# Designing selective TALK-1 inhibitors to reduce beta-cell dysfunction in diabetes > **NIH NIH R01** · VANDERBILT UNIVERSITY · 2021 · $392,391 ## Abstract Insulin levels are inadequate to maintain euglycemia in patients with type-2 diabetes mellitus (T2DM) and in animal models of the disease, which is due in part to perturbations in -cell Ca2+ homeostasis. TALK-1 chan- nels are key regulators of pancreatic -cell electrical excitability, Ca2+ handling and glucose-stimulated insulin secretion (GSIS). KCNK16 the gene that codes for TALK-1 is the most abundant K+ channel transcript of the -cell and TALK-1 is the most islet-restricted ion channel. Moreover, a mutation in KCNK16 results in neonatal diabetes and a nonsynonymous polymorphism in KCNK16 causes a predisposition for developing T2DM. However, our ability to utilize TALK-1 as a therapeutic target to normalize -cell Ca2+ homeostasis in T2DM has not been determined. The long term goal of this research is to determine the therapeutic potential of targeting TALK-1 for treating diabetes. The objective of this project is to identify how TALK-1 influence -cell Ca2+ han- dling, insulin secretion and glucose homeostasis. This project will test the central hypothesis that TALK-1 inhi- bition normalizes -cell Ca2+ homeostasis under diabetic conditions preventing -cell dysfunction and maintain- ing euglycemia. This project is supported by strong preliminary data that has identified TALK-1 an important determinant of human and rodent -cell ER Ca2+ handling and insulin secretion. Further data that has opti- mized a thallium (Tl+) based fluorescent assay for a high throughput screen (HTS) of human TALK-1 to identify small-molecule probes of this channel; pitot screens (3248 small molecules) also identified the first pharmacol- gocial probes of TALK-1 activity. The rationale that underlies this project is that understanding how -cell func- tion is influenced by TALK-1 channel activity with genetic and small-molecule probes will expose novel thera- peutic targets for treating T2DM. This project will be accomplished with the following two specific aims: 1) De- velop potent and selective small-molecule probes of TALK-1 channels; and 2) Determine the therapeutic po- tential of targeting -cell TALK-1 channels for treating diabetes. Under the first aim, small-molecule probes of TALK-1 will be identified with a Tl+ assay based HTS of human TALK-1. This aim will utilize iterative parallel synthesis and verification approaches, to optimize TALK-1 small-molecule probes; testing selectivity (with TALK-1 knockout mouse -cells), potency, toxicity and drug metabolism pharmacokinetic (DMPK) profiles with assays such as Tl+ flux, Ca2+ flux, cytotoxicity and tier one in vitro DMPK. Under the second aim, conditionally ablating, blocking or pharmacologically modulating TALK-1 channels in mouse and human -cells will be uti- lized to determine how these channels influence ER Ca2+ stores, cytoplasmic Ca2+ homeostasis, membrane potential, GSIS, and glucose homeostasis. The roles of -cell TALK-1 will be assessed under physiological conditions as well as under the stressfu... ## Key facts - **NIH application ID:** 10076816 - **Project number:** 5R01DK115620-04 - **Recipient organization:** VANDERBILT UNIVERSITY - **Principal Investigator:** David Aaron Jacobson - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $392,391 - **Award type:** 5 - **Project period:** 2018-01-01 → 2022-12-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10076816 ## Citation > US National Institutes of Health, RePORTER application 10076816, Designing selective TALK-1 inhibitors to reduce beta-cell dysfunction in diabetes (5R01DK115620-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10076816. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*