Front Endocrinol (Lausanne). 2020 Oct 27;11:545638. doi: 10.3389/fendo.2020.545638. PMID: 33193079.
Using human islets from CHI patients and islets from ABCC8 (SUR1) knockout mice, the authors tested several novel compounds to inhibit insulin over-secretion. These novel compounds targeted KATP channels as well as KATP independent channels (such as Ca2+-activated K+ channels of intermediate conductance (KCa3.1) and L-type Ca2+ channels).
Congenital hyperinsulinism (CHI) leads to severe hypoglycaemia in the neonatal and infancy periods. Currently mutations in 14 different genes lead to CHI, most commonly mutations in the genes ABCC8/KCNJ11 which encode the SUR1/KIR6.2 subunits of the pancreatic beta-cell KATP channel. Patients with recessive (or in some cases dominant) mutations in ABCC8/KCNJ11 typically do not respond to conventional medical treatments such as diazoxide (which works by opening the KATP channel) and need near-total pancreatectomy to reduce the severity of hypoglycaemia, but with long-term side-effects of lifelong diabetes mellitus and pancreatic exocrine insufficiency. Thus, there is an urgent need to develop new medical treatment options for these patients.
Compound NN415 is similar to diazoxide but more potent and more selective for the SUR1 protein. This compound altered calcium homeostasis in human CHI islets but not in the mouse SUR1 islets (suggesting it only works if there are some KATP channels). Two other compounds (VU0071063 and DCEBIO which are also known to act on the KATP channels) altered calcium homeostasis in both human and mouse SUR1 islets. Other known drugs (such as dextromethorphan and simvastatin) which are used for treating other medical conditions were also tested and diminished calcium levels in both human and mouse SUR1 islets. Dextromethorphan inhibited L-type calcium channels and lowered the intracellular calcium levels in depolarized beta-cells thus inhibiting insulin secretion. Simvastatin also lowered insulin secretion by diminishing calcium entry via the L-type calcium channels.
These observations suggest potential novel treatments for CHI patients with diffuse disease and these compounds and existing drugs will need to be tested in clinical trials to assess efficacy and safety.