Optical control of insulin release using a photoswitchable sulfonylurea

Abstract

Sulfonylureas are widely prescribed for the treatment of type 2 diabetes mellitus (T2DM). Through their actions on ATP-sensitive potassium (KATP) channels, sulfonylureas boost insulin release from the pancreatic beta cell mass to restore glucose homeostasis. A limitation of these compounds is the elevated risk of developing hypoglycemia and cardiovascular disease, both potentially fatal complications. Here, we describe the design and development of a photoswitchable sulfonylurea, JB253, which reversibly and repeatedly blocks KATP channel activity following exposure to violet-blue light. Using in situ imaging and hormone assays, we further show that JB253 bestows light sensitivity upon rodent and human pancreatic beta cell function. Thus, JB253 enables the optical control of insulin release and may offer a valuable research tool for the interrogation of KATP channel function in health and T2DM.

Optochemical Control of Biological Processes in Cells and Animals

“…In pioneering work by Trauner and co-workers, photo-switchable small molecules have been successfully applied for controlling endogenous G-protein-coupled receptors, [19a] bacterial growth, [19b,20] ion channels, [21] GABA A receptors, [22] nicotinic acetylcholine receptors, [23] insulin release, [24] histone deacetylases, [25] amidohydrolases, [26] and proteasomal function. [27] …”

Remote control of glucose homeostasis in vivo using photopharmacology

“…This process can be switched back and forth using light of the appropriate wavelength, or the dark (hv 1  = photon energy needed for isomerization to achieve channel closure; hv 2  = photon energy needed for isomerization to achieve channel opening, also achievable by thermal relaxation k B T ) (see also ref. 10). ( d ) Representative traces showing that JB253 produced using bulk synthesis allows the reversible optical control of Ca 2+ fluxes in vitro in isolated pancreatic islets incubated with 8 m m D -glucose.…”

Photochromic Materials in Biochemistry

“…As was described in earlier sections of this chapter, an option that avoids genetic modification of channels is the use of small molecule ligands with light-dependent affinity for a biological target. An example described by the Trauner group demonstrates the controlled increase in calcium and insulin levels in human and mouse islet cells using a photochromic inhibitor [87]. The inhibitor structure is based on the known drug, Glimepiride ( Figure 9.12), used to treat glucose imbalances in diabetic patients.…”

“…12 Diabetic drug Glimepiride and a photochromic version that show increased binding affinity for the K ATP channel in the cis-isomer[87].…”