Effects of the long-acting glucagon-like peptide-1 receptor agonist liraglutide in adolescent pigs with impaired glucose-dependent insulinotropic polypeptide receptor function:
Gespeichert in:
| 1. Verfasser: | |
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| Format: | Abschlussarbeit Buch |
| Sprache: | Undetermined |
| Veröffentlicht: |
2013
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| Schlagworte: | |
| Online-Zugang: | kostenfrei https://nbn-resolving.org/urn:nbn:de:bvb:19-168554 Inhaltsverzeichnis |
| Beschreibung: | VI, 174 S. Ill., graph. Darst. |
Internformat
MARC
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| 245 | 1 | 0 | |a Effects of the long-acting glucagon-like peptide-1 receptor agonist liraglutide in adolescent pigs with impaired glucose-dependent insulinotropic polypeptide receptor function |c von Elisabeth Therese Streckel |
| 264 | 1 | |c 2013 | |
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Datensatz im Suchindex
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| adam_text | TABLE OF CONTENTS I
TABLE OF CONTENTS
I. INTRODUCTION 1
II. REVIEW OF THE LITERATURE 3
1. TYPE 2 DIABETES MELLITUS 3
1.1. PREVALENCE OF DIABETES MELLITUS 3
1.2. PATHOPHYSIOLOGY AND CONSEQUENCES OF TYPE 2 DIABETES 4
1.3. DIAGNOSIS CRITERIA FOR TYPE 2 DIABETES IN HUMANS 5
1.4. THERAPEUTIC APPROACHES FOR TYPE 2 DIABETES 6
2. THE INCRETIN HORMONE SYSTEM 7
2.1. DISCOVERY OF THE INCRETIN HORMONES AND THE INCRETIN EFFECT 7
2.2. GLUCAGON-1
IKE PEPTIDE-1 (GLP-1) 9
2.2.1. BIOSYNTHESIS, SECRETION AND DEGRADATION OF GLP-1 9
2.2.2. GLP-1 RECEPTOR (GLP-1 R) AND SIGNAL TRANSDUCTION 10
2.2.3. EFFECTS OF GLP-1 ON THE ENDOCRINE PANCREAS 11
2.2.4. EXTRAPANCREATIC EFFECTS OF GLP-1 12
2.3. GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE (G1P) 13
2.3.1. BIOSYNTHESIS, SECRETION AND DEGRADATION OF GIP 13
2.3.2. GIP RECEPTOR (GIPR) AND SIGNAL TRANSDUCTION 14
2.3.3. BIOLOGICAL FUNCTIONS OF GIP 14
3. LIRAGLUTIDE AS AN INCRETIN-BASED THERAPEUTIC AGENT IS
3.1. FUNDAMENTAL CONCEPT OF INCRETIN-BASED THERAPEUTICS IS
3.1.1. DPP-4 INHIBITORS 16
3.1.2. GLP-1R AGONISTS 17
3.2. PHARMACOKINETICS OF LIRAGLUTIDE 19
3.3. PHARMACODYNAMIC EFFECTS OF LIRAGLUTIDE IN ANIMAL MODELS 21
3.3.1. PHARMACODYNAMIC EFFECTS OF LIRAGLUTIDE IN ANIMAL MODELS OF
DIABETES 21
3.3.1.1. LIRAGLUTIDE ADMINISTRATION IN RODENT MODELS OF DIABETES 21
3.3.1.2. LIRAGLUTIDE ADMINISTRATION IN PORCINE MODELS OF DIABETES 23
3.4. PHARMACODYNAMIC EFFECTS OF LIRAGLUTIDE IN HUMAN CLINICAL TRIALS 24
3.4.1. EFFICACY OF LIRAGLUTIDE ON GLYCEMIC CONTROL DURING LEAD TRIALS 25
3.4.2. EFFICACY OF LIRAGLUTIDE ON BETA-CELL FUNCTION DURING LEAD TRIALS
26
3.4.3. EFFICACY OF LIRAGLUTIDE ON BODY WEIGHT AND BLOOD PRESSURE DURING
LEAD
TRIALS 26
HTTP://D-NB.INFO/1051220289
TABLE OF CONTENTS N
3.4.4. SAFETY AND TOLERABILITY OF LIRAGLUTIDE DURING LEAD TRIALS 27
4. THE GIPR
DN
TRANSGENIC PIG MODEL 28
4.1. THE PIG AS A LARGE ANIMAL MODEL FOR DIABETES RESEARCH 28
4.2. GENERATION AND CHARACTERIZATION OF GIPR*
1
TRANSGENIC PIGS 30
III. RESEARCH DESIGN 36
IV. ANIMALS, MATERIALS AND METHODS 38
1. ANIMALS 38
2. MATERIALS 38
2.1. APPARATUSES 38
2.2. CONSUMABLES 40
2.3. CHEMICALS 41
2.4. ANTIBODIES, DRUGS, ENZYMES, OLIGONUCLEOTIDES 42
2.4.1. ANTIBODIES 42
2.4.2. DRUGS 43
2.4.3. ENZYMES 43
2.4.4. OLIGONUCLEOTIDES X 43
2.5. BUFFERS, MEDIA AND SOLUTIONIS 44
2.5.1. APROTININ DILUTION FOR LIRAGLUTIDE PROFILING 44
2.5.2. BUFFERS, MEDIA AND SOLUTIONS FOR PCR AND AGAROSE GELS 44
2.5.2.1. DNTP-MIX 44
2.5.2.2. LOADING DYE FOR DNA (6X) 44
2.5.2.3. TAE BUFFER (50X) 44
2.5.3. BUFFERS, MEDIA AND SOLUTIONS FOR IMMUNOHISTOCHEMISTRY 45
2.5.3.1. DAB SOLUTION 45
2.5.3.2. TBS BUFFER FOR IMMUNOHISTOCHEMISTRY (LOX) 45
2.5.3.3. 100 MM TRIS HC1 (PH 8.5) 45
2.6. KITS 45
2.7. OTHER REAGENTS 45
2.8. SOFTWARE 46
3. METHODS 46
3.1. GENOTYPING POLYMERASE CHAIN REACTION (PCR) 46
3.1.1. DNA ISOLATION 46
3.1.2. PCR CONDITIONS 47
TABLE OF CONTENTS III
3.1.3. AGAROSE GEL ELECTROPHORESIS 49
3.2. CLINICAL AND METABOLIC ANALYSES DURING THE LIRAGLUTIDE/PLACEBO
TREATMENT
PERIOD 49
3.2.1. ACCOMPLISHMENT OF LIRAGLUTIDE/PLACEBO ADMINISTRATION 49
3.2.2. MONITORING OF BODY WEIGHT, FOOD INTAKE AS WELL AS
CLINICAL-CHEMICAL
PARAMETERS 50
3.2.3. DETERMINATION OF GROWTH-REGULATING POLYPEPTIDES 51
3.2.3.1. DETERMINATION OF PLASMA SOMATOSTATIN LEVELS BY RADIOIMMUNOASSAY
51
3.2.3.2. DETERMINATION OF SERUM INSULIN-LIKE GROWTH FACTOR BINDING
PROTEIN-2 AND -3
(IGFBP-2 AND -3) LEVELS BY WESTERN LIGAND BLOT ANALYSIS 52
3.2.4. DETERMINATION OF SERUM INSULIN-LIKE GROWTH FACTOR-I (IGF-I)
LEVELS BY
ENZYME-LINKED IMMUNOSORBENT ASSAY (EL1SA) 52
3.3. METABOLIC TESTS 53
3.3.1. SURGICAL IMPLANTATION OF CENTRAL VENOUS CATHETERS 53
3.3.2. INTRAVENOUS GLUCOSE TOLERANCE TEST (IVGTT) 56
3.3.3. ORAL GLUCOSE TOLERANCE TEST (OGTT) 56
3.3.4. MEASUREMENT OF PLASMA INSULIN LEVELS BY RADIOIMMUNOASSAY 57
3.3.4.1. STANDARD PREPARATION 57
3.3.4.2. ASSAY SET-UP 57
3.3.5. CALCULATION OF INSULIN SENSITIVITY INDICES 58
3.3.5.1. HOMEOSTASIS MODEL ASSESSMENT (HOMA) 58
3.3.5.2. QUANTITATIVE INSULIN SENSITIVITY CHECK INDEX (QUICKI) 59
3.3.5.3. MATSUDA INDEX (1SI (MACUDA)) 59
3.4. LIRAGLUTIDE PROFILING 59
3.5. MORPHOLOGICAL EVALUATION OF DPR * TRANSGENIC PIGS AT THE END OF
THE
TREATMENT PERIOD 60
3.5.1. NECROPSY 60
3.5.2. PANCREAS PREPARATION AND SAMPLING 60
3.5.3. IMMUNOHISTOCHEMICAL STAINING FOR INSULIN 61
3.5.4. QUANTITATIVE-STEREOLOGICAL ANALYSES OF PANCREATA 63
3.5.5. COUNTING OF NUCLEAR PROFILES 64
3.6. STATISTICS 64
TABLE OF CONTENTS
IV
V. RESULTS 66
1. GENOTYPING OF GIPR
DN
TRANSGENIC PIGS BY PCR 66
2. PLASMA LIRAGLUTIDE LEVELS IN GIPR
D
TRANSGENIC PIGS 67
3. MONITORING OF CLINICAL, METABOLIC AND CLINICAL-CHEMICAL PARAMETERS
DURING LIRAGLUTIDE THERAPY 69
3.1. CLINICAL-CHEMICAL PARAMETERS AND UNCHANGED HEALTH STATUS IN
LIRAGLUTIDE-
TREATED GIPR
DN
TRANSGENIC PIGS 69
3.2. REDUCED FOOD INTAKE AND FEEDING EFFICIENCY IN LIRAGLUTIDE-TREATED
GIPR
1
TRANSGENIC PIGS 72
3.3. REDUCED BODY WEIGHT GAIN IN LIRAGLUTIDE-TREATED GLPR
DN
TRANSGENIC PIGS. 73
3.4. INFLUENCE OF LIRAGLUTIDE TREATMENT ON LEVELS OF GROWTH-REGULATING
POLYPEPTIDES 75
3.4.1. CHANGES IN SOMATOSTATIN LEVELS IN LIRAGLUTIDE- AND
PLACEBO-TREATED GIPR
DN
TRANSGENIC PIGS 75
3.4.2. CHANGES IN IGF-I, IGFBP-2 AND-3 LEVELS IN LIRAGLUTIDE- AND
PLACEBO-TREATED
GIPR
DN
TRANSGENIC PIGS 76
4. EFFECT OF LIRAGLUTIDE TREATMENT ON GLUCOSE CONTROL 78
4.1. IMPROVED ORAL GLUCOSE TOLERANCE AND DECREASED INSULIN SECRETION IN
LIRAGLUTIDE-TREATED GIPR
DN
TRANSGENIC PIGS 78
4.1.1. PROPHYLACTIC GROUP: RESULTS OF ORAL GLUCOSE TOLERANCE TESTS 78
4.1.2. THERAPEUTIC GROUP: RESULTS OF ORAL GLUCOSE TOLERANCE TESTS 80
4.2. IMPROVED INSULIN SENSITIVITY IN LIRAGLUTIDE-TREATED GIPR
1111
TRANSGENIC PIGS84
4.3. IMPROVED INTRAVENOUS GLUCOSE TOLERANCE IN LIRAGLUTIDE-TREATED GIPR
4
TRANSGENIC PIGS 87
4.3.1. PROPHYLACTIC GROUP: RESULTS OF INTRAVENOUS GLUCOSE TOLERANCE
TESTS 87
4.3.2. THERAPEUTIC GROUP: RESULTS OF INTRAVENOUS GLUCOSE TOLERANCE TESTS
89
5. EFFECTS OF LIRAGLUTIDE TREATMENT ON THE BETA-CELL VOLUME OF GIPR
,,
TRANSGENIC PIGS 92
5.1. PANCREAS HISTOLOGY OF LIRAGLUTIDE- AND PLACEBO-TREATED GIPR
DN
TRANSGENIC
PIGS 92
5.2. EFFECT OF LIRAGLUTIDE TREATMENT ON THE TOTAL BETA-CELL VOLUME 93
5.2.1. EVALUATION OF THE BETA-CELL VOLUME IN THE PROPHYLACTIC GROUP 93
5.2.2. EVALUATION OF THE BETA-CELL VOLUME IN THE THERAPEUTIC GROUP 95
TABLE OF CONTENTS V
5.3. UNCHANGED NUCLEAR PROFILE COUNT IN LIRAGLUTIDE- AND PLACEBO-TREATED
GIPR
DN
TRANSGENIC PIGS 97
5.4. INFLUENCE OF LIRAGLUTIDE TREATMENT ON GASTRIC EMPTYING IN GIPR
DN
TRANSGENIC
PIGS 98
5.5. ORGAN WEIGHTS OF LIRAGLUTIDE- AND PLACEBO-TREATED GIPR
LLN
TRANSGENIC
PIGS 98
VI. DISCUSSION 100
1. PLASMA LIRAGLUTIDE LEVELS IN GIPR
DN
TRANSGENIC PIGS 100
2. DRAMATIC BODY WEIGHT AND FOOD INTAKE REDUCING EFFECTS DUE TO
LIRAGLUTIDE TREATMENT 102
2.1. REDUCED FOOD INTAKE AND FEEDING EFFICIENCY IN LIRAGLUTIDE-TREATED
GIPR
DN
TRANSGENIC PIGS 102
2.2. REDUCED BODY WEIGHT GAIN IN LIRAGLUTIDE-TREATED GIPR
DN
TRANSGENIC PIGSL04
2.2.1. REDUCED SECRETION OF THE ANABOLIC HORMONE INSULIN 105
2.2.2. NO EFFECT OF LIRAGLUTIDE ON THE INSULIN-LIKE GROWTH FACTOR SYSTEM
106
2.2.3. SOMATOSTATIN LEVELS IN GIPR
DN
TRANSGENIC PIGS 106
2.2.4. LIRAGLUTIDE DOSAGE RECOMMENDED FOR HUMANS IN ADOLESCENT GIPR
DN
TRANSGENIC PIGS 107
3. EFFECTS OF LIRAGLUTIDE TREATMENT ON GLUCOSE CONTROL IN GIPR
DL1
TRANSGENIC PIGS 109
3.1. IMPROVED GLUCOSE TOLERANCE AND INSULIN SENSITIVITY IN
LIRAGLUTIDE-TREATED
GIPRDN TRANSGENIC PJG
S
109
3.2. REDUCED INSULIN SECRETION IN LIRAGLUTIDE-TREATED GIPR
DN
TRANSGENIC PIGS. 110
3.3. UNCHANGED FASTING BLOOD GLUCOSE IN LIRAGLUTIDE-TREATED GIPR
LN
TRANSGENIC
PIGS 112
4. DECREASED TOTAL BETA-CELL VOLUME IN LIRAGLUTIDE-TREATED GIPR
DI
TRANSGENIC PIGS 112
5. CONCLUDING REMARKS AND PERSPECTIVES 116
VII. SUMMARY 118
VIII. ZUSAMMENFASSUNG 120
IX. INDEX OF FIGURES 122
TABLE OF CONTENTS VI
X. INDEX OF TABLES 124
XI. INDEX OF ABBREVIATIONS 125
XII. REFERENCE LIST 129
XIN. ACKNOWLEDGEMENTS 173
|
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| spelling | Streckel, Elisabeth 1985- Verfasser (DE-588)1049856872 aut Effects of the long-acting glucagon-like peptide-1 receptor agonist liraglutide in adolescent pigs with impaired glucose-dependent insulinotropic polypeptide receptor function von Elisabeth Therese Streckel 2013 VI, 174 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier München, Univ., Diss., 2013 (DE-588)4113937-9 Hochschulschrift gnd-content Erscheint auch als Online-Ausgabe urn:nbn:de:bvb:19-168554 http://edoc.ub.uni-muenchen.de/16855/ Verlag kostenfrei Volltext https://nbn-resolving.org/urn:nbn:de:bvb:19-168554 Resolving-System DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=027238673&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Streckel, Elisabeth 1985- Effects of the long-acting glucagon-like peptide-1 receptor agonist liraglutide in adolescent pigs with impaired glucose-dependent insulinotropic polypeptide receptor function |
| subject_GND | (DE-588)4113937-9 |
| title | Effects of the long-acting glucagon-like peptide-1 receptor agonist liraglutide in adolescent pigs with impaired glucose-dependent insulinotropic polypeptide receptor function |
| title_auth | Effects of the long-acting glucagon-like peptide-1 receptor agonist liraglutide in adolescent pigs with impaired glucose-dependent insulinotropic polypeptide receptor function |
| title_exact_search | Effects of the long-acting glucagon-like peptide-1 receptor agonist liraglutide in adolescent pigs with impaired glucose-dependent insulinotropic polypeptide receptor function |
| title_full | Effects of the long-acting glucagon-like peptide-1 receptor agonist liraglutide in adolescent pigs with impaired glucose-dependent insulinotropic polypeptide receptor function von Elisabeth Therese Streckel |
| title_fullStr | Effects of the long-acting glucagon-like peptide-1 receptor agonist liraglutide in adolescent pigs with impaired glucose-dependent insulinotropic polypeptide receptor function von Elisabeth Therese Streckel |
| title_full_unstemmed | Effects of the long-acting glucagon-like peptide-1 receptor agonist liraglutide in adolescent pigs with impaired glucose-dependent insulinotropic polypeptide receptor function von Elisabeth Therese Streckel |
| title_short | Effects of the long-acting glucagon-like peptide-1 receptor agonist liraglutide in adolescent pigs with impaired glucose-dependent insulinotropic polypeptide receptor function |
| title_sort | effects of the long acting glucagon like peptide 1 receptor agonist liraglutide in adolescent pigs with impaired glucose dependent insulinotropic polypeptide receptor function |
| topic_facet | Hochschulschrift |
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