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      Secretion of parathyroid hormone may be coupled to insulin secretion in humans

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          Abstract

          Objective:

          Parathyroid hormone (PTH) is a key hormone in regulation of calcium homeostasis and its secretion is regulated by calcium. Secretion of PTH is attenuated during intake of nutrients, but the underlying mechanism(s) are unknown. We hypothesized that insulin acts as an acute regulator of PTH secretion.

          Methods:

          Intact PTH was measured in plasma from patients with T1D and matched healthy individuals during 4-h oral glucose tolerance tests (OGTT) and isoglycemic i.v. glucose infusions on 2 separate days. In addition, expression of insulin receptors on surgical specimens of parathyroid glands was assessed by immunochemistry (IHC) and quantitative PCR (qPCR).

          Results:

          The inhibition of PTH secretion was more pronounced in healthy individuals compared to patients with T1D during an OGTT (decrementalAUC 0–240min: −5256 ± 3954 min × ng/L and −2408 ± 1435 min × ng/L, P = 0.030). Insulin levels correlated significantly and inversely with PTH levels, also after adjusting for levels of several gut hormones and BMI ( P = 0.002). Expression of insulin receptors in human parathyroid glands was detected by both IHC and qPCR.

          Conclusion:

          Our study suggests that insulin may act as an acute regulator of PTH secretion in humans.

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          Most cited references32

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          Role of gastrointestinal hormones in postprandial reduction of bone resorption.

          Collagen type I fragments, reflecting bone resorption, and release of gut hormones were investigated after a meal. Investigations led to a dose escalation study with glucagon like peptide-2 (GLP-2) in postmenopausal women. We found a dose-dependent effect of GLP-2 on the reduction of bone resorption. The C-terminal telopeptide region of type I collagen as measured in serum (s-CTX) can be used to assess bone resorption. This marker of bone resorption has a significant circadian variation that is influenced by food intake. However, the mediator of this variation has not been identified. We studied the release of the gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2; a representative of the intestinal proglucagon-derived peptides) after ingestion of glucose, fat, protein, and fructose, as well as their effects after parenteral administration in relation to bone turnover processes in healthy volunteers. Furthermore, we studied the effect on bone turnover of a single subcutaneous injection of GLP-2 in four different dosages (100, 200, 400, or 800 microg GLP-2) or placebo in 60 postmenopausal women (mean age, 61 +/- 5 years). All macronutrients significantly (p < 0.05) reduced bone resorption as assessed by s-CTX (39-52% from baseline), and only the glucagon-like peptides were secreted in parallel. Parenteral administration of GIP and GLP-1 did not result in a reduction of the s-CTX level, whereas GLP-2 caused a statistically significant and dose-dependent reduction in the s-CTX level from baseline compared with placebo (p < 0.05). Urine DPD/creatinine, a marker of bone resorption, was significantly reduced by 25% from baseline in the 800-microg GLP-2 group (p < 0.01). An area under the curve (AUC(0-8h)) analysis for s-CTX after GLP-2 injection confirmed the dose-dependent decrease (ANOVA, p = 0.05). The s-osteocalcin level was unaffected by the GLP-2 treatment. These studies exclude both GIP and GLP-1 as key mediators for the immediate reduction in bone resorption seen after a meal. The dose-dependent reduction of bone resorption markers found after subcutaneous injection of GLP-2 warrants further investigation into the mechanism and importance of GLP-2 for the bone turnover processes.
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            Mechanism of circadian variation in bone resorption.

            The diurnal variation in bone resorption markers is poorly understood and may contain essential information about regulation of bone resorption. To explore the acute regulation of bone resorption we studied bone turnover in 14 postmenopausal women during a randomized, crossover, 24 h study of oral glucose tolerance test (OGTT), normal diet, or fasting. Whereas fasting counteracted variation in bone resorption, as measured by serum C-telopeptide fragments of collagen type 1 degradation (s-CTx), OGTT and normal diet induced a 50% reduction (p < 0.001) over 2 h. For OGTT, s-CTx reverted to baseline levels after 6 h, and for normal diet s-CTx remained suppressed during the afternoon and returned to baseline overnight. Repeated OGTT at 8:00 A.M. and 8:00 P.M. in nine postmenopausal women demonstrated that identical reductions in s-CTx could be obtained at both timepoints with an intermediate return to baseline between tests. A 2 h randomized, crossover study of OGTT and fasting in 23 men and premenopausal women similarly revealed a 50% decrease in s-CTx. A randomized, crossover 2 h study of insulin tolerance test compared with fasting in six men and premenopausal women demonstrated a 20%-30% decrease in s-CTx (p < 0.01-0.05). Nine hour follow-up of ten healthy individuals during a crossover experiment of OGTT, protein, and fat intake revealed a comparable 50% reduction in s-CTx, but distinct profiles of serum glucose and serum insulin. Bone resorption was reduced by intake of food, glucose, fat, and protein and counteracted by fasting, and this seems to have been be independent of age and gender. Both exogenous and endogenous insulin stimulation tests induced a reduction in bone resorption, but this was only partial when compared with the reduction observed during food intake.
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              Glucose-dependent insulinotropic polypeptide inhibits bone resorption in humans.

              In humans, the pronounced postprandial reduction in bone resorption (decreasing bone resorption markers by around 50%) has been suggested to be caused by gut hormones. Glucose-dependent insulinotropic polypeptide (GIP) is a peptide hormone secreted postprandially from the small intestine. The hormone is known as an incretin hormone, but preclinical studies have suggested that it may also influence bone metabolism, showing both antiresorptive and anabolic effects as reflected by changes in biomechanical measures, microarchitecture, and activity of the bone cells in response to GIP stimulation. Its role in human bone homeostasis, however, is unknown.

                Author and article information

                Journal
                Endocr Connect
                Endocr Connect
                EC
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                2049-3614
                July 2020
                01 July 2020
                : 9
                : 7
                : 747-754
                Affiliations
                [1 ]Department of Biomedical Sciences , Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [2 ]Novo Nordisk Foundation Center for Basic Metabolic Research , Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [3 ]Department of Clinical Biochemistry , Rigshospitalet, Copenhagen, Denmark
                [4 ]Department of Endocrinology and Nephrology , Nordsjællands University Hospital, Hillerød, Denmark
                [5 ]Center for Neonatal Screening , Department of Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark
                [6 ]Department of Pathology , Rigshospitalet, Copenhagen, Denmark
                [7 ]Steno Diabetes Center Copenhagen , Gentofte, Denmark
                [8 ]Department of Clinical Medicine , Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [9 ]Center for Clinical Metabolic Research , Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
                Author notes
                Correspondence should be addressed to B Hartmann: bhartmann@ 123456sund.ku.dk
                Article
                EC-20-0092
                10.1530/EC-20-0092
                7424341
                32698134
                c09e24a6-e51c-49ab-8b76-89418a35299e
                © 2020 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                History
                : 09 June 2020
                : 01 July 2020
                Categories
                Research

                t1dm,insulin receptor,igf1 receptor,igf2 receptor,ogtt,iigi
                t1dm, insulin receptor, igf1 receptor, igf2 receptor, ogtt, iigi

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