Gastrin Treatment Stimulates β-Cell Regeneration and Improves Glucose Tolerance in 95% Pancreatectomized Rats

Abstract

β-Cell mass reduction is a central aspect in the development of type 1 and type 2 diabetes, and substitution or regeneration of the lost β-cells is a potentially curative treatment of diabetes. To study the effects of gastrin on β-cell mass in rats with 95% pancreatectomy (95%-Px), a model of pancreatic regeneration, rats underwent 95% Px or sham Px and were treated with [15 leu] gastrin-17 (Px+G and S+G) or vehicle (Px+V and S+V) for 15 d. In 95% Px rats, gastrin treatment reduced hyperglycemia (280 ± 52 mg vs. 436 ± 51 mg/dl, P < 0.05), and increased β-cell mass (1.15 ± 0.15 mg)) compared with vehicle-treated rats (0.67 ± 0.15 mg, P < 0.05). Gastrin treatment induced β-cell regeneration by enhancing β-cell neogenesis (increased number of extraislet β-cells in Px+G: 0.42 ± 0.05 cells/mm(2) vs. Px+V: 0.27 ± 0.07 cells/mm(2), P < 0.05, and pancreatic and duodenal homeobox 1 expression in ductal cells of Px+G: 1.21 ± 0.38% vs. Px+V: 0.23 ± 0.10%, P < 0.05) and replication (Px+G: 1.65 ± 0.26% vs. S+V: 0.64 ± 0.14%; P < 0.05). In addition, reduced β-cell apoptosis contributed to the increased β-cell mass in gastrin-treated rats (Px+G: 0.07 ± 0.02%, Px+V: 0.23 ± 0.05%; P < 0.05). Gastrin action on β-cell regeneration and survival increased β-cell mass and improved glucose tolerance in 95% Px rats, supporting a potential role of gastrin in the treatment of diabetes.

Gastrin induces ductal cell dedifferentiation and β-cell neogenesis after 90% pancreatectomy

“…Ectopic expression of gastrin and transforming growth factor alpha in the pancreas or administration of gastrin in combination with epidermal growth factor or glucagon-like peptide 1 analogues has been shown to increase the b-cell mass and/or to improve glucose tolerance (Wang et al 1993, Rooman et al 2002, Suarez-Pinzon et al 2005, 2008a, supporting a potential role of gastrin in the treatment of diabetes. In a recent study, we have found that long-term gastrin treatment improved glucose tolerance by increasing the functional b-cell mass in 95% pancreatectomised (Px) rats (Téllez et al 2011).…”

“…Subtotal Px results in pancreatic regeneration with increased exocrine and endocrine cell mass expansion (Bonner-Weir et al 1983, 1993, Téllez et al 2011 and has been extensively used as a model for the study of pancreatic endocrine regeneration in the adult (Bonner-Weir et al 1993, Xu et al 1999, Fernández et al 2006, Figeac et al 2012. Increased b-cell replication and neogenesis have been demonstrated to play a role in b-cell regeneration after partial Px, but genetic cell lineage tracing studies have shown discrepant results with respect to the importance of neogenesis during normal growth and after pancreatic injury (Inada et al 2008, Xu et al 2008, Solar et al 2009, Kopinke et al 2011, Kopp et al 2011, Xiao et al 2013.…”

Hope vs hype: where are we in type 1 diabetes?

“…Some have been widely claimed to be of potential importance, such as islet neogenesis-associated protein (INGAP) [38] (or its human counterpart, human proislet peptide [39]), gastrin [40] and betatrophin [41]. INGAP failed in clinical trials [42].…”

Effect of add-on proton pump inhibitors on parameters of glycemic control in type-2 diabetic patients

“…10 It is reported that gastrin promotes β cell neogenesis in pancreatic ductal complex, modest pancreatic β cell replication and improvement of glucose tolerance in animal models in which the remodeling of pancreatic tissues is promoted. 8,[10][11][12][13][14] Nevertheless, resection of the gastric antrum as part of Whipple's operation that reduced serum gastrin levels to very low or undetectable levels was not associated with any diminution of the incretin effect, suggesting that whatever role gastrin played was dispensable, at least in non-diabetic individuals. 14 A report suggesting that, in 95% of the pancreatectomized rats, gastrin treatment not only increased β cells neogenesis from ductal cells but also caused both a modest increase in replication and a decrease in apoptosis in β cells with the resultant improvement of glucose tolerance.…”

“…14 A report suggesting that, in 95% of the pancreatectomized rats, gastrin treatment not only increased β cells neogenesis from ductal cells but also caused both a modest increase in replication and a decrease in apoptosis in β cells with the resultant improvement of glucose tolerance. 12 Zollinger and Ellison's description of peptic ulcer disease attributable to purported gastrinoma included one case where "the pancreatic tissue removed with the tumor showed normal islands with many large beta -cells…".…”