Lesson 1 Fundamentals of Nutrition Mimi Giri MD

Lesson 1 Fundamentals of Nutrition Mimi Giri, MD, Ph. D Department of Endocrinology, University Hospital of Ghent, Belgium

Carbohydrate Nutrition and Metabolism • Introduction & Sources of carbohydrate in the diet • Structures • General functions of carbohydrate & Essentiality • Glucose from dietary carbohydrate: digestion, absorption, transport into cells • Glucose metabolism: glucose disposal & synthesis: • Glucose disposal: Glycolysis, TCA cycle, FFA synthesis, NEAA synthesis; Glycogen synthesis • Glucose synthesis: purpose, glycogen breakdown and gluconeogenesis

• Introduction Humans: ~ 50% of calories ingested as CHO (10 - 85%) 160 g starch, 120 g sucrose, 30 g lactose, 5 g glucose, 5 g fructose, trace maltose

• Introduction Sources of carbohydrate: sucrose: “sugar” lactose: milk maltose: beer fructose: fruit, corn-syrup “processed foods” starch (amylose & amylopectin): wheat, rice, corn, barley, oats, legumes. . glycogen: muscle and liver

• Introduction Glucose: ATP synthesis: all tissues RBC, tissues of eye, renal medulla, brain, intestines, white blood cells, skin: rely primarily on glucose as energy source in the fed state In the fed state, glucose is primarily obtained from dietary carbohydrate (CHO)

• Structures Monosaccharides: Glucose, fructose, galactose Dissacharides: maltose: glucose + glucose lactose: glucose + galactose sucrose: glucose + fructose Polysaccharides: amylose: glucose +. . (linear) amylopectin: glucose +. . (branched) glycogen: glucose +. . . (very branched) +. . .

• General functions of carbohydrates Energy: ATP synthesis (~ 4 kcal/g) NEAA synthesis: carbon skeleton Fat synthesis: via acetyl-Co. A Glycogen synthesis TCA cycle intermediates Nucleotides: sugar portion Glycoproteins Glycolipids

Overview of Metabolism protein polysaccharides ADP + Pi ATP amino acids lipids ADP + Pi ATP hexoses pentoses ADP + Pi ATP fatty acids ADP + Pi ATP pyruvate urea cycle CO 2 ADP + Pi acetyl-Co. A ATP citric acid cycle e- O 2 electron transport chain oxidative phosphorylation ATP

Overview of Catabolic Processes Proteins Fats Carbohydrates Stage 1 Amino acids Fatty acids Simple Sugars Glycolysis Pyruvate ATP Stage 2 Acetyl Co. A Citric acid cycle Oxidative phosphorylation ATP Stage 3

Use of Amino Acids and Fatty Acids Liver Fats and protein can also be used by the body as a source of energy. glycogen Not as easily used as carbohydrates. glucose-6 -P pyruvate Amino Acids or Fatty Acids

• Essentiality of carbohydrates metabolic need is for glucose: ~300 g/d in humans - glucose can be made from most AAs (not Leu) - glucose can be made from propionate (SCFA) - glucose can be made from glycerol - glucose cannot be made from fatty acids CHO not strictly essential in diet Relying solely on AAs etc. as precurser for glucose not prudent or practical (except for carnivores), so. . .

• Glucose from dietary carbohydrate: DIGESTION, ABSORPTION & TRANSPORT into cells Mouth salivary amylase: - hydrolyzes 1 -4 bonds in starch - release: psychic (cephalic) stimuli mechanical stimuli: food in mouth chemical stimuli: food on taste buds - little digestion Stomach: Stomach Negligible

Stage One • Hydrolysis of food into smaller sub-units. Handled by the digestive system.

Stage One • Salivary glands: • Secrete amylase. • - digests starch. • Stomach: • Secretes HCl. • - denatures protein and pepsin. • Pancreas: • Secretes proteolytic enzymes and lipases. • - degrades proteins and fats.

Stage One • Liver and gallbladder: • Deliver bile salts. • - emulsify fat globules - easier to digest. • Small intestine: • Further degradation. • Produces amino acids, hexose sugars, fatty acids and glycerol. • Moves materials into blood for transport to cells.

• CHO: Digestion, Absorption & Transport Small Intestine brush border lumen

CHO Digestion: SMALL INTESTINE LUMEN lumen CCK pancreas digesta enzymes CCK = cholecystekinin

Carbohydrate digestion: SMALL INTESTINE LUMEN pancreas lumen enzymes - -amylase enzymes lumen (duodenum) cuts 1 -4 bond in starch: maltose, limit dex. efficient and fast acting enzyme

Carbohydrate digestion: SMALL INTESTINE Brush border enzymes occur on brush border maltase: cuts maltose -limit dextrinase: cuts 1 -6 bond lactase: cuts lactose sucrase: cuts sucrose result: monosaccharides glucose, galactose, fructose

• Carbohydrate: ABSORPTION SITE OF ABSORPTION Jejunum & Ileum GLUCOSE/GALACTOSE Absorbed by active transport - sugars move against concn gradient - requires ATP Facilitated diffusion of glucose - glucose concentration must be lower in enterocyte

• Carbohydrate: ABSORPTION FRUCTOSE Carrier mediated facilitated diffusion - fructose conc must be lower in enterocyte • CARBOHYDRATE TRANSPORT - enterocyte to portal vein to liver • GLUCOSE UPTAKE INTO CELLS - carrier mediated diffusion - stimulated by insulin (muscle, liver, adipocyte)

• Carbohydrate metabolism: FRUCTOSE liver: fructose F-6 -P GALACTOSE liver: galactose gal-1 -P DHAP G-1 -P glycolytic pathway G-6 -P glucose

• Glucose metabolism: glucose disposal & synthesis SIGNIFICANCE - Control blood glucose concentrations in starvation, exercise, stress, refeeding. . . 4 - 6 mmol/L (humans): 10 m. M after meal high blood sugar: damage lens, kidney etc. complications of diabetes low blood glucose: brain damage & death - Control rate of glucose utilization in tissues

• Control rate of glucose utilization in tissues e. g. How does liver assess how much glucose is being used by muscle or brain? e. g. When a high CHO meal eaten, rate of glucose absorption is high; to maintain normal blood glucose levels, the rate of glucose use in other tissues such as muscle must increase Control & integration of glucose metabolism (disposal & synthesis) among tissues is required Liver plays a major role!!

Liver as Glucostat Diet Gut Glycerol Liver Fat Blood Glucose 4. 5 -5. 5 mmol/L Brain Kidney Urine BG >10 mmol/L Amino Acids Lactic Acid Muscle Glands & other tissues

Factors affecting glucose concentration Tend to raise • Hunger • Glucose absorption from gut • Hepatic glycogenolysis – Adrenaline – Glucagon • Gluconeogenesis in liver • Insulin antagonist – Growth Hormone – Cortisol • Insulin destroying enzymes • • Tend to lower Satiety Glucose diffusion in ECF Muscular exercise Insulin – – Glucose oxidation Glycogen deposition Lipogenesis Gluconeogenesis { glucosuria – in diabetes}

• Fate of glucose glycogen synthesis ATP synthesis GLUCOSE NEAA synthesis FFA synthesis

• Fate of glucose: glycolysis, TCA cycle & FFA synthesis ATP synthesis glucose ATP pyruvate acetyl-Co. A lactate FFA synthesis TCA cycle ATP lots!!

• Fate of glucose: glycolysis & TCA cycle purpose & tissues glucose ATP pyruvate acetyl-Co. A TCA cycle anaerobic glycolysis - RBCs, WBCs - kidney medulla lactate - enterocytes - lens, cornea - skin - (skeletal muscle) FFA - make ATP (2 ATP/glucose) - maintain blood glucose

• Fate of glucose: glycolysis & TCA cycle purpose & tissues glucose ATP pyruvate acetyl-Co. A TCA cycle ATP aerobic glycolysis - brain - liver - skeletal muscle - kidney cortex - etc. - make ATP (32 ATP/glucose) - maintain blood glucose

• Fate of glucose: glycolysis & TCA cycle stimulation and inhibition glucose ATP pyruvate acetyl-Co. A TCA cycle ATP stimulation - high glucose - low ATP lactate - insulin FFA inhibition - high ATP - FFAs

• Fate of glucose: FFA synthesis tissues, stimulation (generally only occurs if excess calories eaten) glucose mainly: liver adipocytes pyruvate diet acetyl-Co. A FFA TCA cycle TG ATP stimulation - high glucose - high ATP * - insulin

• Fate of glucose: NEAA synthesis tissues, stimulation glucose mainly: liver muscles pyruvate diet acetyl-Co. A NEAA TCA cycle Proteins ATP stimulation - high glucose - high ATP * - insulin

• Fate of glucose glycogen synthesis GLUCOSE NEAA synthesis ATP synthesis glycolysis TCA cycle FFA synthesis

• Fate of glucose: glycogen synthesis Liver & Muscle glucose glycogen glucose SI gluc Liver glycogen glucose skeletal muscle

• Fate of glucose: glycogen synthesis Liver & Muscle glucose glycogen stimulation: high glucose (liver) insulin low glycogen (muscle) glycogen glucose SI gluc glycogen + ins glucose Liver pancreas + insulin (ins) glucose skeletal muscle

• Fate of glucose glycogen synthesis ATP synthesis GLUCOSE NEAA synthesis FFA synthesis glucose utilization result: decrease blood glucose level regulate tissue glucose use

• Glucose synthesis: glycogen breakdown gluconeogenesis GLUCOSE glucose synthesis purpose: - maintain blood glucose level: fasting, sustained exercise, stress, hypoglycaemia - regulation of tissue glucose use tissues: liver, muscle, kidney

• Glucose synthesis: glycogen breakdown (LIVER) glucose immediate glucose source glycogen stimulation: inhibition: low blood glucose adrenalin/glucagon insulin glycogen CO 2 + glucagon glucose tissues SI Liver glucagon pancreas

• Glucose synthesis: glycogen breakdown (muscle) glycogen stimulation: G-6 -P (muscle) local use only adrenalin (exercise/stress) glycogen + adr G-6 -P note: glycogen G-6 -P CO 2 lactate glucose skeletal muscle

• Glucose metabolism: disposal & synthesis Liver: major role in regulation of blood glucose high blood glucose: glucose uptake glucose SI glycogen CO 2 FFA +i +i +i glucose Liver +i glucose + i = stimulated by insulin

• Glucose metabolism: disposal & synthesis Liver: major role in regulation of blood glucose low blood glucose: glucose release glycogen ala lactate +g glucose SI Liver alanine lactate glucose + g = stimulated by glucagon

• Physiological importance of gluconeogenesis low CHO diet, early starvation (no CHO intake), infection & trauma (high glucose need) glycogen glucose SI Liver gluconeogenesis glucose brain & anaerobic tissues

• Regulation of glucose use among tissues and role of fatty acids e. g. fed state/high CHO diet glucose uptake and use glycogen ATP + ins glucose gluc SI + ins glucose Liver pancreas insulin (ins)

• Regulation of glucose use fed state/high CHO diet glucose uptake and use glyc ATP CO 2/ATP +ins glucose +ins ? gluc skeletal muscle SI Liver pancreas insulin (ins)

• Regulation of glucose use fed state/high CHO diet role of fatty acids adipocyte TG - ins FFA glyc ATP glucose gluc CO 2/ATP glucose + ins - gluc skeletal muscle SI Liver pancreas insulin (ins)

• CHO metabolism: Vitamin & Mineral Co-factors biotin (carboxylation) Thiamine: Vit B 1 Riboflavin: Vit B 2 (FAD) Niacin: Vit B 3 (NAD) pantothenic acid (Acetly-Co. A) glucose biotin B 3 pyruvate B 3 lactate B 1, B 2, B 3, Mg 2+ pantothenic acid acetyl-Co. A TCA cycle B 1, B 3

Diabetes Mellitus: Metabolism out of control • Introduction • Symptoms and clinical features • Metabolic effects of insulin on CHO metabolism • Metabolic effects on protein & fat metabolism • Lack of insulin (diabetes mellitus) - effect on glucose uptake, utilization & production - effect glucose production - effect on protein synthesis & protein breakdown - effect on TG breakdown (fat cells) - effect on ketone body synthesis (liver)

• Introduction Diabetes Mellitus or Type 1 (previously juvenile onset) or insulin-dependent diabetes mellitus (IDDM) recognized as a disease for 2000 years -cells of Islets of Langerhans (pancreas) damage: inadequate insulin production Diabetes illustrates problems that arise when integration of metabolism is impaired: carbohydrate, protein & lipid metabolism

• Symptoms and clinical features polyuria polydipsia polyphagia weight loss dehydration glycosuria ketosis/ketoacidosis unconsciousness/coma

• Metabolic effects of insulin on CHO metabolism glucose uptake and use decrease blood glucose AAs, lactate glyco -ins CO 2/ATP +ins glucose +ins gluc skeletal muscle SI Liver insulin = ins

• Metabolic effects of insulin on protein metabolism - stimulate amino acid uptake - stimulate protein synthesis - inhibit protein degradation protein +ins AAs SI AAs Liver +ins Amino +ins Acids +ins -ins amino acids skeletal muscle insulin = ins

• Metabolic effects of insulin on lipid metabolism - stimulate triglyceride (TG) synthesis - inhibit triglyceride breakdown - inhibit ketone body synthesis ketone bodies -ins AAs SI FFAs free fatty acids TG +ins -ins FFA adipocyte Liver insulin = ins

• Lack of insulin (diabetes mellitus) - effect on glucose uptake, utilization & production - effect on protein synthesis & protein breakdown - effect on TG breakdown (fat cells) - effect on ketone body synthesis (liver)

• Lack of insulin (diabetes mellitus): effect on glucose uptake, utilization & production decreased glucose uptake and use increased glucose production increased blood glucose AAs, lactate glucose fat SI Liver glucose >10 m. M glucose - glucosuria - polydipsia - dehydration - coma skeletal muscle

• Lack of insulin (diabetes mellitus): effect on protein synthesis & protein breakdown decreased protein synthesis increased protein breakdown protein wasting AAs glucose protein fat AAs SI Liver protein Amino Acids amino acids skeletal muscle

• Lack of insulin (diabetes mellitus): effect on TG breakdown & ketone body synthesis increased TG breakdown weight loss increased ketone body synthesis metabolic acidosis AAs gluc fat ketones FFA Ketones FFA TG FFA adipocyte SI Liver

• Lack of insulin (diabetes mellitus): SUMMARY TG adipocyte FFA AAs glucose fat AAs SI Liver KBs FFA Ketones glucose Amino Acids protein amino acids skeletal muscle

• Lack of insulin (diabetes mellitus): Summary The normal flow of substrates following food intake is largely dependent on the secretion of insulin. Insulin exerts a potent, positive effect on anabolism, while inhibiting catabolic pathways. Diabetes is a vivid negative example that emphasizes the integration of metabolism and the importance of metabolic regulation to continuance of life. from Advanced Nutrition & Human Metabolism Groff & Gropper 2000

. Fibre • Introduction, Definition & Sources • Type of fibre and properties - cellulose, hemicelluloses, -glucans, pectins, lignin - soluble vs. insoluble fibre • Physiological & Metabolic effects - water holding capacity, binding of nutrients, fermentability • Significance • Recommended intakes

• Introduction In humans, pre-1970’s fibre believed to have no nutritional value & antinutrient Since 1970’s, fibre: - energy value - gastrointestinal function - nutrient availability - prevention & treatment of many diseases

• Definition - fibre is not a single entity - difficult to define “Endogenous components of plant material in the diet that are resistant to digestion by enzymes produced by man. They are predominantly non-starch polysaccharides and lignin and may include, in addition, associated substances. ” (Health and Welfare Canada)

• Sources Plant material plant cell wall : 95% of fibre cementing material in plants legumes: beans, peas forages: alpha, timothy hay. . bran of cereals: wheat, oats, corn, rice. . skin of fruits & vegetables

• Type of fibre & properties Cellulose - structural component of cell walls - linear polymer of -D-glucose - forages, bran of grains - high degree of crystallinity fibrous & water insoluble - monogastric animals lack cellulase in SI cannot hydrolyze -1, 4 linkage so indigestible colon: bacteria thus partly fermented

• Type of fibre & properties Hemicelluloses - polymers of: mannose, galactose, glucuronic acid, xylose, arabinose (5 & 6 carbon sugars) with some branching - forages, bran of cereals, legumes - not very water soluble (depends on type) - monogastric animals: hemicelluloses are not digested in SI partly digested in colon by bacteria

• Type of fibre & properties -glucans (gum) - cell walls of grasses - bran coat of barley, oats - glucose polymer: -1, 4 and -1, 3 (branched) - water soluble - monogastric animals: not digested in SI gummy and viscous large intestine: rapidly fermented

• Type of fibre & properties Pectins - structural component of plant cell walls cementing material - polymers of polygalacturonic acid, which may or may not have a methylester group - fruit (skin), forages (alfalfa), rye, - soluble in H 2 O & form gels (branched) - monogastric animals: pectins are not digested in SI digested rapidly colon by bacteria

• Type of fibre & properties Lignin - NOT a carbohydrate - structural component of plant cell walls - aromatic polymer; polyphenolic (hydrophobic) - insoluble in water - not digestible in SI or by bacteria Mucilages & algal polysaccharides - carragenan, agar - water soluble - highly fermentable

• Type of fibre & properties Dietary Fibre Soluble some hemicelluloses -glucans pectins gums, mucilages Insoluble some hemicelluloses cellulose lignin - solubility affects water-holding capacity, fermentability, nutrient adsorption - these exert physiological & metabolic effects

• Physiological & Metabolic effects water-holding capacity ability to hold water faecal bulk colonic transit time (faster) reduce constipation viscous & gel-forming mixing of digestive enzymes with food nutrient diffusion rate slower rate of absorption SI transit time (slow passage) soluble fibre increase satiety

• Physiological & Metabolic effects Adsorption or binding of nutrients by fibre - lignin, pectin, -glucan bind some nutrients bind and reduce absorption of bile acids cholesterol used for more bile acid synthesis lower serum cholesterol reduce Ca 2+, Fe 2+, Zn 2+ absorption COO- bind divalent cations pectins, hemicellulose

• Physiological & Metabolic effects Fermentability - depends on fibre (esp. solubility) - residence time - bacteria population Short chain fatty acids (SCFAs) are made acetate propionate butyrate Gases: H 2, CO 2, methane

• Physiological & Metabolic effects Short chain fatty acids - absorbed acetate (2 C) acetyl-Co. A propionate (3 C) liver ATP or FFAs glucose butyrate (4 C) used as fuel for intestinal cells Fibre that is fermented in can be a source of energy and glucose

• Significance Fibre is not inert Energy (< 4 kcal/g but > 0 kcal/g) Disease prevention & treatment constipation/haemorroids/appendicitis heart disease/plasma cholesterol adult-onset diabetes/glucose absorption obesity/satiety Mineral deficiency rare: intake low and fibre/phytate high

References • Groff and Gropper, 2000. Advanced Nutrition and Human Metabolism