Lia Bally

Day-and-night glycaemic control with closed-loop insulin delivery versus conventional insulin pump therapy in free-living adults with well controlled type 1 diabetes: an open-label, randomised, crossover study

Summary Background Tight control of blood glucose concentration in people with type 1 diabetes predisposes to hypoglycaemia. We aimed to investigate whether day-and-night hybrid closed-loop insulin delivery can improve glucose control while alleviating the risk of hypoglycaemia in adults with HbA1c below 7·5% (58 mmol/mol). Methods In this open-label, randomised, crossover study, we recruited adults (aged ≥18 years) with type 1 diabetes and HbA1c below 7·5% from Addenbrookes Hospital (Cambridge, UK) and Medical University of Graz (Graz, Austria). After a 2–4 week run-in period, participants were randomly assigned (1:1), using web-based randomly permuted blocks of four, to receive insulin via the day-and-night hybrid closed-loop system or usual pump therapy for 4 weeks, followed by a 2–4 week washout period and then the other intervention for 4 weeks. Treatment interventions were unsupervised and done under free-living conditions. During the closed-loop period, a model-predictive control algorithm directed insulin delivery, and prandial insulin delivery was calculated with a standard bolus wizard. The primary outcome was the proportion of time when sensor glucose concentration was in target range (3·9–10·0 mmol/L) over the 4 week study period. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02727231, and is completed. Findings Between March 21 and June 24, 2016, we recruited 31 participants, of whom 29 were randomised. One participant withdrew during the first closed-loop period because of dissatisfaction with study devices and glucose control. The proportion of time when sensor glucose concentration was in target range was 10·5 percentage points higher (95% CI 7·6–13·4; p<0·0001) during closed-loop delivery compared with usual pump therapy (65·6% [SD 8·1] when participants used usual pump therapy vs 76·2% [6·4] when they used closed-loop). Compared with usual pump therapy, closed-loop delivery also reduced the proportion of time spent in hypoglycaemia: the proportion of time with glucose concentration below 3·5 mmol/L was reduced by 65% (53–74, p<0·0001) and below 2·8 mmol/L by 76% (59–86, p<0·0001). No episodes of serious hypoglycaemia or other serious adverse events occurred. Interpretation Use of day-and-night hybrid closed-loop insulin delivery under unsupervised, free-living conditions for 4 weeks in adults with type 1 diabetes and HbA1c below 7·5% is safe and well tolerated, improves glucose control, and reduces hypoglycaemia burden. Larger and longer studies are warranted. Funding Swiss National Science Foundation (P1BEP3_165297), JDRF, UK National Institute for Health Research Cambridge Biomedical Research Centre, and Wellcome Strategic Award (100574/Z/12/Z).

Accuracy of continuous glucose monitoring during differing exercise conditions

AIM Depending on intensity, exercise may induce a strong hormonal and metabolic response, including acid-base imbalances and changes in microcirculation, potentially interfering with the accuracy of continuous glucose monitoring (CGM). The present study aimed at comparing the accuracy of the Dexcom G4 Platinum (DG4P) CGM during continuous moderate and intermittent high-intensity exercise (IHE) in adults with type 1 diabetes (T1DM). METHODS Ten male individuals with well-controlled T1DM (HbA1c 7.0 ± 0.6% [54 ± 6 mmol/mol]) inserted the DG4P sensor 2 days prior to a 90 min cycling session (50% VO2peak) either with (IHE) or without (CONT) a 10s all-out sprint every 10 min. Venous blood samples for reference glucose measurement were drawn every 10 min and euglycemia (target 7 mmol/l) was maintained using an oral glucose solution. Additionally, lactate and venous blood gas variables were determined. RESULTS Mean reference blood glucose was 7.6 ± 0.2 mmol/l during IHE and 6.7 ± 0.2 mmol/l during CONT (p<0.001). IHE resulted in significantly higher levels of lactate (7.3 ± 0.5 mmol/l vs. 2.6 ± 0.3 mmol/l, p<0.001), while pH values were significantly lower in the IHE group (7.27 vs. 7.38, p=0.001). Mean absolute relative difference (MARD) was 13.3 ± 2.2% for IHE and 13.6 ± 2.8% for CONT suggesting comparable accuracy (p=0.90). Using Clarke Error Grid Analysis, 100% of CGM values during both IHE and CONT were in zones A and B (IHE: 77% and 23%; CONT: 78% and 22%). CONCLUSIONS The present study revealed good and comparable accuracy of the DG4P CGM system during intermittent high intensity and continuous moderate intensity exercise, despite marked differences in metabolic conditions. This corroborates the clinical robustness of CGM under differing exercise conditions. CLINICAL TRIAL REGISTRATION NUMBER ClinicalTrials.gov NCT02068638.

Carbohydrate Estimation Supported by the GoCARB system in Individuals With Type 1 Diabetes: A Randomized Prospective Pilot Study

Accurate carbohydrate (CHO) counting to achieve satisfactory glucose control in type 1 diabetes (T1D) remains challenging in practice, and thus novel approaches are still needed (1,2). GoCARB is a computer vision-based application installed in a smartphone device that provides users with CHO content estimations from photos taken of plated meals (3). We present the results of a pilot prospective randomized controlled crossover study (NCT02546063) evaluating the effects of GoCARB on postprandial and overall glucose control in individuals with T1D using sensor-augmented insulin pump (SAP) therapy. One week of GoCARB use was compared with conventional methods to estimate meal CHO content in 20 adults with T1D using SAP therapy (mean age 35 ± 14 years, BMI 25.5 ± 3.8 kg/m2, HbA1c 7.5 ± 0.6% [58.7 ± 5.9 mmol/mol], duration of diabetes 17 ± 10 years, …

Exercise-associated glucose metabolism in individuals with type 1 diabetes mellitus.

Purpose of reviewThe primary focus of this review is threefold: first, to summarize available knowledge on exercise-associated glucose metabolism in individuals with type 1 diabetes mellitus (T1DM); second, to elucidate physiological mechanisms predisposing to glycemic variations in patients in T1DM; and third, to describe novel approaches derived from physiological perceptions applicable to stabilize exercise-related glycemia in individuals with T1DM. Recent findingsRecent studies corroborate the concept that despite partial differences in counter-regulatory mechanisms individuals with T1DM do not fundamentally differ in their glucose response to exercise when compared with healthy individuals if studies are performed under standardized conditions with insulin and glucose levels held close to physiological ranges. Novel approaches derived from a better understanding of exercise-associated glucose metabolism (e.g., the concept of intermittent high-intensity exercise) may provide alternative ways to master the challenges imposed by exercise to individuals with T1DM. SummaryExercise still imposes high demands on patients with T1DM and increases risks for hypoglycemia and hyperglycemia. Deeper insight into the associated metabolic pathways has revealed novel options to stabilize exercise-associated glucose levels in these patients.

Hepatic and intramyocellular glycogen stores in adults with type 1 diabetes and healthy controls

Glycogen levels in liver and skeletal muscle assessed non-invasively using magnetic resonance spectroscopy after a 48-h pre-study period including a standardized diet and withdrawal from exercise did not differ between individuals with well-controlled Type 1 DM and matched healthy controls.

Closed-Loop Insulin Delivery for Glycemic Control in Noncritical Care

Background In patients with diabetes, hospitalization can complicate the achievement of recommended glycemic targets. There is increasing evidence that a closed‐loop delivery system (artificial pancreas) can improve glucose control in patients with type 1 diabetes. We wanted to investigate whether a closed‐loop system could also improve glycemic control in patients with type 2 diabetes who were receiving noncritical care. Methods In this randomized, open‐label trial conducted on general wards in two tertiary hospitals located in the United Kingdom and Switzerland, we assigned 136 adults with type 2 diabetes who required subcutaneous insulin therapy to receive either closed‐loop insulin delivery (70 patients) or conventional subcutaneous insulin therapy, according to local clinical practice (66 patients). The primary end point was the percentage of time that the sensor glucose measurement was within the target range of 100 to 180 mg per deciliter (5.6 to 10.0 mmol per liter) for up to 15 days or until hospital discharge. Results The mean (±SD) percentage of time that the sensor glucose measurement was in the target range was 65.8±16.8% in the closed‐loop group and 41.5±16.9% in the control group, a difference of 24.3±2.9 percentage points (95% confidence interval [CI], 18.6 to 30.0; P<0.001); values above the target range were found in 23.6±16.6% and 49.5±22.8% of the patients, respectively, a difference of 25.9±3.4 percentage points (95% CI, 19.2 to 32.7; P<0.001). The mean glucose level was 154 mg per deciliter (8.5 mmol per liter) in the closed‐loop group and 188 mg per deciliter (10.4 mmol per liter) in the control group (P<0.001). There was no significant between‐group difference in the duration of hypoglycemia (as defined by a sensor glucose measurement of <54 mg per deciliter; P=0.80) or in the amount of insulin that was delivered (median dose, 44.4 U and 40.2 U, respectively; P=0.50). No episode of severe hypoglycemia or clinically significant hyperglycemia with ketonemia occurred in either trial group. Conclusions Among inpatients with type 2 diabetes receiving noncritical care, the use of an automated, closed‐loop insulin‐delivery system resulted in significantly better glycemic control than conventional subcutaneous insulin therapy, without a higher risk of hypoglycemia. (Funded by Diabetes UK and others; ClinicalTrials.gov number, NCT01774565.)

Glucose-responsive insulin delivery for type 1 diabetes: The artificial pancreas story.

ABSTRACT Insulin replacement therapy is integral to the management of type 1 diabetes, which is characterised by absolute insulin deficiency. Optimal glycaemic control, as assessed by glycated haemoglobin, and avoidance of hyper‐ and hypoglycaemic excursions have been shown to prevent diabetes‐related complications. Insulin pump use has increased considerably over the past decade with beneficial effects on glycaemic control, quality of life and treatment satisfaction. The advent and progress of ambulatory glucose sensor technology has enabled continuous glucose monitoring based on real‐time glucose levels to be integrated with insulin therapy. Low glucose and predictive low glucose suspend systems are currently used in clinical practice to mitigate against hypoglycaemia, and provide the first step towards feedback glucose control. The more advanced technology approach, an artificial pancreas or a closed‐loop system, gradually increases and decreases insulin delivery in a glucose‐responsive fashion to mitigate against hyper‐ and hypoglycaemia. Randomised outpatient clinical trials over the past 5 years have demonstrated the feasibility, safety and efficacy of the approach, and the recent FDA approval of the first single hormone closed‐loop system establishes a new standard of care for people with type 1 diabetes.

Methodological and physiological test-retest reliability of (13) C-MRS glycogen measurements in liver and in skeletal muscle of patients with type 1 diabetes and matched healthy controls.

Glycogen is a major substrate in energy metabolism and particularly important to prevent hypoglycemia in pathologies of glucose homeostasis such as type 1 diabetes mellitus (T1DM). 13C‐MRS is increasingly used to determine glycogen in skeletal muscle and liver non‐invasively; however, the low signal‐to‐noise ratio leads to long acquisition times, particularly when glycogen levels are determined before and after interventions. In order to ease the requirements for the subjects and to avoid systematic effects of the lengthy examination, we evaluated if a standardized preparation period would allow us to shift the baseline (pre‐intervention) experiments to a preceding day.

Inhibition of Hippocampal Regeneration by Adjuvant Dexamethasone in Experimental Infant Rat Pneumococcal Meningitis

ABSTRACT Pneumococcal meningitis (PM) causes neurological sequelae in up to half of surviving patients. Neuronal damage associated with poor outcome is largely mediated by the inflammatory host response. Dexamethasone (DXM) is used as an adjuvant therapy in adult PM, but its efficacy in the treatment of pneumococcal meningitis in children is controversially discussed. While DXM has previously been shown to enhance hippocampal apoptosis in experimental PM, its impact on hippocampal cell proliferation is not known. This study investigated the impact of DXM on hippocampal proliferation in infant rat PM. Eleven-day-old nursing Wistar rats (n = 90) were intracisternally infected with Streptococcus pneumoniae to induce experimental meningitis. Treatment with DXM or vehicle was started 18 h after infection, concomitantly with antibiotics (ceftriaxone 100 mg/kg of body weight twice a day [b.i.d.]). Clinical parameters were monitored, and the amount of cells with proliferating activity was assessed using in vivo incorporation of bromodeoxyuridine (BrdU) and an in vitro neurosphere culture system at 3 and 4 d postinfection. DXM significantly worsened weight loss and survival. Density of BrdU-positive cells, as an index of cells with proliferating activity, was significantly lower in DXM-treated animals compared to vehicle controls (P < 0.0001). In parallel, DXM reduced neurosphere formation as an index for stem/progenitor cell density compared to vehicle treatment (P = 0.01). Our findings provide clear evidence that DXM exerts an antiproliferative effect on the hippocampus in infant rat PM. We conclude that an impairment of regenerative hippocampal capacity should be taken into account when considering adjuvant DXM in the therapeutic regimen for PM in children.

Metabolic Effects of Glucose-Fructose Co-Ingestion Compared to Glucose Alone during Exercise in Type 1 Diabetes

This paper aims to compare the metabolic effects of glucose-fructose co-ingestion (GLUFRU) with glucose alone (GLU) in exercising individuals with type 1 diabetes mellitus. Fifteen male individuals with type 1 diabetes (HbA1c 7.0% ± 0.6% (53 ± 7 mmol/mol)) underwent a 90 min iso-energetic continuous cycling session at 50% VO2max while ingesting combined glucose-fructose (GLUFRU) or glucose alone (GLU) to maintain stable glycaemia without insulin adjustment. GLUFRU and GLU were labelled with 13C-fructose and 13C-glucose, respectively. Metabolic assessments included measurements of hormones and metabolites, substrate oxidation, and stable isotopes. Exogenous carbohydrate requirements to maintain stable glycaemia were comparable between GLUFRU and GLU (p = 0.46). Fat oxidation was significantly higher (5.2 ± 0.2 vs. 2.6 ± 1.2 mg·kg−1·min−1, p < 0.001) and carbohydrate oxidation lower (18.1 ± 0.8 vs. 24.5 ± 0.8 mg·kg−1·min−1 p < 0.001) in GLUFRU compared to GLU, with decreased muscle glycogen oxidation in GLUFRU (10.2 ± 0.9 vs. 17.5 ± 1.0 mg·kg−1·min−1, p < 0.001). Lactate levels were higher (2.2 ± 0.2 vs. 1.8 ± 0.1 mmol/L, p = 0.012) in GLUFRU, with comparable counter-regulatory hormones between GLUFRU and GLU (p > 0.05 for all). Glucose and insulin levels, and total glucose appearance and disappearance were comparable between interventions. Glucose-fructose co-ingestion may have a beneficial impact on fuel metabolism in exercising individuals with type 1 diabetes without insulin adjustment, by increasing fat oxidation whilst sparing glycogen.