Islet β-cell-produced NUCB2/nesfatin-1 maintains insulin secretion and glycemia along with suppressing UCP-2 in β-cells

Abstract

Nesfatin-1 is a hypothalamic anorexigenic peptide processed from nucleobindin 2 (NUCB2). Central and peripheral administration of NUCB2/nesfatin-1 enhances glucose metabolism and insulin release. NUCB2/nesfatin-1 is also localized in pancreatic islets, while its function remains unknown. To explore the role of pancreatic β-cell-produced NUCB2/nesfatin-1, we developed pancreatic β-cell-specific NUCB2 knockout (βNUCB2 KO) mice and NUCB2 gene knockdown (shNUCB2) MIN6 β-cell line. In βNUCB2 KO mice, casual blood glucose was elevated from 12 weeks of age. In a glucose tolerance test at 12 weeks, insulin secretion at 15 min was reduced and blood glucose at 2 h increased in βNUCB2 KO mice fasted 8 h. In islets isolated from βNUCB2 KO mice, high glucose-stimulated insulin secretion (GSIS) was impaired. In shNUCB2 MIN6 cells, GSIS was reduced and UCP-2 mRNA expression was elevated. These results show impaired GSIS possibly associated with UCP-2 overexpression in NUCB2-silenced β-cells, suggesting that β-cell-produced NUCB2/nesfatin-1 maintains GSIS and thereby glycemia.

Nucleobindin-2 consists of two structural components: The Zn2+-sensitive N-terminal half, consisting of nesfatin-1 and -2, and the Ca2+-sensitive C-terminal half, consisting of nesfatin-3

“…Notably, an elevated expression level of Nucb2 was found in the central nervous system, i.e., the hypothalamus and pituitary gland [38] , [96] , and in pancreatic β cells [45] . Additionally, it was shown that Nucb2 and nesfatin-1 promote insulin secretion, which suggests the antidiabetic properties of these proteins [97] . The physiological importance of Zn 2+ for Nucb2 function has not been determined.…”

Nucleobindin-2/Nesfatin-1—A New Cancer Related Molecule?

“…Nesfatin-1 was reported as a suppressor of gastric emptying and an inhibitor of gastroduodenal motility in mice and rats [ 21 , 29 ]. The expression of NUCB2/NESF-1 was also observed in pancreatic islets, which suggests its role in glucose homeostasis [ 30 ]. Su et al demonstrated that nesfatin-1 reduced blood glucose levels in hyperglycemic db/db mice [ 31 ].…”

<p>Antioxidant, Anti-Inflammatory and Anti-Apoptotic Activities of Nesfatin-1: A Review</p>

“…5 Subsequent studies have shown that nesfatin-1 is widely expressed in other regions of the brain also, like brainstem, including dorsal vagal complex (DVC), Edinger-Westphal nucleus, locus coeruleus (LC), lateral parabrachial nucleus, ventrolateral medulla (VLM), 10,11 insular cortex, central amygdala, ventrolateral medulla, cerebellar Purkinje cell, pterygopalatine parasympathetic preganglionic neurons, and spinal cord at the lumbar and sacral region. 11 In addition to being widely expressed in the central nervous system, nesfatin-1 is also expressed in peripheral tissues, like esophagus, 12 stomach, small intestine, 13 colon, pancreas, 14 liver, adipocytes, 15 cardiomyocytes, 16 testes, 17 ovaries, 18 uterus and epididymis. 19…”