The Effect of Rapid and Slow Glucose Fall on the Subsequent Glucose Production in People With Type 1 Diabetes

Steno Diabetes Center Copenhagen10 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

SINGLE

Enrollment

Eligibility

Sex: ALLMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Positive incremental area under the glucose curve (PI-AUC) (using the plasma glucose concentration before glucagon administration as basal level)

Time frame: from 0-120 minutes after glucagon administration

Secondary Outcomes

Total area under the glucose curve (AUC)

Time frame: from 0-120 minutes after glucagon administration

Peak plasma glucose

Time frame: from 0-120 minutes after glucagon administration

Incremental plasma glucose peak

Time frame: from 0-120 minutes after glucagon administration

Time-to-peak plasma glucose

Time frame: from 0-120 minutes after glucagon administration

Plasma glucose level

Time frame: 120 minutes after glucagon administration

Duration of plasma glucose above 4.0 mmol/l

Time frame: from 0-120 minutes after glucagon administration

Duration of plasma glucose above baseline

Time frame: 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

Time frame: 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

Time frame: throughout phase 4 (until 120 minutes after glucagon administration)

Time from glucagon administration to reaching a plasma glucose level > 3,9 mmol/l

Time frame: from 0-120 minutes after glucagon administration

Duration of a plasma glucose level in the range of 3.9-10 mmol/l

Time frame: from 0-120 minutes after glucagon administration

Duration of a plasma glucose level in the range of 3.9-7.8 mmol/l

Time frame: from 0-120 minutes after glucagon administration

Change in insulin levels (measured as area under the curve)

Time frame: 0-120 minutes after glucagon administration

Change in insulin levels (measured as peak change)

Time frame: from baseline to 120 minutes after glucagon administration

Change in glucagon levels (measured as area under the curve)

Time frame: 0-120 minutes after glucagon administration

Change in glucagon levels (measured as peak change)

Time frame: 0-120 minutes after glucagon administration

Average changes in Edinburgh Hypoglycemia Scale

Time frame: 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

Time frame: 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

Time frame: from 0-120 minutes after glucagon administration

The Effect of Rapid and Slow Glucose Fall on the Subsequent Glucose Production in People With Type 1 Diabetes

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes