Blockade of Pancreatic Islet–Derived Ghrelin Enhances Insulin Secretion to Prevent High-Fat Diet–Induced Glucose Intolerance

Abstract

The gastric hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), are expressed in pancreas. Here, we report that ghrelin is released from pancreatic islets to regulate glucose-induced insulin release. Plasma concentrations of ghrelin, as well as insulin, were higher in pancreatic veins than in arteries. GHSR antagonist and immunoneutralization of endogenous ghrelin enhanced glucose-induced insulin release from perfused pancreas, whereas exogenous ghrelin suppressed it. GHSR antagonist increased plasma insulin levels in gastrectomized and normal rats to a similar extent. Ghrelin knockout mice displayed enhanced glucose-induced insulin release from isolated islets, whereas islet density, size, insulin content, and insulin mRNA levels were unaltered. Glucose tolerance tests (GTTs) in ghrelin knockout mice showed increased insulin and decreased glucose responses. Treatment with high-fat diet produced glucose intolerance in GTTs in wild-type mice. In ghrelin knockout mice, the high-fat diet-induced glucose intolerance was largely prevented, whereas insulin responses to GTTs were markedly enhanced. These findings demonstrate that ghrelin originating from pancreatic islets is a physiological regulator of glucose-induced insulin release. Antagonism of the ghrelin function can enhance insulin release to meet increased demand for insulin in high-fat diet-induced obesity and thereby normalize glycemic control, which may provide a potential therapeutic application to counteract the progression of type 2 diabetes. Diabetes 55: 3486 -3493, 2006

Ghrelin treatment protects lactotrophs from apoptosis in the pituitary of diabetic rats

“…Ghrelin modulates insulin secretion and glucose metabolism (Reimer et al, 2003), augmenting glycemia by decreasing glucose-induced insulin release from pancreatic islets (Dezaki et al, 2006). However, we found no effect of ghrelin treatment on glycemia or serum insulin levels in diabetic rats.…”

“…Ghrelin has both endocrine and non-endocrine activities including regulation of food intake and energy homeostasis (Wren et al, 2001), induction of adiposity (Tschop et al, 2000), actions on insulin secretion and glucose metabolism (Egido et al, 2002;Dezaki et al, 2006;Reimer et al, 2003) and stimulation of pituitary hormones including GH, prolactin and ACTH (Kojima et al, 1999;Arvat et al, 2001;Cheng et al, 1993;Broglio et al, 2003;Tassone et al, 2003). In addition, anti-inflammatory and anti-apoptotic actions of ghrelin have been reported in different organs and tissues Dixit et al, 2004;Granado et al, 2005;Granata et al, 2006).…”

Ghrelin-producing epsilon cells in the developing and adult human pancreas

“…An insulinostatic function of endogenous ghrelin within islets has been suggested [13,15,17,[29][30][31]. It was also recently shown to exert inhibitory effects on expression and production of inflammatory cytokines [32] and to attenuate the development of acute pancreatitis in rats by reducing inflammatory infiltrates of pancreatic tissues [33].…”

“…In human and rodent pancreases of neonates and adults, a few epsilon cells remain visible in marginal areas of the islets [4,5,13]. An insulinostatic function of endogenous ghrelin within islets has been suggested [15][16][17]. In fact, pharmacological, immunological and genetic blockade of ghrelin or ghrelin action in pancreatic islets all markedly enhanced glucose-induced insulin release [15][16][17].…”

A study on the short-term effect of cafeteria diet and pioglitazone on insulin resistance and serum levels of adiponectin and ghrelin

“…The onset of insulin resistance and compensatory hyperinsulinemia in obesity is probably the reason for the suppression of ghrelin levels (13). Ghrelin has been characterized in earlier studies as an enhancer of insulin secretion (14,15), while more recent studies with mice have shown that the antagonism of its effects could promote the secretion of insulin and prevent glucose intolerance induced by a high-fat diet (16,17). …”