Possible New Strategies for the Treatment of Congenital Hyperinsulinism

Congenital hyperinsulinism (CHI) is a rare disease characterized by persistent hypoglycemia as a result of inappropriate insulin secretion, which can lead to irreversible neurological defects in infants. Poor efficacy and strong adverse effects of the current medications impede successful treatment. The aim of the study was to investigate new approaches to silence β-cells and thus attenuate insulin secretion.

In the scope of our research, we tested substances more selective and more potent than the gold standard diazoxide that also interact with neuroendocrine ATP-sensitive K⁺ (K_ATP) channels. Additionally, K_ATP channel-independent targets as Ca²⁺-activated K⁺ channels of intermediate conductance (K_Ca3.1) and L-type Ca²⁺ channels were investigated. Experiments were performed using human islet cell clusters isolated from tissue of CHI patients (histologically classified as pathological) and islet cell clusters obtained from C57BL/6N (WT) or SUR1 knockout (SUR1^-/-) mice. The cytosolic Ca²⁺ concentration ([Ca²⁺]_c) was used as a parameter for the pathway regulated by electrical activity and was determined by fura-2 fluorescence. The mitochondrial membrane potential (ΔΨ) was determined by rhodamine 123 fluorescence and single channel currents were measured by the patch-clamp technique.

The selective K_ATP channel opener NN414 (5 µM) diminished [Ca²⁺]_c in isolated human CHI islet cell clusters and WT mouse islet cell clusters stimulated with 10 mM glucose. In islet cell clusters lacking functional K_ATP channels (SUR1^-/-) the drug was without effect. VU0071063 (30 µM), another K_ATP channel opener considered to be selective, lowered [Ca²⁺]_c in human CHI islet cell clusters. The compound was also effective in islet cell clusters from SUR1^-/- mice, showing that [Ca²⁺]_c is influenced by additional effects besides K_ATP channels. Contrasting to NN414, the drug depolarized ΔΨ in murine islet cell clusters pointing to severe interference with mitochondrial metabolism. An opener of K_Ca3.1 channels, DCEBIO (100 µM), significantly decreased [Ca²⁺]_c in SUR1^-/- and human CHI islet cell clusters. To target L-type Ca²⁺ channels we tested two already approved drugs, dextromethorphan (DXM) and simvastatin. DXM (100 µM) efficiently diminished [Ca²⁺]_c in stimulated human CHI islet cell clusters as well as in stimulated SUR1^-/- islet cell clusters. Similar effects on [Ca²⁺]_c were observed in experiments with simvastatin (7.2 µM).

NN414 seems to provide a good alternative to the currently used K_ATP channel opener diazoxide. Targeting K_Ca3.1 channels by channel openers or L-type Ca²⁺ channels by DXM or simvastatin might be valuable approaches for treatment of CHI caused by mutations of K_ATP channels not sensitive to K_ATP channel openers.