Glucose-dependent insulinotropic peptide is an integrative hormone with osteotropic effects

Bollag, Roni J.; Zhong, Qing; Ding, Ke; Phillips, P.D.; Zhong, Like; Qin, Feng; Cranford, Jack A.; Mulloy, Anthony L.; Cameron, Richard S.; Isales, Carlos M.

doi:10.1016/s0303-7207(01)00405-1

Cited by 127 publications

(88 citation statements)

References 42 publications

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“…A considerable body of evidence suggests that increased body weight and/or fat mass is associated with higher bone density and reduced risk of fragility fracture (7,18,19). Recently, several hormones that regulate or reflect nutritional status, such as insulin (20), leptin (19), amylin (7), and others (3,25), have been found to impact directly on bone metabolism. In general, the accumulated evidence from these studies is consistent with the hypothesis that the increased levels of several nutrition-related hormones, derived from the pancreatic ␤-cell and adipocyte, that are observed in the peripheral circulation of overweight subjects contribute to the higher bone mass and lower fracture risk associated with obesity.…”

Section: Discussionmentioning

confidence: 99%

Preptin, another peptide product of the pancreatic β-cell, is osteogenic in vitro and in vivo

Cornish¹,

Callon²,

Bava³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Several hormones that regulate nutritional status also impact on bone metabolism. Preptin is a recently isolated 34-amino acid peptide hormone that is cosecreted with insulin and amylin from the pancreatic ␤-cells. Preptin corresponds to Asp 69 -Leu 102 of pro-IGF-II. Increased circulating levels of a pro-IGF-II peptide complexed with IGF-binding protein-2 have been implicated in the high bone mass phenotype observed in patients with chronic hepatitis C infection. We have assessed preptin's activities on bone. Preptin dose-dependently stimulated the proliferation (cell number and DNA synthesis) of primary fetal rat osteoblasts and osteoblast-like cell lines at periphysiological concentrations (Ͼ10 Ϫ11 M). In addition, thymidine incorporation was stimulated in murine neonatal calvarial organ culture, likely reflecting the proliferation of cells from the osteoblast lineage. Preptin did not affect bone resorption in this model. Preptin induced phosphorylation of p42/p44 MAP kinases in osteoblastic cells in a dose-dependent manner (10 Ϫ8-10 Ϫ10 M), and its proliferative effects on primary osteoblasts were blocked by MAP kinase kinase inhibitors. Preptin also reduced osteoblast apoptosis induced by serum deprivation, reducing the number of apoptotic cells by Ͼ20%. In vivo administration of preptin increased bone area and mineralizing surface in adult mice. These data demonstrate that preptin, which is cosecreted from the pancreatic ␤-cell with amylin and insulin, is anabolic to bone and may contribute to the preservation of bone mass observed in hyperinsulinemic states such as obesity.osteoblast; bone-active hormone; bone anabolic THE MAINTENANCE OF THE MECHANICAL INTEGRITY of the skeleton depends on bone remodelling, the well-coordinated balance between bone formation by osteoblasts and bone resorption by osteoclasts. The coupled action of osteoblasts and osteoclasts is regulated by the action of many local and circulating hormones and factors. More recently, leptin-mediated central regulation of bone mass has been demonstrated (14). This appears to be mediated by a neurological rather than an endocrine mechanism (1). If there is uncoupling of the components of bone remodeling, such that bone resorption exceeds bone formation, bone loss occurs, leading to osteoporosis and fragility fractures. Current therapies for prevention of osteoporosis target osteoclastic bone resorption in the main, but these agents have limited ability to improve bone mass. There is great interest, therefore, in agents that may positively affect bone mass by stimulating bone formation.Recently, the importance of nutritional hormones in maintaining skeletal health has been recognized. This is reflected in the lower prevalence of osteoporosis in those with obesity. Thus hormones circulating at higher levels in obesity have received attention as potential anabolic agents in bone, including the products of pancreatic ␤-cells and of adipocytes. Obesity is associated with hyperinsulinemia, arising from resistance to the hypoglycemic effects of insu...

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Section: Discussionmentioning

confidence: 99%

Preptin, another peptide product of the pancreatic β-cell, is osteogenic in vitro and in vivo

Cornish¹,

Callon²,

Bava³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…If such action was also defective, it could contribute to the hypetriglyceridemia of impaired glucosetolerant states. GIP also has anabolic effects on bone-derived cells and GIP administration-prevented bone loss associated with ovariectomy in rodents (31,32). Thus, GIP may play an integrative role in peripheral tissues by helping coordinate targeted nutrient absorption and distribution, a homeostatic control mechanism in which disruption could be associated with hallmarks of glucose intolerance and characteristic features of the metabolic syndrome.…”

Section: Modified Ogtt In Blsa Subjectsmentioning

confidence: 99%

Elevated Plasma Glucose-Dependent Insulinotropic Polypeptide Associates With Hyperinsulinemia in Impaired Glucose Tolerance

et al. 2004

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OBJECTIVE -The role of gut-derived incretin, glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory peptide [GIP]), in compensatory ␤-cell hypersecretion during insulin-resistant states and in transition to ␤-cell failure in type 2 diabetes is unknown.RESEARCH DESIGN AND METHODS -We carried out oral glucose tolerance testing followed by blood sampling 10 times for 2 h on 68 age-and BMI-matched participants of the Baltimore Longitudinal Study on Aging (BLSA) with normal glucose tolerance (34 subjects), impaired glucose tolerance (IGT) (18 subjects with both impaired fasting and 2-h plasma glucose levels), and type 2 diabetes (16 subjects with both diabetic fasting and 2-h plasma glucose levels). We assayed plasma glucose, insulin, C-peptide, glucagon, and intact and total GIP levels and quantitated glucose and hormone responses to the oral glucose tolerance test. We also compared GIP and insulin release and sensitivity indexes between groups.RESULTS -After glucose ingestion, subjects with IGT had both hyperinsulinemia and hyperemia, while subjects with type 2 diabetes had both ␤-and GIP-cell deficiency. In the former group, there was also a significant positive correlation between the augmented plasma intact and total GIP levels and both fasting and post-oral glucose load plasma insulin levels.CONCLUSIONS -Elevated plasma GIP levels are correlated with hyperinsulinemia in the impaired glucose-tolerant state, whereas type 2 diabetes is associated with a failure to secrete adequate amounts of both GIP and insulin, indicating a common pathway of resistance to and eventually failure of glucose responsiveness in ␤-and GIP-cells. Diabetes Care 27:1692-1698, 2004I n patients with type 2 diabetes, ␤-cells within the islets of Langerhans in the pancreas fail to meet the increased need for insulin created by the insulinresistant state (1). Before ␤-cell failure occurs, however, subjects compensate for insulin resistance for many years by increasing their secretory capacity, resulting in hyperinsulinemia (2). The failure of ␤-cells to continue to hypersecrete insulin underlies the conversion to clinical diabetes. The term enteroinsular axis (3) encompasses the neuro-humoral interactions long thought to exist between the endocrine pancreas and gut cell populations. In fact, the enteroendocrine system constitutes the largest system of endocrine cells in humans, both in terms of number of cells and variety of hormones produced (4). Islets of Langerhans also lie in this system, as well as the incretinproducing cells of the gut, which synthesize and release vital mediators of foodstimulated, glucose-dependent insulin secretion, which account for up to 60% of the insulin secretory response following an oral glucose load (5). The two main, if not the only physiologically relevant, incretins are glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory peptide [GIP]) and glucagonlike peptide-1 (GLP-1) (6,7). The proGIP gene is expressed in gut K-cells, the majority of which are located i...

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“…However, the role of GIP in bone physiology remains unclear. In vitro, it seems that GIP stimulates the synthesis of collagen type I and TGF-β by osteoblasts [10,11]. However, the possible role that GIP might have in controlling bone resorption and/or bone remodeling in vivo is more controversial.…”

Section: Introductionmentioning

confidence: 99%

Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice

Gaudin-Audrain¹,

Irwin²,

Mansur³

et al. 2013

Bone

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A role for the gastro-intestinal tract in controlling bone remodeling is suspected since serum levels of bone remodeling markers are affected rapidly after a meal. Glucose-dependent insulinotropic polypeptide (GIP) represents a suitable candidate in mediating this effect. The aim of the present study was to investigate the effect of total inhibition of GIP signaling on trabecular bone volume, microarchitecture and quality. We used GIP receptor (GIPR) knockout mice and investigated trabecular bone volume and microarchitecture by microCT and histomorphometry. GIPR-deficient animals at 16 weeks of age presented with a significant (20%) increase in trabecular bone mass accompanied by an increase (17%) in trabecular number. In addition, the number of osteoclasts and bone formation rate was significantly reduced and augmented, respectively in these animals when compared with wild-type littermates. These modifications of trabecular bone microarchitecture are linked to a remodeling in the expression pattern of adipokines in the GIPR-deficient mice. On the other hand, despite significant enhancement in bone volume, intrinsic mechanical properties of the bone matrix was reduced as well as the distribution of bone mineral density and the ratio of mature/immature collagen cross-links. Taken together, these results indicate an increase in trabecular bone volume in GIPR KO animals associated with a reduction in bone quality.

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Glucose-dependent insulinotropic peptide is an integrative hormone with osteotropic effects

Cited by 127 publications

References 42 publications

Preptin, another peptide product of the pancreatic β-cell, is osteogenic in vitro and in vivo

Preptin, another peptide product of the pancreatic β-cell, is osteogenic in vitro and in vivo

Elevated Plasma Glucose-Dependent Insulinotropic Polypeptide Associates With Hyperinsulinemia in Impaired Glucose Tolerance

Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice

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