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The principal investigator is leaving Yale University and will not be continuing the work at her new institution.
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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).
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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| FD/MAS with diabetes mellitus | 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. |
| |
| FD/MAS without diabetes mellitus | 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. |
| |
| FD/MAS without diabetes and without IPMN | 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. |
| |
| FD/MAS without diabetes and with IPMN | 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. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Hyperinsulinemic Euglycemic Clamp and 2H20 | Procedure | Test is used to assess insulin effects on hepatic glucose production. |
|
| 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 |
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Maturity-Onset Diabetes of Young (MODY) genetic testing | The test detects deletions in the HNF4A, GCK, HNF1A, HNF1B genes and mutations in the HNF4A, GCK, HNF1A, HNF1B and IPF1. Will be obtained at baseline before the start of oral glucose tolerance test only in those subjects with an existing diagnosis of diabetes mellitus. | Baseline |
Inclusion Criteria:
Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) group:
Control group:
Exclusion Criteria:
Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) group:
Control group:
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The study population will include adult Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) subjects (> 18 years-old) with diabetes, without diabetes, with and without intraductal papillary mucinous neoplasms (IPMNs). FD/MAS subjects, who are enrolled in the National Institutes of Health (NIH) Natural History Study and who have already been screened with an MRI of the abdomen or magnetic resonance cholangiopancreatography for pancreatic lesions, will be invited to participate in the current study based on an existing diagnosis of diabetes and/or IPMNs. In addition, seven adult healthy volunteers will be screened and recruited by the investigator from Yale Center for Clinical Investigation (YCCI) Recruitment Database.
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| Name | Affiliation | Role |
|---|---|---|
| Cemre Robinson, MD | Yale University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Yale New Haven Hospital | New Haven | Connecticut | 06510 | United States |
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| Healthy Controls | Participants will receive the following interventions: Hyperinsulinemic Euglycemic Clamp and 2H20; Hyperglycemic Clamp; and Oral Glucose Tolerance Test. |
|
| Hyperglycemic Clamp | Procedure | Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose. |
|
| Oral Glucose Tolerance Test | Diagnostic Test | 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. |
|
| 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 |
| ID | Term |
|---|---|
| D005359 | Fibrous Dysplasia, Polyostotic |
| D005357 | Fibrous Dysplasia of Bone |
| D003920 | Diabetes Mellitus |
| ID | Term |
|---|---|
| D010009 | Osteochondrodysplasias |
| D001848 | Bone Diseases, Developmental |
| D001847 | Bone Diseases |
| D009140 | Musculoskeletal Diseases |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D005951 | Glucose Tolerance Test |
| ID | Term |
|---|---|
| D001774 | Blood Chemical Analysis |
| D019963 | Clinical Chemistry Tests |
| D019411 | Clinical Laboratory Techniques |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D003940 | Diagnostic Techniques, Endocrine |
| D008919 | Investigative Techniques |
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