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

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ClinicalTrials.gov Identifier: NCT03520153
Recruitment Status : Withdrawn (The principal investigator is leaving Yale University and will not be continuing the work at her new institution.)
First Posted : May 9, 2018
Last Update Posted : September 4, 2019
Sponsor:
Information provided by (Responsible Party):
Yale University

Brief Summary:
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).

Condition or disease Intervention/treatment
McCune-Albright Syndrome Fibrous Dysplasia Intraductal Papillary Mucinous Neoplasm Diabetes Mellitus Procedure: Hyperinsulinemic Euglycemic Clamp and 2H20 Procedure: Hyperglycemic Clamp Diagnostic Test: Oral Glucose Tolerance Test

Detailed Description:

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:

  1. Establish the etiology of diabetes in FD/MAS
  2. Increase understanding of the role of IPMNs in pathogenesis of diabetes
  3. Provide critical insights into the pathogenesis of diabetes in FD/MAS

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Study Type : Observational
Actual Enrollment : 0 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Characterization of Diabetes Mellitus in Fibrous Dysplasia/McCune-Albright Syndrome
Estimated Study Start Date : August 7, 2018
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : August 2021


Group/Cohort Intervention/treatment
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.

Procedure: Hyperinsulinemic Euglycemic Clamp and 2H20
Test is used to assess insulin effects on hepatic glucose production.

Procedure: Hyperglycemic Clamp
Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.

Diagnostic Test: Oral Glucose Tolerance 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.

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.

Procedure: Hyperinsulinemic Euglycemic Clamp and 2H20
Test is used to assess insulin effects on hepatic glucose production.

Procedure: Hyperglycemic Clamp
Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.

Diagnostic Test: Oral Glucose Tolerance 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.

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.

Procedure: Hyperinsulinemic Euglycemic Clamp and 2H20
Test is used to assess insulin effects on hepatic glucose production.

Procedure: Hyperglycemic Clamp
Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.

Diagnostic Test: Oral Glucose Tolerance 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.

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.

Procedure: Hyperinsulinemic Euglycemic Clamp and 2H20
Test is used to assess insulin effects on hepatic glucose production.

Procedure: Hyperglycemic Clamp
Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.

Diagnostic Test: Oral Glucose Tolerance 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.

Healthy Controls
Participants will receive the following interventions: Hyperinsulinemic Euglycemic Clamp and 2H20; Hyperglycemic Clamp; and Oral Glucose Tolerance Test.
Procedure: Hyperinsulinemic Euglycemic Clamp and 2H20
Test is used to assess insulin effects on hepatic glucose production.

Procedure: Hyperglycemic Clamp
Test of beta-cell function and insulin secretion. Involves increasing and maintaining blood glucose concentration with IV variable infusion of dextrose.

Diagnostic Test: Oral Glucose Tolerance 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.




Primary Outcome Measures :
  1. Glucose tolerance status [ Time Frame: Baseline ]
    An oral glucose tolerance test will be performed to assess glucose tolerance status to determine if subjects have pre-IGT, IGT or diabetes

  2. Insulin sensitivity [ Time Frame: Baseline ]
    This primary outcome will be obtained from the oral glucose tolerance test

  3. Insulin secretion [ Time Frame: Baseline ]
    This primary outcome will be obtained from the hyperglycemic clamp

  4. Beta cell capacity [ Time Frame: Baseline ]
    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.

  5. Hepatic glucose fluxes (gluconeogenesis and glycogenolysis) [ Time Frame: At least 2 weeks post baseline testing ]
    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


Secondary Outcome Measures :
  1. Islet cell antibodies (ICA), [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  2. Glutamic acid decarboxylase antibodies (GAD65) [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  3. Islet antigen-2 antibodies (IA-2A) [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  4. Zinc transporter 8 (ZnT8) [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  5. Fasting lipid panel [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  6. Fasting incretins [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  7. Prandial incretins [ Time Frame: Baseline ]
    Peripheral blood draw at the end of the oral glucose tolerance test

  8. Free fatty acids [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  9. Growth hormone [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  10. Insulin-like growth factor-1 (IGF-1) [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  11. Renal function (BUN and creatinine) [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  12. Hemoglobin A1c [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  13. Urinalysis [ Time Frame: Baseline ]
    Will be obtained at baseline before the start of oral glucose tolerance test to look for albuminuria

  14. Glycerol [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  15. Leptin [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  16. Adiponectin [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  17. Liver function tests (AST and ALT) [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  18. C-reactive protein (CRP) [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  19. Interleukin 6 (IL-6) [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test

  20. Tumor necrosis factor alpha (TNF-alpha) [ Time Frame: Baseline ]
    Peripheral blood draw before the start of oral glucose tolerance test


Other Outcome Measures:
  1. Maturity-Onset Diabetes of Young (MODY) genetic testing [ Time Frame: Baseline ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
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.
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03520153


Locations
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United States, Connecticut
Yale New Haven Hospital
New Haven, Connecticut, United States, 06510
Sponsors and Collaborators
Yale University
Investigators
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Principal Investigator: Cemre Robinson, MD Yale University

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Responsible Party: Yale University
ClinicalTrials.gov Identifier: NCT03520153     History of Changes
Other Study ID Numbers: 2000022658
First Posted: May 9, 2018    Key Record Dates
Last Update Posted: September 4, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Fibrous Dysplasia of Bone
Fibrous Dysplasia, Polyostotic
Diabetes Mellitus
Syndrome
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Disease
Pathologic Processes
Osteochondrodysplasias
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases