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Jens J. Holst - One of the best experts on this subject based on the ideXlab platform.

  • Glucose-Dependent Insulinotropic Peptide in the High-Normal Range Is Associated With Increased Carotid Intima-Media Thickness.
    Diabetes care, 2020
    Co-Authors: Amra Jujic, Jens J. Holst, Peter M Nilsson, Tiinamaija Tuomi, Paul W Franks, Naeimeh Atabaki-pasdar, Anna Dieden, Signe S. Torekov, Susana Ravassa, Javier Díez
    Abstract:

    OBJECTIVE While existing evidence supports beneficial cardiovascular effects of glucagon-like Peptide 1 (GLP-1), emerging studies suggest that Glucose-Dependent Insulinotropic Peptide (GIP) and/or signaling via the GIP receptor may have untoward cardiovascular effects. Indeed, recent studies show that fasting physiological GIP levels are associated with total mortality and cardiovascular mortality, and it was suggested that GIP plays a role in pathogenesis of coronary artery disease. We investigated the associations between fasting and postchallenge GIP and GLP-1 concentrations and subclinical atherosclerosis as measured by mean intima-media thickness in the common carotid artery (IMTmeanCCA) and maximal intima-media thickness in the carotid bifurcation (IMTmaxBulb). RESEARCH DESIGN AND METHODS Participants at reexamination within the Malmo Diet and Cancer–Cardiovascular Cohort study (n = 3,734, mean age 72.5 years, 59.3% women, 10.8% subjects with diabetes, fasting GIP available for 3,342 subjects, fasting GLP-1 available for 3,299 subjects) underwent oral glucose tolerance testing and carotid ultrasound. RESULTS In linear regression analyses, each 1-SD increment of fasting GIP was associated with increased (per mm) IMTmeanCCA (β = 0.010, P = 0.010) and IMTmaxBulb (β = 0.014; P = 0.040) in models adjusted for known risk factors and glucose metabolism. In contrast, each 1-SD increment of fasting GLP-1 was associated with decreased IMTmaxBulb (per mm, β = −0.016, P = 0.014). These associations remained significant when subjects with diabetes were excluded from analyses. CONCLUSIONS In a Swedish elderly population, physiologically elevated levels of fasting GIP are associated with increased IMTmeanCCA, while GLP-1 is associated with decreased IMTmaxBulb, further emphasizing diverging cardiovascular effects of these two incretin hormones.

  • Measurement of the incretin hormones: glucagon-like Peptide-1 and Glucose-Dependent Insulinotropic Peptide.
    Journal of diabetes and its complications, 2014
    Co-Authors: Rune E. Kuhre, Nicolai J. Wewer Albrechtsen, Bolette Hartmann, Carolyn F. Deacon, Jens J. Holst
    Abstract:

    The two incretin hormones, glucagon-like Peptide 1 (GLP-1) and Glucose-Dependent Insulinotropic Peptide (GIP), are secreted from the gastrointestinal tract in response to meals and contribute to the regulation of glucose homeostasis by increasing insulin secretion. Assessment of plasma concentrations of GLP-1 and GIP is often an important endpoint in both clinical and preclinical studies and, therefore, accurate measurement of these hormones is important. Here, we provide an overview of current approaches for the measurement of the incretin hormones, with particular focus on immunological methods.

  • impact of exogenous hyperglucagonemia on postprandial concentrations of gastric inhibitory polyPeptide and glucagon like Peptide 1 in humans
    The Journal of Clinical Endocrinology and Metabolism, 2010
    Co-Authors: Juris J Meier, Michael A. Nauck, Carolyn F. Deacon, Peter R Ritter, Alexandra Jacob, Bjoern A Menge, W E Schmidt, Jens J. Holst
    Abstract:

    Background: Postprandial secretion of glucagon-like Peptide 1 (GLP-1) has been found diminished in some patients with type 2 diabetes mellitus (T2DM) and high glucagon concentrations. We examined the effects of exogenous glucagon on the release of incretin hormones. Patients and Methods: Ten patients with T2DM and 10 healthy controls were examined with a meal test during the iv administration of glucagon 0.65 ng/kg · min and placebo. Results: GLP-1 plasma concentration increased after meal ingestion in both groups (P < 0.0001), but postprandial GLP-1 plasma levels were not affected by glucagon administration. However, immediately after cessation of the glucagon infusion, GLP-1 levels increased by about 2-fold to levels of 51.8 ± 14.6 pmol/liter in the T2DM patients and 58.9 ± 20.0 pmol/liter in controls (P < 0.05). The time courses of Glucose-Dependent Insulinotropic Peptide Glucose-Dependent Insulinotropic Peptide and GLP-1 concentrations were not different between T2DM patients and controls during the p...

  • glucagon like Peptide 1 but not glucose dependent Insulinotropic Peptide inhibits glucagon secretion via somatostatin receptor subtype 2 in the perfused rat pancreas
    Diabetologia, 2008
    Co-Authors: J. Heer, C. Rasmussen, D. H. Coy, Jens J. Holst
    Abstract:

    Aims/hypothesis The glucose-lowering effect of glucagon-like Peptide-1 (GLP-1) is based not only upon its potent Insulinotropic actions but also on its ability to restrain glucagon secretion. Surprisingly, the closely related Glucose-Dependent Insulinotropic Peptide (GIP) stimulates glucagon release. We examined whether the islet hormone somatostatin, which strongly inhibits glucagon secretion, is involved in this divergent behaviour.

  • Dipeptidyl Peptidase-4 Inhibition— Advances in our Understanding of Diabetes Management
    US endocrinology, 2008
    Co-Authors: Carolyn F. Deacon, Jens J. Holst
    Abstract:

    Glucagon-like Peptide-1 (GLP-1) and Glucose-Dependent Insulinotropic Peptide (GIP) are the two major incretin hormones in humans. These Peptides are released from endocrine cells in the intestinal mucosa in response to food ingestion, and play a pivotal role in blood glucose regulation. Among other actions, they act on pancreatic islet cells to enhance glucose-induced insulin secretion. This so-called ‘incretin effect’ explains why a greater amount of insulin is released in response to an oral glucose load compared with that elicited by an isoglycemic intravenous glucose challenge, 1 and in healthy subjects it accounts for up to 70% of glucoseinduced insulin secretion. 1

Kehong Ding - One of the best experts on this subject based on the ideXlab platform.

  • Impact of Glucose-Dependent Insulinotropic Peptide on age-induced bone loss.
    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 2007
    Co-Authors: Kehong Ding, Qing Zhong, Roni J. Bollag, Ding Xie, Wendy B Bollag, Baolin Kang, Xing Ming Shi, William D. Hill, Walter Washington
    Abstract:

    GIP is an important hormonal link between nutrition and bone formation. We show for the first time that BMSCs express functional GIP receptors, that expression decreases with aging, and that elevations in GIP can prevent age-associated bone loss. Introduction: We previously showed that C57BL/6 mice lose bone mass as they age, particularly between 18 and 24 mo of age. The mechanisms involved in this age-dependent induced bone loss are probably multifactorial, but adequate nutrition and nutritional signals seem to be important. Glucose-Dependent Insulinotropic Peptide (GIP) is an enteric hormone whose receptors are present in osteoblasts, and GIP is known to stimulate osteoblastic activity in vitro. In vivo, GIP-overexpressing C57BL/6 transgenic (GIP Tg+) mice have increased bone mass compared with controls. Bone histomorphometric data suggest that GIP increases osteoblast number, possibly by preventing osteoblastic apoptosis. However, potential GIP effects on osteoblastic precursors, bone marrow stromal cells (BMSCs), had not previously been examined. In addition, effects of GIP on age-induced bone loss were not known. Materials and Methods: Changes in BMD, biomechanics, biomarkers of bone turnover, and bone histology were assessed in C57BL/6 GIP Tg+ versus Tg− (littermate) mice between the ages of 1 and 24 mo of age. In addition, age-related changes in GIP receptor (GIPR) expression and GIP effects on differentiation of BMSCs were also assessed as potential causal factors in aging-induced bone loss. Results: We report that bone mass and bone strength in GIP Tg+ mice did not drop in a similar age-dependent fashion as in controls. In addition, biomarker measurements showed that GIP Tg+ mice had increased osteoblastic activity compared with wildtype control mice. Finally, we report for the first time that BMSCs express GIPR, that the expression decreases in an age-dependent manner, and that stimulation of BMSCs with GIP led to increased osteoblastic differentiation. Conclusions: Our data show that elevated GIP levels prevent age-related loss of bone mass and bone strength and suggest that age-related decreases in GIP receptor expression in BMSCs may play a pathophysiological role in this bone loss. We conclude that elevations in GIP may be an effective countermeasure to age-induced bone loss.

  • Glucose-Dependent Insulinotropic Peptide-overexpressing transgenic mice have increased bone mass
    Bone, 2007
    Co-Authors: Ding Xie, Kehong Ding, Qing Zhong, Roni J. Bollag, Wendy B Bollag, Karl L. Insogna, Hua Cheng, Sandra Williams, Daniel J. Correa, Nancy Troiano
    Abstract:

    Glucose-Dependent Insulinotropic Peptide (GIP) is an intestinally secreted hormone the release of which is stimulated by nutrient ingestion. We previously reported that GIP receptors are present in osteoblastic cells and that GIP increases collagen type I synthesis and alkaline phosphatase activity in isolated osteoblasts. We have also shown that osteoclasts express GIP receptors and that GIP inhibits osteoclastic activity and differentiation. In addition, using GIP receptor knockout mice we demonstrated that absence of GIP receptor signaling resulted in a low bone mass phenotype. To further define GIP's role as an anabolic hormone in vivo, we utilized a genetically altered mouse model, a transgenic mouse overexpressing GIP under the control of the metallothionein promoter (Tg+). Tg+ mice had significantly higher mean GIP levels even in the absence of added dietary zinc. Tg+ animals also had a significant increase in markers of bone formation and a decrease in markers of bone resorption. Consistent with these biochemical data, GIP transgenic mice had a significant increase in bone mass as measured by densitometry and histomorphometry. These data support the conclusion that GIP inhibits bone resorption and stimulates bone formation and that excess signaling through the GIP receptor results in gain of bone mass. In view of GIP's role in nutrient absorption, our data suggest that this hormone may serve an important role in linking nutrient ingestion to bone formation.

  • Effects of Glucose-Dependent Insulinotropic Peptide on osteoclast function.
    American journal of physiology. Endocrinology and metabolism, 2006
    Co-Authors: Qing Zhong, Kehong Ding, Roni J. Bollag, Ding Xie, Wendy B Bollag, Baolin Kang, Supriya Sridhar, Takashi Itokawa, Mark W. Hamrick, Karl L. Insogna
    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 β-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.

  • Effects of Glucose-Dependent Insulinotropic Peptide on behavior
    Peptides, 2006
    Co-Authors: Kehong Ding, Qing Zhong, Roni J. Bollag, Ding Xie, Huan Xin Chen, Mary Anne Della-fera, Wendy B Bollag, Ravinder Gujral, Baolin Kang, Supriya Sridhar
    Abstract:

    Glucose-Dependent Insulinotropic Peptide (GIP) is an incretin hormone that rises rapidly in response to nutrient ingestion. The GIP receptor is widely expressed in the brain including the brain stem, telencephalon, diencephalon, olfactory bulb, pituitary, and cerebellum. Until recently it was not clear what the endogenous ligand for this receptor was because no GIP expression had been demonstrated in the brain. GIP synthesis has now been documented in the dentate gyrus of the hippocampus. To define GIP effects on behavior we utilized a mouse model a GIP-overexpressing transgenic mouse (GIP Tg). Specifically, anxiety-related behavior, exploration, memory, and nociception were examined. Compared to age-matched adult male C57BI/6 controls GIP Tg mice displayed enhanced exploratory behavior in the open-field locomotor activity test. GIP Tg mice also demonstrated increased performance in some of the motor function tests. These data suggest that the GIP receptor plays a role in the regulation of locomotor activity and exploration. To our knowledge, this is the first report of effects of GIP on behavior.

  • Glucose-Dependent Insulinotropic Peptide: differential effects on hepatic artery vs. portal vein endothelial cells.
    American journal of physiology. Endocrinology and metabolism, 2004
    Co-Authors: Kehong Ding, Qing Zhong, Carlos M. Isales
    Abstract:

    Glucose-Dependent Insulinotropic Peptide (GIP) has been reported to have opposing effects on splanchnic blood flow. GIP infusion in dogs results in an increase in portal vein circulation but a drop...

J. Heer - One of the best experts on this subject based on the ideXlab platform.

J. J. Holst - One of the best experts on this subject based on the ideXlab platform.

Chi-chuan Tseng - One of the best experts on this subject based on the ideXlab platform.

  • Role of regulator of G protein signaling in desensitization of the Glucose-Dependent Insulinotropic Peptide receptor.
    Endocrinology, 1998
    Co-Authors: Chi-chuan Tseng, Xiao-ying Zhang
    Abstract:

    The Glucose-Dependent Insulinotropic Peptide receptor (GIP-R) is a member of the G protein-coupled receptors. Recent studies have indicated that elevated serum GIP concentrations in type II diabetic patients might induce desensitization of the GIP-R, and this mechanism could contribute to impaired insulin secretion. The cellular and molecular mechanisms governing GIP desensitization are unknown. Here, we report the results of studies on a new family of proteins known as regulators of G protein signaling (RGS) that have been shown to mediate the desensitization process of other receptors. GIP-R and RGS1, -2, -3, and -4 complementary DNAs were cotransfected into human embryonic kidney cells (L293). GIP-stimulated cAMP generation in control cells and in those coexpressing RGS1, -3, and -4 displayed a dose-dependent increase 10 min after GIP treatment. In contrast, RGS2 expression inhibited the GIP-induced cAMP response by 50%, a response similar to that of cells desensitized by preincubation with 10−7 m GIP....

  • THE CYSTEINE OF THE CYTOPLASMIC TAIL OF Glucose-Dependent Insulinotropic Peptide RECEPTOR MEDIATES ITS CHRONIC DESENSITIZATION AND DOWN-REGULATION
    Molecular and Cellular Endocrinology, 1998
    Co-Authors: Chi-chuan Tseng, Xiao-ying Zhang
    Abstract:

    Abstract The Glucose-Dependent Insulinotropic Peptide receptor (GIP-R) is a member of G-protein-coupled, seven transmembrane-spanning receptors. Recent studies have shown that elevated serum GIP level in diabetic patients may induce chronic desensitization of the GIP-R, and that this mechanism could contribute to impaired insulin secretion. The cellular basis of down-regulation and chronic desensitization of GIP-R is unclear. To explore the role of the carboxyl terminus of the GIP-R in mediating these processes, five truncated GIP-Rs (T395, T399, T420, T431, T455) were created to delete consecutive serines from the carboxyl end. All mutants except T395 exhibit an identical ligand-binding affinity to the WT receptor. The T395 mutant, which had the entire carboxyl tail removed, does not bind to ligand. Down-regulation and desensitization was assessed by measuring the receptor number and the ability of agonist-induced cAMP or [Ca2+] generation after pre-exposure to 10−7 M GIP for 24 h. The wild-type (WT) and T420, T431, T455 mutant GIP-Rs are maximally down-regulated by GIP preincubation, whereas T399 mutant does not, indicating that the sequence between amino acids 399 and 420 is critical for this process. Mutation analysis of this area by alanine scanning mutagenesis reveals two critical residues: serine 406 and cysteine 411. Replacement of serine 406 with arginine (S406R) or alanine (S406A) partly attenuates agonist-induced down-regulation and desensitization. In contrast, mutation of the cysteine 411 to glycine (C411G) or alanine (C411A) markedly attenuates both processes. Mutant SCRG, in which both serine 406 and cysteine 411 are mutated, behaves similar to C411G or C411A. The data suggest that chronic desensitization and down-regulation of the GIP-R may be mediated by similar mechanisms, and that the cysteine in the carboxyl terminus plays an essential role in regulating both processes.

  • A point mutation in the Glucose-Dependent Insulinotropic Peptide receptor confers constitutive activity.
    Biochemical and biophysical research communications, 1997
    Co-Authors: Chi-chuan Tseng, Li Lin
    Abstract:

    The Glucose-Dependent Insulinotropic Peptide receptor (GIP-R) is a member of the secretin and parathyroid hormone (PTH) family of seven transmembrane-spanning receptors. Point mutations of a histidine at the junction between the first intracellular loop and the second membrane-spanning domain and a threonine in the sixth membrane-spanning domain of the human PTH-receptor have been reported to be associated with constitutive activation of the PTH receptor in Jansen-type metaphyseal chondrodysplasia. In this study, we explored whether such mutations in the GIP-R might similarly induce constitutive, ligand-independent activation of the receptor. Single amino acid substitutions in the GIP receptor were made by site-directed mutagenesis and receptor binding and cAMP levels were measured in transfected human embryonal kidney cell line (L293). Mutation of the threonine at position 340 in the sixth transmembrane spanning domain to proline (T340P) led to agonist-independent constitutive activity and exhibited a four-fold increase in basal cAMP level as compared to the wild-type GIP-R. The increase in cAMP level in T340P mutant was proportional to the amount of transfected plasmid and corresponded to the receptor number on the cell surface. Despite its high basal cAMP level, the T340P mutant could be further stimulated by GIP, with maximal cAMP generation comparable to the wild-type receptor. The change of amino acid histidine at position 169 to arginine (H169R), however, behaved like the wild type receptor and did not possess constitutive activity. These results illustrate that a point mutation of threonine to proline at position 340 results in constitutive activation of the GIP receptor, without affecting its sensitivity to agonist stimulation.

  • Glucose-Dependent Insulinotropic Peptide (GIP) gene expression in the rat salivary gland.
    Molecular and cellular endocrinology, 1995
    Co-Authors: Chi-chuan Tseng, Linda A. Jarboe, Erin K. Williams, Michael O. Boylan, Mary E. Sunday, M. Michael Wolfe
    Abstract:

    Previous studies have indicated that following nutrient ingestion, GIP is released principally from the upper small intestine. In addition to its presence in the rat small intestine, GIP transcripts have also been localized to the submandibular salivary gland (SSG). The present studies were directed to further characterize expression of the GIP gene in the SSG. Pregnant rats were sacrificed at gestational days 18 and 20, followed by the removal of rat fetuses. The duodenum pancreas, and SSG were then excised from the fetuses, as well as from neonatal pups at ages 1, 3, 7, 10, 14, and 21 days. RNA was extracted and measured by Northern blot analysis using specific rat GIP probes. GIP transcripts were first detected in the duodenum in the 18-day fetus and reached maximum levels at birth. In contrast, GIP mRNA was not observed in the SSG until 10 days postnatally and was not detected at all in either the fetal or neonatal pancreas. In situ hybridization of the SSG using an 35S-labelled antisense GIP RNA probe demonstrated expression of the GIP gene to be limited to ductal cells, with no transcripts present in acini. In separate experiments, rats fasted overnight were given water or 10% glucose. While no changes were detected in water-fed rats following oral glucose ingestion, small, but significant increases in SSG GIP gene expression were detected at 60 and 240 min. The results of these initial studies suggest the possibility of a functional role for GIP in the rat salivary gland by the demonstration of GIP mRNA in the SSG by Northern analysis and in situ hybridization, as well as by an increase in SSG GIP gene expression following a glucose meal.

  • Glucose-Dependent Insulinotropic Peptide: structure of the precursor and tissue-specific expression in rat.
    Proceedings of the National Academy of Sciences of the United States of America, 1993
    Co-Authors: Chi-chuan Tseng, Linda A. Jarboe, Steven B. Landau, Erin K. Williams, M. Michael Wolfe
    Abstract:

    Glucose-Dependent Insulinotropic Peptide (GIP) is a 42-amino acid gastrointestinal regulatory Peptide that stimulates insulin secretion from pancreatic beta cells in the presence of glucose. Approximately 7.8 x 10(5) recombinant clones of a neonatal rat intestinal cDNA library were screened by using plaque hybridization, and three clones were identified and sequenced with the dideoxynucleotide chain-termination method. The translated amino acid sequence deduced from the nucleotide sequence of the cDNA indicated that rat GIP was derived by proteolytic processing of a 144-amino acid precursor polyPeptide. The mature Peptide is flanked by a 43-amino acid NH2-terminal Peptide that contains a 21-amino acid signal Peptide and by a 59-amino acid COOH-terminal Peptide. Analysis of the nucleotide and amino acid sequence of rat GIP revealed only two substitutions from the known human GIP Peptide. The use of high-stringency RNA blot-hybridization analysis of total RNA extracted from various organs demonstrated expression of the GIP gene in the duodenum and jejunum and, to a lesser extent, in the ileum. In addition, expression of the GIP gene was observed in the submandibular salivary gland both by RNA analysis and RIA. In response to duodenal perfusion of a 20% Lipomul meal for 60 min, duodenal mucosal GIP mRNA concentrations increased by 42.8% and 48.2% at 30 and 60 min, respectively.