Carbohydrate Digestion and Absorption

1. Carbohydrate Digestion and Absorption Gregg Kobak, MD Christine Waasdorp Hurtado, MD, MSCS, FAAP University of Colorado School of Medicine Children’s Hospital Colorado Expert Reviewers: Jeremiah Levine, MD Richard Grand, MD

2. NASPGHAN Physiology Education Series Series Editors: Christine Waasdorp Hurtado, MD, MSCS, FAAP Christine.Waasdorp@childrenscolorado.org Daniel Kamin, MD Daniel.Kamin@childrens.harvard.edu

3. Overview • Carbohydrates are composed of carbon and water • Composition = Cn(H2O)n. • Carbohydrates are the major exogenous source of glucose • 40-60% of calories in the diet • Higher in protein scarce diet • Provide 4 calories per gram • No single carbohydrate is essential

4. Carbohydrate Overview • Monosaccharides • Glucose • Galactose • Fructose • Disaccharides • Sucrose • Lactose • Maltose • Complex Carbohydrates • Starch • Amylose • Amylopectin • Dietary Fiber • Glycogen Image from - E. Generalic. http://glossary.periodni.com/glossary.php?en=carbohydrate

5. Simple Carbohydrates • Monosaccharides - • Basic unit of Carbohydrates • Most are 6 carbon hexoses • Ribose is 5 • Different molecular arrangements result in varying sweetness • Common Monosaccharides • Glucose • Fructose • Galactose • Xylose • Ribose Image from: E. Generalic, http://glossary.periodni.com/glossary.php?en=monosaccharide

6. Disaccharides -Pairs of monosaccharides • Joined by condensation • Separated by hydrolysis • Lactose • Glucose-Galactose • Found in nature primarily in mammalian milk • Maltose • Glucose-Glucose • Product of starch digestion • Sucrose • Glucose-Fructose • Table Sugar Image from: E. Generalic, http://glossary.periodni.com/glossary.php?en=monosaccharide

7. Complex carbohydrates • Polysaccharides • Starch • Dietary fiber • Glycogen

8. Starch • Provides a large portion of dietary calories in humans worldwide • Major carbohydrate for energy storage • Plant source • Amylopectin – • branched polymers of glucose (a1,6) • Amylose – • simple straight chain glucose polymers (a1,4) • 25% of starch Image from: E. Generalic, http://glossary.periodni.com/glossary.php?en=monosaccharide

9. Fiber • Found in most plant derived food • Cellulose • Pectin • Lignins • Structural parts of plants • Polymers are not digested by luminal hydrolases • Provides bulk to stool • Broken down in colon by bacterial hydrolase • Generate Short Chain Fatty Acids (SCFA) = energy for colonocytes Image from: E. Generalic, http://glossary.periodni.com/glossary.php?en=monosaccharide

10. Glycogen • Major storage carbohydrate in animals • Long straight glucose polymers (a1,4) • Branched glucose polymers (a1,6) • More branched than starch • Not found in plants • Not an important dietary source of carbohydrate Image from: E. Generalic, http://glossary.periodni.com/glossary.php?en=monosaccharide

11. Carbohydrate Overview • Carbohydrates are hydrophilic • Series of reactions are required to digest • Polymers are too large for transport • Specific hydrolases for digestion • Most are broken down to monomers for absorption • Fiber is not broken down to monomer • Specific receptors for absorption

12. Digestion of Carbohydrates • Monosaccharides • Do not require hydrolysis before absorption • Di- and poly-saccharides • Must be hydrolyzed prior to absorption • Most hydrolyzed to monosaccharides Monosaccharides can be absorbed at brush border!

13. Overview of Carbohydrate Digestion 2 Types of enzymes in the digestion of carbohydrates Disaccharidases Amylase Convert disaccharides to monosaccharides for absorption Convert polysaccharides to disaccharides Salivary amylase Maltase Sucrase-Isomaltase Pancreatic amylase Lactase Trehalase

14. Carbohydrate Digestion -Mouth • Begins in mouth • Chewing releases saliva and salivary amylase • Synthesized in serous cells of the salivary glands • Regulated by neurohumoral signals • Increased secretion when diet is high in carbohydrates • Breaks down starch at α1,4 linkages into polysaccharides and maltose • 5% of starch is broken down due to limited exposure • Amylase sensitive to acid pH Image from Dr Droual: http://droualb.faculty.mjc.edu/Course%20Materials/Physiology%20101/Chapter%20Notes/Fall%202007/chapter_20%20Fall%202007%20Phy%20101.htm

15. Carbohydrate Digestion -Mouth • Clinical correlation • Salivary amylase has increased importance in a few clinical scenarios • Infants – Low levels of pancreatic enzymes in the first year • Pancreatic insufficiency – i.e. – Cystic Fibrosis • Breast milk contains amylase • Increased role in neonates and premature infants with low pancreatic amylase production

16. Carbohydrate Digestion -Stomach • Minimal carbohydrate digestion occurs in the stomach. • No enzymes available to break down starch. • Digestion by salivary amylase continues only until food mixed with acidic stomach secretions. • Low pH inhibits amylase activity • Gastric HCl hydrolyzes small amount of sucrose to fructose and glucose

17. Carbohydrate Digestion -Intestine • Small intestine • Majority of carbohydrate digestion takes place in small intestine (SI) • Pancreatic amylase is released • Secreted by pancreatic acinar cells • Secreted following stimulus of secretin and CCK • Targets α1,4 bonds • Terminal bonds and α1,6 bonds resist digestion • Starch in SI is digested into a mixture (simplest structures derived from branched amylopectin) • Maltose (glucose dimer) • Maltotriose (glucose trimer) • α–Limit dextrins (branched amylopectin remnants) Image from: www.quizlet.com

18. Carbohydrate Digestion -Intestine • Oligosaccharides and disaccharides are digested at the brush border. • Further digestion required for all, but monosaccharides • Specific enzymes finish the job • Enzymes are synthesized in the enterocytes and trafficked to the apical membranes • Enzymes are glycosylated in Golgi apparatus to protect from proteolysis • Anchored by trans-membrane segment • Higher concentration of enzymes in the proximal SI • Higher concentration on villi and lower in crypts • Enzymes • Lactase • lactose into glucose and galactose • Sucrase • sucrose into glucose and fructose • Isomaltase • α1,6 bonds of limit dextrins • Maltase • Maltose into glucose and glucose Image from: www.wikipedia.com

19. Sucrose • Sucrose = Table sugar • No luminal digestion • Brush border digestion by sucrase • Product is glucose and fructose • Rate limiting step is the uptake at apical membrane Image from: http://www.indiana.edu/~oso/Fructose/Sources.html

20. Lactose • Lactose is a disaccharide consisting of glucose and galactose • Brush border digestion by lactase • 2 identical active sites with a single polypeptide chain • Glucose and galactose collect against concentration gradient • Rate limiting step is hydrolysis • Clinical correlation • Decreasing lactase with age • Lactase is inhibited by glucose Image from: http://www.indiana.edu/~oso/Fructose/Sources.html

21. Maltose • Breakdown product of starch • Maltose is a disaccharide consisting of glucose and glucose • Brush border digestion by maltase

22. Digestion in Large Intestine • Non-digestible carbohydrates • 10% starches, cellulose and hemicellulose from fruit and vegetables, some lactose and fructose, and monosaccharides lactulose, sorbitol and sucrulose • Limited mainly to anaerobic fermentation by colonic bacteria • Short-chain fatty acids produced by microbial digestion of fiber and undigested carbohydrates • Propionate • Butyrate • Acetate • Lactate • Methane and hydrogen also produced = flatus

23. Carbohydrate Absorption • Glucose is absorbed in the mouth in small quantities • No significant absorption occurs in stomach • Majority of sugars are absorbed in small intestine at apical membrane and transferred out at basolateral membrane to portal circulation. • Carrier mediated due to size of molecules • active transport down Na+ gradient • glucose and galactose • facilitated diffusion • fructose • Passive transport in small amounts

24. Carbohydrate Digestion/Absorption “coupling” Image from: Tsai - http://www.studyblue.com/notes/note/n/ph3-05-06-digestion-and-absorption/deck/1101242

25. Glucose Absorption • Glucose absorption via SGLT-1 transporter • Active transport • Sodium-glucose co-transporter • Accumulate glucose against the gradient Image from: Wright. Am J Phsy 1998

26. Fructose Absorption • Fructose uses Glut5 and Glut2 • Na-independent • Facilitated diffusion GLUT5 Image from: Wright. Am J Phsy 1998

27. Passive Transport From: Breves. Livestock Science 2010

28. Regulation of Carbohydrate Absorption • All enzymes and transporters are present at birth • Lactase activity is hard wired • Lactase persistence • Lactase remains at infantile levels • Lactase non-persistence • Lactase decreases starting at 3-5 years of age • Varies with race and ethnicity • Sucrase-isomaltase (SI) and maltase-glucoamylase levels are inducible • Transcriptional regulation mechanism

29. Control of enzyme secretion • Sucrase-isomaltase (SI) • 5’ flanking region of the SI gene has several DNA regulatory regions that control the initiation of gene transcription. • Transcriptional proteins • hepatocyte nuclear factor (HNF-1), GATA-type zinc finger transcription factors, and caudal-related homeodomain proteins (Cdx). • Hormonal influences have also been proposed and are currently being studied further. • Lactase • Cdx, HNF-1 and GATA 5, along with other transcription factors all interact with the proximal promoter region and result in transcription initiation. • Possible repressor region exists that down regulates lactase expression. Lactase persistent people failed to bind at this repressor region due to single nucleotide polymorphisms (SNP).  

30. Clinical Correlations • Glucose-Galactose Malabsorption • Mutation of SGLT-1 • Defective transporter • Severe diarrhea at birth • Osmotic diarrhea due to glucose and galactose malabsorption • FTT and malnutrition • Very rare • Treatment is fructose containing formula

31. Congenital Sucrase-Isomaltase Deficiency • Congenital Sucrase-Isomaltase Deficiency • Homozygous or heterozygous mutation in the SI gene • Autosomal recessive • 1 in 5,000 North Americans, 10% Eskimos • Maldigestion of sucrose and maltose • Presentation – osmotic diarrhea, abdominal pain and FTT • Treatment – • Sucrose and starch free diet. • Slowly introduce starch when sucrose free • Sucraid supplementation

32. Clinical Correlations • Small Bowel Bacterial Overgrowth • Increased bacteria Increased fermentation • Bacterial fermentation prevents small bowel absorption • Breath test - malabsorption results in increased breath H+

33. Clinical Correlations • Pancreatic Insufficiency • Cystic fibrosis, pancreatitis, obstruction (tumor) • Mechanisms • Decreased enzyme volume • <10% baseline before symptoms • Failure to alkalinize fluid in small intestine • Enzymes are inactivated in acidic environment = malabsorption

34. Clinical Correlations • Celiac disease • Decreased absorptive capacity secondary to decreased villus length • Decreased enzymes due to decreased brush border surface area • Decreased number of transporters • Malabsorption and diarrhea

35. Summary • Carbohydrates are the major exogenous source of glucose • Three main types • Monosaccharides, disaccharides, and complex carbohydrates • Digestion requires a series of steps • Salivary and pancreatic amylase • Brush border enzymes • Non-digested carbohydrates are digested in the colon creating SCFA

36. Review Questions: • A 9y.o Asian boy is brought to your office by his mother. They report that he has had worsening diarrhea for the past 6 months following a viral acute gastroenteritis. What is the most likely reason for his diarrhea? • Celiac disease • Lactose Non-persistence • Pancreatic Insufficiency • Infection • What enzymes involved in carbohydrate digestion are induced by increasing dietary intake? • Lactase • Sucrase-isomaltase • Maltase-glucoamylase • Amylase

37. Questions? • Please send any questions or comments to Christine.waasdorp@childrenscolorado.org and Daniel.Kamin@childrens.harvard.edu