GABA induces a hormonal counter-regulatory response in subjects with long-standing type 1 diabetes

IntroductionExperimentally, gamma-aminobutyric acid (GABA) has been found to exert immune-modulatory effects and induce beta-cell regeneration, which make it a highly interesting substance candidate for the treatment of type 1 diabetes (T1D). In many countries, including those in the European Union, GABA is considered a pharmaceutical drug. We have therefore conducted a safety and dose escalation trial with the first controlled-release formulation of GABA, Remygen (Diamyd Medical).Research design and methodsSix adult male subjects with long-standing T1D (age 24.8±1.5 years, disease duration 14.7±2.2 years) were enrolled in an 11-day dose escalation trial with a controlled-release formulation of GABA, Remygen. Pharmacokinetics, glucose control and hormonal counter-regulatory response during hypoglycemic clamps were evaluated at every dose increase (200 mg, 600 mg and 1200 mg).ResultsDuring the trial there were no serious and only a few, transient, adverse events reported. Without treatment, the counter-regulatory hormone response to hypoglycemia was severely blunted. Intake of 600 mg GABA more than doubled the glucagon, epinephrine, growth hormone and cortisol responses to hypoglycemia.ConclusionsWe find that the GABA treatment was well tolerated and established a counter-regulatory response to hypoglycemia in long-standing T1D. Further studies regarding not only the clinical potential of Remygen for beta-cell regeneration but also its potential use as hypoglycemic prophylaxis are warranted.Trail registration numberNCT03635437 and EudraCT2018-001115-73.

Reappearance of C-Peptide During the Third Trimester of Pregnancy in Type 1 Diabetes: Pancreatic Regeneration or Fetal Hyperinsulinism?

Objective: We assessed longitudinal patterns of maternal C-peptide concentration to examine the hypothesis of beta-cell regeneration in type 1 diabetes pregnancy. <p>Research Design & Methods: C-peptide was measured on maternal serum samples from 127 participants (12, 24, 34 weeks) and cord blood during the continuous glucose monitoring in type 1 diabetes pregnancy trial (CONCEPTT). C-peptide was measured using a highly sensitive direct and solid-phase competitive electrochemiluminescent immunoassay. </p> <p>Results: Three discrete patterns of maternal C-peptide trajectory were identified: Pattern 1 undetectable throughout pregnancy, n=74 (58%, maternal C-peptide <3 pmol/l); Pattern 2 detectable at baseline, n=22 (17%, maternal C-peptide 7-272 pmol/l at baseline); Pattern 3 undetectable maternal C-peptide at 12 and 24 weeks which first became detectable at 34 weeks, n=31 (24%; maternal C-peptide 4-26 pmol/l at 34 weeks). Baseline characteristics and third trimester glucose profiles of women with pattern 1 and pattern 3 C-peptide trajectories were similar but women in pattern 3 had suboptimal glycemia (50% time above range) at 24 weeks gestation. Offspring of women with pattern 3 C-peptide trajectories had elevated cord blood C-peptide (geometric mean 1319 vs 718 pmol/l; p=0.007), increased rates of large-for-gestational-age (90% vs 60%; p=0.002) neonatal hypoglycemia (42% vs 14%; p=0.001), and neonatal intensive care admission (45% vs 23%; p=0.023) compared to pattern 1 offspring. </p> <p>Conclusion: First maternal C-peptide appearance at 34 weeks was associated with mid-trimester hyperglycemia, elevated cord blood C-peptide and high rates of neonatal complications. This suggests transfer of C-peptide from fetal to maternal serum and is inconsistent with pregnancy-related beta-cell regeneration.</p>

Reappearance of C-Peptide During the Third Trimester of Pregnancy in Type 1 Diabetes: Pancreatic Regeneration or Fetal Hyperinsulinism?

Objective: We assessed longitudinal patterns of maternal C-peptide concentration to examine the hypothesis of beta-cell regeneration in type 1 diabetes pregnancy. <p>Research Design & Methods: C-peptide was measured on maternal serum samples from 127 participants (12, 24, 34 weeks) and cord blood during the continuous glucose monitoring in type 1 diabetes pregnancy trial (CONCEPTT). C-peptide was measured using a highly sensitive direct and solid-phase competitive electrochemiluminescent immunoassay. </p> <p>Results: Three discrete patterns of maternal C-peptide trajectory were identified: Pattern 1 undetectable throughout pregnancy, n=74 (58%, maternal C-peptide <3 pmol/l); Pattern 2 detectable at baseline, n=22 (17%, maternal C-peptide 7-272 pmol/l at baseline); Pattern 3 undetectable maternal C-peptide at 12 and 24 weeks which first became detectable at 34 weeks, n=31 (24%; maternal C-peptide 4-26 pmol/l at 34 weeks). Baseline characteristics and third trimester glucose profiles of women with pattern 1 and pattern 3 C-peptide trajectories were similar but women in pattern 3 had suboptimal glycemia (50% time above range) at 24 weeks gestation. Offspring of women with pattern 3 C-peptide trajectories had elevated cord blood C-peptide (geometric mean 1319 vs 718 pmol/l; p=0.007), increased rates of large-for-gestational-age (90% vs 60%; p=0.002) neonatal hypoglycemia (42% vs 14%; p=0.001), and neonatal intensive care admission (45% vs 23%; p=0.023) compared to pattern 1 offspring. </p> <p>Conclusion: First maternal C-peptide appearance at 34 weeks was associated with mid-trimester hyperglycemia, elevated cord blood C-peptide and high rates of neonatal complications. This suggests transfer of C-peptide from fetal to maternal serum and is inconsistent with pregnancy-related beta-cell regeneration.</p>

Generation of a Transgenic Zebrafish Model for Pancreatic Beta Cell Regeneration

Background: Diabetes is a major worldwide health problem. It is widely accepted that the beta cell mass decreases in type I diabetes (T1D). Accordingly, beta cell regeneration is a promising approach to increase the beta cell mass in T1D patients. However, the underlying mechanisms of beta cell regeneration have yet to be elucidated. One promising avenue is to create a relevant animal model to explore the underlying molecular and cellular mechanisms of beta cell regeneration. The zebrafish can be considered a model in beta cell regeneration studies because the pancreas structure and gene expression pattern are highly conserved between human and zebrafish. Materials and Methods: In this study, the Tol2 transposase was exploited to generate a Tg(Ins:egfp-nfsB) zebrafish model that expressed a fusion protein composed of enhanced green fluorescent protein (EGFP) and nitroreductase (NTR) under control of the Ins promoter. Results: Metronidazole (MTZ) treatment of Tg(ins:egfp-nfsB) zebrafish larvae led to selective ablation of beta cells. Proof-of-concept evidence for beta cell regeneration in the transgenic larvae was observed two days after withdrawal of MTZ. Conclusion: This study suggests that the Tg(ins:egfp-nfsB) zebrafish can be used as a disease model to study beta cell regeneration and elucidate underlying mechanisms during the regeneration process. [GMJ.2019;8:e1056]