipping insulin pumps and sensors with wireless capabilities, as well as studies focusing on control efficacy and patient-oriented clinical outcomes.

Background: Continuous glucose monitoring system (CGMS) accuracy is of critical importance both in delivering therapeutic value and as a component of a closed-loop system. This study aims at assessing the differences between accuracy assessments of CGMS at home and at the clinical research center (CRC)., Methods: Twelve patients with type 1 diabetes used the Dexcom® SEVEN® PLUS (DexCom, Inc.) CGMS for 7 days. Patients performed ≥6 finger pricks [self-measurement of blood glucose (SMBG)] per day while at home. Reference blood glucose measurements were taken during a 24 h CRC admission (YSI 2300 STAT Plus™). Continuous glucose monitoring system data were compared with YSI and SMBG values. Outcome measures included mean absolute relative difference (MARD) and Clarke error grid analysis (CEGA)., Results: During CRC admission, the MARD of CGMS vs YSI glucose values was 19.2% (n = 509)--significantly higher than 16.8% at home (n = 611) (p = .004). In the hypoglycemic range, MARD was 23.9% at CRC (n = 26)--not significantly different from 41.6% at home (n = 39) (p = .269). In the hyperglycemic range, CRC MARD at 20.3% (n = 115) was significantly higher than home MARD at 11.2% (n = 118) (p = .001). Clarke error grid analysis showed no significant difference in distribution of data pairs (overall p = .317)., Conclusions: This study illustrates the importance of the setting used when assessing CGMS accuracy. Continuous glucose monitoring system accuracy at home appeared better than at the CRC. This is probably due to the higher sampling rate of reference measurements, feasible only in the CRC. Testing CGMS accuracy in the CRC provides valuable information over and above home testing., (© 2012 Diabetes Technology Society.)

Background: In 2008-2009, the first multinational study was completed comparing closed-loop control (artificial pancreas) to state-of-the-art open-loop therapy in adults with type 1 diabetes mellitus (T1DM)., Methods: The design of the control algorithm was done entirely in silico, i.e., using computer simulation experiments with N=300 synthetic "subjects" with T1DM instead of traditional animal trials. The clinical experiments recruited 20 adults with T1DM at the Universities of Virginia (11); Padova, Italy (6); and Montpellier, France (3). Open-loop and closed-loop admission was scheduled 3-4 weeks apart, continued for 22 h (14.5 h of which were in closed loop), and used a continuous glucose monitor and an insulin pump. The only difference between the two sessions was that insulin dosing was performed by the patient under a physician's supervision during open loop, whereas insulin dosing was performed by a control algorithm during closed loop., Results: In silico design resulted in rapid (less than 6 months compared to years of animal trials) and cost-effective system development, testing, and regulatory approvals in the United States, Italy, and France. In the clinic, compared to open-loop, closed-loop control reduced nocturnal hypoglycemia (blood glucose below 3.9 mmol/liter) from 23 to 5 episodes (p<.01) and increased the amount of time spent overnight within the target range (3.9 to 7.8 mmol/liter) from 64% to 78% (p=.03)., Conclusions: In silico experiments can be used as viable alternatives to animal trials for the preclinical testing of insulin treatment strategies. Compared to open-loop treatment under identical conditions, closed-loop control improves the overnight regulation of diabetes., (© 2010 Diabetes Technology Society.)

Type 1 diabetes is an autoimmune disease that is accompanied by an immune response against pancreatic cells. As gangliosides are expressed in both peripheral nerves and pancreatic cells, we examined the possibility of correlation between type 1 diabetes, anti-ganglioside autoantibodies, and neuropathy. Fifty diabetic patients and 30 controls with other autoimmune diseases underwent neurological examination and search for antibodies to gangliosides, glutamic acid decarboxylase (GAD(65)), and tyrosine phosphatase (IA2). Sixteen (32%) diabetic patients had neuropathy. Twelve diabetic sera were found to have anti-ganglioside autoantibodies. Twenty sera were positive for anti-GAD(65) and nine for anti-IA2 antibody. Sera from three control patients had anti-ganglioside autoantibodies. No significant correlation was found between autoantibodies, neuropathy, and disease duration. Disease duration was shorter in patients with antibodies to GAD(65) and IA2 and longer in neuropathic patients. The higher prevalence of antibodies in diabetic patients compared to controls may reflect the common pattern of antigens shared by peripheral nerve and pancreatic islet cells.

New effort has been made to develop closed-loop glucose control, using subcutaneous (SC) glucose sensing and continuous subcutaneous insulin infusion (CSII) from a pump, and a control algorithm. An approach based on a model predictive control (MPC) algorithm has been utilized during closed-loop control in type 1 diabetes patients. Here we describe the preliminary clinical experience with this approach. Six type 1 diabetes patients (three in each of two clinical investigation centers in Padova and Montpellier), using CSII, aged 36 +/- 8 and 48 +/- 6 years, duration of diabetes 12 +/- 8 and 29 +/- 4 years, hemoglobin A1c 7.4% +/- 0.1% and 7.3% +/- 0.3%, body mass index 23.2 +/- 0.3 and 28.4 +/- 2.2 kg/m(2), respectively, were studied on two occasions during 22 h overnight hospital admissions 2-4 weeks apart. A Freestyle Navigator(R) continuous glucose monitor and an OmniPod insulin pump were applied in each trial. Admission 1 used open-loop control, while admission 2 employed closed-loop control using our MPC algorithm. In Padova, two out of three subjects showed better performance with the closed-loop system compared to open loop. Altogether, mean overnight plasma glucose (PG) levels were 134 versus 111 mg/dl during open loop versus closed loop, respectively. The percentage of time spent at PG > 140 mg/dl was 45% versus 12%, while postbreakfast mean PG was 165 versus 156 mg/dl during open loop versus closed loop, respectively. Also, in Montpellier, two patients out of three showed a better glucose control during closed-loop trials. Avoidance of nocturnal hypoglycemic excursions was a clear benefit during algorithm-guided insulin delivery in all cases. This preliminary set of studies demonstrates that closed-loop control based entirely on SC glucose sensing and insulin delivery is feasible and can be applied to improve glucose control in patients with type 1 diabetes, although the algorithm needs to be further improved to achieve better glycemic control., (2009 Diabetes Technology Society.)

Thirty years after its introduction, the use of continuous subcutaneous insulin infusion (CSII) keeps increasing, especially among children and adolescents. The technique, when used properly, is safe and effective.Compared with traditional NPH-based multiple daily injections (MDI), CSII provides a small but clinically important reduction of HbA(1c) levels, diminishes blood glucose variability, decreases severe hypoglycaemic episodes and offers a better way to cope with the dawn phenomenon.Insulin analogues have improved the treatment of diabetes, eroding part of the place previously occupied by CSII, but CSII still remains the first option for patients experiencing severe hypoglycaemic episodes, high HbA(1c) values or marked glucose variability while being treated with optimized MDI. Furthermore CSII is better than MDI considering the effects on quality of life and the possibility to adjust insulin administration according to physical activity or food intake.CSII may be limited by cost. Present estimates suggest that CSII may be cost-effective just for patients experiencing a marked improvement in HbA(1c) or a decrease in severe hypoglycaemic episodes, but the effects on quality of life are difficult to measure.CSII does not merely imply wearing an external device; it requires a multidisciplinary team, intensive patient education and continuous follow up., (Copyright (c) 2009 John Wiley & Sons, Ltd.)

Background: Widespread use of carbohydrate (CHO) counting is limited by its complex educational needs, but a telemedicine system could simplify the patients' training., Methods: The Diabetes Interactive Diary (DID) was set up on patients' mobile phones and allowed to record the blood glucose values and quantify the total CHO intake during a meal, by choosing the specific food and the amount ingested from a list of pictures. It also suggested the most appropriate insulin bolus in relation to the patient's CHO/insulin ratio. Data were sent to the physician by Short Message Service (also known as text message). Two pilot studies were carried out to investigate the feasibility and acceptability of the system and its effectiveness in improving metabolic control., Results: In the first study, 50 patients were involved in a survey with questionnaires administered before and 12 weeks after the start of the DID. The system was considered by almost all the patients as easy to use and very helpful. CHO counting and insulin bolus calculation were ranked as the most useful functions. In the second study, 41 consecutive patients using DID under routine clinical practice conditions were evaluated after a median of 9 months of follow-up. DID was associated with a nonstatistically significant reduction in fasting blood glucose (FBG), postprandial glucose (PPG), and hemoglobin A1c levels. FBG and PPG coefficient of variation (CV) values were significantly reduced: FBG-CV decreased by 6.7% (95% confidence interval -11.9, -1.6; P = 0.02), while PPG-CV decreased by 11.5% (95% confidence interval -19.3, -3.7; P = 0.01). No patients reported serious hypoglycemic episodes requiring medical intervention., Conclusions: DID can represent a useful, safe, and easy-to-use tool to help the patient with type 1 diabetes promote dietary freedom. Adjustment of insulin doses according to CHO intake allowed the reduction of glucose variability, increasingly recognized as an important, independent risk factor for cardiovascular events.

Amiodarone interferes with the endocytic pathway, inhibits proteolysis, and causes the formation of vacuoles, but uptake and intracellular distribution of the drug, origin of vacuoles, and functional consequences of amiodarone accumulation remain unclear. Our objective was to study amiodarone uptake, clarify the origin of vacuoles, and investigate the effect of amiodarone on the life cycle of the coronavirus responsible for the Severe Acute Respiratory Syndrome (SARS), which, to enter cells, relies on the proteolytic cleavage of a viral spike protein by the endosomal proteinase cathepsin L. Using alveolar macrophages, we studied uptake of (125)I-amiodarone and (125)I-B2, an analog lacking the lateral group diethylamino-beta-ethoxy, and analyzed the effects of amiodarone on the distribution of endosomal markers and on the uptake of an acidotropic dye. Furthermore, using Vero cells, we tested the impact of amiodarone on the in vitro spreading of the SARS coronavirus. We found that (1) amiodarone associates with different cell membranes and accumulates in acidic organelles; (2) the diethylamino-beta-ethoxy group is an important determinant of uptake; (3) vacuoles forming upon exposure to amiodarone are enlarged late endosomes; (4) amiodarone inhibits the spreading in vitro of SARS coronavirus; and (5) trypsin cleavage of the viral spike protein before infection, which permits virus entry through the plasma membrane, does not impair amiodarone antiviral activity. We conclude that amiodarone alters late compartments of the endocytic pathway and inhibits SARS coronavirus infection by acting after the transit of the virus through endosomes.

Amiodarone, an antiarrhythmic drug toxic toward the lung, is metabolized through sequential modifications of the diethylaminoethoxy group to mono-N-desethylamiodarone (MDEA), di-N-desethylamiodarone (DDEA), and amiodarone-EtOH (B2-O-EtOH), whose effects on lung cells are unclear. To clarify this, we exposed rabbit alveolar macrophages to analogs with different modifications of the diethylaminoethoxy group and then searched for biochemical signs of cell damage, formation of vacuoles and inclusion bodies, and interference with the degradation of surfactant protein A, used as a tracer of the endocytic pathway. The substances studied included MDEA, DDEA, and B2-O-EtOH, analogs with different modifications of the diethylaminoethoxy group, fragments of the amiodarone molecule, and the antiarrhythmic agents dronedarone (SR-33589) and KB-130015. We found the following: 1). MDEA, DDEA, and B2-O-EtOH rank in order of decreasing toxicity toward alveolar macrophages, indicating that dealkylation and deamination of the diethylaminoethoxy group represent important mechanisms of detoxification; 2). dronedarone has greater, and KB-130015 has smaller, toxicity than amiodarone toward alveolar macrophages; and 3). the benzofuran moiety, which is toxic to liver cells, is not directly toxic toward alveolar macrophages.

The purpose of this cross-sectional study was to evaluate the degree of metabolic control, the prevalence of microvascular complications (nephropathy, retinopathy, and peripheral neuropathy) and their association with risk factors for cardiovascular diseases in all adult Type 1 diabetic out-patients attending 2 Diabetes Clinics of Northern Italy over 12 months. A total of 458 patients (mean age 37 +/- 12 yr, duration of diabetes 15.3 +/- 10.6 yr, BMI 23.2 +/- 3.1 kg/m2) were studied. Clinical characteristics and microvascular complications were evaluated. The proportion of patients with a good glycaemic control (HbA1c < 7%) was 14.7%. Nephropathy was observed in 24.4%, retinopathy in 41%, peripheral neuropathy in 23.7%. The prevalence of hypertension was 30.3%. Microvascular complications were associated with age, duration of diabetes, systolic blood pressure, creatinine, triglycerides and cholesterol plasma levels. Mean HbA1c was 8.5 +/- 1.6. Patients with HbA1c levels < 7% presented a lower prevalence of complications and lower levels of cholesterol, triglycerides, systolic blood pressure than patients with HbA1c > 9%. Our study indicates that an acceptable metabolic control is achieved in a too low proportion of Type 1 diabetic patients, even under multiple insulin injections. The association of poor metabolic control and microalbuminuria identifies a group of patients at higher risk of diabetic complications.

Background: Alcohol may impair protein turnover and insulin sensitivity in vivo., Objective: The acute effects of moderate wine intake on amino acid kinetics and on the fractional synthetic rate (FSR) of albumin and fibrinogen in patients with type 1 diabetes were studied., Design: Six patients with type 1 diabetes ingested an elementary mixed meal (46 kJ/kg) over 4 h, first without and 3 mo later with approximately 300 mL red wine. Postprandial glucose concentrations were maintained at <10 mmol/L., Results: Postprandially, the FSR of fibrinogen was approximately 30% greater (21.5 +/- 6.6% compared with 14.1 +/- 3.6% of pool/d; P < 0.01) and glucagon concentrations were approximately 40% greater (103 +/- 20 compared with 61 +/- 13 ng/L; P < 0.015) with wine than without wine. However, the FSR of albumin and the rates of appearance of total and endogenous phenylalanine and leucine were not significantly different between treatments. First-pass splanchnic uptake (in micromol*kg(-1)*min(-1)) of dietary phenylalanine (0.22 +/- 0.02 compared with 0.19 +/- 0.02) and leucine (0.25 +/- 0.04 compared with 0.14 +/- 0.02) were greater with wine (P < 0.05), whereas dietary phenylalanine oxidation was lower with wine, by approximately 25% (0.10 +/- 0.02 compared with 0.14 +/- 0.01 micromol.kg(-1).min(-1); P < 0.05). Selected amino acid concentrations were significantly lower but glutamate concentrations were significantly higher with wine., Conclusions: In insulin-infused patients with type 1 diabetes, moderate wine intake with a meal resulted in 1) a higher fibrinogen FSR, glucagon concentration, and first-pass splanchnic uptake of leucine and phenylalanine; 2) lower dietary phenylalanine oxidation; 3) selective changes in plasma amino acid concentrations; 4) and no impairment in endogenous proteolysis and albumin synthesis.

Amiodarone may induce lung damage by direct toxicity or indirectly through inflammation. To clarify the mechanism of direct toxicity, we briefly exposed rabbit alveolar macrophages to amiodarone and analyzed their morphology, synthesis, and degradation of dipalmitoylphosphatidylcholine (DPPC); distribution of lysosomal enzymes; and uptake of diphtheria toxin and surfactant protein (SP) A used as tracers of the endocytic pathway. Furthermore, in newborn rabbits, we studied the clearance of DPPC and SP-A instilled into the trachea together with increasing amounts of amiodarone. We found that in vitro amiodarone decreases the surface density of mitochondria and lysosomes while increasing the surface density of inclusion bodies, increases the incorporation of choline into DPPC, modifies the distribution of lysosomal enzymes, and does not affect the uptake and processing of diphtheria toxin but inhibits the degradation of SP-A. In vivo amiodarone inhibits the degradation of SP-A but not of DPPC. We conclude that the acute exposure to amiodarone perturbs the endocytic pathway acting after the early endosomes, alters the traffic of lysosomal enzymes, and interferes with the turnover of SP-A.

Carbohydrates (CHO) are a major determinant of post-prandial blood glucose in the diet of people with Type 1 diabetes mellitus, but patients frequently fail to evaluate CHO food content. Poor education is thought to contribute heavily to this failure. Our aim was to plan and evaluate a simple educational program to improve dietary knowledge and teach how to count CHO in Type 1 diabetic subjects. Forty-eight patients (age 27+/-1 yr, diabetes duration 11+/-1 yr, HbA1c 9%) attended 4 interactive meetings held at monthly intervals. The targets of the course were: 1) to identify sources of CHO, fats and proteins; 2) to count CHO and to split them among meals; 3) to assume CHO-rich foods without changing daily calorie or carbohydrate intake; 4) to modify the diet so as to correct hypoglycaemic events. To evaluate the effect of the course, patients completed a 7-day food record and answered a questionnaire covering the targets of the course at baseline, at the end of the course and 7 months later. After the course dietary knowledge improved significantly. The number of patients who weighed foods, estimated CHO food content and correctly distributed CHO among meals also increased. After the course patients reacted better when faced with hypoglycaemia. The knowledge acquired persisted 7 months after the end of the course. Therefore, we conclude that a simple teaching program can improve diet knowledge in Type 1 diabetics and establish a sustained habit of counting CHO.

Background and Aim: While lispro insulin has been reported to lower postprandial blood glucose concentrations, less consistent effects have been shown for glycosylated hemoglobin (HbA1c) levels. Aim of this study was to determine whether pre-meal association of NPH, an intermediate-acting insulin, with lispro improves overall glycemic control in type 1 diabetic patients., Methods and Results: Eighty-five type 1 diabetic patients were studied in a multicenter randomized comparative (human regular vs lispro insulin) crossover (3-month) study in which NPH insulin was given as a dinner or bedtime injection and at breakfast and lunch if necessary. The number of injections was kept constant: 42% and 58% of patients injected insulin 3 and 4 times per day, respectively. Fasting and preprandial blood glucose levels were similar, while postprandial levels improved after lispro compared to human regular insulin (breakfast: 8.28 +/- 2.39 vs 9.28 +/- 2.72 mmol/l; lunch: 8.33 +/- 2.67 vs 9.06 +/- 2.67 mmol/l, dinner: 8.06 +/- 2.72 vs 9.28 +/- 2.44 mmol/l, ANOVA: p = 0.003). HbA1c also improved after lispro: 8.1 +/- 0.9 vs 8.3 +/- 0.8%, p < 0.05. The rate of hypoglycemia was similar. Patients showed better acceptance of lispro treatment (p < 0.001)., Conclusions: Lispro improves overall blood glucose control in type 1 diabetic patients without increasing the incidence of hypoglycemia. This can be achieved by an optimal combination of lispro insulin with NPH whenever the time intervals between meals are too long.

Alveolar macrophages degrade surfactant protein (SP) A and saturated phosphatidycholine [dipalmitoylphosphatidylcholine (DPPC)]. To clarify this process, using rabbit alveolar macrophages, we analyzed the effect of drugs known to affect phagocytosis, pinocytosis, clathrin-mediated uptake, caveolae, the cytoskeleton, lysosomal pH, protein kinase C, and phosphatidylinositol 3-kinase (PI3K) on the degradation of SP-A and DPPC. We found the following: 1) SP-A binds to the plasma membrane, is rapidly internalized, and then moves toward degradative compartments. Uptake could be clathrin mediated, whereas phagocytosis, pinocytosis, or the use of caveolae are less likely. An intact cytoskeleton and an acidic milieu are necessary for the degradation of SP-A. 2) Stimulation of protein kinase C increases the degradation of SP-A. 3) PI3K influences the degradation of SP-A by regulating both the speed of internalization and subsequent intracellular steps, but its inhibition does not prevent SP-A from reaching the lysosomal compartment. 4) The degradation of DPPC is unaffected by most of the treatments able to influence the degradation of SP-A. Thus it appears that DPPC is degraded by alveolar macrophages through mechanisms very different from those utilized for the degradation of SP-A.

A retrospective analysis of blood glucose control was performed in 17 type 1 diabetic patients who regularly monitored their blood glucose concentration by visual strips over a period of 3-83 months. Analysis was performed by a patient management software loaded on a personal computer. In this cohort of patients the average daily blood glucose reading was 1.6 +/- 0.3. Blood glucose readings were collected more frequently following meal ingestion (40.3%) than in the post-absorptive state (24.6%; P less than 0.05). Blood glucose concentration fluctuated from a basal level of 146 +/- 5 mg/dl to 167 +/- 4 mg/dl in the post-prandial phases with an average daily value of 156 +/- 2 mg/dl. Blood glucose values below 80 mg/dl were evenly distributed throughout the day, while hyperglycemia (greater than 300 mg/dl) occurred more commonly after meals (42%). Daily blood glucose was higher during weekends (164 +/- 5 mg/dl) than during weekdays (155 +/- 2 mg/dl; P less than 0.05). A weak correlation was found between the number of blood glucose readings/day and daily blood glucose level. These results suggest that long-term maintenance of satisfactory metabolic control is attainable in type 1 diabetic patients and that this is mainly dependent upon subject self awareness.

We evaluated the effect of a diet rich in natural (NF) or extractive fibres (guar gum) on 12 male IDD (insulin-dependent diabetes) out-patients. The treatment lasted for 2 months. During the first month the patients were on an isocaloric diet containing 30 g of fibres and then they were randomly subdivided into two groups. One group followed an isocaloric diet rich in fibres (70 g/day), the second group an isocaloric diet enriched by guar (9 g of guar added to 30 g of natural fibres/day). Reduced serum levels of HbA1c and several amino acids showed that metabolic control significantly improved under each dietary regimen.

We report the case of a highly motivated diabetic patient who designed and developed an insulin injector for himself. During 4 years of use of this injector, a strict control was achieved and the frequency of hypoglycemic episodes was reduced. During this period there was no evidence of progression of diabetic complications.

Diabetes secondary to pancreatic disease (PD) represents a useful model for the study of the effects of chronic hyperglycemia on microangiopathic complications in the absence of those genetic factors predisposing to Type I diabetes. Our aim was to evaluate the prevalence of nephropathy and retinopathy in a group of 86 patients with PD. The genetic pattern, assessed by the determination of HLA antigens, was different than in patients with Type I diabetes. A family history of diabetes was present in 53% of the patients. The prevalence of retinopathy was 37%. Eighteen percent of the patients with duration of diabetes less than 10 years showed an albumin excretion rate (AER) greater than 40 mg/24 hr. The prevalence of pathologic microalbuminuria (greater than 40 mg/24 hr) was found in 29% of the patients with duration of diabetes greater than 10 years. The prevalence of pathologic microalbuminuria is related to the duration of diabetes. Both diastolic and systolic blood pressure is positively correlated to albumin excretion rate (p less than 0.02), suggesting a possible role of hypertension in the evolution of nephropathy. Sixty-one percent of the patients with AER greater than 40 mg/24 h had retinopathy, thus confirming the close association between renal and ocular complications. Abnormal microalbuminuria and retinopathy were not influenced by a family history of diabetes. We conclude that the prevalence of microangiopathic complications is similar to that seen in Type I diabetes, and the metabolic abnormalities of diabetes can play a direct role in the development of diabetic microangiopathy.