Practical implementation of automated closed-loop insulin delivery: A French position statement.

Automated closed-loop (CL) insulin therapy has come of age. This major technological advance is expected to significantly improve the quality of care for adults, adolescents and children with type 1 diabetes. To improve access to this innovation for both patients and healthcare professionals (HCPs), and to promote adherence to its requirements in terms of safety, regulations, ethics and practice, the French Diabetes Society (SFD) brought together a French Working Group of experts to discuss the current practical consensus. The result is the present statement describing the indications for CL therapy with emphasis on the idea that treatment expectations must be clearly defined in advance. Specifications for expert care centres in charge of initiating the treatment were also proposed. Great importance was also attached to the crucial place of high-quality training for patients and healthcare professionals. Long-term follow-up should collect not only metabolic and clinical results, but also indicators related to psychosocial and human factors. Overall, this national consensus statement aims to promote the introduction of marketed CL devices into standard clinical practice.

Practical implementation, education and interpretation guidelines for continuous glucose monitoring: A French position statement.

The use by diabetes patients of real-time continuous interstitial glucose monitoring (CGM) or the FreeStyle Libre® (FSL) flash glucose monitoring (FGM) system is becoming widespread and has changed diabetic practice. The working group bringing together a number of French experts has proposed the present practical consensus. Training of professionals and patient education are crucial for the success of CGM. Also, institutional recommendations must pay particular attention to the indications for and reimbursement of CGM devices in populations at risk of hypoglycaemia. The rules of good practice for CGM are the precursors of those that need to be enacted, given the oncoming emergence of artificial pancreas devices. It is necessary to have software combining user-friendliness, multiplatform usage and average glucose profile (AGP) presentation, while integrating glucose and insulin data as well as events. Expression of CGM data must strive for standardization that facilitates patient phenotyping and their follow-up, while integrating indicators of variability. The introduction of CGM involves a transformation of treatment support, rendering it longer and more complex as it also includes specific educational and technical dimensions. This complexity must be taken into account in discussions of organization of diabetes care.

Psychological outcomes of evening and night closed-loop insulin delivery under free living conditions in people with Type 1 diabetes: a 2-month randomized crossover trial.

AIM: To assess the impact on fear of hypoglycaemia and treatment satisfaction with an artificial pancreas system used for 2 consecutive months, as well as participant acceptance of the artificial pancreas system. METHODS: In a randomized crossover trial patient-related outcomes associated with an evening-and-night artificial pancreas and sensor-augmented pump therapy were compared. Both intervention periods lasted 8 weeks. The artificial pancreas acceptance questionnaire (range 0-90, higher scores better), Hypoglycaemia Fear Survey II (range 0-72, higher scores worse) and Diabetes Treatment Satisfaction Questionnaire (range 0-36, higher scores better) were completed by 32 participants. Semi-structured interviews were conducted after study completion in a subset of six participants. Outcomes were compared using a repeated-measures anova model or paired t-test when appropriate. RESULTS: The total artificial pancreas acceptance questionnaire score at the end of the artificial pancreas period was 69.1 (sd 14.7; 95% CI 63.5, 74.7), indicating a positive attitude towards the artificial pancreas. No significant differences were found among the scores at baseline, end of sensor-augmented pump therapy period or end of the artificial pancreas period with regard to fear of hypoglycaemia [28.2 (sd 17.5), 23.5 (sd 16.6) and 23.5 (sd 16.7), respectively; P = 0.099] or diabetes treatment satisfaction [29.0 (sd 3.9), 28.2 (sd 5.2) and 28.0 (sd 7.1), respectively; P = 0.43]. Themes frequently mentioned in the interviews were 'positive effects at work', 'improved blood glucose', 'fewer worries about blood glucose', but also 'frequent alarms', 'technological issues' and 'demand for an all-in-one device'. CONCLUSIONS: The psychological outcomes of artificial pancreas and sensor-augmented pump therapy were similar. Current artificial pancreas technology is promising but user concerns should be taken into account to ensure utility of these systems.

Multicenter outpatient dinner/overnight reduction of hypoglycemia and increased time of glucose in target with a wearable artificial pancreas using modular model predictive control in adults with type 1 diabetes.

AIMS: To test in an outpatient setting the safety and efficacy of continuous subcutaneous insulin infusion (CSII) driven by a modular model predictive control (MMPC) algorithm informed by continuous glucose monitoring (CGM) measurement. METHODS: 13 patients affected by type 1 diabetes participated to a non-randomized outpatient 42-h experiment that included two evening meals and overnight periods (in short, dinner & night periods). CSII was patient-driven during dinner & night period 1 and MMPC-driven during dinner&night period 2. The study was conducted in hotels, where patients could move around freely. A CGM system (G4 Platinum; Dexcom Inc., San Diego, CA, USA) and insulin pump (AccuChek Combo; Roche Diagnostics, Mannheim, Germany) were connected wirelessly to a smartphone-based platform (DiAs, Diabetes Assistant; University of Virginia, Charlottesville, VA, USA) during both periods. RESULTS: A significantly lower percentage of time spent with glucose levels <3.9 mmol/l was achieved in period 2 compared with period 1: 1.96 ± 4.56% vs 12.76 ± 15.84% (mean ± standard deviation, p < 0.01), together with a greater percentage of time spent in the 3.9-10 mmol/l target range: 83.56 ± 14.02% vs 62.43 ± 29.03% (p = 0.04). In addition, restricting the analysis to the overnight phases, a lower percentage of time spent with glucose levels <3.9 mmol/l (1.92 ± 4.89% vs 12.7 ± 19.75%; p = 0.03) was combined with a greater percentage of time spent in 3.9-10 mmol/l target range in period 2 compared with period 1 (92.16 ± 8.03% vs 63.97 ± 2.73%; p = 0.01). Average glucose levels were similar during both periods. CONCLUSIONS: The results suggest that MMPC managed by a wearable system is safe and effective during evening meal and overnight. Its sustained use during this period is currently being tested in an ongoing randomized 2-month study.

Accuracy of two continuous glucose monitoring systems: a head-to-head comparison under clinical research centre and daily life conditions.

AIMS: To assess the accuracy and reliability of the two most widely used continuous glucose monitoring (CGM) systems. METHODS: We studied the Dexcom®G4 Platinum (DG4P; Dexcom, San Diego, CA, USA) and Medtronic Paradigm Veo Enlite system (ENL; Medtronic, Northridge, CA, USA) CGM systems, in 24 patients with type 1 diabetes. The CGM systems were tested during 6-day home use and a nested 6-h clinical research centre (CRC) visit. During the CRC visit, frequent venous blood glucose samples were used as reference while patients received a meal with an increased insulin bolus to induce an aggravated postprandial glucose nadir. At home, patients performed at least six reference capillary blood measurements per day. A Wilcoxon signed-rank test was performed using all data points ≥15 min apart. RESULTS: The overall mean absolute relative difference (MARD) value [standard deviation (s.d.)] measured at the CRC was 13.6 (11.0)% for the DG4P and 16.6 (13.5)% for the ENL [p < 0.0002, confidence interval of difference (CI Δ) 1.7-4.3%, n = 530]. The overall MARD assessed at home was 12.2 (12.0)% for the DG4P and 19.9 (20.5)% for the ENL (p < 0.0001, CI Δ = 5.8-8.7%, n = 839). During the CRC visit, the MARD in the hypoglycaemic range [≤3.9 mmol/l (70 mg/dl)], was 17.6 (12.2)% for the DG4P and 24.6 (18.8)% for the ENL (p = 0.005, CI Δ 3.1-10.7%, n = 117). Both sensors showed higher MARD values during hypoglycaemia than during euglycaemia [3.9-10 mmol/l (70-180 mg/dl)]: for the DG4P 17.6 versus 13.0% and for the ENL 24.6 versus 14.2%. CONCLUSIONS: During circumstances of intended use, including both a CRC and home phase, the ENL was noticeably less accurate than the DG4P sensor. Both sensors showed lower accuracy in the hypoglycaemic range. The DG4P was less affected by this negative effect of hypoglycaemia on sensor accuracy than was the ENL.

Effect of a high dose of simvastatin on muscle mitochondrial metabolism and calcium signaling in healthy volunteers.

Statin use may be limited by muscle side effects. Although incompletely understood to date, their pathophysiology may involve oxidative stress and impairments of mitochondrial function and of muscle Ca(2+) homeostasis. In order to simultaneously assess these mechanisms, 24 male healthy volunteers were randomized to receive either simvastatin for 80 mg daily or placebo for 8 weeks. Blood and urine samples and a stress test were performed at baseline and at follow-up, and mitochondrial respiration and Ca(2+) spark properties were evaluated on a muscle biopsy 4 days before the second stress test. Simvastatin-treated subjects were separated according to their median creatine kinase (CK) increase. Simvastatin treatment induced a significant elevation of aspartate amino transferase (3.38±5.68 vs -1.15±4.32 UI/L, P<0.001) and CK (-24.3±99.1±189.3 vs 48.3 UI/L, P=0.01) and a trend to an elevation of isoprostanes (193±408 vs 12±53 pmol/mmol creatinine, P=0.09) with no global change in mitochondrial respiration, lactate/pyruvate ratio or Ca(2+) sparks. However, among statin-treated subjects, those with the highest CK increase displayed a significantly lower Vmax rotenone succinate and an increase in Ca(2+) spark amplitude vs both subjects with the lowest CK increase and placebo-treated subjects. Moreover, Ca(2+) spark amplitude was positively correlated with treatment-induced CK increase in the whole group (r=0.71, P=0.0045). In conclusion, this study further supports that statin induced muscular toxicity may be related to alterations in mitochondrial respiration and muscle calcium homeostasis independently of underlying disease or concomitant medication.

Towards an artificial pancreas at home.

AIM: To review the recent clinical research related to the development of an artificial pancreas and the current perspectives for its home use. METHODS: All clinical investigations assessing closed-loop insulin delivery systems in diabetic patients in the literature were collected and analyzed to identify any significant advances as well as bottlenecks. RESULTS: The development of an artificial pancreas for ambulatory use offering an optimal substitute for insulin secretion has shown promising evolution over the past decade. The accumulated improvements achieved on the performance of insulin pumps using subcutaneous and intraperitoneal routes, continuous glucose monitoring and algorithms driving insulin infusion according to glucose measurement have led to numerous clinical trials recently, albeit only in a hospital setting so far. The key obstacles to achieving permanent normal glucose control are related to the delay of insulin action when infused subcutaneously or, at a lesser extent, into the peritoneal cavity, and blood glucose estimation made by subcutaneous interstitial measurement. These time lags impair the reactivity of the system, and suggest a need to develop complex algorithms aiming at their compensation. So far, manual interventions are needed at times of food intake to prevent hyper- or hypoglycaemic excursions when insulin changes rapidly. CONCLUSION: The most recent models using subcutaneous insulin infusion and glucose measurements linked by predictive control algorithms offer sufficient effectiveness and safety to consider their forthcoming use at home, during the night as a first step.

Direct rosiglitazone-induced modifications in insulin secretion, action and clearance: a single-dose hyperglycaemic clamp study.

AIMS/HYPOTHESIS: In addition to the improvement in insulin sensitivity, it has been shown that thiazolidinediones modulate beta cell function and insulin clearance in type 2 diabetic subjects. However, interactions between all these actions, and confounding factors due to co-morbidities and co-treatments in diabetic individuals, complicate the identification of specific effects. The aim of this pilot study was to investigate the potential acute effects of rosiglitazone on beta cell function and insulin sensitivity by the hyperglycaemic clamp technique in healthy volunteers. SUBJECTS AND METHODS: Twelve healthy men were included in a randomised, double-blind crossover study. Rosiglitazone (8 mg) or placebo was given orally 45 min before the hyperglycaemic clamp (10 mmol/l for 2 h). RESULTS: The second phase of the insulin response was significantly decreased by rosiglitazone: 13,066 +/- 1,531 vs 16,316 +/- 2,813 pmol l(-1) 110 min in controls (p < 0.05), without change in the first phase. Serum C-peptide was not modified. Rosiglitazone treatment significantly increased insulin clearance (molar ratio of the C-peptide to insulin AUCs: 12.80 +/- 1.34 vs 11.38 +/- .33, p < 0.05) and the insulin sensitivity index (12.0 +/- 1.5 vs 8.5 +/- 1.1 micromol m(-2) min(-1) pmol(-1)l, p < 0.01). CONCLUSIONS/INTERPRETATION: The present results show that a single dose of rosiglitazone rapidly increases insulin clearance and insulin sensitivity index in healthy volunteers, with no direct effect on insulin secretion. The precise mechanisms mediating these actions remain to be determined.

Resting energy expenditure and fuel metabolism following laparoscopic adjustable gastric banding in severely obese women: relationships with excess weight lost.

BACKGROUND: Although adjustable gastric banding is increasingly proposed for massively obese patients, little is known about the modifications of resting metabolic rate and substrate oxidation or about metabolic determinants of weight loss following this type of bariatric surgery. OBJECTIVES: To evaluate the relationships between excess weight loss, resting metabolic rate (RMR) and substrate oxidation, and to identify metabolic predictive factors of weight loss after adjustable gastric banding. SUBJECTS: Seventy-three obese nondiabetic women aged 39.1+/-10.4 years (18.4-64.8). DESIGN: Resting metabolic rate and substrate oxidation (indirect calorimetry), body composition (bio-impedance), lipid profile and insulin sensitivity indexes were assessed before and after (13.3+/-6.0 months, range 6.0-31.1) adjustable gastric banding. Patients were classified according to postsurgery time: group A (6-12 months, n=39); group B (12-18 months, n=21); group C (>18 months, n=13). Metabolic parameters associated with the percentage of excess weight lost (EWL) 1 year after surgery were analyzed in univariate and multivariate regressions. RESULTS: Mean weight loss was 26.2+/-11.4 kg. Mean fat mass loss was 17.3+/-8.1 kg. All biological parameters associated with excess weight improved after surgery. Excess weight lost at 1 year was 45.9+/-17.1% in group A, 47.4+/-17.1% in group B and 51.4+/-18.5% in group C (P=NS). Resting metabolic rate/fat-free mass (FFM) slightly decreased (28.9+/-3.26 vs 30.3+/-2.8, P<0.00001) and RMR/body weight slightly increased (18.5+/-2.8 vs 17.3+/-1.9, P<0.00001) after surgery. Respiratory quotient (0.81+/-0.06 vs 0.82+/-0.05) and FFM-adjusted lipid oxidation (1.10+/-0.41 vs 1.05+/-0.33 mg/min/kg FFM) were not significantly modified after surgery. In multiple linear regression analysis, difference in RMR/body weight, difference in energy sparing, baseline BMI and postsurgery time, were significantly and independently correlated with EWL (total R2=72.5%). CONCLUSIONS: Adjustable gastric banding promotes gradual but sustained weight loss and is associated with long-term conservation of lipid oxidation and energy expenditure. The individual variability in energy sparing mechanisms predicts weight loss during the first year after surgery.

P2Y purinergic potentiation of glucose-induced insulin secretion and pancreatic beta-cell metabolism.

Purine nucleotides and their analogs increase insulin secretion through activation of pancreatic beta-cell P2Y receptors. The present study aimed at determining the role of glucose metabolism in the response to P2Y agonists and whether ATP-activated K+ channels (KATP channels) are involved in this response. The experiments were performed in the rat isolated pancreas, perfused with a Krebs-bicarbonate buffer supplemented with 2 g/l bovine serum albumin under dynamic glucose conditions from 5 mmol/l baseline to 11 mmol/l. ADPbetaS (0.5 micromol/l) was selected as a stable and selective P2Y agonist. This compound, ineffective on the 5 mmol/l glucose background, induced a significant threefold increase in insulin release triggered by the glucose challenge. The effect of ADPbetaS was markedly reduced (P <0.001) in the presence of an inhibitor of glucose metabolism. In addition to glucose, the ADP analog also amplified the beta-cell insulin response to 15 mmol/l methyl pyruvate (P <0.05), but it was ineffective on the insulin response to 2.5 mmol/l methyl succinate. A nonmetabolic stimulus was applied using tolbutamide (185 micromol/l). Insulin secretion induced by the KATP channel blocker was strongly reinforced by ADPbetaS (P <0.001), which prompted us to check a possible interplay of KATP channels in the effect of ADPbetaS. In the presence of diazoxide 250 micromol/l and 21 mmol/l KCl, ADPbetaS still amplified the second phase of glucose-induced insulin secretion (P <0.001). We conclude that P2Y receptor activation is able to promote insulin secretion through a mechanism, involving beta-cell metabolism and a rise in intracellular calcium; this effect does not result from a direct inhibitory effect on KATP channels.

Suprarenal aorta reconstruction using a saphenous spiral graft: case report.

We report a case of gunshot wound to the suprarenal aorta with restoration of blood flow through a saphenous spiral graft in an 18-year-old man. He was followed for a period of 27 months. The follow-up showed a progressive dilatation of the graft. This original technique for wounds of the aorta seems a reasonable alternative for trauma cases in which there is no vascular prosthetic graft.