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

Withdrawn

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

• Registration Number: NCT03520153
• Lead Sponsor: 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).

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 Timeline

• Study First Submitted: 2018-04-26
• Study First Submitted QC: 2018-04-26
• Study First Posted: 2018-05-09
• Study Start: 2018-08-07
• Status Verified: 2019-07
• Last Update Submitted: 2019-08-30
• Last Update Posted: 2019-09-04
• Primary Completion: 2021-08
• Study Completion: 2021-08

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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

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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

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
FD/MAS with diabetes mellitus	Hyperinsulinemic Euglycemic Clamp and 2H20	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 and with IPMN	Hyperinsulinemic Euglycemic Clamp and 2H20	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.
FD/MAS without diabetes mellitus	Hyperglycemic Clamp	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 mellitus	Oral Glucose Tolerance Test	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 with diabetes mellitus	Hyperglycemic Clamp	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 with diabetes mellitus	Oral Glucose Tolerance Test	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 and without IPMN	Hyperglycemic Clamp	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.
Healthy Controls	Hyperinsulinemic Euglycemic Clamp and 2H20	Participants will receive the following interventions: Hyperinsulinemic Euglycemic Clamp and 2H20; Hyperglycemic Clamp; and Oral Glucose Tolerance Test.
FD/MAS without diabetes mellitus	Hyperinsulinemic Euglycemic Clamp and 2H20	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	Hyperinsulinemic Euglycemic Clamp and 2H20	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 without IPMN	Oral Glucose Tolerance Test	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	Hyperglycemic Clamp	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.
FD/MAS without diabetes and with IPMN	Oral Glucose Tolerance Test	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.
Healthy Controls	Hyperglycemic Clamp	Participants will receive the following interventions: Hyperinsulinemic Euglycemic Clamp and 2H20; Hyperglycemic Clamp; and Oral Glucose Tolerance Test.
Healthy Controls	Oral Glucose Tolerance Test	Participants will receive the following interventions: Hyperinsulinemic Euglycemic Clamp and 2H20; Hyperglycemic Clamp; and Oral Glucose Tolerance Test.

Primary Outcome Measures

Name	Time	Method
Insulin secretion	Baseline	This primary outcome will be obtained from the hyperglycemic clamp
Glucose tolerance status	Baseline	An oral glucose tolerance test will be performed to assess glucose tolerance status to determine if subjects have pre-IGT, IGT or diabetes
Insulin sensitivity	Baseline	This primary outcome will be obtained from the oral glucose tolerance test
Beta cell capacity	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.
Hepatic glucose fluxes (gluconeogenesis and glycogenolysis)	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

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

Trial Locations

Locations (1)

Yale New Haven Hospital; 🇺🇸 New Haven, Connecticut, United States