A randomized trial of oral gamma aminobutyric acid (GABA) or the combination of GABA with glutamic acid decarboxylase (GAD) on pancreatic islet endocrine function in children with newly diagnosed type 1 diabetes.

Gamma aminobutyric acid(GABA) is synthesized by glutamate decarboxylase(GAD) in ß-cells. Regarding Type 1 diabetes(T1D), animal/islet-cell studies found that GABA promotes insulin secretion, inhibits α-cell glucagon and dampens immune inflammation, while GAD immunization may also preserve ß-cells. We evaluated the safety and efficacy of oral GABA alone, or combination GABA with GAD, on the preservation of residual insulin secretion in recent-onset T1D. Herein we report a single-center, double-blind, one-year, randomized trial in 97 children conducted March 2015 to June 2019(NCT02002130). Using a 2:1 treatment:placebo ratio, interventions included oral GABA twice-daily(n = 41), or oral GABA plus two-doses GAD-alum(n = 25), versus placebo(n = 31). The primary outcome, preservation of fasting/meal-stimulated c-peptide, was not attained. Of the secondary outcomes, the combination GABA/GAD reduced fasting and meal-stimulated serum glucagon, while the safety/tolerability of GABA was confirmed. There were no clinically significant differences in glycemic control or diabetes antibody titers. Given the low GABA dose for this pediatric trial, future investigations using higher-dose or long-acting GABA formulations, either alone or with GAD-alum, could be considered, although GABA alone or in combination with GAD-alum did nor preserve beta-cell function in this trial.

Proinsulin to C-Peptide Ratio in the First Year After Diagnosis of Type 1 Diabetes.

OBJECTIVE: The proinsulin to C-peptide (PI:C) ratio is reputedly a biomarker of ß-cell endoplasmic reticulum (ER) stress. OBJECTIVE: This study examined the natural history of the PI:C ratio and its correlation with residual ß-cell function in childhood new-onset type 1 diabetes (T1D). Over the first year of T1D, the temporal trend in fasting and nutrient-stimulated PI data is limited. METHODS: PI was a secondary pre-planned analysis of our 1-year, randomized, double-blind, placebo-controlled gamma aminobutyric acid (GABA) trial in new-onset T1D. Of the 99 participants in the primary study, aged 4 to 18 years, 30 were placebo. This study only involved the 30 placebo patients; all were enrolled within 5 weeks of T1D diagnosis. A liquid mixed meal tolerance test was administered at baseline and 5 and 12 months for determination of C-peptide, PI, glucose, and hemoglobin A1C. RESULTS: Both the fasting (P = 0.0003) and stimulated (P = 0.00008) PI:C ratios increased from baseline to 12 months, indicating escalating ß-cell ER stress. The baseline fasting PI correlated with the fasting change in C-peptide at 12 months (P = 0.004) with a higher PI correlating with greater decline in C-peptide. Patients with an insulin-adjusted A1C >9% (hence, not in remission) had higher fasting PI:C ratios. Younger age at diagnosis correlated with a higher PI:C ratio (P = 0.04). CONCLUSION: Children with new-onset T1D undergo progressive ß-cell ER stress and aberrant proinsulin processing, as evidenced by increasing PI:C ratios. Moreover, the PI:C ratio reflects more aggressive ß-cell onslaught with younger age, as well as diminished glycemic control.

Effect of gamma aminobutyric acid (GABA) or GABA with glutamic acid decarboxylase (GAD) on the progression of type 1 diabetes mellitus in children: Trial design and methodology.

BACKGROUND: Evidence suggests that GABA may reduce pancreatic inflammation, protect ß-cells from autoimmune destruction, and potentiate the regeneration of new ß-cells in the setting of type 1 diabetes mellitus (T1DM). The enzyme GAD, also expressed in human pancreatic ß-cells, is an antigenic target of reactive T cells. We hypothesized that treatment of children with recent onset T1DM with GABA or combination GABA with GAD will preserve ß-cell function and ameliorate autoimmune dysregulation. METHODS: This is a one-year, prospective, randomized, double-blind, placebo-controlled trial. Ninety-nine patients aged 4-18 years with newly diagnosed T1DM are randomized into three treatment groups: 1) oral GABA twice daily in addition to two injections of recombinant GAD enzyme, 2) oral GABA plus placebo GAD injections, or 3) placebo GABA and placebo GAD. Patients are evaluated at baseline and months 1, 5, 8 and 12. Mixed meal tolerance testing is performed at all but the 8-month visit. Laboratory studies will assess indices of beta and alpha cell function, glycemic control, immunophenotyping, and diabetes-related autoantibodies. RESULTS: The primary outcome is the effect on pancreatic ß-cell function as measured by meal-stimulated c-peptide secretion compared between the treatment groups before and after one year of treatment. Secondary outcomes include: 1) fasting and meal stimulated glucagon and proinsulin levels, 2) response in insulin usage by participants, 3) indices of immune cell function, and 4) effect on autoantibodies GAD65, ICA512, and ZnT8. CONCLUSIONS: This trial will determine the safety and efficacy of GABA and combination GABA/GAD therapy to delay T1DM progression in children.

SDHB-Associated Paraganglioma in a Pediatric Patient and Literature Review on Hereditary Pheochromocytoma-Paraganglioma Syndromes.

Pheochromocytoma and paraganglioma are rare in the pediatric population occurring in approximately 1 in 50,000 children. While some cases are sporadic, they have commonly been associated with syndromes such as von Hippel-Lindau, multiple endocrine neoplasia types IIa and IIb, neurofibromatosis type 1, and hereditary pheochromocytoma-paraganglioma syndromes. In children less than 18 years of age approximately 60% of pheochromocytomas and paragangliomas are associated with a germline mutation. We present an 11-year-old child with an abdominal paraganglioma related to a succinate dehydrogenase subunit B gene mutation whose father had a previously resected abdominal paraganglioma and was found to carry the same mutation. In addition, we review the etiology, genetics, diagnostic approach, and challenges of preoperative management of secretory pheochromocytomas and paragangliomas in children.