Diabetes Mellitus, Type 1
Conditions
Brief summary
The researchers plan to test the following hypothesis: A good level of glucose control in Type 1 Diabetes Mellitus (T1DM) is dependent on two levels of feedback from the body: 1. the transport of insulin through small blood vessels: suggesting that hypoglycemia leads to increased insulin sensitivity which then causes recurrent hypoglycemia; 2. the endocrine level, defined as insulin-glucose interaction and hormonal counter-regulation. The researchers plan to investigate the relationships between hypoglycemia, insulin transport, and counter-regulation. This study will ultimately lead to a better understanding of risk for recurrent hypoglycemia.
Interventions
PROCEDUREHyperinsulinemic, euglycemic and hypoglycemic clamp
At 21:30h, an overnight insulin infusion was titrated to control the subjects' BG overnight between 100 and 150mg/dL by blood sampling for plasma glucose via a YSI analyzer every 30min and adjusting the rate of insulin infusion as needed. At the beginning of the clamp, the overnight insulin was replaced by an insulin infusion via a Harvard pump given as a 20mU/kg priming over a 10-min period, followed by a constant rate delivery of 1mU/kg/min until the end of the clamp. Blood was sampled for plasma glucose, and glucose was clamped at basal levels for the euglycemic control period of 150min via a variable-rate infusion of 20% dextrose. Then the glucose concentration was lowered at a rate of 1mg/dL/min to a minimum of 50mg/dL, where it was held constant for 30min. Finally, the glucose concentration was increased at a rate of 1mg/dL/min to 90mg/dL, where it was held for an additional 30min. Blood was sampled for epinephrine during euglycemia, hypoglycemia, and recovery.
Sponsors
University of Virginia
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participated in and satisfied all of the inclusion criteria of NCT00315939 * 18 years of age or older * Have Type 1 Diabetes Mellitus defined by American Diabetes Association criteria or judgment of physician * Since our major goal is the investigation of hypoglycemia, we will preferentially recruit patients with a history of severe hypoglycemia/moderate hypoglycemia anticipating that approximately (\ ) half of the recruited subjects will have had two or more severe or moderate hypoglycemia episodes in the past 12 months
Exclusion criteria
* Age \< 18 * Pregnancy * Use of oral steroids * Hematocrit \< 36% (females); \< 38% (males) * Symptomatic heart disease (e.g., history of myocardial infarction, history of coronary bypass or stenting procedure, angina, episode of chest pain of cardiac etiology with documented EKG changes, positive stress test or catheterization with coronary blockages \> 50%) * History of an ischemic cerebrovascular event * Active substance abuse * Psychosis * Mental retardation * Severe depression
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Epinephrine Response (LBGI Groups) | 285 min (time of clamp) | Mean maximum epinephrine response during induced hypoglycemia is the average of subjects' maximum concentration of all epinephrine measurements taken at plasma glucose level lower than 70mg/dL. Low blood glucose index (LBGI) is a metric to calculate the risk for hypoglycemia based on frequency and extent of past events based on SMBG readings. In studies, the LBGI typically accounted for 40-55% of the variance of future significant hypoglycemia in the subsequent 3-6 months. The LBGI has established risk categories: Low Risk, LBGI \< 2.5; Moderate Risk, 2.5 \< LBGI \< 5; and High Risk, LBGI \> 5, indicating an over 10-fold increase in future severe hypoglycemia from the lowest to the highest risk category. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Epinephrine Response (ADRR Groups) | 285 min (time of clamp) | Mean maximum epinephrine response during induced hypoglycemia is the average of subjects' maximum concentration of all epinephrine measurements taken at plasma glucose level lower than 70mg/dL. Average Daily Risk Range (ADRR) is associated with glycemic variability and risk of both hyper- and hypoglycemia. Low Risk, ADRR \< 20; Moderate Risk, 20 \< ADRR \< 40; and High Risk,ADRR \> 40. |
Countries
United States
Participant flow
Recruitment details
Recruitment period: 2/2006-5/2009. Recruitment included outpatients at UVA clinics, former research subjects, and local advertising. All subjects ≥18 years of age and had type 1 diabetes defined by American Diabetes Association criteria or judgment of the study endocrinologist after review of the clinical history.
Participants by arm
| Arm | Count |
|---|---|
| Adults With T1DM From Subjects Subjects with type 1 diabetes performed self-monitoring of blood glucose (SMBG) for a month, followed by an inpatient hyperinsulinemic euglycemic and hypoglycemic clamp. SMBG field data were used to calculate measures of glucose variability and risk of hypoglycemia, while the clamp procedure was used to evaluate insulin sensitivity and epinephrine response during induced hypoglycemia. | 34 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 4 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Adults With T1DM From Subjects |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 34 Participants |
| Age, Continuous | 37 years STANDARD_DEVIATION 2.1 |
| Glycosylated hembglobin (HbA1c) | 7.6 percent STANDARD_DEVIATION 0.21 |
| Region of Enrollment United States | 34 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 8 / 34 |
| serious Total, serious adverse events | 3 / 34 |
Outcome results
Primary
Maximum Epinephrine Response (LBGI Groups)
Mean maximum epinephrine response during induced hypoglycemia is the average of subjects' maximum concentration of all epinephrine measurements taken at plasma glucose level lower than 70mg/dL. Low blood glucose index (LBGI) is a metric to calculate the risk for hypoglycemia based on frequency and extent of past events based on SMBG readings. In studies, the LBGI typically accounted for 40-55% of the variance of future significant hypoglycemia in the subsequent 3-6 months. The LBGI has established risk categories: Low Risk, LBGI \< 2.5; Moderate Risk, 2.5 \< LBGI \< 5; and High Risk, LBGI \> 5, indicating an over 10-fold increase in future severe hypoglycemia from the lowest to the highest risk category.
Time frame: 285 min (time of clamp)
Population: 3 participants did not have adequate epinephrine data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Adults With T1DM From Subjects | Maximum Epinephrine Response (LBGI Groups) | LBGI < 2.5 | 495 pg/ml | Standard Deviation 60 |
| Adults With T1DM From Subjects | Maximum Epinephrine Response (LBGI Groups) | LBGI >= 2.5 | 217 pg/ml | Standard Deviation 40 |
Secondary
Maximum Epinephrine Response (ADRR Groups)
Mean maximum epinephrine response during induced hypoglycemia is the average of subjects' maximum concentration of all epinephrine measurements taken at plasma glucose level lower than 70mg/dL. Average Daily Risk Range (ADRR) is associated with glycemic variability and risk of both hyper- and hypoglycemia. Low Risk, ADRR \< 20; Moderate Risk, 20 \< ADRR \< 40; and High Risk,ADRR \> 40.
Time frame: 285 min (time of clamp)
Population: 3 participants did not have enough epinephrine data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Adults With T1DM From Subjects | Maximum Epinephrine Response (ADRR Groups) | ADRR < 40 | 417 pg/ml | Standard Deviation 45 |
| Adults With T1DM From Subjects | Maximum Epinephrine Response (ADRR Groups) | ADRR >= 40 | 167 pg/ml | Standard Deviation 45 |