Emerging Anti-Diabetic Drugs for Beta-Cell Protection in Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) is a chronic autoimmune disorder that damages beta cells in the pancreatic islets of Langerhans and results in hyperglycemia due to the loss of insulin. Exogenous insulin therapy can save lives but does not halt disease progression. Thus, an effective therapy may require beta-cell restoration and suppression of the autoimmune response. However, currently, there are no treatment options available that can halt T1D. Within the National Clinical Trial (NCT) database, a vast majority of over 3000 trials to treat T1D are devoted to insulin therapy. This review focuses on non-insulin pharmacological therapies. Many investigational new drugs fall under the category of immunomodulators, such as the recently FDA-approved CD-3 monoclonal antibody teplizumab. Four intriguing candidate drugs fall outside the category of immunomodulators, which are the focus of this review. Specifically, we discuss several non-immunomodulators that may have more direct action on beta cells, such as verapamil (a voltage-dependent calcium channel blocker), gamma aminobutyric acid (GABA, a major neurotransmitter with effects on beta cells), tauroursodeoxycholic acid (TUDCA, an endoplasmic reticulum chaperone), and volagidemab (a glucagon receptor antagonist). These emerging anti-diabetic drugs are expected to provide promising results in both beta-cell restoration and in suppressing cytokine-derived inflammation.

Keywords: beta cells; hyperglycemia; investigational new drugs; type 1 diabetes.

Figure 1

Verapamil, a calcium channel blocker, reduces intracellular calcium and inhibits mitochondrial TXNIP activity to prevent apoptosis of the beta cells.

Figure 2

Possible mechanisms of GABA in the beta and alpha cells. (A) In the beta cells, GABA binds the GABA receptor and causes an efflux of chloride ions. This leads to depolarization of the membrane, which opens L-type calcium ion channels and allows calcium ions to enter the cell, facilitating insulin secretion. (B) In the alpha cell, there is an influx of chloride ions after GABA binds the GABA receptor, and this causes membrane hyperpolarization, preventing glucagon from being secreted out of the cell.

Figure 3

Possible mechanisms of action for TUDCA in the beta cells. (A) TUDCA binds to many receptors, including transmembrane receptors GPCR1, S1PR, and a5b1, and intracellular receptors FXR, VDR, PXR, GR, and CAR. (B) TUDCA can modulate insulin secretion through the TGR5 receptor. Activating the TGR5 pathway inhibits the pro-inflammatory factor NF-kB and activates adenylate cyclase, which converts ATP to cAMP, leading to insulin secretion.

Figure 4

Volagidemab binds the glucagon receptor to prevent glucagon binding, which inhibits glycogenolysis and gluconeogenesis. It also increases alpha-cell mass and allows excess alpha cells to be transdifferentiated to beta cells.