Duration of The Honeymoon Phase of Type 1 Diabetes: A Comparison of Insulins Detemir, Glargine and NPH
Duration of The Honeymoon Phase of Type 1 Diabetes: A Comparison of Insulins Detemir, Glargine and NPH
To determine whether using a long-acting insulin analog at the time of diagnosis, instead of
 intermediate-acting insulin, affects the rate of loss of the body's ability to make insulin
 in children with newly diagnosed type 1 diabetes.
BACKGROUND: Type 1 diabetes (or insulin dependent diabetes mellitus (IDDM)) is a very common
 disorder affecting 1/400 persons by the age of 18 years and over 1 million people in the
 United States alone. An autoimmune disorder affecting the endocrine pancreas, it causes, in
 the untreated state, high blood glucose levels and ketosis. Over longer periods of time it
 can contribute to growth failure, malnutrition, and even death. It is responsible for a
 disproportionate percentage of the diabetes associated retinopathy and nephropathy seen in
 adults with diabetes (although type 1 diabetes only accounts for a small percentage of the
 total populace of patients with diabetes). Although insulin allows most children with this
 disease to grow and develop normally, it will not provide a permanent cure.

 Many techniques have been studied to attempt to prevent the onset or progression of the
 autoimmune destruction of islets associated with type 1 diabetes, including a variety of
 immunomodulatory drugs, nicotinamide and small doses of insulin itself. Thus far nothing has
 proven completely successful. Some investigators have suggested that intensive control early
 in the disease process will slow the progression of the disease, but these results remain
 controversial. Ultimately, any treatment aimed at the prevention or cure of diabetes must
 have as its goal the preservation of the insulin secretory capacity of the pancreas.

 In recent years, a number of insulin analogs have been developed which have different
 time-action profiles in humans. Currently, all children diagnosed with type 1 diabetes are
 placed on a combination of a long-acting insulin (such as insulins detemir or glargine) or a
 moderate-acting insulin (such as NPH), and a short acting insulin (such as lispro, aspart or
 regular insulin) as soon as they demonstrate they are able to resume a regular diet after
 their initial presentation. Each of the long- and moderate-acting insulins are given once or
 twice daily and the short-acting insulins at least twice and up to 4-5 times daily.

 Normally, the pancreas secretes a basal level of insulin at rest, and then when challenged
 with a carbohydrate load, responds with an acute surge of insulin release. Intuitively, one
 might surmise that a pharmaceutical preparation that more closely mimics the normal
 physiological profile of the pancreas might be beneficial over the long term to pancreatic
 beta cell function. Levemir (insulin detemir) and Lantus (insulin glargine) are two
 relatively new insulin analogs known for their consistent and reproducible absorption
 profiles and steady time-action profiles. In comparison, insulin NPH is a product that had
 been the standard of care for children with diabetes for many years until the availability of
 the newer analogs, but is characterized by a peaking profile (with onset of action 2-4 hours
 after injection and peak effect 8-10 hours after injection). The combination of an insulin
 which mimics the basal insulin production of a pancreas at rest (i.e., glargine or detemir),
 together with a short-acting insulin with meals which mimics the bolus production of insulin
 generated in response to a carbohydrate load (regular, lispro or aspart), might allow for
 smoother blood glucose trends when compared to a combination of two "peaking" insulins (such
 as NPH and aspart).

 In addition to the therapeutic benefit of better blood glucose control, we hypothesize that
 the maintenance of a steady baseline level of insulin with use of the newer insulin analogs
 may contribute to a longer period of pancreatic rest in the child newly diagnosed with
 diabetes. Many children with diabetes enter what is known as a "honeymoon phase" shortly
 after their diagnosis, which is characterized by relative ease of blood glucose control and
 relatively lower insulin requirements. This period represents a time during which the body is
 still able to make some insulin on its own.

 We have retrospective data to suggest that children started on insulin glargine at diagnosis
 do, in fact, achieve significantly better glycemic control than age-matched children started
 on insulin NPH. This was assessed by HgbA1c measurements, which averaged a full percentage
 point lower at their 9 month visit for the glargine treated patients (Figure 1). A failure to
 see a significant improvement in patients switched from NPH to glargine well after diagnosis
 suggests that there is something to the initiation of treatment with glargine: perhaps the
 reason for improved control is a prolonged honeymoon period, in which the preservation of a
 small amount of innate insulin production allows for easier disease management.

 What effect, if any, our current treatment modalities - specifically the choice of the longer
 acting insulin - have on the preservation of innate insulin secretory capacity remains
 unknown. If treatments aimed at the prevention or cure of diabetes are to maximize this
 secretory capacity, optimizing the insulin regimen may be imperative, and lack of attention
 to this parameter may confound trials of other interventions.

 CONCISE SUMMARY OF PROJECT: Children aged 6-18 years who have been diagnosed with type 1
 diabetes within the past 2 weeks will be randomized and placed in one of three treatment
 groups. 24 children will be randomized to each of three treatment arms differentiated by the
 choice of the longer-acting insulin (i.e. either detemir, glargine or NPH). All children will
 be treated with insulin aspart as the short-acting insulin to be used in combination with
 their longer-acting insulin. The insulin secretory capacity of the pancreas will be measured
 and compared between the groups by measuring C-peptide levels following a mixed meal
 tolerance test (using Boost) at 1, 6 and 12 months after diagnosis. Current standard of care
 as practiced at our institution is for these children to be seen every 3 months by a
 physician or advanced practice nurse at Children's Medical Center, Dallas. At each of these
 visits the children will have HgbA1c values measured and total daily insulin doses recorded.
 These will be secondary outcome measures for the purpose of this study.
Inclusion Criteria:

 -  Newly diagnosed type 1 diabetes within 1 week of diagnosis

 -  Age 6 - 18 years

 -  Care provided at Children's Medical Center, Dallas

 Exclusion Criteria:

 -  Actual treatment with oral drugs influencing beta cell function or blood glucose
 levels (e.g. oral hypoglycemic agents)

 -  Actual treatment with drugs influencing insulin sensitivity (e.g. Metformin, or
 systemic steroids)

 -  Significant concomitant disease likely to interfere with glucose metabolism (children
 with active bacterial infections at the time of diagnosis must be cured prior to
 entry)

 -  Expected poor compliance

 -  Pregnancy

 -  Any other condition that by the judgement of the investigator may be potentially
 harmful to the patients