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Jens J Holst - One of the best experts on this subject based on the ideXlab platform.
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administration of a dipeptidyl peptidase IV inhibitor enhances the intestinal adaptation in a mouse model of short bowel syndrome
Surgery, 2011Co-Authors: Manabu Okawada, Jens J Holst, Daniel H TeitelbaumAbstract:Background Glucagon-like peptide-2 induces small intestine mucosal epithelial cell proliferation and may have benefit for patients who suffer from short bowel syndrome. However, glucagon-like peptide-2 is inactIVated rapidly in vIVo by dipeptidyl peptidase IV. Therefore, we hypothesized that selectIVely inhibiting dipeptidyl peptidase IV would prolong the circulating life of glucagon-like peptide-2and lead to increased intestinal adaptation after development of short bowel syndrome. Methods Eight-week old C57BL/6J mice underwent a 50% proximal small bowel resection and were treated with either sitagliptin, a dipeptidyl peptidase IV-inhibitor, starting 1 day before surgery versus placebo. The efficacy of dipeptidyl peptidase IV-inhibitor was assessed 3 days after resection, including intestinal morphology, epithelial cell apoptosis, and epithelial cell proliferation. AdaptIVe mechanisms were assessed with quantitatIVe real-time polymerase chain reaction, and plasma bioactIVe glucagon-like peptide-2 was measured by radioimmunoassay. Results Body weight loss and peripheral blood glucose levels did not change compared with short bowel syndrome controls. Dipeptidyl peptidase IV-inhibitor treatment led to significant increases in villus height and crypt depth. Dipeptidyl peptidase IV-inhibitor treatment did not change EC apoptosis rates significantly, but it did increase crypt epithelial cell proliferation significantly versus placebo-short bowel syndrome controls. Dipeptidyl peptidase IV-inhibitor treatment markedly increased messenger RNA expression of β-catenin and c-myc in ileal mucosa. Plasma glucagon-like peptide-2 levels increased significantly (∼40.9%) in dipeptidyl peptidase IV-inhibitor short bowel syndrome mice. Conclusion Dipeptidyl peptidase IV-inhibitor treatment increased short bowel syndrome adaptation and might potentially be useful for short bowel syndrome patients.
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Dipeptidyl peptidase IV inhibitors: a promising new therapeutic approach for the management of type 2 diabetes.
The international journal of biochemistry & cell biology, 2005Co-Authors: Carolyn F Deacon, Jens J HolstAbstract:Glucagon-like peptide-1 is an insulinotropic hormone with antidiabetic potential due to its spectrum of effects, which include glucose-dependent stimulation of insulin and inhibition of glucagon secretion, tropic effects on the pancreatic beta-cells, inhibition of gastric emptying and the reduction of appetite. Glucagon-like peptide-1 is, however, extremely rapidly inactIVated by the serine peptidase, dipeptidyl peptidase IV, so that the natIVe peptide is not useful clinically. A new approach to utilise the beneficial effects of glucagon-like peptide-1 in the treatment of type 2 diabetes has been the development of orally actIVe dipeptidyl peptidase IV inhibitors. Preclinical studies have demonstrated that this approach is effectIVe in enhancing endogenous levels of glucagon-like peptide-1, resulting in improved glucose tolerance in glucose-intolerant and diabetic animal models. In recent studies of 3-12 months duration in patients with type 2 diabetes, dipeptidyl peptidase IV inhibitors have proved efficacious, both as monotherapy and when gIVen in combination with metformin. Fasting and postprandial glucose concentrations were reduced, leading to reductions in glycosylated haemoglobin levels, while beta-cell function was preserved. Current information suggests dipeptidyl peptidase IV inhibitors are body weight neutral and are well tolerated. A number of dipeptidyl peptidase IV inhibitors are now in the late stages of clinical development. These have different properties, in terms of their duration of action and anticipated dosing frequency, but data from protracted dosing studies is presently not available to allow comparison of their clinical efficacy.
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Dipeptidyl peptidase IV inhibitors: a promising new therapeutic approach for the management of type 2 diabetes.
The International Journal of Biochemistry & Cell Biology, 2005Co-Authors: Carolyn F Deacon, Jens J HolstAbstract:Abstract Glucagon-like peptide-1 is an insulinotropic hormone with antidiabetic potential due to its spectrum of effects, which include glucose-dependent stimulation of insulin and inhibition of glucagon secretion, tropic effects on the pancreatic β-cells, inhibition of gastric emptying and the reduction of appetite. Glucagon-like peptide-1 is, however, extremely rapidly inactIVated by the serine peptidase, dipeptidyl peptidase IV, so that the natIVe peptide is not useful clinically. A new approach to utilise the beneficial effects of glucagon-like peptide-1 in the treatment of type 2 diabetes has been the development of orally actIVe dipeptidyl peptidase IV inhibitors. Preclinical studies have demonstrated that this approach is effectIVe in enhancing endogenous levels of glucagon-like peptide-1, resulting in improved glucose tolerance in glucose-intolerant and diabetic animal models. In recent studies of 3–12 months duration in patients with type 2 diabetes, dipeptidyl peptidase IV inhibitors have proved efficacious, both as monotherapy and when gIVen in combination with metformin. Fasting and postprandial glucose concentrations were reduced, leading to reductions in glycosylated haemoglobin levels, while β-cell function was preserved. Current information suggests dipeptidyl peptidase IV inhibitors are body weight neutral and are well tolerated. A number of dipeptidyl peptidase IV inhibitors are now in the late stages of clinical development. These have different properties, in terms of their duration of action and anticipated dosing frequency, but data from protracted dosing studies is presently not available to allow comparison of their clinical efficacy.
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dipeptidyl peptidase IV resistant analogues of glucagon like peptide 1 which have extended metabolic stability and improved biological actIVity
Diabetologia, 1998Co-Authors: Carolyn F Deacon, Liselotte Bjerre Knudsen, K Madsen, F C Wiberg, O Jacobsen, Jens J HolstAbstract:Glucagon-like peptide 1 (GLP-1) has great potential in diabetes therapy due to its glucose-dependent stimulation of insulin secretion, but this is limited by its rapid degradation, primarily by dipeptidyl peptidase IV. Four analogues, N-terminally substituted with threonine, glycine, serine or α-aminoisobutyric acid, were synthesised and tested for metabolic stability. All were more resistant to dipeptidyl peptidase IV in porcine plasma in vitro, ranging from a t1/2 of 159 min (Gly8 analogue) to undetectable degradation after 6 h (Aib8 analogue; t1/2 for GLP-1 (7–36) amide, 28 min). During i. v. infusion in anaesthetised pigs, over 50 % of each analogue remained undegraded compared to 22.7 % for GLP-1 (7–36) amide. In vIVo, analogues had longer N-terminal t1/2 (intact peptides: means, 3.3–3.9 min) than GLP-1 (7–36) amide (0.9 min; p Gly8 > Ser8 > Thr8). N-terminal modification of GLP-1 confers resistance to dipeptidyl peptidase IV degradation. Such analogues are biologically actIVe and have prolonged metabolic stability in vIVo, which, if associated with greater potency and duration of action, may help to realise the potential of GLP-1 in diabetes therapy. [Diabetologia (1998) 41: 271–278]
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dipeptidyl peptidase IV resistant analogues of glucagon like peptide 1 which have extended metabolic stability and improved biological actIVity
Diabetologia, 1998Co-Authors: Carolyn F Deacon, K Madsen, F C Wiberg, O Jacobsen, Lotte Bjerre Knudsen, Jens J HolstAbstract:Glucagon-like peptide 1 (GLP-1) has great potential in diabetes therapy due to its glucose-dependent stimulation of insulin secretion, but this is limited by its rapid degradation, primarily by dipeptidyl peptidase IV. Four analogues, N-terminally substituted with threonine, glycine, serine or alpha-aminoisobutyric acid, were synthesised and tested for metabolic stability. All were more resistant to dipeptidyl peptidase IV in porcine plasma in vitro, ranging from a t1/2 of 159 min (Gly8 analogue) to undetectable degradation after 6 h (Aib8 analogue; t1/2 for GLP-1 (7-36) amide, 28 min). During i. v. infusion in anaesthetised pigs, over 50% of each analogue remained undegraded compared to 22.7 % for GLP-1 (7-36) amide. In vIVo, analogues had longer N-terminal t1/2 (intact peptides: means, 3.3-3.9 min) than GLP-1 (7-36) amide (0.9 min; p Gly8 > Ser8 > Thr8). N-terminal modification of GLP-1 confers resistance to dipeptidyl peptidase IV degradation. Such analogues are biologically actIVe and have prolonged metabolic stability in vIVo, which, if associated with greater potency and duration of action, may help to realise the potential of GLP-1 in diabetes therapy.
Aleksi Sedo - One of the best experts on this subject based on the ideXlab platform.
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'Dipeptidyl peptidase-IV actIVity and/or structure homologs' (DASH) in growth-modulated glioma cell lines.
Biological chemistry, 2004Co-Authors: Aleksi Sedo, Květoslava Vlašicová, Radek Malík, Petr Busek, Eva Scholzova, Sofia Janackova, Vladislav MaresAbstract:Dipeptidyl peptidase-IV has been demonstrated to play a role in cancer biology by many authors. Since then, additional proteins possessing similar enzymatic actIVity have been described and their role in cancerogenesis has been hypothesized. To assess the complexity of these 'Dipeptidyl peptidase-IV actIVity and/or structure homologs' (DASH) in glioma cells, we have studied their presence in cell lines of different degree of transformation. Our results provide evidence of cell line-specific expression and distribution of dipeptidyl peptidase-IV enzyme actIVity-bearing molecules and their dynamics associated with cell growth conditions. The biologic outcome of DASH pattern of composition probably depends on the regulatory peptides/DASH substrates in the cellular environment.
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Quaternary benzo[c]phenanthridine alkaloids as inhibitors of aminopeptidase N and dipeptidyl peptidase IV.
Phytotherapy Research, 2002Co-Authors: Aleksi Sedo, Květoslava Vlašicová, Petr Barták, Jaroslav Vičar, Radim Vespalec, Vilím Šimánek, Jitka UlrichovaAbstract:Chelerythrine, sanguinarine and an alkaloid extract from Macleaya cordata—sanguiritrin—were found to be inhibitors of aminopeptidase A and dipeptidyl peptidase IV, while fagaronine inhibited dipeptidyl peptidase IV only. At 50 μM, chelerythrine, sanguinarine and sanguiritrin inhibited aminopeptidase N by 82%, 82%, 88%, DPP IV by 38%, 62%, 57%, and fagaronine by 34%, respectIVely. When bovine serum albumin (500 μg/mL) was added, the inhibition of both proteases by quaternary benzo[c]phenanthridine alkaloids (QBA) (50 μM) was significantly diminished. Strong interaction of chelerythrine and sanguinarine with bovine and human serum albumin was proved by electrophoretic determination of their respectIVe conditional binding constants. Copyright © 2002 John Wiley & Sons, Ltd.
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Quaternary benzo[c]phenanthridine alkaloids as inhibitors of aminopeptidase N and dipeptidyl peptidase IV
Phytotherapy research : PTR, 2002Co-Authors: Aleksi Sedo, Květoslava Vlašicová, Petr Barták, Jaroslav Vičar, Radim Vespalec, Vilím Šimánek, Jitka UlrichovaAbstract:Chelerythrine, sanguinarine and an alkaloid extract from Macleaya cordata--sanguiritrin--were found to be inhibitors of aminopeptidase A and dipeptidyl peptidase IV, while fagaronine inhibited dipeptidyl peptidase IV only. At 50 microM, chelerythrine, sanguinarine and sanguiritrin inhibited aminopeptidase N by 82%, 82%, 88%, DPP IV by 38%, 62%, 57%, and fagaronine by 34%, respectIVely. When bovine serum albumin (500 microg/mL) was added, the inhibition of both proteases by quaternary benzo[c]phenanthridine alkaloids (QBA) (50 microM) was significantly diminished. Strong interaction of chelerythrine and sanguinarine with bovine and human serum albumin was proved by electrophoretic determination of their respectIVe conditional binding constants.
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Dipeptidyl peptidase IV in C6 rat glioma cell line differentiation.
Biological chemistry, 1998Co-Authors: Aleksi Sedo, Radek Malík, Evzen KrepelaAbstract:The C6 rat glioma cell line is broadly used as a model in studies of glial cell differentiation. In the present study we demonstrated a significantly higher total cellular, but especially membrane-associated, actIVity of dipeptidyl peptidase IV in differentiated C6 cells in comparison with their proliferating counterparts. The majority, but not all, of enzyme isoelectric focusing isoforms from differentiated C6 cells displayed a substantially higher actIVity compared to the proliferating cells, with G-P-NHMec as the substrate. Non-denaturing polyacrylamide gradient gel electrophoresis showed the presence of one major peak of actIVity, dipeptidyl peptidase IV (Mr of about 220000), in both proliferating and differentiated C6 cells. The results indicate that dipeptidyl peptidase IV regulation is associated with C6 rat glioma cell differentiation.
Michael Szelke - One of the best experts on this subject based on the ideXlab platform.
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2 cyanopyrrolidides as potent stable inhibitors of dipeptidyl peptidase IV
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Doreen M Ashworth, Butrus Atrash, Graham R Baker, Andrew John Baxter, Paul D Jenkins, Michael D Jones, Michael SzelkeAbstract:Abstract A novel series of stable, potent inhibitors of dipeptidyl peptidase IV has been developed. A number of dipeptide analogues, incorporating a 2-cyanopyrrolidide, were found to have K i values of less than 5 nM versus human DP-IV and half-lIVes of >48h in aqueous solusion (pH 7.4).
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4-cyanothiazolidides as very potent, stable inhibitors of dipeptidyl peptidase IV
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Doreen M Ashworth, Butrus Atrash, Graham R Baker, Andrew John Baxter, Paul D Jenkins, D. Michael Jones, Michael SzelkeAbstract:Abstract A series of stable, very potent inhibitors of dipeptidyl peptidase IV has been developed. A number of dipeptide analogues, incorporating a 4-cyanothiazolidide, were found to have Ki values of less than 1 nM versus human DP-IV and half-lIVes of between 5 and 27h in aqueous solution (pH 7.4).
Carolyn F Deacon - One of the best experts on this subject based on the ideXlab platform.
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Dipeptidyl peptidase IV inhibitors: a promising new therapeutic approach for the management of type 2 diabetes.
The international journal of biochemistry & cell biology, 2005Co-Authors: Carolyn F Deacon, Jens J HolstAbstract:Glucagon-like peptide-1 is an insulinotropic hormone with antidiabetic potential due to its spectrum of effects, which include glucose-dependent stimulation of insulin and inhibition of glucagon secretion, tropic effects on the pancreatic beta-cells, inhibition of gastric emptying and the reduction of appetite. Glucagon-like peptide-1 is, however, extremely rapidly inactIVated by the serine peptidase, dipeptidyl peptidase IV, so that the natIVe peptide is not useful clinically. A new approach to utilise the beneficial effects of glucagon-like peptide-1 in the treatment of type 2 diabetes has been the development of orally actIVe dipeptidyl peptidase IV inhibitors. Preclinical studies have demonstrated that this approach is effectIVe in enhancing endogenous levels of glucagon-like peptide-1, resulting in improved glucose tolerance in glucose-intolerant and diabetic animal models. In recent studies of 3-12 months duration in patients with type 2 diabetes, dipeptidyl peptidase IV inhibitors have proved efficacious, both as monotherapy and when gIVen in combination with metformin. Fasting and postprandial glucose concentrations were reduced, leading to reductions in glycosylated haemoglobin levels, while beta-cell function was preserved. Current information suggests dipeptidyl peptidase IV inhibitors are body weight neutral and are well tolerated. A number of dipeptidyl peptidase IV inhibitors are now in the late stages of clinical development. These have different properties, in terms of their duration of action and anticipated dosing frequency, but data from protracted dosing studies is presently not available to allow comparison of their clinical efficacy.
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Dipeptidyl peptidase IV inhibitors: a promising new therapeutic approach for the management of type 2 diabetes.
The International Journal of Biochemistry & Cell Biology, 2005Co-Authors: Carolyn F Deacon, Jens J HolstAbstract:Abstract Glucagon-like peptide-1 is an insulinotropic hormone with antidiabetic potential due to its spectrum of effects, which include glucose-dependent stimulation of insulin and inhibition of glucagon secretion, tropic effects on the pancreatic β-cells, inhibition of gastric emptying and the reduction of appetite. Glucagon-like peptide-1 is, however, extremely rapidly inactIVated by the serine peptidase, dipeptidyl peptidase IV, so that the natIVe peptide is not useful clinically. A new approach to utilise the beneficial effects of glucagon-like peptide-1 in the treatment of type 2 diabetes has been the development of orally actIVe dipeptidyl peptidase IV inhibitors. Preclinical studies have demonstrated that this approach is effectIVe in enhancing endogenous levels of glucagon-like peptide-1, resulting in improved glucose tolerance in glucose-intolerant and diabetic animal models. In recent studies of 3–12 months duration in patients with type 2 diabetes, dipeptidyl peptidase IV inhibitors have proved efficacious, both as monotherapy and when gIVen in combination with metformin. Fasting and postprandial glucose concentrations were reduced, leading to reductions in glycosylated haemoglobin levels, while β-cell function was preserved. Current information suggests dipeptidyl peptidase IV inhibitors are body weight neutral and are well tolerated. A number of dipeptidyl peptidase IV inhibitors are now in the late stages of clinical development. These have different properties, in terms of their duration of action and anticipated dosing frequency, but data from protracted dosing studies is presently not available to allow comparison of their clinical efficacy.
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dipeptidyl peptidase IV resistant analogues of glucagon like peptide 1 which have extended metabolic stability and improved biological actIVity
Diabetologia, 1998Co-Authors: Carolyn F Deacon, Liselotte Bjerre Knudsen, K Madsen, F C Wiberg, O Jacobsen, Jens J HolstAbstract:Glucagon-like peptide 1 (GLP-1) has great potential in diabetes therapy due to its glucose-dependent stimulation of insulin secretion, but this is limited by its rapid degradation, primarily by dipeptidyl peptidase IV. Four analogues, N-terminally substituted with threonine, glycine, serine or α-aminoisobutyric acid, were synthesised and tested for metabolic stability. All were more resistant to dipeptidyl peptidase IV in porcine plasma in vitro, ranging from a t1/2 of 159 min (Gly8 analogue) to undetectable degradation after 6 h (Aib8 analogue; t1/2 for GLP-1 (7–36) amide, 28 min). During i. v. infusion in anaesthetised pigs, over 50 % of each analogue remained undegraded compared to 22.7 % for GLP-1 (7–36) amide. In vIVo, analogues had longer N-terminal t1/2 (intact peptides: means, 3.3–3.9 min) than GLP-1 (7–36) amide (0.9 min; p Gly8 > Ser8 > Thr8). N-terminal modification of GLP-1 confers resistance to dipeptidyl peptidase IV degradation. Such analogues are biologically actIVe and have prolonged metabolic stability in vIVo, which, if associated with greater potency and duration of action, may help to realise the potential of GLP-1 in diabetes therapy. [Diabetologia (1998) 41: 271–278]
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dipeptidyl peptidase IV resistant analogues of glucagon like peptide 1 which have extended metabolic stability and improved biological actIVity
Diabetologia, 1998Co-Authors: Carolyn F Deacon, K Madsen, F C Wiberg, O Jacobsen, Lotte Bjerre Knudsen, Jens J HolstAbstract:Glucagon-like peptide 1 (GLP-1) has great potential in diabetes therapy due to its glucose-dependent stimulation of insulin secretion, but this is limited by its rapid degradation, primarily by dipeptidyl peptidase IV. Four analogues, N-terminally substituted with threonine, glycine, serine or alpha-aminoisobutyric acid, were synthesised and tested for metabolic stability. All were more resistant to dipeptidyl peptidase IV in porcine plasma in vitro, ranging from a t1/2 of 159 min (Gly8 analogue) to undetectable degradation after 6 h (Aib8 analogue; t1/2 for GLP-1 (7-36) amide, 28 min). During i. v. infusion in anaesthetised pigs, over 50% of each analogue remained undegraded compared to 22.7 % for GLP-1 (7-36) amide. In vIVo, analogues had longer N-terminal t1/2 (intact peptides: means, 3.3-3.9 min) than GLP-1 (7-36) amide (0.9 min; p Gly8 > Ser8 > Thr8). N-terminal modification of GLP-1 confers resistance to dipeptidyl peptidase IV degradation. Such analogues are biologically actIVe and have prolonged metabolic stability in vIVo, which, if associated with greater potency and duration of action, may help to realise the potential of GLP-1 in diabetes therapy.
Doreen M Ashworth - One of the best experts on this subject based on the ideXlab platform.
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2 cyanopyrrolidides as potent stable inhibitors of dipeptidyl peptidase IV
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Doreen M Ashworth, Butrus Atrash, Graham R Baker, Andrew John Baxter, Paul D Jenkins, Michael D Jones, Michael SzelkeAbstract:Abstract A novel series of stable, potent inhibitors of dipeptidyl peptidase IV has been developed. A number of dipeptide analogues, incorporating a 2-cyanopyrrolidide, were found to have K i values of less than 5 nM versus human DP-IV and half-lIVes of >48h in aqueous solusion (pH 7.4).
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4-cyanothiazolidides as very potent, stable inhibitors of dipeptidyl peptidase IV
Bioorganic & Medicinal Chemistry Letters, 1996Co-Authors: Doreen M Ashworth, Butrus Atrash, Graham R Baker, Andrew John Baxter, Paul D Jenkins, D. Michael Jones, Michael SzelkeAbstract:Abstract A series of stable, very potent inhibitors of dipeptidyl peptidase IV has been developed. A number of dipeptide analogues, incorporating a 4-cyanothiazolidide, were found to have Ki values of less than 1 nM versus human DP-IV and half-lIVes of between 5 and 27h in aqueous solution (pH 7.4).