The Effect of Rapid and Slow Glucose Fall on the Subsequent Glucose Production in People With Type 1 Diabetes (RaSlo-19)

In the effort of better understanding the glucose control in people with type 1 diabetes, in-depth insight into the physiology of hepatic glucose production and its influencing factors is essential. Previously, a number of potential influencing factors of hepatic glucose production have been investigated, including insulin-on-board, low carbohydrate diet, preceding ethanol intake, exercise and multiple stimulations of hepatic glucose production. Previous post-hoc analysis of dual-hormone closed-loop systems has indicated that the rate of fall in blood glucose influences the following stimulation of hepatic glucose response. However, the rate of fall in blood glucose is highly related to insulin levels, which may explain those findings. Thus, in this study the investigators want to examine whether the different rates of fall in blood glucose with similar insulin levels on board affect the hepatic glucose response in individuals with type 1 diabetes. In the study, which will be conducted at Steno Diabetes Center Copenhagen, participants will complete two study visits. On each visit, a hypoglycemic clamp technique will be used to lower the blood glucose levels of the participants (using either a rapid or slow decline rate), whereupon hepatic glucose production will be stimulated using low-dose glucagon. The study days are divided into four phases: 1) preparation phase, 2) hyperinsulinemic euglycemic phase (stabilization of blood glucose), 3) hyperinsulinemic hypoglycemic phase (rapid or slow decline in blood glucose) and 4) post-glucagon administration phase. This design will allow the investigators to examine whether differences in hepatic glucose response exist depending on preceding rate of fall in blood glucose. We hypothesize that the rate of fall in blood glucose does not affect the hepatic glucose production.

Study Overview

• Status: Completed
• Conditions: Glucose Metabolism Disorders; Type 1 Diabetes; Blood Glucose, Low
• Intervention / Treatment: Other: Rapid lowering of plasma glucose; Other: Slow lowering of plasma glucose

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Gentofte, Denmark, 2820
    • Steno Diabetes Center Copenhagen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 18-70 years
• Duration of Type 1 Diabetes ≥ 3 years
• Insulin pump use > 6 months

Exclusion Criteria:

• Use of anti-diabetic medicine (other than insulin), corticosteroids or other drugs affecting glucose metabolism during the study period or within 30 days prior to study start
• Allergy or intolerance to lactose or GlucaGen (Novo Nordisk, Bagsværd, DK)
• Use of medications that are known to cause QT interval prolongation
• Females who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods
• Females who have different basal insulin pattern depending on their menstrual cycle
• Inability to understand the individual information and to give informed consent
• Current participation in another clinical trial that, in the judgment of the principle investigator, will compromise the results of the study or the safety of the subject
• Other concomitant medical or psychological condition that according to the investigator's assessment makes the individual unsuitable for study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rapid-Slow; This arm will begin with intervention "rapid" (rapid rate of fall in plasma glucose) for the first study visit and proceed to intervention "slow" (slow rate of fall in plasma glucose) for the second study visit.	Other: Rapid lowering of plasma glucose; Rapid lowering of plasma glucose using hypoglycemic clamp technique; Other: Slow lowering of plasma glucose; Slow lowering of plasma glucose using hypoglycemic clamp technique
Experimental: Slow-Rapid; This arm will begin with intervention "slow" (slow rate of fall in plasma glucose) for the first study visit and proceed to intervention "rapid" (rapid rate of fall in plasma glucose) for the second study visit.	Other: Rapid lowering of plasma glucose; Rapid lowering of plasma glucose using hypoglycemic clamp technique; Other: Slow lowering of plasma glucose; Slow lowering of plasma glucose using hypoglycemic clamp technique

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Positive incremental area under the glucose curve (PI-AUC) (using the plasma glucose concentration before glucagon administration as basal level)	from 0-120 minutes after glucagon administration

Secondary Outcome Measures

Outcome Measure	Time Frame
Total area under the glucose curve (AUC)	from 0-120 minutes after glucagon administration
Peak plasma glucose	from 0-120 minutes after glucagon administration
Incremental plasma glucose peak	from 0-120 minutes after glucagon administration
Time-to-peak plasma glucose	from 0-120 minutes after glucagon administration
Plasma glucose level	120 minutes after glucagon administration
Duration of plasma glucose above 4.0 mmol/l	from 0-120 minutes after glucagon administration
Duration of plasma glucose above baseline	from 0-120 minutes after glucagon administration
Number of subjects who, after reaching a plasma glucose value > 3.9 mmol/l following glucagon administration, maintain a plasma glucose level in the range of 3.9-10 mmol/l	throughout phase 4 (until 120 minutes after glucagon administration)
Number of subjects who, after reaching a PG > 3.9 mmol/l following glucagon administration, maintain a plasma glucose level in the range of 3.9-7.8 mmol/l	throughout phase 4 (until 120 minutes after glucagon administration)
Time from glucagon administration to reaching a plasma glucose level > 3,9 mmol/l	from 0-120 minutes after glucagon administration
Duration of a plasma glucose level in the range of 3.9-10 mmol/l	from 0-120 minutes after glucagon administration
Duration of a plasma glucose level in the range of 3.9-7.8 mmol/l	from 0-120 minutes after glucagon administration
Change in insulin levels (measured as area under the curve)	0-120 minutes after glucagon administration
Change in insulin levels (measured as peak change)	from baseline to 120 minutes after glucagon administration
Change in glucagon levels (measured as area under the curve)	0-120 minutes after glucagon administration
Change in glucagon levels (measured as peak change)	0-120 minutes after glucagon administration
Average changes in Edinburgh Hypoglycemia Scale	measured at baseline, 5 minutes prior to the end of phase 2, 5 minutes prior to the end of phase 3 and 30 and 115 minutes after glucagon administration
Average change in visual analogue scale score for nausea, headache, stomach ache and palpitations	measured at baseline, 5 minutes prior to the end of phase 2, 5 minutes prior to the end of phase 3 and 30 and 115 minutes after glucagon administration
Number of subjects experiencing vomiting	from 0-120 minutes after glucagon administration

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Collaborators: University of Copenhagen

Study record dates

Study Major Dates

• Study Start (Actual): September 12, 2019
• Primary Completion (Actual): January 15, 2020
• Study Completion (Actual): January 15, 2020

Study Registration Dates

• First Submitted: September 11, 2019
• First Submitted That Met QC Criteria: September 20, 2019
• First Posted (Actual): September 23, 2019

Study Record Updates

• Last Update Posted (Actual): June 25, 2020
• Last Update Submitted That Met QC Criteria: June 24, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Hypoglycemia; Type 1 Diabetes; Glucagon; Glucose Metabolism
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Metabolic Diseases; Glucose Metabolism Disorders
• Other Study ID Numbers: H-19034585

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No