Mark L. Evans

Overnight closed loop insulin delivery (artificial pancreas) in adults with type 1 diabetes: crossover randomised controlled studies

Objective To compare the safety and efficacy of overnight closed loop delivery of insulin (artificial pancreas) with conventional insulin pump therapy in adults with type 1 diabetes. Design Two sequential, open label, randomised controlled crossover, single centre studies. Setting Clinical research facility. Participants 24 adults (10 men, 14 women) with type 1 diabetes, aged 18-65, who had used insulin pump therapy for at least three months: 12 were tested after consuming a medium sized meal and the other 12 after consuming a larger meal accompanied by alcohol. Intervention During overnight closed loop delivery, sensor measurements of glucose were fed into a computer algorithm, which advised on insulin pump infusion rates at 15 minute intervals. During control nights, conventional insulin pump settings were applied. One study compared closed loop delivery of insulin with conventional pump therapy after a medium sized evening meal (60 g of carbohydrates) at 1900, depicting the scenario of “eating in.” The other study was carried out after a later large evening meal (100 g of carbohydrates) at 2030, accompanied by white wine (0.75 g/kg ethanol) and depicted the scenario of “eating out.” Main outcome measures The primary outcome was the time plasma glucose levels were in target (3.91-8.0 mmol/L) during closed loop delivery and a comparable control period. Secondary outcomes included pooled data analysis and time plasma glucose levels were below target (≤3.9 mmol/L). Results For the eating in scenario, overnight closed loop delivery of insulin increased the time plasma glucose levels were in target by a median 15% (interquartile range 3-35%), P=0.002. For the eating out scenario, closed loop delivery increased the time plasma glucose levels were in target by a median 28% (2-39%), P=0.01. Analysis of pooled data showed that the overall time plasma glucose was in target increased by a median 22% (3-37%) with closed loop delivery (P<0.001). Closed loop delivery reduced overnight time spent hypoglycaemic (plasma glucose ≤3.9 mmol/L) by a median 3% (0-20%), P=0.04, and eliminated plasma glucose concentrations below 3.0 mmol/L after midnight. Conclusion These two small crossover trials suggest that closed loop delivery of insulin may improve overnight control of glucose levels and reduce the risk of nocturnal hypoglycaemia in adults with type 1 diabetes. Trial registration ClinicalTrials.gov NCT00910767 and NCT00944619.

Home Use of an Artificial Beta Cell in Type 1 Diabetes

BACKGROUND The feasibility, safety, and efficacy of prolonged use of an artificial beta cell (closed-loop insulin-delivery system) in the home setting have not been established. METHODS In two multicenter, crossover, randomized, controlled studies conducted under free-living home conditions, we compared closed-loop insulin delivery with sensor-augmented pump therapy in 58 patients with type 1 diabetes. The closed-loop system was used day and night by 33 adults and overnight by 25 children and adolescents. Participants used the closed-loop system for a 12-week period and sensor-augmented pump therapy (control) for a similar period. The primary end point was the proportion of time that the glucose level was between 70 mg and 180 mg per deciliter for adults and between 70 mg and 145 mg per deciliter for children and adolescents. RESULTS Among adults, the proportion of time that the glucose level was in the target range was 11.0 percentage points (95% confidence interval [CI], 8.1 to 13.8) greater with the use of the closed-loop system day and night than with control therapy (P<0.001). The mean glucose level was lower during the closed-loop phase than during the control phase (difference, -11 mg per deciliter; 95% CI, -17 to -6; P<0.001), as were the area under the curve for the period when the glucose level was less than 63 mg per deciliter (39% lower; 95% CI, 24 to 51; P<0.001) and the mean glycated hemoglobin level (difference, -0.3%; 95% CI, -0.5 to -0.1; P=0.002). Among children and adolescents, the proportion of time with the nighttime glucose level in the target range was higher during the closed-loop phase than during the control phase (by 24.7 percentage points; 95% CI, 20.6 to 28.7; P<0.001), and the mean nighttime glucose level was lower (difference, -29 mg per deciliter; 95% CI, -39 to -20; P<0.001). The area under the curve for the period in which the day-and-night glucose levels were less than 63 mg per deciliter was lower by 42% (95% CI, 4 to 65; P=0.03). Three severe hypoglycemic episodes occurred during the closed-loop phase when the closed-loop system was not in use. CONCLUSIONS Among patients with type 1 diabetes, 12-week use of a closed-loop system, as compared with sensor-augmented pump therapy, improved glucose control, reduced hypoglycemia, and, in adults, resulted in a lower glycated hemoglobin level. (Funded by the JDRF and others; AP@home04 and APCam08 ClinicalTrials.gov numbers, NCT01961622 and NCT01778348.).

Serotonin 2C Receptor Agonists Improve Type 2 Diabetes via Melanocortin-4 Receptor Signaling Pathways

Summary The burden of type 2 diabetes and its associated premature morbidity and mortality is rapidly growing, and the need for novel efficacious treatments is pressing. We report here that serotonin 2C receptor (5-HT2CR) agonists, typically investigated for their anorectic properties, significantly improve glucose tolerance and reduce plasma insulin in murine models of obesity and type 2 diabetes. Importantly, 5-HT2CR agonist-induced improvements in glucose homeostasis occurred at concentrations of agonist that had no effect on ingestive behavior, energy expenditure, locomotor activity, body weight, or fat mass. We determined that this primary effect on glucose homeostasis requires downstream activation of melanocortin-4 receptors (MC4Rs), but not MC3Rs. These findings suggest that pharmacological targeting of 5-HT2CRs may enhance glucose tolerance independently of alterations in body weight and that this may prove an effective and mechanistically novel strategy in the treatment of type 2 diabetes.

Insulin Pump Therapy With Automated Insulin Suspension in Response to Hypoglycemia: Reduction in nocturnal hypoglycemia in those at greatest risk

OBJECTIVE To evaluate a sensor-augmented insulin pump with a low glucose suspend (LGS) feature that automatically suspends basal insulin delivery for up to 2 h in response to sensor-detected hypoglycemia. RESEARCH DESIGN AND METHODS The LGS feature of the Paradigm Veo insulin pump (Medtronic, Inc., Northridge, CA) was tested for 3 weeks in 31 adults with type 1 diabetes. RESULTS There were 166 episodes of LGS: 66% of daytime LGS episodes were terminated within 10 min, and 20 episodes lasted the maximum 2 h. LGS use was associated with reduced nocturnal duration ≤2.2 mmol/L in those in the highest quartile of nocturnal hypoglycemia at baseline (median 46.2 vs. 1.8 min/day, P = 0.02 [LGS-OFF vs. LGS-ON]). Median sensor glucose was 3.9 mmol/L after 2-h LGS and 8.2 mmol/L at 2 h after basal restart. CONCLUSIONS Use of an insulin pump with LGS was associated with reduced nocturnal hypoglycemia in those at greatest risk and was well accepted by patients.

Altered hierarchy of protective responses against severe hypoglycemia in normal aging in healthy men

OBJECTIVE To investigate the effect of normal aging on the protective responses against hypoglycemia, in view of the fact that type II diabetes is primarily a disease of aging, and its treatment is associated with risk of hypoglycemia with cognitive impairment. RESEARCH DESIGN AND METHODS Plasma glucose was lowered stepwise from 5 to 2.4 mmol/l and restored by manipulation of an infusion of 20% glucose during 220-min intravenous infusion of 1.5 mU · kg−1 · min−1 soluble insulin in 14 men; 7 were aged 60–70 years and the other 7 were 22–26 years. Changes in neurohumoral responses, subjective awareness, and choice reaction time were assessed. RESULTS Hormonal responses were similar in the two groups, but symptoms began earlier in the younger men (at a plasma glucose of 3.6 ± 0.1 vs. 3.0 ± 0.2 mmol/l, P = 0.02) and were more intense (P = 0.03). Four-choice reaction time, a measure of psychomotor coordination, deteriorated earlier in the older men (at a plasma glucose of 3.0 ± 0.1 vs. 2.6 ± 0.1 mmol/l, P = 0.07) and to a greater degree. The difference between the glucose level for subjective awareness of hypoglycemia and the onset of cognitive dysfunction was lost in the older men (0.0 ± 0.2 vs. 0.8 ± 0.1 mmol/l, P < 0.007). CONCLUSIONS Older men are prone to more severe cognitive impairment during hypoglycemia than younger men and are less likely to experience prior warning symptoms if blood glucose falls. This effect of normal aging may contribute to the risk of severe hypoglycemia in older diabetic patients treated with sulfonylureas and insulin.

Home use of closed-loop insulin delivery for overnight glucose control in adults with type 1 diabetes: a 4-week, multicentre, randomised crossover study.

BACKGROUND Closed-loop insulin delivery is a promising option to improve glycaemic control and reduce the risk of hypoglycaemia. We aimed to assess whether overnight home use of automated closed-loop insulin delivery would improve glucose control. METHODS We did this open-label, multicentre, randomised controlled, crossover study between Dec 1, 2012, and Dec 23, 2014, recruiting patients from three centres in the UK. Patients aged 18 years or older with type 1 diabetes were randomly assigned to receive 4 weeks of overnight closed-loop insulin delivery (using a model-predictive control algorithm to direct insulin delivery), then 4 weeks of insulin pump therapy (in which participants used real-time display of continuous glucose monitoring independent of their pumps as control), or vice versa. Allocation to initial treatment group was by computer-generated permuted block randomisation. Each treatment period was separated by a 3-4 week washout period. The primary outcome was time spent in the target glucose range of 3·9-8·0 mmol/L between 0000 h and 0700 h. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01440140. FINDINGS We randomly assigned 25 participants to initial treatment in either the closed-loop group or the control group, patients were later crossed over into the other group; one patient from the closed-loop group withdrew consent after randomisation, and data for 24 patients were analysed. Closed loop was used over a median of 8·3 h (IQR 6·0-9·6) on 555 (86%) of 644 nights. The proportion of time when overnight glucose was in target range was significantly higher during the closed-loop period compared to during the control period (mean difference between groups 13·5%, 95% CI 7·3-19·7; p=0·0002). We noted no severe hypoglycaemic episodes during the control period compared with two episodes during the closed-loop period; these episodes were not related to closed-loop algorithm instructions. INTERPRETATION Unsupervised overnight closed-loop insulin delivery at home is feasible and could improve glucose control in adults with type 1 diabetes. FUNDING Diabetes UK.

An exploratory comparative study of volatile compounds in exhaled breath and emitted by skin using selected ion flow tube mass spectrometry

Selected ion flow tube mass spectrometry (SIFT-MS) has been used to carry out a pilot parallel study on five volunteers to determine changes occurring in several trace compounds present in exhaled breath and emitted from skin into a collection bag surrounding part of the arm, before and after ingesting 75 g of glucose in the fasting state. SIFT-MS enabled real-time quantification of ammonia, methanol, ethanol, propanol, formaldehyde, acetaldehyde, isoprene and acetone. Following glucose ingestion, blood glucose and trace compound levels were measured every 30 min for 2 h. All the above compounds, except formaldehyde, were detected at the expected levels in exhaled breath of all volunteers; all the above compounds, except isoprene, were detected in the collection bag. Ammonia, methanol and ethanol were present at lower levels in the bag than in the breath. The aldehydes were present at higher levels in the bag than in breath. The blood glucose increased to a peak about 1 h post-ingestion, but this change was not obviously correlated with temporal changes in any of the compounds in breath or emitted by skin, except for acetone. The decrease in breath acetone was closely mirrored by skin-emitted acetone in three volunteers. Breath and skin acetone also clearly change with blood glucose and further work may ultimately enable inferences to be drawn of the blood glucose concentration from skin or breath measurements in type 1 diabetes.

Recovery of Hypoglycemia Awareness in Long-Standing Type 1 Diabetes: A Multicenter 2 × 2 Factorial Randomized Controlled Trial Comparing Insulin Pump With Multiple Daily Injections and Continuous With Conventional Glucose Self-Monitoring (HypoCOMPaSS)

OBJECTIVE To determine whether impaired awareness of hypoglycemia (IAH) can be improved and severe hypoglycemia (SH) prevented in type 1 diabetes, we compared an insulin pump (continuous subcutaneous insulin infusion [CSII]) with multiple daily injections (MDIs) and adjuvant real-time continuous glucose monitoring (RT) with conventional self-monitoring of blood glucose (SMBG). RESEARCH DESIGN AND METHODS A 24-week 2 × 2 factorial randomized controlled trial in adults with type 1 diabetes and IAH was conducted. All received comparable education, support, and congruent therapeutic targets aimed at rigorous avoidance of biochemical hypoglycemia without relaxing overall control. Primary end point was between-intervention difference in 24-week hypoglycemia awareness (Gold score). RESULTS A total of 96 participants (mean diabetes duration 29 years) were randomized. Overall, biochemical hypoglycemia (≤3.0 mmol/L) decreased (53 ± 63 to 24 ± 56 min/24 h; P = 0.004 [t test]) without deterioration in HbA1c. Hypoglycemia awareness improved (5.1 ± 1.1 to 4.1 ± 1.6; P = 0.0001 [t test]) with decreased SH (8.9 ± 13.4 to 0.8 ± 1.8 episodes/patient-year; P = 0.0001 [t test]). At 24 weeks, there was no significant difference in awareness comparing CSII with MDI (4.1 ± 1.6 vs. 4.2 ± 1.7; difference 0.1; 95% CI −0.6 to 0.8) and RT with SMBG (4.3 ± 1.6 vs. 4.0 ± 1.7; difference −0.3; 95% CI −1.0 to 0.4). Between-group analyses demonstrated comparable reductions in SH, fear of hypoglycemia, and insulin doses with equivalent HbA1c. Treatment satisfaction was higher with CSII than MDI (32 ± 3 vs. 29 ± 6; P = 0.0003 [t test]), but comparable with SMBG and RT (30 ± 5 vs. 30 ± 5; P = 0.79 [t test]). CONCLUSIONS Hypoglycemia awareness can be improved and recurrent SH prevented in long-standing type 1 diabetes without relaxing HbA1c. Similar biomedical outcomes can be attained with conventional MDI and SMBG regimens compared with CSII/RT, although satisfaction was higher with CSII.

Regional Differences in Cerebral Blood Flow and Glucose Utilization in Diabetic Man: The Effect of Insulin

To determine the effect of insulin on regional cerebral blood flow (rCBF) and glucose metabolism (CMRglu), we performed quantitative dynamic PET scanning of labeled water (H215O) and deoxyglucose (18FDG) using two protocols in 10 diabetic men. In protocol A, to test reproducibility of the technique, insulin was infused at 1.5 mU·kg−1·min−1 twice (n = 5). In protocol B, low (0.3 mU·kg−1·min−1) and high (3 mU·kg−1·min−1) dose insulin was given on separate occasions (n = 5). Euglycemia (5 mmol/L) was maintained by glucose infusion. In protocol A, CMRglu was 6% higher during the first infusion, and catecholamines were also increased, indicating stress. Blood flow was not different. Changing free insulin levels from 20.5 ± 4.8 to 191 ± 44.5 mU/L (P < 0.001, low versus high dose, protocol B) did not alter total or regional CMRglu (whole brain 36.6 ± 4.0 versus 32.8 ± 6.2 μmol·100 g−1·min−1, P = 0.32) or CBF (41.7 ± 5.1 and 45.6 ± 9.7 mL·100 g−1·min−1, P = 0.4) or rCBF. In cerebellum, CMRglu was lower than in cortex and the ratio between rate constants for glucose uptake and phosphorylation (K1 and k3) was reversed. There are regional differences in cerebral metabolic capacity that may explain why cerebral cortex is more sensitive to hypoglycemia than cerebellum. Brain glucose metabolism is not sensitive to insulin concentration within the physiologic range. This suggests that intracerebral insulin receptors have a different role from those in the periphery.

Day and Night Closed-Loop Control in Adults With Type 1 Diabetes: A comparison of two closed-loop algorithms driving continuous subcutaneous insulin infusion versus patient self-management

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.