The Role of Amylin and Glucagon in T1DM
The Role of Amylin and Glucagon in T1DM
The purpose of this study is to see if giving pramlintide and insulin before a meal would
 lower high blood sugar and if a glucagon (a naturally made hormone in the body but reduced in
 diabetes and its role is in prevention of low blood sugar) shot given in the late "after
 meal" time would prevent low blood sugar. The studies outlined in this proposal might help in
 developing new treatment options to target "after meal" high blood sugar and before meal low
 blood sugar in children. This would possibly help improve overall blood sugar control and
 prevent the long-term complications of diabetes.
Objective: To develop a new treatment approach in the prevention of hypo and hyperglycemia in
 children with type 1diabetes.

 Background/Rationale: The diabetes control and complications trial (DCCT) showed that
 improving blood sugar control for individuals with type 1 diabetes (T1DM) stopped or delayed
 the onset of long-term complications. As a result of the study, intensive management to
 control blood sugar and glycosylated hemoglobin as near to normal as safely as possible is
 advocated. However, hypoglycemia was increased 3 fold in the DCCT study and is the major
 limiting factor in gaining "tight" control of blood sugar in T1DM.

 Description of Project: In health individuals, "after meal" blood sugar level is very
 carefully controlled. Insulin (the hormone that lowers blood sugar) and glucagon (the hormone
 that raises blood sugar) play a key role in maintaining this careful balance. Recently we
 understand that a hormone called amylin also contributes to this careful after meal blood
 glucose balance. Amylin in the immediate after meal period works by reducing glucagon, which
 in turn reduces the liver releasing stored sugar into the blood stream.

 In T1DM, there is the lack of insulin and failure of glucagon suppression leading to
 hyperglycemia immediately following when food is eaten. Also, glucagon is not regulated
 correctly after a meal. The glucagon normally produced by the body does not increase in
 response to hypoglycemia thus interfering with the delicate balance between glucose
 production and glucose used. Therefore, it is difficult to get normal blood sugar when
 someone has type1 diabetes.

 Currently, the treatment for mild to moderate hypoglycemia causing a sudden feeling of racing
 heart, feeling sweaty, weak or hungry is to eat or drink carbohydrate in the awake person.
 Severe hypoglycemia (unconsciousness due to low blood sugar) is treated with a glucagon shot.
 Unfortunately, there are no treatments to prevent mild or severe hypoglycemia.

 The purpose of this study is to see if giving pramlintide (manmade amylin) and insulin before
 a meal would lower hyperglycemia and if a glucagon shot given in the late "after meal" time
 would prevent hypoglycemia and allow the blood sugar levels to improve in people with T1DM.
 The studies outlined in this proposal might help in developing new treatment options to
 target "after meal" hyperglycemia high blood glucose and before meal hypoglycemia in
 children. This study for the first time will investigate the role of glucagon in the
 causation of hyperglycemia and its role in the prevention of hypoglycemia.

 Relevance to Type 1 diabetes: Using naturally occurring hormones that are dysregulated or
 deficient in T1DM we wish to restore normal glucose concentration in T1DM. Such treatment if
 successful would be a major breakthrough in the prevention of hyper and hypoglycemia and in
 decreasing both short and long-term complications associated with T1DM.
Inclusion Criteria:

 1. Age >12 years < 19 years

 2. Have diabetes for at least 2 years and in good control (HbA1C < 8%).

 3. Be on continuous subcutaneous insulin infusion using an insulin pump.

 4. Subjects must be otherwise healthy except for their T1DM and treated for
 hypothyroidism.

 5. Menstruating women must have negative pregnancy test.

 6. Hemoglobin equal to or > than 12 g/dL before each study.

 7. Weight more than 44 kg.

 Exclusion Criteria:

 1. Age >18 or < 12 y at the time of study

 2. Any chronic disease (leukemia, asthma, inflammatory bowel disease, cystic fibrosis,
 juvenile rheumatoid arthritis, etc that directly, or as a result of treatment,
 directly or indirectly affect glucose homeostasis

 3. Hemoglobin less than 12 g/dl (If before any of the studies the hemoglobin is lower
 than 12 g/dl, subjects will be excluded from further studies)

 4. Lack of a supportive family environment

 5. Positive pregnancy test in menstruating young women

 6. Evidence or history of chemical abuse

 7. Hgb A1c >8.0 % in a diabetic subject

 8. BMI > 90 % tile for age or < 10 % tile for age

 9. Allergy to local anesthetics (ELAMAX Cream)

 10. Weight less than 44 kg

 11. Children of staff members