Dawn Phenomenon, Type 1 Diabetes
Conditions
Keywords
glucose, cortisol, growth hormone, glucagon, insulin
Brief summary
1. To investigate the effect of insulin glargine (Lantus™) vs NPH insulin regarding glycemic control during the early AM (dawn phenomenon) in individuals with type 1 diabetes. 2. To measure hormones implicated in the pathogenesis of the dawn phenomenon in individuals with type 1 diabetes.
Detailed description
Title: COMPARISON of LANTUS and NPH INSULIN IN THE DAWN PHENOMENON I. Background and Significance Diabetes mellitus affects greater than 6% of the population, with type 2 more prevalent than type 1. For individuals with type 1 diabetes, the challenge has been to replicate insulin secretion of the healthy pancreas to maintain blood glucose as close to the non-diabetic range as possible. Insulin regimes using insulins with varied activity profiles (multiple daily injections or MDI) and continuous subcutaneous insulin infusion (CSII) have been somewhat successful in mimicking normal pancreatic function (1, 2). For individuals with type 1 diabetes, the benefits of near-normal, long-term glycemic control in delaying the development and slowing the progression of long-term complications was demonstrated in the Diabetes Control and Complications Trial (3). Intensive insulin therapy to achieve near-normal glycemic control has been limited by a three-fold increase in episodes of hypoglycemia (3, 4). Insulin analogs that provide more stable physiologic insulin levels have led to the development of newer MDI regimes (5). Glargine (Lantus) is a long-acting recombinant human insulin analog demonstrated to provide a continuous, smooth supply of insulin with no pronounced peak over a 24-hour period (6). An increase in blood glucose in type 1 and type 2 diabetics, and an increase in insulin secretion to maintain normoglycemia in non-diabetics, was documented in several studies in the 1980s (15-17). This physiological requirement for more insulin delivery (or secretion) in the early (4:00-6:00 AM) hours was termed the dawn phenomenon. The mechanism for the dawn phenomenon was thought to be the overnight increase in growth hormone section, rather than diurnal glucocorticoids (16, 18, 19). Most intensive treatment regimens of the 1980-90's, with MDI or CSII, were designed to provide more insulin in the 4:00-7:00 AM period to cope with the dawn phenomenon which cannot be be achieved with glargine (20-21). Continuous monitoring of blood glucose has revealed that individuals treated with CSII had significantly better glycemic control than glargine treated individuals (22). Whether the dawn phenomenon, with increased area under the curve blood glucose levels during the dawn period is limiting the effectiveness of regimens with glargine is of crucial importance.
Interventions
DRUGLantus (glargine)
Described in Arm Description
Sponsors
Sanofi
Massachusetts General Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent obtained prior to performing screening evaluations. * Male or female, 18 yrs or older. * Diagnosis of type 1 diabetes made 5 years prior to screening visit. * A1C \> 6.0% and 9.0% at screening visit. * Body Mass Index (BMI) 35 kg/m2 at screening visit. * Documented undetectable C-Peptide * Ability to follow instructions for Continuous Glucose Monitoring System (CGMS). * Multiple daily injection participants on at least 3 injections per day. May be treated with NPH or glargine.
Exclusion criteria
* Pregnant or lactating females, or females planning to become pregnant during the study or not using an acceptable method of contraception. Females of childbearing potential must have a negative pregnancy test at Visit 3 and Visit 5. Females who become pregnant during the study will be discontinued. * Type 2 diabetes. * Two or more severe hypoglycemic episodes (requiring assistance) within six months of Screening. * Drugs known to affect glycemia (eg. steroids, beta blockers) or conditions that are likely to require steroid therapy or cause metabolic instability in the next 6 months. * History of allergy or intolerance to NPH or glargine. * History of hypoglycemia unawareness i.e. no warning symptoms accompanying low (\<50 mg/dl) blood glucose levels. * Unable and/or unlikely to comprehend and/or follow the study protocol (including self blood glucose monitoring, CGMS). * Currently using an insulin pump. * Pituitary disorder (Acromegaly, Cushing's, Hypothyroidism etc.) or tumor. * Two or more severe hypoglycemic episodes (requiring assistance) within six months of Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Blood Glucose Area Under the Curve (AUC) | Overnight | Cumulative sum of repeatedly measured blood glucose values (mg/dl) beginning at 22:00, then hourly till 08:00. Participants were monitored during two overnight sampling periods. One overnight was while the participant was on neutral protamine Hagedorn (NPH) insulin as the long acting insulin; the other overnight was glargine (Lantus) insulin as the the long acting insulin. |
| Blood Glucose | Overnight | Average value of repeatedly measured absolute values beginning at 22:00, then hourly till 08:00. Participants were monitored during two overnight sampling periods. One overnight was while the participant was on NPH insulin as the long acting insulin; the other overnight was glargine(Lantus) insulin as the the long acting insulin. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin Dose | Overnight | NPH or glargine (Lantus) was given at 22:00 to provide blood glucose coverage during the overnight hours. |
| Cortisol | Overnight | Mean cortisol nmol/l during NPH or glargine (Lantus) overnight visit. Hourly cortisol was determined from 22:00 to 8:00. |
| Glucagon | Overnight | Mean glucagon mcg/l during NPH or glargine (Lantus) overnight visit. Hourly glucagon was determined from 22:00 to 8:00. |
| Growth Hormone | Overnight | Mean growth hormone ug/l during NPH or glargine (Lantus) overnight visit. Hourly growth hormone was determined from 22:00 to 8:00. |
Countries
United States
Participant flow
Recruitment details
Recruitment began in January 2007 and ended on January 2011. Individuals were recruited from the MGH Diabetes Center, MGH internal Research Broadcast for research volunteers. Advertisements were placed in the local metro and flyers posted around the institution, altho no participants contacted study staff from these latter advertisemens.
Pre-assignment details
200 participants were recruited; 43 were phone screened; 27 signed consent forms, 12 exluded (3 did not meet inclusion criteria, 7 no longer wanted to participate and 3 lost to follow-up).
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Lantus insulin once per day and blood glucose outcomes was studied during the first overnight visit; then the subject was discharged on NPH on twice per day NPH. Upon the second overnight visit, NPH insulin and blood glucose outcomes was studied.
If the participant entered the study on NPH, NPH insulin given twice per day and blood glucose outcomes was studied during the first overnight visit; then the subject was discharged on once per day Lantus. Upon the second overnight visit, Lantus insulin and blood glucose outcomes was studied | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (3-4 Weeks) | Did not meet entrance criteria | 2 | 1 |
| First Intervention (3-4 Weeks) | Lost to Follow-up | 1 | 1 |
| First Intervention (3-4 Weeks) | Withdrawal by Subject | 7 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants |
| Age, Continuous | 46.5 years STANDARD_DEVIATION 12.5 |
| Body Mass Index (BMI) | 25.8 kg/m2 STANDARD_DEVIATION 3.3 |
| C-peptide | 0.1 nmole/L STANDARD_DEVIATION 0 |
| Diabetes duration | 22.8 years STANDARD_DEVIATION 10.2 |
| Fast Acting Insulin Humalog | 8 participants |
| Fast Acting Insulin Novolog | 6 participants |
| Fast Acting Insulin Regular | 1 participants |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 7 Participants |
| Type of Insulin at First Overnight Visit Lantus (glargine) | 10 participants |
| Type of Insulin at First Overnight Visit NPH | 5 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 15 |
Outcome results
Primary
Blood Glucose
Average value of repeatedly measured absolute values beginning at 22:00, then hourly till 08:00. Participants were monitored during two overnight sampling periods. One overnight was while the participant was on NPH insulin as the long acting insulin; the other overnight was glargine(Lantus) insulin as the the long acting insulin.
Time frame: Overnight
Population: All participants received either NPH or glargine (Lantus) on separate overnight sampling periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glargine (Lantus) Insulin | Blood Glucose | 9.6 mmol/l | Standard Deviation 0.3 |
| NPH Insulin | Blood Glucose | 7.9 mmol/l | Standard Deviation 3.7 |
p-value: <0.05t-test, 2 sided
Primary
Blood Glucose Area Under the Curve (AUC)
Cumulative sum of repeatedly measured blood glucose values (mg/dl) beginning at 22:00, then hourly till 08:00. Participants were monitored during two overnight sampling periods. One overnight was while the participant was on neutral protamine Hagedorn (NPH) insulin as the long acting insulin; the other overnight was glargine (Lantus) insulin as the the long acting insulin.
Time frame: Overnight
Population: All participants received either NPH or glargine (Lantus) on separate overnight sampling periods.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glargine (Lantus) Insulin | Blood Glucose Area Under the Curve (AUC) | 1673.33 mg*10hr/dL | Standard Deviation 760.7 |
| NPH Insulin | Blood Glucose Area Under the Curve (AUC) | 1395 mg*10hr/dL | Standard Deviation 384.9 |
p-value: <0.0595% CI: [-75.9, 631.6]t-test, 2 sided
Secondary
Cortisol
Mean cortisol nmol/l during NPH or glargine (Lantus) overnight visit. Hourly cortisol was determined from 22:00 to 8:00.
Time frame: Overnight
Population: Participants completing both overnight visits were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glargine (Lantus) Insulin | Cortisol | 380.45 nmol/l | Standard Deviation 143.48 |
| NPH Insulin | Cortisol | 388.61 nmol/l | Standard Deviation 122.1 |
Secondary
Glucagon
Mean glucagon mcg/l during NPH or glargine (Lantus) overnight visit. Hourly glucagon was determined from 22:00 to 8:00.
Time frame: Overnight
Population: Participants completing both overnight visits were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glargine (Lantus) Insulin | Glucagon | 58.8 mcg/l | Standard Deviation 19 |
| NPH Insulin | Glucagon | 54.3 mcg/l | Standard Deviation 19 |
Secondary
Growth Hormone
Mean growth hormone ug/l during NPH or glargine (Lantus) overnight visit. Hourly growth hormone was determined from 22:00 to 8:00.
Time frame: Overnight
Population: Participants completing both overnight visits were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glargine (Lantus) Insulin | Growth Hormone | 1.09 ug/l | Standard Deviation 1.61 |
| NPH Insulin | Growth Hormone | 1.27 ug/l | Standard Deviation 2.3 |
Secondary
Insulin Dose
NPH or glargine (Lantus) was given at 22:00 to provide blood glucose coverage during the overnight hours.
Time frame: Overnight
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Glargine (Lantus) Insulin | Insulin Dose | 20.2 units | Standard Deviation 11.7 |
| NPH Insulin | Insulin Dose | 20.7 units | Standard Deviation 10 |
p-value: <0.05t-test, 2 sided