A Recent Update on the Role of Ghrelin in Glucose Homeostasis

Briggs, Dana I; Andrews, Zane B.

doi:10.2174/157339911795843140

Cited by 32 publications

(22 citation statements)

References 66 publications

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“…The majority of the newly ghrelin-expressing cells are positioned at the periphery of the islet, like alpha cells, but further analysis is required to determine the origin of these cells. Ghrelin is predominantly expressed in the stomach in adulthood and is involved in regulating food intake, hepatic glucose production and preventing glucose disposal in muscle and adipose tissue [46]. The predicted increase in ghrelin production, coupled with the marked reduction in insulin expression, may explain the rapid onset of diabetes in our animals [47].…”

Section: Discussionmentioning

confidence: 90%

The Developmental Regulator Pax6 Is Essential for Maintenance of Islet Cell Function in the Adult Mouse Pancreas

et al. 2013

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The transcription factor Pax6 is a developmental regulator with a crucial role in development of the eye, brain, and olfactory system. Pax6 is also required for correct development of the endocrine pancreas and specification of hormone producing endocrine cell types. Glucagon-producing cells are almost completely lost in Pax6-null embryos, and insulin-expressing beta and somatostatin-expressing delta cells are reduced. While the developmental role of Pax6 is well-established, investigation of a further role for Pax6 in the maintenance of adult pancreatic function is normally precluded due to neonatal lethality of Pax6-null mice. Here a tamoxifen-inducible ubiquitous Cre transgene was used to inactivate Pax6 at 6 months of age in a conditional mouse model to assess the effect of losing Pax6 function in adulthood. The effect on glucose homeostasis and the expression of key islet cell markers was measured. Homozygous Pax6 deletion mice, but not controls, presented with all the symptoms of classical diabetes leading to severe weight loss requiring termination of the experiment five weeks after first tamoxifen administration. Immunohistochemical analysis of the pancreata revealed almost complete loss of Pax6 and much reduced expression of insulin, glucagon, and somatostatin. Several other markers of islet cell function were also affected. Notably, strong upregulation in the number of ghrelin-expressing endocrine cells was observed. These findings demonstrate that Pax6 is essential for adult maintenance of glucose homeostasis and function of the endocrine pancreas.

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Section: Discussionmentioning

confidence: 90%

The Developmental Regulator Pax6 Is Essential for Maintenance of Islet Cell Function in the Adult Mouse Pancreas

et al. 2013

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“…We demonstrated previously that whereas ghrelin gene ablation in wild-type mice has no effect on hyperphagia or obesity, ghrelin ablation in leptin-deficient ob/ob mice ameliorates the diabetic condition (44). Studies have demonstrated that exogenous ghrelin administration inhibits insulin secretion both in vivo and in vitro (4,16,41,44), confirming ghrelin as a negative regulator of insulin secretion and implying that ghrelin has an important role in glucose homeostasis.…”

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confidence: 82%

Ablation of ghrelin receptor in leptin-deficient ob/ob mice has paradoxical effects on glucose homeostasis when compared with ablation of ghrelin in ob/ob mice

Lin

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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The orexigenic hormone ghrelin is important in diabetes because it has an inhibitory effect on insulin secretion. Ghrelin ablation in leptin-deficient ob/ob (Ghrelin(-/-):ob/ob) mice increases insulin secretion and improves hyperglycemia. The physiologically relevant ghrelin receptor is the growth hormone secretagogue receptor (GHS-R), and GHS-R antagonists are thought to be an effective strategy for treating diabetes. However, since some of ghrelin's effects are independent of GHS-R, we have utilized genetic approaches to determine whether ghrelin's effect on insulin secretion is mediated through GHS-R and whether GHS-R antagonism indeed inhibits insulin secretion. We investigated the effects of GHS-R on glucose homeostasis in Ghsr-ablated ob/ob mice (Ghsr(-/-):ob/ob). Ghsr ablation did not rescue the hyperphagia, obesity, or insulin resistance of ob/ob mice. Surprisingly, Ghsr ablation worsened the hyperglycemia, decreased insulin, and impaired glucose tolerance. Consistently, Ghsr ablation in ob/ob mice upregulated negative β-cell regulators (such as UCP-2, SREBP-1c, ChREBP, and MIF-1) and downregulated positive β-cell regulators (such as HIF-1α, FGF-21, and PDX-1) in whole pancreas; this suggests that Ghsr ablation impairs pancreatic β-cell function in leptin deficiency. Of note, Ghsr ablation in ob/ob mice did not affect the islet size; the average islet size of Ghsr(-/-):ob/ob mice is similar to that of ob/ob mice. In summary, because Ghsr ablation in leptin deficiency impairs insulin secretion and worsens hyperglycemia, this suggests that GHS-R antagonists may actually aggravate diabetes under certain conditions. The paradoxical effects of ghrelin ablation and Ghsr ablation in ob/ob mice highlight the complexity of the ghrelin-signaling pathway.

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“…Numerous studies support a role for ghrelin in blood glucose homeostasis [130, 278, 279]. Glucose homeostasis is regulated by insulin secreted by pancreatic β cells and the insulin responsiveness of peripheral tissues.…”

Section: Physiological Functionsmentioning

confidence: 99%

Structure and Physiological Actions of Ghrelin

2013

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Ghrelin is a gastric peptide hormone, discovered as being the endogenous ligand of growth hormone secretagogue receptor. Ghrelin is a 28 amino acid peptide presenting a unique n-octanoylation modification on its serine in position 3, catalyzed by ghrelin O-acyl transferase. Ghrelin is mainly produced by a subset of stomach cells and also by the hypothalamus, the pituitary, and other tissues. Transcriptional, translational, and posttranslational processes generate ghrelin and ghrelin-related peptides. Homo- and heterodimers of growth hormone secretagogue receptor, and as yet unidentified receptors, are assumed to mediate the biological effects of acyl ghrelin and desacyl ghrelin, respectively. Ghrelin exerts wide physiological actions throughout the body, including growth hormone secretion, appetite and food intake, gastric secretion and gastrointestinal motility, glucose homeostasis, cardiovascular functions, anti-inflammatory functions, reproductive functions, and bone formation. This review focuses on presenting the current understanding of ghrelin and growth hormone secretagogue receptor biology, as well as the main physiological effects of ghrelin.

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A Recent Update on the Role of Ghrelin in Glucose Homeostasis

Cited by 32 publications

References 66 publications

The Developmental Regulator Pax6 Is Essential for Maintenance of Islet Cell Function in the Adult Mouse Pancreas

The Developmental Regulator Pax6 Is Essential for Maintenance of Islet Cell Function in the Adult Mouse Pancreas

Ablation of ghrelin receptor in leptin-deficient ob/ob mice has paradoxical effects on glucose homeostasis when compared with ablation of ghrelin in ob/ob mice

Structure and Physiological Actions of Ghrelin

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