Unacylated ghrelin and obestatin increase islet cell mass and prevent diabetes in streptozotocin-treated newborn rats

Abstract

The ghrelin gene products, namely acylated ghrelin (AG), unacylated ghrelin (UAG), and obestatin (Ob), were shown to prevent pancreatic beta-cell death and to improve beta-cell function under treatment with cytokines, which are major cause of beta-cell destruction in diabetes. Moreover, AG had been described previously to prevent streptozotocin (STZ)-induced diabetes in rats; however, the effect of either UAG or Ob has never been examined in this context. In the present study, we investigated the potential of UAG and Ob to increase islet beta-cell mass and to reduce diabetes at adult age in STZ-treated neonatal rats. One-day-old rats were injected with STZ and subsequently administered with either AG, UAG or Ob for 7 days. On day 70, plasma glucose levels, plasma and pancreatic insulin levels, pancreatic islet area and number, insulin and pancreatic/duodenal homeobox-1 (Pdx1) gene expression, and antiapoptotic BCL2 protein expression were determined. Similarly to AG, both UAG and Ob counteracted STZ-induced high glucose levels and improved plasma and pancreatic insulin levels, which were reduced by the diabetogenic compound. UAG and Ob increased islet area, islet number, and beta-cell mass with respect to STZ treatment alone. Finally, in STZ-treated animals, UAG and Ob up-regulated insulin and Pdx1 mRNA and increased the expression of BCL2 similarly to AG. Taken together, our results suggest that in STZ-treated newborn rats, UAG and Ob improve glucose metabolism and preserve islet cell mass, granting a therapeutic potential in medical conditions associated with impaired beta-cell function.

Des-Acyl Ghrelin Fragments and Analogues Promote Survival of Pancreatic β-Cells and Human Pancreatic Islets and Prevent Diabetes in Streptozotocin-Treated Rats

“…Five experimental groups were studied, following a previously described protocol: (25) (1) control, rats received a single ip injection of citrate buffer (0.05 mM, pH 4.5) at day 1 of birth; (2) STZ, single ip injection of STZ (100 mg/kg body weight), dissolved in citrate buffer (day 1); (3) STZ + compound 1, single ip injection of STZ (day 1) followed by compound 1 (30 nmol/kg sc, twice daily), from day 2 to day 8; (4) STZ + compound 6, single ip injection of STZ (day 1) followed by compound 6 (30 nmol/kg sc, twice daily), from day 2 to day 8; (5) STZ + compound 6, single ip injection of STZ (day 1) followed by compound 6 (100 nmol/kg sc, twice daily), from day 2 to day 8. Dams were randomly assigned to the five groups, and pups from the same litter were assigned to the same group.…”

“…des-acyl ghrelin (1)(2)(3)(4)(5) GSSFL-NH 2 compd peptide sequence 5 des-acyl ghrelin (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28) ESKKPPAKLQPR-COOH 6 des-acyl ghrelin (6)(7)(8)(9)(10)(11)(12)(13) SPEHQRVQ-NH 2 7 des-acyl ghrelin (8)(9)(10)(11)(12)(13) EHQRVQ-NH 2 8 des-acyl ghrelin (8)(9)(10)(11)(12) EHQRV-NH 2 9…”

Ghrelin Gene Products in Acute and Chronic Inflammation

“…Successive works, however, did not support these assertions (Bassil et al 2007;Chartrel et al 2007;Lauwers et al 2006), and the biological role of obestatin is still debated (Lacquaniti et al 2011). Nevertheless, obestatin has several biological activities, including protective effects on the cardiovascular system (Agnew et al 2012;Alloatti et al 2010;Aragno et al 2012), promotion of adipocytes survival, differentiation, and metabolism Gurriarán-Rodríguez et al 2011;Miegueu et al 2011;Pruszynska-Oszmalek et al 2013), induction of myoblasts differentiation and promotion of skeletal muscle regeneration (Gurriarán-Rodríguez et al 2012), inhibition of pancreatic b-cell and islets apoptosis, stimulation of glucose-stimulated insulin secretion in both normal and diabetic animal models, and enhancement of functional bcell generation from pancreatic precursor cells (Baragli et al 2013;Granata et al 2008Granata et al , 2010. Notably by an evolutionary point of view, while ghrelin is mainly involved in food intake, obestatin has an inhibitory effect on water drinking by acting on mechanisms involved in the thirst (Samson et al 2007) and decreases vasopressin concentration in plasma (Samson et al 2008).…”

Implications of ghrelin and hexarelin in diabetes and diabetes-associated heart diseases

“…UAG and Obstatin increased islet area, islet number, and beta cell mass with respect to STZ treatment alone [86]. These findings strongly suggest that beta cells damaged by STZ administration during the neonatal stage or reduced by pancreatectomy can be regenerated or replicated following ghrelin treatment.…”

“…PDX1 is a transcriptional factor which is essential for insulin transcription and maintenance of beta cell mass [85]. Similarly, UAG and obstatin, which is encoded in the same gene as ghrelin, increased islet area, islet number, and beta cell mass and insulin and PDX1 mRNA compared to the pancreas of STZ-treated rat and also increased the expression of antiapoptotic gene, BCL-2 [86]. Both UAG and AG induced cell survival and protection against apoptosis in isolated human islets of Langerhans [82,87].…”