scholarly journals Glucose-Dependent Insulinotropic Polypeptide (GIP) Inhibits Bone Resorption Independently of Insulin and Glycemia

2017 ◽  
Vol 103 (1) ◽  
pp. 288-294 ◽  
Author(s):  
Mikkel B Christensen ◽  
Asger Lund ◽  
Salvatore Calanna ◽  
Niklas R Jørgensen ◽  
Jens J Holst ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Insulin Release ◽  
Plasma Glucose ◽  
Saline Infusion ◽  
Bone Homeostasis ◽  
Collagen Crosslinks ◽  
Procollagen Type ◽  
Endogenous Insulin ◽  
Gut Hormone

Abstract Context The gut hormone glucose-dependent insulinotropic polypeptide (GIP) causes postprandial insulin release and inhibits bone resorption assessed by carboxy-terminal collagen crosslinks (CTX). Objective To study if GIP affects bone homeostasis biomarkers independently of insulin release and glycemic level. Design Randomized, double-blinded, crossover study with 5 study days. Patients Ten male C-peptide-negative patients with type 1 diabetes. Interventions On 3 matched days with “low glycemia” (plasma glucose in the interval 3 to 7 mmol/L for 120 minutes), we administered intravenous (IV) GIP (4 pmol × kg−1 × min−1), glucagon-like peptide 1 (1 pmol × kg−1 × min−1), or placebo (saline), and on 2 matched days with “high glycemia” (plasma glucose 12 mmol/L for 90 minutes), we administered either GIP or saline. Main Outcome Measures CTX, procollagen type 1 N-terminal propeptide (P1NP), and parathyroid hormone (PTH). Results During low glycemia: GIP progressively suppressed CTX from baseline by up to 59 ± 18% compared with 24 ± 10% during saline infusion (P < 0.0001). Absolute values of P1NP and PTH did not differ between days. During high glycemia: GIP suppressed CTX from baseline by up to 59 ± 19% compared with 7 ± 9% during saline infusion (P < 0.0001). P1NP did not differ between days. GIP suppressed PTH after 60 minutes compared with saline (P < 0.01), but this difference disappeared after 90 minutes. Conclusions Short-term GIP infusions robustly reduce bone resorption independently of endogenous insulin secretion and during both elevated and low plasma glucose, but have no effect on P1NP or PTH after 90 minutes.

scholarly journals Glucose-Dependent Insulinotropic Polypeptide (GIP) Reduces Bone Resorption in Patients With Type 2 Diabetes

2020 ◽  
Vol 4 (9) ◽  
Author(s):  
Mikkel B Christensen ◽  
Asger B Lund ◽  
Niklas R Jørgensen ◽  
Jens J Holst ◽  
Tina Vilsbøll ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Bone Resorption ◽  
Bone Resorption Marker ◽  
Bone Biomarkers ◽  
Short Term ◽  
Collagen Crosslinks ◽  
Procollagen Type ◽  
Placebo Infusion

Abstract Context In healthy individuals, glucose-dependent insulinotropic polypeptide (GIP) enhances insulin secretion and reduces bone resorption by up to 25% estimated by absolute placebo-corrected changes in carboxy-terminal type 1 collagen crosslinks (CTX) during GIP and glucose administration. In patients with type 2 diabetes (T2D), GIP’s insulinotropic effect is impaired and effects on bone may be reduced. Objective To investigate GIP’s effect on bone biomarkers in patients with T2D. Design Randomized, double-blinded, crossover study investigating 6 interventions. Patients Twelve male patients with T2D. Interventions A primed continuous 90-minute GIP infusion (2 pmol/kg/min) or matching placebo (saline) administered at 3 plasma glucose (PG) levels (i.e., paired days with “insulin-induced hypoglycemia” (PG lowered to 3 mmol/L), “fasting hyperglycemia” (mean PG ~8 mmol/L), or “aggravated hyperglycemia” (mean PG ~12 mmol/L). Main Outcome Measures Bone biomarkers: CTX, procollagen type 1 N-terminal propeptide (P1NP) and PTH. Results On days with insulin-induced hypoglycemia, CTX was suppressed by up to 40 ± 15% during GIP administration compared with 12 ± 11% during placebo infusion (P < 0.0001). On days with fasting hyperglycemia, CTX was suppressed by up to 36 ± 15% during GIP administration, compared with 0 ± 9% during placebo infusion (P < 0.0001). On days with aggravated hyperglycemia, CTX was suppressed by up to 47 ± 23% during GIP administration compared with 10 ± 9% during placebo infusion (P = 0.0005). At all glycemic levels, P1NP and PTH concentrations were similar between paired days after 90 minutes. Conclusions Short-term GIP infusions reduce bone resorption by more than one-third (estimated by absolute placebo-corrected CTX reductions) in patients with T2DM, suggesting preserved bone effects of GIP in these patients. Précis Short-term GIP infusions reduce the bone resorption marker CTX by one-third in patients with type 2 diabetes independent of glycemic levels.

scholarly journals Effect of carbohydrate feeding on the bone metabolic response to running

2015 ◽  
Vol 119 (7) ◽  
pp. 824-830 ◽  
Author(s):  
Craig Sale ◽  
Ian Varley ◽  
Thomas W. Jones ◽  
Ruth M. James ◽  
Jonathan C. Y. Tang ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Metabolic Response ◽  
Maximal Oxygen Consumption ◽  
Area Under The Curve ◽  
Acute Effect ◽  
Treadmill Running ◽  
Short Term ◽  
Procollagen Type ◽  
Carbohydrate Feeding

Bone resorption is increased after running, with no change in bone formation. Feeding during exercise might attenuate this increase, preventing associated problems for bone. This study investigated the immediate and short-term bone metabolic responses to carbohydrate (CHO) feeding during treadmill running. Ten men completed two 7-day trials, once being fed CHO (8% glucose immediately before, every 20 min during, and immediately after exercise at a rate of 0.7 g CHO·kg body mass−1·h−1) and once being fed placebo (PBO). On day 4 of each trial, participants completed a 120-min treadmill run at 70% of maximal oxygen consumption (V̇o2 max). Blood was taken at baseline (BASE), immediately after exercise (EE), after 60 (R1) and 120 (R2) min of recovery, and on three follow-up days (FU1-FU3). Markers of bone resorption [COOH-terminal telopeptide region of collagen type 1 (β-CTX)] and formation [NH2-terminal propeptides of procollagen type 1 (P1NP)] were measured, along with osteocalcin (OC), parathyroid hormone (PTH), albumin-adjusted calcium (ACa), phosphate, glucagon-like peptide-2 (GLP-2), interleukin-6 (IL-6), insulin, cortisol, leptin, and osteoprotogerin (OPG). Area under the curve was calculated in terms of the immediate (BASE, EE, R1, and R2) and short-term (BASE, FU1, FU2, and FU3) responses to exercise. β-CTX, P1NP, and IL-6 responses to exercise were significantly lower in the immediate postexercise period with CHO feeding compared with PBO (β-CTX: P = 0.028; P1NP: P = 0.021; IL-6: P = 0.036), although there was no difference in the short-term response (β-CTX: P = 0.856; P1NP: P = 0.721; IL-6: P = 0.327). No other variable was significantly affected by CHO feeding during exercise. We conclude that CHO feeding during exercise attenuated the β-CTX and P1NP responses in the hours but not days following exercise, indicating an acute effect of CHO feeding on bone turnover.

No Evidence for Short-Term Regulation of Plasminogen Activator Inhibitor Activity by Insulin in Man

1992 ◽  
Vol 67 (01) ◽  
pp. 117-120 ◽  
Author(s):  
Helena Vuorinen-Markkola ◽  
llpo Puhakainen ◽  
Hannele Yki-Järvinen
Keyword(s):  
Plasminogen Activator ◽  
Plasma Glucose ◽  
Serum Triglyceride ◽  
Plasminogen Activator Inhibitor ◽  
Saline Infusion ◽  
Serum Triglycerides ◽  
Serum Free ◽  
Free Insulin ◽  
Activator Inhibitor ◽  
Pai 1

SummaryIn crossectional studies a positive correlation has been found between circulating insulin, triglycerides and plasminogen activator inhibitor (PAI-1) activity. To directly examine the effect of insulin on PAI-1 activity in vivo, we determined the response of PAI-1 activity in 17 normal subjects to acute hyperinsulinemia (serum free insulin 92 ± 8 mU/l) during maintenance of normoglycemia (plasma glucose 5.1 ± 0.1 mmol/l). In 12 matched control subjects PAI-1 activity was measured during infusion of saline (serum free insulin 3.6 ± 0.3 mU/l, plasma glucose 5.2 ± 0.1 mmol/l). Plasma PAI-1 activity decreased during the insulin infusion from 9.0 α 1.4 to 5.6 α 0.8 U/ml (p <0.01), and during saline infusion from 7.0 ± 1.4 to 4.3 ± 0.6 U/ml (p <0.05). Serum triglyceride concentrations decreased from 1.09 ± 0.20 to 0.76 ± 0.09 mmol/l (p < 0.001) during hyperinsulinemia but remained unchanged during the saline infusion (1.04 ± 0.11 vs. 1.02 ± 0.12 mmol/l, NS). We conclude that insulin does not acutely change plasma PAI-1 activity, and that acute insulin-induced changes in serum triglycerides occur independently from those of PAI-1 activity.

89-LB: The Effect of GIP on Plasma Glucose in a Setting of Prandial Insulin Overdose and Physical Activity after Meal Intake in Patients with Type 1 Diabetes

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 89-LB ◽  
Author(s):  
BJØRN HOE ◽  
SEBASTIAN M. NGUYEN HEIMBÜRGER ◽  
LÆRKE S. GASBJERG ◽  
MADS B. LYNGGAARD ◽  
BOLETTE HARTMANN ◽  
...  
Keyword(s):  
Physical Activity ◽  
Type 1 Diabetes ◽  
Plasma Glucose ◽  
Prandial Insulin ◽  
Meal Intake ◽  
Insulin Overdose

Insulin secretion and substrate homeostasis in prolonged hypothermia in rats

1988 ◽  
Vol 255 (6) ◽  
pp. R1035-R1040
Author(s):  
R. Hoo-Paris ◽  
M. L. Jourdan ◽  
L. C. Wang ◽  
R. Rajotte
Keyword(s):  
Insulin Secretion ◽  
Plasma Glucose ◽  
Low Temperatures ◽  
Plasma Insulin ◽  
Glucose Utilization ◽  
Exogenous Insulin ◽  
Metabolic Substrate ◽  
Endogenous Insulin ◽  
Dose Dependent Decrease ◽  
Dose Dependent

In hypothermia, impairment of metabolic substrate mobilization and utilization may be a factor limiting survival. By use of a newly developed technique, substrate profiles and their regulation by insulin were examined in hypothermic rats (body temperature 19 degrees C) over 24 h. Plasma glucose concentrations increased to approximately 300 mg/dl during cooling and remained high throughout the period of hypothermia. Free fatty acid (FFA) concentration was not altered during cooling or during the first 10 h of hypothermia (approximately 700 mu eq/l) but progressively decreased thereafter, reaching 420 mu eq/l by 20 h. Plasma insulin decreased dramatically during cooling and remained very low (9 +/- 2 microU/ml) during the whole period of hypothermia, reflecting the suppression of insulin secretion by isolated islets at low temperatures. To test he hypothesis that suppression of endogenous insulin secretion may hamper glucose utilization and thus limit survival in hypothermia, exogenous insulin was administered. At doses of 0.1, 0.5, and 1 U/kg intravenously, insulin slowly decreased plasma glucose and FFA. However, at 0.1 and 1 U/kg intraperitoneally, insulin resulted in a dose-dependent decrease in survival time in the hypothermic rat. It is possible that the antilipolytic effect of insulin may have outweighed any beneficial effect of improving glucose utilization in hypothermia.

scholarly journals Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 199
Author(s):  
Urara Tanaka ◽  
Shunichi Kajioka ◽  
Livia S. Finoti ◽  
Daniela B. Palioto ◽  
Denis F. Kinane ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bone Resorption ◽  
Bone Loss ◽  
Inflammatory Cytokines ◽  
Osteoclast Differentiation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Dependent Manner ◽  
Bone Homeostasis ◽  
Osteoblastic Cell Line ◽  
Anti Inflammatory

DNA methylation controls several inflammatory genes affecting bone homeostasis. Hitherto, inhibition of DNA methylation in vivo in the context of periodontitis and osteoclastogenesis has not been attempted. Ligature-induced periodontitis in C57BL/6J mice was induced by placing ligature for five days with Decitabine (5-aza-2′-deoxycytidine) (1 mg/kg/day) or vehicle treatment. We evaluated bone resorption, osteoclast differentiation by tartrate-resistant acid phosphatase (TRAP) and mRNA expression of anti-inflammatory molecules using cluster differentiation 14 positive (CD14+) monocytes from human peripheral blood. Our data showed that decitabine inhibited bone loss and osteoclast differentiation experimental periodontitis, and suppressed osteoclast CD14+ human monocytes; and conversely, that it increased bone mineralization in osteoblastic cell line MC3T3-E1 in a concentration-dependent manner. In addition to increasing IL10 (interleukin-10), TGFB (transforming growth factor beta-1) in CD14+ monocytes, decitabine upregulated KLF2 (Krüppel-like factor-2) expression. Overexpression of KLF2 protein enhanced the transcription of IL10 and TGFB. On the contrary, site-directed mutagenesis of KLF2 binding site in IL10 and TFGB abrogated luciferase activity in HEK293T cells. Decitabine reduces bone loss in a mouse model of periodontitis by inhibiting osteoclastogenesis through the upregulation of anti-inflammatory cytokines via KLF2 dependent mechanisms. DNA methyltransferase inhibitors merit further investigation as a possible novel therapy for periodontitis.

scholarly journals Pathogenic variants in GNPTAB and GNPTG encoding distinct subunits of GlcNAc-1-phosphotransferase differentially impact bone resorption in patients with mucolipidosis type II and III

2021 ◽  
Author(s):  
Giorgia Di Lorenzo ◽  
Lena M. Westermann ◽  
Timur A. Yorgan ◽  
Julian Stürznickel ◽  
Nataniel F. Ludwig ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Remodeling ◽  
Bone Cells ◽  
Collagen Crosslinks ◽  
Clinical Criteria ◽  
Pathogenic Variants ◽  
Bone Biopsies ◽  
Appropriate Therapy ◽  
Alpha Beta ◽  
Deficient Mice

Abstract Purpose Pathogenic variants in GNPTAB and GNPTG, encoding different subunits of GlcNAc-1-phosphotransferase, cause mucolipidosis (ML) II, MLIII alpha/beta, and MLIII gamma. This study aimed to investigate the cellular and molecular bases underlying skeletal abnormalities in patients with MLII and MLIII. Methods We analyzed bone biopsies from patients with MLIII alpha/beta or MLIII gamma by undecalcified histology and histomorphometry. The skeletal status of Gnptgkoand Gnptab-deficient mice was determined and complemented by biochemical analysis of primary Gnptgko bone cells. The clinical relevance of the mouse data was underscored by systematic urinary collagen crosslinks quantification in patients with MLII, MLIII alpha/beta, and MLIII gamma. Results The analysis of iliac crest biopsies revealed that bone remodeling is impaired in patients with GNPTAB-associated MLIII alpha/beta but not with GNPTG-associated MLIII gamma. Opposed to Gnptab-deficient mice, skeletal remodeling is not affected in Gnptgko mice. Most importantly, patients with variants in GNPTAB but not in GNPTG exhibited increased bone resorption. Conclusion The gene-specific impact on bone remodeling in human individuals and in mice proposes distinct molecular functions of the GlcNAc-1-phosphotransferase subunits in bone cells. We therefore appeal for the necessity to classify MLIII based on genetic in addition to clinical criteria to ensure appropriate therapy.

Bone turnover marker reference intervals in young females

2016 ◽  
Vol 54 (4) ◽  
pp. 438-447 ◽  
Author(s):  
Emma T Callegari ◽  
Alexandra Gorelik ◽  
Suzanne M Garland ◽  
Cherie Y Chiang ◽  
John D Wark
Keyword(s):  
Bone Turnover ◽  
Bone Turnover Markers ◽  
Bone Turnover Marker ◽  
Reference Intervals ◽  
Cross Linking ◽  
Young Females ◽  
Procollagen Type ◽  
Turnover Markers ◽  
Carboxy Terminal

Background The use of bone turnover markers in clinical practice and research in younger people is limited by the lack of normative data and understanding of common causes of variation in bone turnover marker values in this demographic. To appropriately interpret bone turnover markers, robust reference intervals specific to age, development and sex are necessary. This study aimed to determine reference intervals of bone turnover markers in females aged 16–25 years participating in the Safe-D study. Methods Participants were recruited through social networking site Facebook and were asked to complete an extensive, online questionnaire and attend a site visit. Participants were tested for serum carboxy-terminal cross-linking telopeptide of type 1 collagen and total procollagen type 1 N-propeptide using the Roche Elecsys automated analyser. Reference intervals were determined using the 2.5th to 97.5th percentiles of normalized bone turnover marker values. Results Of 406 participants, 149 were excluded due to medical conditions or medication use (except hormonal contraception) which may affect bone metabolism. In the remaining 257 participants, the reference interval was 230–1000 ng/L for serum carboxy-terminal cross-linking telopeptide of type 1 collagen and 27–131  µg/L for procollagen type 1 N-propeptide. Both marker concentrations were inversely correlated with age and oral contraceptive pill use. Therefore, intervals specific to these variables were calculated. Conclusions We defined robust reference intervals for cross-linking telopeptide of type 1 collagen and procollagen type 1 N-propeptide in young females grouped by age and contraceptive pill use. We examined bone turnover markers’ relationship with several lifestyle, clinical and demographic factors. Our normative intervals should aid interpretation of bone turnover markers in young females particularly in those aged 16 to 19 years where reference intervals are currently provisional.

scholarly journals Estrogen Decreases Cytoskeletal Organization by Forming an ERα/SHP2/c-Src Complex in Osteoclasts to Protect against Ovariectomy-Induced Bone Loss in Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 619
Author(s):  
Hyun-Jung Park ◽  
Malihatosadat Gholam-Zadeh ◽  
Sun-Young Yoon ◽  
Jae-Hee Suh ◽  
Hye-Seon Choi
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Ring Formation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Actin Ring ◽  
Collagen Crosslinks ◽  
Trap Staining ◽  
Src Activation

Loss of ovarian function is closely related to estrogen (E2) deficiency, which is responsible for increased osteoclast (OC) differentiation and activity. We aimed to investigate the action mechanism of E2 to decrease bone resorption in OCs to protect from ovariectomy (OVX)-induced bone loss in mice. In vivo, tartrate-resistant acid phosphatase (TRAP) staining in femur and serum carboxy-terminal collagen crosslinks-1 (CTX-1) were analyzed upon E2 injection after OVX in mice. In vitro, OCs were analyzed by TRAP staining, actin ring formation, carboxymethylation, determination of reactive oxygen species (ROS) level, and immunoprecipitation coupled with Western blot. In vivo and in vitro, E2 decreased OC size more dramatically than OC number and Methyl-piperidino-pyrazole hydrate dihydrochloride (MPPD), an estrogen receptor alpha (ERα) antagonist, augmented the OC size. ERα was found in plasma membranes and E2/ERα signaling affected receptor activator of nuclear factor κB ligand (RANKL)-induced actin ring formation by rapidly decreasing a proto-oncogene tyrosine-protein kinase, cellular sarcoma (c-Src) (Y416) phosphorylation in OCs. E2 exposure decreased physical interactions between NADPH oxidase 1 (NOX1) and the oxidized form of c-Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), leading to higher levels of reduced SHP2. ERα formed a complex with the reduced form of SHP2 and c-Src to decrease c-Src activation upon E2 exposure, which blocked a signal for actin ring formation by decreased Vav guanine nucleotide exchange factor 3 (Vav3) (p–Y) and Ras-related C3 botulinum toxin substrate 1 (Rac1) (GTP) activation in OCs. E2/ERα signals consistently inhibited bone resorption in vitro. In conclusion, our study suggests that E2-binding to ERα forms a complex with SHP2/c-Src to attenuate c-Src activation that was induced upon RANKL stimulation in a non-genomic manner, resulting in an impaired actin ring formation and reducing bone resorption.

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