Effects of glucose-dependent insulinotropic peptide on osteoclast function

Abstract

-Acute nutrient ingestion leads to a rapid inhibition of bone resorption while effects on makers of bone formation are less marked or absent, suggesting that there is a transient shift toward skeletal accretion in the immediate postprandial period. The cellular bases for these effects are not clear. Glucose-dependent insulinotropic peptide (GIP), a known modulator of glucose-induced insulin secretion, is secreted from intestinal endocrine cells in response to nutrient ingestion. In addition to the effect of GIP on pancreatic ␤-cells, GIP receptors are expressed by osteoblastic cells in bone, suggesting a role for this incretin hormone in bone formation. To determine whether GIP also plays a role in the anti-resorptive effect of nutrient ingestion, osteoclasts were analyzed for the presence of GIP receptors by PCR, immunohistochemical and immunocytochemical analyses of bone tissue, and freshly isolated mature osteoclasts and osteoclast-like cells cultured in vitro. Osteoclast function was assessed by fetal long bone resorption assay and by use of the Osteologic disc assay. Our results demonstrate that GIP receptor transcripts and protein are present in osteoclasts. In addition, with the use of an in vitro organ culture system and mature osteoclasts, GIP was found to inhibit bone resorption in the organ culture system and the resorptive activity of mature osteoclasts. These data are consistent with the hypothesis that GIP inhibits bone breakdown through a direct effect on osteoclast-resorptive activity and suggest one mechanism for the postprandial reduction in markers of bone breakdown. nutrition; bone breakdown; incretin SERUM AND URINE MARKERS OF bone breakdown have been shown to decrease after a meal or an oral glucose tolerance test, suggesting that nutrient-induced elevations of a gastrointestinal factor are capable of inhibiting bone resorption (1). Although postprandial elevations in insulin were initially felt to be involved in preventing bone breakdown and have an impact on bone turnover (1,7,9,22), subsequent insulin clamp studies have shown that insulin had no effect on bone turnover if blood sugar was maintained constant (9), suggesting that other gastrointestinal factors play a role in suppressing bone turnover (7, 9). Two gut-secreted hormones known to be important modulators of glucose-induced insulin secretion ("incretin" hormones) are glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) (13).Our laboratory has previously reported that GIP receptors are present on osteoblasts, osteocytes, and chondrocytes and that addition of GIP to osteoblast-like cells leads to an increase in collagen type I expression and alkaline phosphatase activity, consistent with an anabolic effect (3). In addition, intermittent injection of GIP was shown to prevent bone loss in an ovariectomized rat model (2), while absence of the GIP receptor in GIP receptor knockout mice resulted in decreased bone formation, increased bone breakdown, and significantly lower bone mass (24,25). To further eva...

Impact of Glucose-Dependent Insulinotropic Peptide on Age-Induced Bone Loss

“…(3) GIP stimulates collagen type I synthesis and increases alkaline phosphatase activity in osteoblasts consistent with an anabolic effect on these cells. (2) In addition, GIP inhibits osteoclastic differentiation and activity.…”

“…(2) In addition, GIP inhibits osteoclastic differentiation and activity. (3) The net effect in vivo is that elevations of GIP result in an increase in bone mass, (4) whereas the absence of GIP signaling results in significantly lower bone mass. (5,6) We have previously reported on the development and characterization of GIP-overexpressing transgenic (Tg + ) mice.…”

Chronic Reduction of GIP Secretion Alleviates Obesity and Insulin Resistance Under High-Fat Diet Conditions

“…There are GIP-specific receptors located on osteoblasts (25) and osteoclasts (26). GIP operates as an anabolic hormone in the bone, where it stimulates incorporation of meal-derived Ca 2+ into bone and bone building (13), and reduces bone absorption by inhibiting osteoclastic activity.…”

Bariatric surgery and bone disease: from clinical perspective to molecular insights

“…93 Further, GIP inhibits osteoclast differentiation, resulting in decreased resorption. 94 Fasting and postprandial GIP levels were found to be reduced after RYGB. 95 In one study GIP levels were found to be reduced after RYGB but only in diabetic patients.…”