COVID precautions prevented enrollment of healthy controls, funding ended.

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.

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.

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

Patients with PHP1A/PPHP and matched controls