ESPE Yearbook of Paediatric Endocrinology

Sci Transl Med. 2024;16(755):eadg3456. PMID: 38985854

Brief summary: In this experimental study, a combination of a dual tyrosine-regulated kinase 1A (DYRK1A) inhibitor (harmine) with a glucagon-like peptide 1 receptor agonist (GLP1RA) (extendin-4) increased in vivo human β-cell mass by 4- to 7-fold in both diabetic and nondiabetic mice over a 3-month period and reversed diabetes. The proposed mechanisms involved enhanced human β-cell proliferation, function, and survival.

Type 1 diabetes (T1D) is characterised by insufficient insulin-producing β-cells, and so far, no treatment is available to restore the β-cell numbers. Recent data suggest that small molecules that inhibit dual tyrosine-regulated kinase 1A (DYRK1A) can induce immunohistochemical markers of human β-cell replication, and this effect is enhanced by drugs that stimulate the glucagon-like peptide 1 (GLP1) receptor (GLP1R), such as extendin-4, on β-cells (1). It remains to be demonstrated whether these immunohistochemical findings translate into an increase in human β-cell numbers in vivo. It is also unknown whether DYRK1A inhibitors together with GLP1RA affect human β-cell survival.

To address these questions, human islets were transplanted under the kidney capsule of immunodeficient mice, both diabetic (streptozotocin induced) and non diabetic. These mice were treated for up to 3 months with either a vehicle control, the DYRK1A inhibitor harmine, the GLP1RA extendin-4 or a combination of harmine and extendin-4. β-cell mass and survival were quantified using 3D iDISCO imaging, which combines a tissue clearing technique with a light sheet microscopy approach. The combination of a DYRK1A inhibitor with extendin-4 resulted in a 4- to 7-fold increase in human β-cell mass compared to controls, in both diabetic and non diabetic mice over 3 months, and reversed diabetes. The augmentation in human β-cell mass occurred through mechanisms, including enhanced human β-cell proliferation, function, and survival.

Together, these findings demonstrate the therapeutic potential and favorable preclinical safety profile of the DYRK1A inhibitor-GLP1RA combination for increasing human β-cell mass in vivo. However, further studies are needed to elucidate the underlying mechanisms of action and to determine whether the therapeutic benefits and safety of this approach will translate to humans.

Reference: 1. Ackeifi C, Wang P, Karakose E, et al. GLP-1 receptor agonists synergize with DYRK1A inhibitors to potentiate functional human β cell regeneration. Sci Transl Med 2020;12(530).