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

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).

Study Overview

• Status: Withdrawn
• Conditions: Diabetes Mellitus; Fibrous Dysplasia; McCune-Albright Syndrome; Intraductal Papillary Mucinous Neoplasm
• Intervention / Treatment: Diagnostic test: Oral Glucose Tolerance Test; Procedure: Hyperinsulinemic Euglycemic Clamp and 2H20; Procedure: Hyperglycemic Clamp

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

• Study Type: Observational

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale New Haven Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

5

Cohorts and Interventions

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.	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.; 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.
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.	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.; 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.
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.	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.; 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.
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.	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.; 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.
Healthy Controls; Participants will receive the following interventions: Hyperinsulinemic Euglycemic Clamp and 2H20; Hyperglycemic Clamp; and Oral Glucose Tolerance Test.	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.; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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

Other Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Yale University
• Investigators: Principal Investigator: Cemre Robinson, MD, Yale University

Study record dates

Study Major Dates

• Study Start (Anticipated): August 7, 2018
• Primary Completion (Anticipated): August 1, 2021
• Study Completion (Anticipated): August 1, 2021

Study Registration Dates

• First Submitted: April 26, 2018
• First Submitted That Met QC Criteria: April 26, 2018
• First Posted (Actual): May 9, 2018

Study Record Updates

• Last Update Posted (Actual): September 4, 2019
• Last Update Submitted That Met QC Criteria: August 30, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Disease; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Developmental; Osteochondrodysplasias; Diabetes Mellitus; Syndrome; Fibrous Dysplasia of Bone; Fibrous Dysplasia, Polyostotic
• Other Study ID Numbers: 2000022658

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No