Role of Glucagon In Glucose Control in Cystic Fibrosis Related Diabetes

Study Overview
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Brief Summary
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This project is designed to begin to characterize the abnormalities of glucagon secretion in subjects with cystic fibrosis related diabetes along the spectrum of glucose tolerance. Cystic fibrosis patients with normal glucose tolerance as well as cystic fibrosis related diabetes as well as control subjects will undergo an oral glucose tolerance test, mixed meal tolerance test, and one step hypoglycemic clamp. Cystic fibrosis patients will then return 12 months later to undergo repeat mixed meal tolerance test and hypoglycemic clamp test.

Detailed Description
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This project is designed to begin to characterize the abnormalities of glucagon secretion in subjects with cystic fibrosis related diabetes along the spectrum of glucose tolerance. This will be a descriptive, cross-sectional and longitudinal cohort study in a sample of children and young adults with CF and a continuum of glucose tolerance compared to healthy age-matched controls. Cystic fibrosis patients with normal glucose tolerance as well as cystic fibrosis related diabetes as well as control subjects will be admitted to the research unit on three separate occasions to undergo an oral glucose tolerance test, mixed meal tolerance test, and one step hypoglycemic clamp. Cystic fibrosis patients will then return 12 months later to undergo repeat mixed meal tolerance test and hypoglycemic clamp test.

Official Title
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Role of Glucagon in Glucose Control in Cystic Fibrosis Related Diabetes

Conditions
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Cystic Fibrosis, Cystic Fibrosis Related Diabetes

Intervention / Treatment
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* Other: Oral Glucose Tolerance Test
* Other: Mixed Meal Tolerance Test
* Other: Hypoglycemic Clamp


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of CF by clinical or genetic determination Normal glucose tolerance or CFRD Subjects routinely taking systemic or inhaled glucocorticoids on stable regimen are eligible Exclusion Criteria: Subjects with active pulmonary infection requiring supplemental doses of corticosteroids Use of any oral diabetes medications Subjects who are pregnant/lactating Subjects with poor compliance with pancreatic enzyme replacement therapy Control Subjects: Approximately 10 control subjects who are matched for age, gender, are expected to be enrolled in the study. Non-CF subjects must be >12 years old, in good health and not taking any medications or have any medical problems the doctor feels would prevent the subject from completing the study and have BMI between 15-85% for age and gender. Control subjects whose fasting blood glucose is found to be >110 mg/dL will not be continued in the study.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CF with Normal Glucose Tolerance<br>Individuals with CF without cystic fibrosis related diabetes | Other: Oral Glucose Tolerance Test<br>* Subjects will be instructed to fast after midnight the night prior to the study. Subjects will be admitted to the research unit on the morning of the test for placement of blood-drawing IV for frequent sampling. Patients will drink 1.75 gm/kg glucose (Glucola) to a maximum of 75 gm. Venous samples for glucose and c-peptide will be drawn from the IV at 0, 30, 60, 90 and 120 minutes. Subjects will be instructed to eat at least 75 gm carbohydrates daily in the week prior to this test.<br>Other: Mixed Meal Tolerance Test<br>* Subjects will be instructed to fast after midnight the night prior to the study. Subjects will be admitted to the research unit on the morning of the test for placement of blood-drawing IV for frequent sampling. Subjects will consume 6 kcal/kg (6 ml/kg) Boost High Protein Nutritional Energy Drink (Mead-Johnson) over five minutes to a maximum of 360 ml. Venous samples for glucose, glucagon, GLP-1, GIP, and c-peptide will be drawn at -10, 0, 15, 30, 60, 90, 120, 150, 180, 210, and 240 minutes.<br>Other: Hypoglycemic Clamp<br>* All subjects with CF and adult (but not pediatric) controls will undergo one-step hypoglycemic clamp. Subjects will be instructed to fast after midnight the night prior to the study. Subjects will be admitted to the research unit on the morning of the test for placement of blood-drawing IV for frequent sampling and a second IV for infusion of insulin and dextrose.<br>|
| Experimental: Cystic Fibrosis Related Diabetes<br>Individuals with cystic fibrosis and cystic fibrosis related diabetes | Other: Oral Glucose Tolerance Test<br>* Subjects will be instructed to fast after midnight the night prior to the study. Subjects will be admitted to the research unit on the morning of the test for placement of blood-drawing IV for frequent sampling. Patients will drink 1.75 gm/kg glucose (Glucola) to a maximum of 75 gm. Venous samples for glucose and c-peptide will be drawn from the IV at 0, 30, 60, 90 and 120 minutes. Subjects will be instructed to eat at least 75 gm carbohydrates daily in the week prior to this test.<br>Other: Mixed Meal Tolerance Test<br>* Subjects will be instructed to fast after midnight the night prior to the study. Subjects will be admitted to the research unit on the morning of the test for placement of blood-drawing IV for frequent sampling. Subjects will consume 6 kcal/kg (6 ml/kg) Boost High Protein Nutritional Energy Drink (Mead-Johnson) over five minutes to a maximum of 360 ml. Venous samples for glucose, glucagon, GLP-1, GIP, and c-peptide will be drawn at -10, 0, 15, 30, 60, 90, 120, 150, 180, 210, and 240 minutes.<br>Other: Hypoglycemic Clamp<br>* All subjects with CF and adult (but not pediatric) controls will undergo one-step hypoglycemic clamp. Subjects will be instructed to fast after midnight the night prior to the study. Subjects will be admitted to the research unit on the morning of the test for placement of blood-drawing IV for frequent sampling and a second IV for infusion of insulin and dextrose.<br>|
| Active Comparator: Control<br>Age matched control subjects | Other: Oral Glucose Tolerance Test<br>* Subjects will be instructed to fast after midnight the night prior to the study. Subjects will be admitted to the research unit on the morning of the test for placement of blood-drawing IV for frequent sampling. Patients will drink 1.75 gm/kg glucose (Glucola) to a maximum of 75 gm. Venous samples for glucose and c-peptide will be drawn from the IV at 0, 30, 60, 90 and 120 minutes. Subjects will be instructed to eat at least 75 gm carbohydrates daily in the week prior to this test.<br>Other: Mixed Meal Tolerance Test<br>* Subjects will be instructed to fast after midnight the night prior to the study. Subjects will be admitted to the research unit on the morning of the test for placement of blood-drawing IV for frequent sampling. Subjects will consume 6 kcal/kg (6 ml/kg) Boost High Protein Nutritional Energy Drink (Mead-Johnson) over five minutes to a maximum of 360 ml. Venous samples for glucose, glucagon, GLP-1, GIP, and c-peptide will be drawn at -10, 0, 15, 30, 60, 90, 120, 150, 180, 210, and 240 minutes.<br>Other: Hypoglycemic Clamp<br>* All subjects with CF and adult (but not pediatric) controls will undergo one-step hypoglycemic clamp. Subjects will be instructed to fast after midnight the night prior to the study. Subjects will be admitted to the research unit on the morning of the test for placement of blood-drawing IV for frequent sampling and a second IV for infusion of insulin and dextrose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucagon levels | Glucagon levels in response to to a mixed meal stimulus | baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| C-peptide levels | C-peptide levels during oral glucose tolerance test and mixed meal tolerance test | baseline | 
| C-peptide levels | C-peptide levels during oral glucose tolerance test and mixed meal tolerance test | 12 months | 
| Epinephrine levels | Epinephrine and norepinephrine levels during hypoglycemic clamp | baseline | 
| Epinephrine levels | Epinephrine and norepinephrine levels during hypoglycemic clamp | 12 months | 
| Norepinephrine levels | norepinephrine levels during hypoglycemic clamp | baseline | 
| Norepinephrine levels | norepinephrine levels during hypoglycemic clamp | 12 months | 
| Hypoglycemia unawareness scores | Hypoglycemia unawareness scores in subjects during hypoglycemic clamps as measured by the Clarke Hypoglycemia Awareness survey | Baseline | 
| Hypoglycemia unawareness scores | Hypoglycemia unawareness scores in subjects during hypoglycemic clamps as measured by the Clarke Hypoglycemia Awareness survey | 12 months | 
| GLP-1 and GIP levels | GLP-1 and GIP levels in response to mixed meal stimulus | Baseline | 
| GLP-1 and GIP levels | GLP-1 and GIP levels in response to mixed meal stimulus | 12 months | 
| Glucagon levels | Glucagon levels in response to to a mixed meal stimulus and difference from baseline | 12 months |