Abstract
Glucose homeostasis is initially regulated by the pancreatic hormone insulin. Glucose-stimulated insulin secretion in β-cells is composed of two cellular mechanisms: a high glucose concentration not only depolarizes the membrane potential of the β-cells by ATP-sensitive K+ channels but also induces cell inflation, which is sufficient to release insulin granules. However, the molecular identity of the stretch-activated cation channel responsible for the latter pathway remains unknown. Here, we demonstrate that Tentonin 3/TMEM150C (TTN3), a mechanosensitive channel, contributes to glucose-stimulated insulin secretion by mediating cation influx. TTN3 is expressed specifically in β-cells and mediates cation currents to glucose and hypotonic stimulations. The glucose-induced depolarization, firing activity, and Ca2+ influx of β-cells were significantly lower in Ttn3-/- mice. More importantly, Ttn3-/- mice show impaired glucose tolerance with decreased insulin secretion invivo. We propose that TTN3, as a stretch-activated cation channel, contributes to glucose-stimulated insulin secretion.
Highlights
Type 2 diabetes is a metabolic disorder characterized by impaired glucose tolerance (Kahn, 2000)
We identified Tentonin 3/TMEM150C (TTN3) as a cation channel activated by mechanical stimulation with unique slow inactivation kinetics (Hong et al, 2016)
To further analyze the detailed localization pattern of TTN3 in the pancreas, sections of wildtype (WT) and Ttn3 knocked out (KO) murine pancreas were stained with TTN3 antibody together with pancreatic cell markers
Summary
Type 2 diabetes is a metabolic disorder characterized by impaired glucose tolerance (Kahn, 2000). When the b-cells produce an insufficient amount of insulin or when the body cannot use the insulin properly, it leads to high blood glucose levels or hyperglycemia, which is the hallmark of diabetes mellitus (Ashcroft and Rorsman, 2012; Porte and Kahn, 2001). Diabetes mellitus is expected to be the seventh leading cause of death in 2030 (Mathers and Loncar, 2006; Zheng et al, 2018). It has serious complications such as blindness, neuropathy, heart attacks, stroke, and kidney failure (Zhuo et al, 2013). Development in the treatment of diabetes is important to improve one’s quality of life through increasing insulin sensitivity or the amount of insulin secretion in the pancreas
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