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Gastrointestinal Physiology Valerie Parker, DVM, DACVIM February 16, 2012.

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Presentation on theme: "Gastrointestinal Physiology Valerie Parker, DVM, DACVIM February 16, 2012."— Presentation transcript:

1 Gastrointestinal Physiology Valerie Parker, DVM, DACVIM February 16, 2012

2 Objectives  We will cover  GI hormones/secretions/glands  Pertinent veterinary literature  We will not cover  Anatomy  GI motility  Digestion

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4 GI hormones  Gastrin  Cholecystokinin (CCK)  Secretin  Motilin  Incretins

5 Hormone  Origin  Stimulus  Effect

6 Gastrin  G-cell  Antrum of stomach  Stimulated by  Gastric distension  Protein digestion  Gastrin releasing peptide  Acetylcholine (ACh)

7 Gastrin  Effects  Stimulates gastric acid secretion  Stimulates growth of gastric mucosa

8 Gastrin  Measured in 125 fasted (healthy) dogs  78 males and 47 females  Differences in sex/age  As age increased – [gastrin] higher in males  No difference between sexes when younger  [Gastrin] = / pg/ml Torres JA, et al. Medicina Veterinaria. 2000;17:54-62

9 Gastrinoma  Non-β-cell islet (delta?) cell tumors  Autonomously secrete excessive gastrin  Leads to gastric acid hypersecretion   GI erosions/ulceration  Gastrinomas may secrete other hormones  Eg, insulin, ACTH

10 Gastrinoma  Gastrinoma = APUDoma  Peptide-secreting cell tumor  APUD = amine precursor uptake & decarboxylation

11 Zollinger-Ellison syndrome  Triad of  Hypergastrinemia  Neuroendocrine neoplasm  Gastrointestinal ulceration

12 Diagnosis  Typically have clinical evidence  Gastric concentration  pg/ml in dogs w/ gastrinoma  350, 1000 pg/ml in cats  Most animals have [gastrin] > 3x normal  Not pathognomonic  Normal gastrin does not rule-out gastrinoma

13 Additional testing  Provocative stimulation tests  Secretin stimulation test  Calcium stimulation test  Combined secretin-calcium stimulation

14 Gastrinoma  Treatment  Surgical procedure (if possible)  Partial gastrectomy  Acid reduction  H 2 -receptor antagonists  Proton-pump inhibitors*  Somatostatin analogue (octreotide)

15 Cholecystokinin (CCK)  I-cell  Mucosa of duodenum & jejujum  Stimulated by  Fat digestion

16 CCK  Effects  Gall bladder contraction  Inhibits gastric contraction  Allows time for fat digestion

17 Secretin  S-cell  Mucosa of duodenum  Stimulated by  Acidic gastric fluid in duodenum  Effects  Pancreatic secretion of bicarbonate  Mild effect on GI motility

18 Motilin  Upper duodenum  Fasted state  Released cyclically  Effects  Increases GI motility

19 Incretins  Hormones secreted in response to nutrients in intestinal lumen  Glucose-dependent insulinotropic polypeptide (GIP)  Aka gastric inhibitory peptide  Glucagon-like polypeptide-1 (GLP-1)

20 Gastric inhibitory peptide (GIP)  K cell (intestine)  Stimulated by  Fat & protein digestion  Lesser extent CHO digestion  Effects  Decreases gastric emptying

21 Glucagon-like peptide-1 (GLP-1)  L-cell (intestine)  Actions  Glucose-dependent stimulation of insulin  Suppresses glucagon secretion

22 Incretins  Actions  Stimulate insulin release  Reduce gastric emptying  Slow rate of nutrient absorption  Inhibit glucagon release  Inactivated by dipeptidyl peptidase-4 (DDP-4)

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24  Exenatide = GLP-1 mimetic  Increases insulin secretion  Delays gastric emptying  Increases satiety  Improves β-cell function

25  9 healthy cats  Isoglycemic glucose clamps  To mimic [BG] of oral glucose tolerance test  1 ug/kg exenatide SQ  Measured BG, insulin, exenatide concentrations

26  Insulin increased within 15 minutes  Quickly returned to baseline  Increased again w/ dextrose infusion

27  Exenatide peaked at 45 minutes  Detectable in some cats up to 8 hrs  Vs. GLP-1 – t-½ = 1-2 min  No adverse effects noted  1 cat developed hypoglycemia  54 1 hr post-injection

28  Conclusions  Exenatide affects insulin secretion in cats in a glucose-dependent manner  May benefit survival of pancreatic β-cells in cats with NIDDM

29 Somatostatin  D-cell  Stimulated by  Gastric pH < 3

30 Somatostatin  Decreases  Gastrin  Histamine  Acid secretion  Inhibits  Insulin  Glucagon  Growth hormone

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32 Alimentary glands  Mucous glands  Crypts of Lieberkühn  Tubular glands  Oxyntic (gastric)  Pyloric  Extra-GI  Salivary glands  Pancreaatic  Hepatic

33 Tubular glands  Oxyntic (gastric) glands  Pyloric glands

34 Pyloric glands  Antrum  Distal 20% stomach  Secrete  Mucus  Gastrin

35 Pyloric gland cellularity  Mostly mucous cells  Lubrication  food movement  Protection of stomach wall from acid  G-cells  Gastrin

36 Oxyntic (aka gastric) glands  Oxyntic = acid-forming  Body & fundus  Proximal 80% stomach

37 Oxyntic gland cellularity  Mucous neck cell  Peptic (chief) cell  Pepsinogen  Parietal (oxyntic) cell  Hydrochloric acid  Intrinsic factor (dog)*

38 Cobalamin absorption 1. Binds to R protein 2. Then gastric/pancreatic intrinsic factor 3. Finally to receptors in ileum

39 Hypocobalaminemia in LSA  58 dogs w/ multicentric LSA  Hypocobalaminemia (< 252 ng/L)  Present in 16%  Associated with poor outcome  May be prognostic Cook AC, et al. J Am Vet Med Assoc 2009;235:1437–1441

40 Hypocobalaminemia in LSA

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42 Pepsinogen  From peptic (chief) cell  Activated by contact with HCl  Forms pepsin  Proteolytic actions in acidic pH ( )  Inactivated by pH > 5

43 Pepsinogen  Secreted by peptic cells  Stimulated by ACh  Also indirectly in response to acid  Pepsinogen  pepsin (active)

44 Acid Secretion  Many stimuli  Gastrin (G-cell) = most potent  Histamine  Enterochromaffin-like cell (ECL)  Mast cell  Acetylcholine  Inhibited by somatostatin

45 Hydrochloric acid  Secreted by parietal cell (oxyntic gland)  Rate of secretion directly related to histamine release (ECL-cell)  Affected by gastrin

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47 Histamine & gastrin in MCT  17 dogs with mast cell tumor  [Histamine] higher in MCT vs. normal dogs  [Gastrin] lower in MCT vs. normal dogs  Inversely related to histamine  Indirect evidence for hyperacidity from hyperhistaminemia Fox LE, et al. J Vet Intern Med 1990;4:

48 Protection from acid  Gastric mucosal barrier (GMB)  Epithelial cells  Bicarbonate-rich mucus layer  Mucosal blood supply  Bicarbonate  Oxygen  Nutrients  Prostaglandins  PGE 2

49 Pancreatic digestive enzymes  Protein digestion  Trypsin  Chymotrypsin  Split proteins  peptides (not amino acids)  Carboxypolypeptidase  Can break peptides into amino acids

50 Pancreatic digestive enzymes  Enzymes secreted as inactive zymogens  Activated after secreted into intestine  Eg. Trypsinogen activated by enterokinase  Activation is self-perpetuated  Trypsinogen activated by trypsin  Inhibited by trypsin inhibitor

51 Pancreatic digestive enzymes  Carbohydrate digestion  Pancreatic amylase  Hydrolysis of starch, glycogen, etc.  Not cellulose

52 Pancreatic digestive enzymes  Fat digestion  Pancreatic lipase  Fat hydrolysis  fatty acids & monoglycerides  Cholesterol esterase  Hydrolysis of cholesterol esters  Phospholipase  Splits fatty acids from phospholipase

53 Spec cPL in 11 healthy dogs  Measured daily, weekly, monthly  14 times over 12 weeks  Goals  Determine biological variability  Validity of applying reference range  Difference needed for sequential results Carney PC, et al. J Vet Intern Med 2011;25:825–830

54 Spec cPL

55  Mean serum concentration = 62.3 mg/L  Range = 29.0–516.2 mg/L  Interindividual variability = 49%  Intraindividual variability = 194%  ~ 5-fold difference must be seen to reflect a change in the animal rather than biological variation (healthy dogs)

56 Pancreatic juice  In addition to enzymes  Bicarbonate  Water  Bicarb secretion can exceed 5x [plasma]  Neutralizes HCl in duodenum

57 Pancreatic stimuli  Acetylcholine  CCK  Stimulates acinar cells  Large quantities enzymes  Less water, electrolytes  Secretin  Stimulates secretion of water/bicarbonate

58 Bile secretion  Bile stimulated by CCK  Response to fat digestion  Also stimulated by ACh

59 Bile  Bile composition  Mostly bile salts  Bilirubin  Cholesterol  Lecithin  Electrolytes

60 Bile acids  BAs synthesized in liver (cholesterol)  Conjugated to taurine (cat) or glycine  Stored in gall bladder  CCK stimulates release (fat digestion)  Transported from ileum to portal circulation

61 Bile acids  Primary BAs = cholic & chenodeoxycholic acids  Formed in liver  90-95% absorbed from ileum (Na-K ATPase pump)  5-10% primary BAs reach colon  Secondary BAs = deoxycholic & lithocholic acids

62 Enterohepatic circulation

63 Small intestinal secretions  Brunner’s glands (mucus glands)  Located in proximal duodenum  Secrete alkaline mucus in response to:  Irritating stimuli  ACh (vagal stimuli)  Secretin  Inhibited by sympathetic stimulation

64 Small intestinal secretions  Crypts of Lieberkuhn  Located between villi  2 cell types  Goblet cell  mucus  Enterocytes  Crypts secrete water & electrolytes  Villi reabsorb

65 Small intestinal enzymes  Protein digestion  Peptidases  CHO digestion  Sucrase  Maltase/isomaltase  Lactase  Fat digestion  Intestinal lipase

66 Summary  There’s a lot going on in the GI tract!  Good references:  Guyton/Ganong physiology  Feldman/Nelson Endocrinology/Reproduction  GI hormones (page 646)  Ettinger

67 Questions?


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