Characterization of Diabetes Mellitus in Fibrous Dysplasia/McCune-Albright Syndrome

Study Overview
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Brief Summary
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The investigators' objective is to understand the pathogenesis of diabetes mellitus in Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) by: 1) establishing the contributions of insulin resistance versus impaired insulin secretion, 2) investigating presence of excess glucagon signaling by measuring gluconeogenesis and glycogenolysis, and 3) investigating a potential interaction between diabetes and intraductal papillary mucinous neoplasms (IPMNs).

Detailed Description
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Specific project aims include: Aim 1: Determine insulin secretion and sensitivity in subjects with MAS-associated diabetes. Aim 2: Measure gluconeogenesis and glycogenolysis in MAS-associated diabetes to investigate a potential role for excess glucagon signaling. Aim 3: Determine if IPMN development is associated with impairment of insulin secretion prior to development of overt diabetes. The authors expect that this study will: Establish the etiology of diabetes in FD/MAS Increase understanding of the role of IPMNs in pathogenesis of diabetes Provide critical insights into the pathogenesis of diabetes in FD/MAS

Official Title
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Characterization of Diabetes Mellitus in Fibrous Dysplasia/McCune-Albright Syndrome

Conditions
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McCune-Albright Syndrome, Fibrous Dysplasia, Intraductal Papillary Mucinous Neoplasm, Diabetes Mellitus

Intervention / Treatment
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* Procedure: Hyperinsulinemic Euglycemic Clamp and 2H20
* Procedure: Hyperglycemic Clamp
* Diagnostic Test: Oral Glucose Tolerance Test


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) group: Must be diagnosed based on clinical grounds and/or mutation testing on bone and/or affected tissue Control group: Must be at least 18 years old Exclusion Criteria: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) group: Unwilling to fully cooperate with the evaluation Unable to provide informed consent Control group: History of diabetes, insulin resistance, pancreatic disease, pancreatic cysts or amylase/lipase abnormality Use of any type of oral diabetes medications and/or insulin Unable to provide informed consent

Ages Eligible for Study
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Minimum Age: 18 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| FD/MAS with diabetes mellitus<br>Fibrous Dysplasia/McCune-Albright Syndrome with diabetes mellitus. Participants will receive the following interventions: Hyperinsulinemic Euglycemic Clamp and 2H20; Hyperglycemic Clamp; and Oral Glucose Tolerance Test. | Procedure: Hyperinsulinemic Euglycemic Clamp and 2H20<br>* Test is used to assess insulin effects on hepatic glucose production.<br>Procedure: Hyperglycemic Clamp<br>* Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.<br>Diagnostic Test: Oral Glucose Tolerance Test<br>* The oral glucose tolerance test (OGTT) measures the body's ability to use a type of sugar, called glucose, that is the body's main source of energy. An OGTT can be used to diagnose prediabetes and diabetes.<br>|
| FD/MAS without diabetes mellitus<br>Fibrous Dysplasia/McCune-Albright Syndrome without diabetes mellitus. Participants will receive the following interventions: Hyperinsulinemic Euglycemic Clamp and 2H20; Hyperglycemic Clamp; and Oral Glucose Tolerance Test. | Procedure: Hyperinsulinemic Euglycemic Clamp and 2H20<br>* Test is used to assess insulin effects on hepatic glucose production.<br>Procedure: Hyperglycemic Clamp<br>* Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.<br>Diagnostic Test: Oral Glucose Tolerance Test<br>* The oral glucose tolerance test (OGTT) measures the body's ability to use a type of sugar, called glucose, that is the body's main source of energy. An OGTT can be used to diagnose prediabetes and diabetes.<br>|
| FD/MAS without diabetes and without IPMN<br>Fibrous Dysplasia/McCune-Albright Syndrome without diabetes mellitus and without intraductal papillary mucinous neoplasms. Participants will receive the following interventions: Hyperinsulinemic Euglycemic Clamp and 2H20; Hyperglycemic Clamp; and Oral Glucose Tolerance Test. | Procedure: Hyperinsulinemic Euglycemic Clamp and 2H20<br>* Test is used to assess insulin effects on hepatic glucose production.<br>Procedure: Hyperglycemic Clamp<br>* Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.<br>Diagnostic Test: Oral Glucose Tolerance Test<br>* The oral glucose tolerance test (OGTT) measures the body's ability to use a type of sugar, called glucose, that is the body's main source of energy. An OGTT can be used to diagnose prediabetes and diabetes.<br>|
| FD/MAS without diabetes and with IPMN<br>Fibrous Dysplasia/McCune-Albright Syndrome without diabetes mellitus and with intraductal papillary mucinous neoplasms. Participants will receive the following interventions: Hyperinsulinemic Euglycemic Clamp and 2H20; Hyperglycemic Clamp; and Oral Glucose Tolerance Test. | Procedure: Hyperinsulinemic Euglycemic Clamp and 2H20<br>* Test is used to assess insulin effects on hepatic glucose production.<br>Procedure: Hyperglycemic Clamp<br>* Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.<br>Diagnostic Test: Oral Glucose Tolerance Test<br>* The oral glucose tolerance test (OGTT) measures the body's ability to use a type of sugar, called glucose, that is the body's main source of energy. An OGTT can be used to diagnose prediabetes and diabetes.<br>|
| Healthy Controls<br>Participants will receive the following interventions: Hyperinsulinemic Euglycemic Clamp and 2H20; Hyperglycemic Clamp; and Oral Glucose Tolerance Test. | Procedure: Hyperinsulinemic Euglycemic Clamp and 2H20<br>* Test is used to assess insulin effects on hepatic glucose production.<br>Procedure: Hyperglycemic Clamp<br>* Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.<br>Diagnostic Test: Oral Glucose Tolerance Test<br>* The oral glucose tolerance test (OGTT) measures the body's ability to use a type of sugar, called glucose, that is the body's main source of energy. An OGTT can be used to diagnose prediabetes and diabetes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose tolerance status | An oral glucose tolerance test will be performed to assess glucose tolerance status to determine if subjects have pre-IGT, IGT or diabetes | Baseline | 
| Insulin sensitivity | This primary outcome will be obtained from the oral glucose tolerance test | Baseline | 
| Insulin secretion | This primary outcome will be obtained from the hyperglycemic clamp | Baseline | 
| Beta cell capacity | AIRmax stimulation test during the hyperglycemic clamp to ascertain the maximal acute insulin response (AIR) to arginine, which is a measure of functional beta cell capacity. | Baseline | 
| Hepatic glucose fluxes (gluconeogenesis and glycogenolysis) | Measurements from the Hyperinsulinemic Euglycemic Clamp/ 2H20 Study will be used to assess insulin effects on hepatic glucose production and glycerol kinetics isotopes and the deuterium enrichment at carbons 2 and 5 (C2 and C5) of plasma glucose providing information on glucose fluxes | At least 2 weeks post baseline testing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Islet cell antibodies (ICA), | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| Glutamic acid decarboxylase antibodies (GAD65) | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| Islet antigen-2 antibodies (IA-2A) | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| Zinc transporter 8 (ZnT8) | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| Fasting lipid panel | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| Fasting incretins | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| Prandial incretins | Peripheral blood draw at the end of the oral glucose tolerance test | Baseline | 
| Free fatty acids | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| Growth hormone | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| Insulin-like growth factor-1 (IGF-1) | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| Renal function (BUN and creatinine) | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| Hemoglobin A1c | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| Urinalysis | Will be obtained at baseline before the start of oral glucose tolerance test to look for albuminuria | Baseline | 
| Glycerol | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| Leptin | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| Adiponectin | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| Liver function tests (AST and ALT) | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| C-reactive protein (CRP) | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| Interleukin 6 (IL-6) | Peripheral blood draw before the start of oral glucose tolerance test | Baseline | 
| Tumor necrosis factor alpha (TNF-alpha) | Peripheral blood draw before the start of oral glucose tolerance test | Baseline |