Can GABA turn pancreatic α-cells into β-cells?

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Functional β-cell mass loss leads to the pathogenesis of type 1 diabetes mellitus (T1DM) and also adds to type 2 diabetes mellitus (T2DM). Genetically induced downregulation of Arx, a key transcription factor for glucagon-producing α-cell specification and phenotype, in α-cells converts them into insulin-producing β-like cells in vivo, as shown by Nouha Ben-Othman and co-workers in 2013. The compounds have then identified that lead to a similar outcome and found the neurotransmitter GABA inhibits Arx expression in α-cells. GABA treatment induced two rounds of β-like cell neogenesis following two cycles of streptozotocin-induced β-cell death, twice reverting severe streptozotocin-induced diabetes mellitus.

Another study was done and found that antimalarial drugs from the artemisinin family (particularly artemether) also induced the conversion of α-cells into β-like cells by enhancing GABA signalling in vivo. These effects were observed initially in a mouse cell line, then confirmed in vivo in mice (using lineage tracing), rats and zebrafish. Artemether also improved insulin secretion in human islets. These splendid observations could open the way for clinical trials with GABA or artemisinins to restore the lost β-cell population in patients with T1DM. The immune system would probably attack these newly formed β-cells, but GABA could be a promising adjuvant therapy for new therapies to re-educate or mildly suppress the immune system.

However, later in 2017, another article indicated that artemether did not convert mouse α-cells into β-cells over a 72 h follow-up and, of particular concern, induced de-differentiation and dysfunction of mouse β-cell and, at least for some experiments, human β-cells. Also, a subsequent mouse study indicated that neither GABA nor the artemisinin artesunate induced mouse α-cell to β-cell transdifferentiation in vivo. Ackermann and colleagues used in vivo genetic α-cell lineage tracing with a tamoxifen-inducible Glucagon–CreERT2 system, which labels >90% of α-cells and enables accurate quantification of mature α-cell to β-cell transdifferentiation. The investigators treated mice for 3 months with intraperitoneal GABA injections at the same concentrations used by Ben-Othman and colleagues. At the end of this period, the authors reported no changes in blood levels of glucose or insulin as determined by intraperitoneal glucose tolerance test and found no indications of α-cell to β-cell transdifferentiation above basal levels.

To resolve this controversy and elucidate whether GABA and related compounds will move into clinical trials in patients with diabetes mellitus, a collaborative effort is suggested between two (although more would be ideal) laboratories that have access to validated mouse models for lineage tracing of α-cell to β-cell conversion as well as human islets. These laboratories should use the same GABA.

The investigators should perform at least 4–5 independent experiments with islets from different donors. At the end of the treatment phase, an independent laboratory should count the percentage of glucagon-positive and insulin-positive cells in coded samples.

 

Reference: [Decio L. Eizirik & Esteban N. Gurzov.2018; Nature Reviews Endocrinology]

https://www.nature.com/articles/s41574-018-0101-6

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