Glucose Homeostasis in Pseudohypoparathyroidism

Glucose Homeostasis and Beta Cell Function in Pseudohypoparathyroidism

It is increasingly recognized that Pseudohypoparathyroidism type 1A (PHP1A) is associated with an increased risk of type 2 diabetes but the mechanism is unknown. In this pilot study we will assess β-cell function in patients with PHP1A and pseudopseudohypoparathyroidism PPHP.

Study Overview

• Status: Terminated
• Conditions: Albright Hereditary Osteodystrophy; Pseudohypoparathyroidism and Pseudopseudohypoparathyroidism; Pseudohypoparathyroidism Type Ia

Detailed Description

Pseudohypoparathyroidism type 1A (PHP1A) is a rare, genetic disorder caused by impaired stimulatory G-protein signaling due to heterozygous mutations in the gene, GNAS. The most severe form of the disease, PHP1A occurs when a GNAS mutation is inherited on the preferentially expressed maternal allele. A less severe form of the disease, pseudopseudohypoparathyroidism (PPHP), occurs when a GNAS mutation is inherited on the paternal allele. Clinically, PHP1A is characterized by multi-hormone resistance, cognitive impairment and early-onset obesity while PPHP has a mild phenotype without multi-hormone resistance. It is increasingly recognized that PHP1A is associated with an increased risk of type 2 diabetes but the mechanism is unknown. Glucose homeostasis and diabetes risk has not been studied in PPHP. As part of the parent K23 award, we investigated glucose tolerance in children with PHP1A. In contrast to the adult literature, we found that children with PHP1A had greater insulin sensitivity than matched controls. When challenged with an oral glucose load, however, children with PHP1A had persistent hyperglycemia and 25% met criteria for impaired glucose tolerance. The goal of this proposal is to quantify β-cell function in PHP1A. It is plausible that these individuals have a) impaired β-cell function, b) differences in insulin sensitivity, and c) impaired incretin function. Thus, in this pilot study we will definitively assess one of these, β-cell function, using the frequently sampled intravenous glucose tolerance test in patients with PHP1A and PPHP (aim 1). We will also assess oral glucose tolerance over time by bringing back children and young adults with PHP1A from our original cohort for repeat glucose tolerance testing (aim 2). The ultimate goal is to rigorously define glucose homeostasis defects in PHP1A in order to design and conduct an intervention study for glucose intolerance and type 2 diabetes in PHP1A.

• Study Type: Observational
• Enrollment (Actual): 14

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 50 years (Child, Adult)
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Patients with PHP1A/PPHP and matched controls

Description

Inclusion Criteria:

1. Diagnosis of PHP1A/PPHP
2. Age between 6 and 50 years old

Controls will be matched based on:

1. Gender
2. Race
3. Age (±2 years if <25 years old or ±5 years if ≥25 years old)
4. BMI (±2 kg/m2)
5. Diabetes status

Exclusion Criteria:

1. Treatment with appetite-altering drug or initiation of a new weight loss program in the past 3 months
2. Type 1 diabetes
3. Type 2 diabetes treated with insulin or GLP-1 receptor agonists or A1c >9%at their most recent clinic visit
4. Pregnant or lactating women

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Pseudphypoparathyroidism type 1A (PHP1A); Case
Pseudopseudohypoparathyroidism (PPHP); Case
Controls; Matched control group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Insulin sensitivity (Si)	baseline

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Investigators: Principal Investigator: Ashley H Shoemaker, MD, Vanderbilt University Medical Center

Publications and helpful links

General Publications

• Perez KM, Curley KL, Slaughter JC, Shoemaker AH. Glucose Homeostasis and Energy Balance in Children With Pseudohypoparathyroidism. J Clin Endocrinol Metab. 2018 Nov 1;103(11):4265-4274. doi: 10.1210/jc.2018-01067.

Helpful Links

• Vanderbilt PHP Research Page

Study record dates

Study Major Dates

• Study Start (Actual): June 19, 2019
• Primary Completion (Actual): April 30, 2021
• Study Completion (Actual): April 30, 2021

Study Registration Dates

• First Submitted: November 29, 2018
• First Submitted That Met QC Criteria: November 29, 2018
• First Posted (Actual): December 3, 2018

Study Record Updates

• Last Update Posted (Actual): May 4, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Diseases; Musculoskeletal Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Bone Diseases, Metabolic; Metal Metabolism, Inborn Errors; Calcium Metabolism Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Pseudohypoparathyroidism; Pseudopseudohypoparathyroidism
• Other Study ID Numbers: Shoemaker R03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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