Comparison of Lantus and Neutral Protamine Hagedorn (NPH) Insulin in the Dawn Phenomenon
Comparison of Lantus and Neutral Protamine Hagedorn (NPH) Insulin in the Dawn Phenomenon
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.
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.
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.