SUGAR-DIP trial: Oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Introduction In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. Methods The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. Ethics and dissemination The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals

The artificial pancreas, a challenge to research

The first attempts for automated glucose control were made in the seventies of the last century. Nowadays several prototypes for closed-loop glucose control are being tested, most of them in clinical research centers. Systems for automated glucose control, also named ‘artificial pancreas’ or ‘closed-loop system’ consist of three parts; the first part concerns the input or glucose measurement, the second part a mathematical model or control algorithm incorporated in a computer and the last part the output, delivery of glucose regulatory hormones, insulin and sometimes glucagon. For ambulatory human use, the system consists of subcutaneous continuous glucose monitor and subcutaneous administration of insulin and sometimes glucagon. In this thesis it is demonstrated that: - Administration of rapid-acting mealtime insulin 15 minutes before a meal resulted in better postprandial glucose control. - Mechanical occlusion of the infusion set of CSII should lead to an occlusion alert. The time to an alert differed per basal rate, length of the infusion catheter and the device. Furthermore: - A questionnaire was developed to test the intention to use the artificial pancreas. - Heart rate and acceleration as markers for exercise were used. No clear association between heart rate and acceleration and glucose values were seen because the study was too small. - Three different prototypes of a bihormonal reactive closed-loop were tested. Glucose control was feasible by using this closed loop system and significantly lower glucose values were seen in the last 24 hours of the third portable closed-loop prototype

Premeal Injection of Rapid-Acting Insulin Reduces Postprandial Glycemic Excursions in Type 1 Diabetes

OBJECTIVE-To assess the effect of three premeal timings of rapid-acting insulin on post-prandial glucose excursions in type 1 diabetes. RESEARCH DESIGN AND METHODS - Ten subjects participated in a three-way randomized crossover trial. Mean +/- SD age was 45.5 +/- 12.1 years, A1C was 8.55 +/- 1.50%, duration of diabetes was 23.8 +/- 7.8 years, and duration of continuous subcutaneous insulin infusion therapy was 8.5 +/- 6.1 years. Insulin aspart was administered at 30, 15, or 0 min before mealtime. RESULTS - Area under the curve was lower in the -15 stratum (0.41 +/- 0.51 mmol/l/min) than that in the -30 stratum (1.89 +/- 0.72 mmol/l/min, P=0.029) and 0 stratum (2.11 +/- 0.66 mmol/l/min, P=0.030). Maximum glucose excursion was lower in the -15 stratum (4.77 +/- 0.52 mmol/l) than that in the -30 (6.48 +/- 0.76 mmol/l, P=0.025) and 0 stratum (6.93 +/- 0.76 mmol/l, P=0.022). Peak glucose level was lower in the -15 stratum (9.26 +/- 0.72 mmol/l) than that in the -30 stratum (11.74 +/- 0.80 mmol/l, P=0.007) and the 0 stratum (12.29 +/- 0.93, P=0.009). Time spent in the 3.5-10 mmol/l range was higher in the -15 stratum (224.5 +/- 25.0 min) than that in the 0 stratum (90.5 +/- 23.2 min, P=0.001). There was no significant difference in occurrence of glucose levels <3.5 mmol/l between strata (P=0.901). CONCLUSIONS - Administration of rapid-acting insulin analogs 15 min before mealtime results in lower postprandial glucose excursions and more time spent in the 3.5-10.0 mmol/l range, without increased risk of hypoglycemi

Fully Closed Loop Glucose Control With a Bihormonal Artificial Pancreas in Adults With Type 1 Diabetes: An Outpatient, Randomized, Crossover Trial

OBJECTIVE: To demonstrate the performance and safety of a bihormonal (insulin and glucagon) artificial pancreas (AP) in adults with type 1 diabetes. RESEARCH DESIGN AND METHODS: In this outpatient, randomized, crossover trial, 2-week fully closed loop glucose control (AP therapy) was compared with 2-week open loop control (patient's normal insulin pump therapy with a glucose sensor if they had one). RESULTS: A total of 23 patients were included in the analysis. Time in range (70-180 mg/dL [3.9-10 mmol/L]) was significantly higher during closed loop (median 86.6% of time [interquartile range 84.9-88.5]) compared with open loop (53.9% [49.7-67.2]; P < 0.0001). CONCLUSIONS: Compared with insulin pump therapy, the bihormonal AP provided superior glucose control, without meal or exercise announcements, and was safe in adults with type 1 diabetes

Acceptance of the Artificial Pancreas: Comparing the Effect of Technology Readiness, Product Characteristics, and Social Influence Between Invited and Self-Selected Respondents

Background: Psychosocial factors that may affect acceptance of artificial pancreas (AP) systems have been investigated in small sample sizes of highly motivated, self-selected persons with type 1 diabetes (T1DM) with a focus on product characteristics. We aimed to develop a valid survey to investigate the association of technology readiness and social influence with AP acceptance in a larger sample, including both self-selected and invited respondents with T1DM. Methods: An online survey was developed based on established questionnaires. Intention to use the AP was chosen as measure of AP acceptance. T1DM patients who signed up themselves for scientific research into AP systems represented the self-selected group, while patients treated at a teaching hospital represented the invited group. Questionnaire values were compared using independent t-tests and regression analyses. Results: The developed survey showed reliability and validity. The survey was completed by 425 self-selected and 109 invited persons. Intention to use the AP was high in both groups, but was significantly higher among self-selected respondents. In both groups, intention to use the AP was most strongly related to product compatibility, followed by product complexity, technology readiness, and product usefulness among invited respondents; and followed by product usefulness and technology innovativeness among self-selected respondents. Conclusions: Product characteristics have a stronger relationship with AP acceptance than technology readiness, while social influence does not seem to be associated with AP acceptance. As the (strength of) factors differ between self-selected and invited persons, researchers and product developers should be cautious when relying on self-selected persons with T1DM in the design, development, and testing of AP systems

Exercise in Closed-Loop Control: A Major Hurdle

Background: People with type 1 diabetes mellitus (T1DM) are at risk for exercise-induced hypoglycemia. Prevention of such hypoglycemia in a closed-loop setting is a major challenge. Markers for automated detection of physical activity could be heart rate (HR) and body acceleration counts (AC). Correlations between HR, AC, and glucose concentrations before and after moderate intensity exercise were examined in T1DM patients during open-loop control. Method: Eleven T1DM subjects treated with an insulin pump performed moderate intensity exercise of 30 min. Glucose profiles, insulin concentrations, HR, and acceleration were measured. Results: Mean (range) glucose decrease during exercise was 1.4 (0 to 3.3) mmol/liter. The mean increase in HR was 45.2 beats per minutes (15 to 106 bpm). Mean increase in AC was 18,000 (3,000 to 25,000). No correlations were seen between the glucose drop and HR or AC. A trend was observed between the increase in HR and increase in AC. Conclusion: Moderate intensity exercise resulted in increased HR and body AC while it decreased glucose concentrations but, in this real-time setting, no association could be demonstrated between the glucose decrease and increase in HR or AC.

Future acceptance of an artificial pancreas in adults with type 1 diabetes

The purpose of this study was to examine future acceptance of an artificial pancreas (AP) and its perceived usefulness, ease of use, and trust in the device. A questionnaire, based on the Technology Acceptance Model, was developed to examine future acceptance with its determinants and intention to use the AP. One hundred thirty-two patients with diabetes type 1 treated with insulin pump therapy completed the questionnaire. Using factor analysis and reliability analysis, the number of items was reduced from 34 to 15. The response rate was 66%. The subjects had a mean age of 43 years, and 34% were male. Almost 75% had the intention to use an AP. There were high scores on perceived usefulness (expected improvement of glucose control: 35.6% moderately agreed and 53% strongly agreed), perceived ease of use (expectation that the AP can be easily handled: 33.3% moderately agreed and 53.8% strongly agreed), and trust (administration of correct insulin dose and reliability of glucose measurement: 40.9% and 38.9% moderately agreed, whereas 32.6% and 28.2% strongly agreed, respectively). A newly developed questionnaire examining the acceptance of an AP indicated that most patients with continuous subcutaneous insulin infusion-treated type 1 diabetes have the intention to use an AP system and have a positive attitude toward perceived usefulness, ease of use, and trus