Carbohydrate Metabolism: An Overview

Carbohydrate Metabolism Overview

• Carbohydrate metabolism involves the fate of food molecules post-digestion and absorption.
• Metabolic pathways are categorized into anabolic, catabolic, and amphibolic types.
• Anabolic pathways synthesize compounds, requiring energy, such as protein synthesis.
• Catabolic pathways break down compounds, releasing energy in the form of ATP or reducing equivalents like NADH+H and FADH2.
• Amphibolic pathways act as a link between catabolic and anabolic pathways, e.g., the citric acid cycle.

Carbohydrates in Diet

• Carbohydrates typically provide 50% of daily caloric intake.
• Complete oxidation of glucose yields 4 Kcal/gram.
• Starches constitute about 50% of dietary carbohydrates that can be metabolized; examples include potatoes, grains, and flour.
• Monosaccharides like fructose and glucose are found in fruits and honey.
• Disaccharides, such as sucrose and lactose, make up most of the remaining carbohydrate intake.
• Polysaccharides and disaccharides cannot be directly absorbed into the intestinal mucosa.
• Enzymes convert starches and disaccharides into absorbable monosaccharides.

Digestion of Carbohydrates

• Carbohydrate digestion begins in the mouth with salivary amylase, which converts starch and glycogen to dextrins.
• Pancreatic amylase then completes the digestion of dextrins into maltose.
• Maltase, lactase, and sucrase enzymes hydrolyze disaccharides into monosaccharides such as glucose, fructose, and galactose, which are then absorbed.
• Absorbed glucose releases energy through oxidation, producing CO2 and H2O in the tissues, and is stored as ATP.
• It can also be synthesized into other carbohydrates like pentoses, galactose, and lactose.
• Glucose can be converted to glycogen in the skeletal muscle and liver via glycogenesis.
• Glucose intermediates form the carbon skeleton of non-essential amino acids and synthesize long-chain fatty acids (lipogenesis) and cholesterol from Acetyl-CoA.

Metabolic Pathways of Carbohydrates

• After monosaccharide absorption, only glucose circulates in the blood.
• Glucose passes into 2 main pathways: catabolic and anabolic.
• Catabolic pathways involve oxidative processes:
  • Glycolysis oxidizes glucose to pyruvic or lactic acid.
  • The citric acid cycle completely oxidizes acetyl CoA to CO2 and H2O.
  • Glycogenolysis breaks down glycogen into glucose.
  • The hexose monophosphate shunt oxidizes glucose to produce pentoses and reducing equivalents.
  • The uronic acid pathway converts glucose into glucuronic acid and pentoses.
• Anabolic pathways:
  • Gluconeogenesis synthesizes glucose from non-carbohydrate sources (glycerol, lactic acid, propionic acid, and amino acids).
  • Glycogenesis synthesizes glycogen from glucose.

Glycolysis

• Glycolysis is the primary pathway for glucose oxidation, taking place in the cytosol.
• It provides the main route for fructose and galactose metabolism.
• Glycolysis can produce ATP without oxygen, enabling skeletal muscle performance during contraction.
• Deficiencies in glycolysis enzymes can lead to hemolytic anemia and fatigue.
• Glucose is converted to glucose-6-phosphate by glucokinase or hexokinase.

Glucokinase vs Hexokinase

• Glucokinase is present only in liver cells, whereas hexokinase is present in all cells except liver cells.
• Glucokinase has low affinity (high Km) for glucose, whereas hexokinase has high affinity (low Km) for glucose.
• Glucokinase is specific for glucose, whereas hexokinase catalyzes the phosphorylation of other hexoses at a slower rate.
• Glucokinase removes glucose from the blood post-meal, and its synthesis is induced by insulin.
• Hexokinase supplies glucose to tissues, even at low blood glucose levels, and is allosterically inhibited by G-6-p.

Pyruvate Fate After Glycolysis

• Under aerobic conditions, pyruvate oxidizes into the citric acid cycle after converting to Acetyl-CoA.
• Under anaerobic conditions, pyruvate reduces to lactate, catalyzed by lactate dehydrogenase, utilizing NADH+H+, and regenerating NAD+ to allow glycolysis to proceed.

ATP Production in Glycolysis

• The glyceraldehyde-3-phosphate dehydrogenase reaction generates 6 ATP when 2 NADH are oxidized in the respiratory chain, (occurrs in presence of oxygen).
• Phosphoglycerate kinase and pyruvate kinase respectively generate 2 ATP (at the substrate level).
• Glycolysis yields 10 ATP in the presence of oxygen and 4 ATP without it.
• 2 ATP molecules are lost during the hexokinase and phosphofructokinase reactions.
• Glycolysis produces a net gain of 8 ATP in the presence of oxygen and 2 ATP in its absence.
• Fluoride inhibits enolase during glycolysis and is used in vitro.

Aerobic vs. Anaerobic Glycolysis

• Aerobic glycolysis nets 8 ATP vs. anaerobic glycolysis production of 2 ATP.
• Aerobic glycolysis’s NAD+ regeneration occurs in the respiratory chain with available krebs', while anaerobic glycolysis occurs via lactate formation, because there is no krebs'
• Aerobic glycolysis yields pyruvate, while anaerobic glycolysis results in Lactate.

Regulation of Glycolysis

• Most glycolysis reactions are reversible, except those catalyzed by hexokinase, phosphofructokinase-1, and pyruvate kinase which are irreversible.
• Hexokinase is allosterically inhibited by glucose-6-phosphate.
• Pyruvate kinase is regulated by covalent modification, and is inactivated by phosphorylation.
• Phosphofructokinase-1 is allosterically regulated, inhibited by citrate and ATP, and activated by AMP.

Oxidation of Pyruvate to Acetyl CoA

• Pyruvic acid, an α-keto acid, results from glucose oxidation via glycolysis.
• Pyruvate must enter the citric acid cycle in the mitochondria to oxidize glucose completely.
• Pyruvate is transported into the mitochondria by a specific pyruvate transporter.
• Oxidative decarboxylation of pyruvate to acetyl CoA, occurs in the mitochondria and is catalyzed by the pyruvate dehydrogenase complex, it requires 5 coenzymes, including TPP, lipoic acid, CoASH, FAD, and NAD.
• Pyruvic acid can undergo oxidative decarboxylation to Acetyl-CoA via the pyruvate dehydrogenase enzyme complex.
• Pyruvic acid can be carboxylated to oxaloacetic acid by the pyruvate carboxylase enzyme.
• Pyruvic acid can be reduced to lactic acid by the lactate dehydrogenase enzyme.

Citric Acid Cycle (Krebs Cycle)

• The citric acid cycle oxidizes Acetyl-CoA into CO2, H2O, producing energy and occurs in the mitochondrial matrix.
• It acts as the final pathway for carbohydrate, lipid, and protein oxidation, as glucose, fatty acids, and amino acids are metabolized to Acetyl-CoA or intermediates.
• The citric acid cycle plays a key role in gluconeogenesis, transamination, deamination, and lipogenesis, producing NADH+H+ and FADH2 that are oxidized in the respiratory chain to form ATP.
• Each acetyl CoA molecule yields 12 ATP molecules per cycle turn.
• Reaction (4): NADH+H+ yields 3 ATP through the respiratory chain.
• Reaction (5): NADH+H+ yields 3 ATP through the respiratory chain.
• Reaction (6): Substrate level phosphorylation yields 1 ATP.
• Reaction (7): FADH2 yields 2 ATP through the respiratory chain.
• Reaction (9): NADH+H+ yields 3 ATP through the respiratory chain.
• Total ATP produced: 12ATP in a complete run.
• Glucose Oxidation products: 8 ATP molecules are produced by glycolysis, 6 ATP molecules are produced from oxidative decarboxylation of 2 pyruvic acid molecules for 2 Acetyl CoA molecule, and 24 ATP molecules are produced from 2 acetate molecules oxidized in the cycle, so, 38 total ATP molecules are produced per one molecule of glucose oxidized.
• The citric acid cycle produces ATP; High ATP inhibits the cycle, and low ATP (or high ADP) stimulates the cycle.

Hexose Monophosphate Shunt (Pentose Phosphate Pathway)

• An alternative pathway for glucose oxidation, and neither produces nor utilizes ATP, happening in the cytoplasm, within liver, lactating mammary gland, adipose tissues, erythrocytes, and adrenal cortex.
• NADPH+H+ Generation: Essential for reductive synthesis in fatty acid, steroid, and amino acid synthesis, and in the synthesis of reduced glutathione in erythrocytes.
• Ribose Residues Generation: Used for nucleotide and nucleic acid synthesis (DNA & RNA).
• Favism is a disease that results from deficiency of the enzyme glucose-6-phosphate dehydrogenase, leading to impairment of the pentose phosphate pathway with consequent deficiency of NADPH+H+.
• Glutathione peroxidase uses reduced glutathione to attack and hydrolyze H2O2 to H2O.
• Glucose-6-phosphate deficiency leads to a reduced glutathione deficiency, thus making the red blood cell susceptible to oxidizing agents like H2O2, Fava beans, sulfonamides, antimalarial drugs, and aspirin, causing hemolysis.

Uronic Acid Pathway

• Uronic acid is for glucose to glucuronic acid as well as pentose conversion.
• A path that does not lead to ATP production in the cytoplasm, with many tissues involved.
• Glucuronic acid production, is used in the form of UDP-glucuronic acid for synthesis of proteoglycans and conjugation reactions with steroid hormones, certain drugs, and bilirubin.
• This also leads to pentose production, and ascorbic acid production can occur in most animals (except humans and certain primates), because only they contain the L. glunolactone oxidase enzyme.

Glycogen Metabolism Overview

• Glycogen is the storage form of carbohydrates in animals, mainly in the liver and muscle.

Liver vs Muscle Glycogen

• Liver glycogen occurs in the liver, while muscle glycogen occurs in muscle.
• Liver glycogen constitutes up to 5% of liver weight (90 gm), whereas muscle glycogen remains at 1% total muscle weight (245 gm).
• Liver glycogen maintains blood glucose in early fasting.
• Muscle glycogen acts as a hexose unit source for glycolysis
• Liver Glycogen depletes after 12–18 hours of fasting, whereas muscle glycogen depletes after prolonged vigorous exercise.
• Glucagon stimulates liver glycogenolysis, having no effect on muscle glycogenolysis.

Glycogenesis

• Glycogenesis synthesizes glycogen from glucose in the cytoplasm of the liver and muscle.

Glycogenolysis

• Glycogenolysis is the process of glycogen degradation, not the inverse of glycogenesis, and occurs in the cytoplasm of the liver and muscle.

Glycogen Metabolism Regulation

• Regulation occurs via covalent modification of regulatory enzymes.

Glycogenesis Regulation

• Glycogen synthase regulates glycogenesis and exists in 2 forms:
  • Phosphorylated form is glycogen synthase b, the inactive form.
  • Dephosphorylated form is glycogen synthase a, the active form.

Glycogenolysis Regulation

• Phosphorylase regulates glycogenolysis existing in 2 forms:
  • Phosphorylated form is phosphorylase a, the active form.
  • Dephosphorylated form is phosphorylase b, the inactive form.

Hormonal Regulation of Glycogen Metabolism

• Insulin activates glycogen synthase (glycogenesis) and inactivates glycogen phosphorylase (glycogenolysis) in the liver and muscle.
• Glucagon (in liver) and epinephrine (in liver and muscle) inactivate glycogen synthase (glycogenesis) and activate glycogen phosphorylase (glycogenolysis).
• Increased calcium ions stimulate glycogen phosphorylase (glycogenolysis) during muscular contraction.

Glycogen Storage Diseases

• Glycogen storage diseases are inherited disorders characterized by abnormal glycogen deposition in tissues; there are ten types.
• Type I (Von Gierke’s disease) results from glucose-6-phosphatase deficiency in the liver and kidney.

Von Gierke`s disease

• Glycogen accumulates in the liver (hepatomegaly) and renal tubular cells and leads to fasting hypoglycemia, ketosis, hyperlipidemia, and hyperuricemia, first occuring within the first year.
• In this disease, glucose-6-phosphate accumulates and is channeled to the HMP shunt, producing more ribose and nucleotides, which leads to hyperuricemia.
• Excess NADPH is produced by the HMP shunt, leading to lipogenesis, hyperlipidemia, and ketosis.
• Diagnosis through liver biopsy shows liver cells loaded with glycogen, and glucose-6-phosphatase is completely absent.

Gluconeogenesis

• Gluconeogenesis converts non-carbohydrate substances into glucose or glycogen, primarily in the liver (90%) and kidneys (10%).
• Gluconeogenesis provides glucose during starvation, and clears metabolic byproducts from blood, including lactate from muscle and RBCs and glycerol from adipose tissue.
• The irreversible glycolytic reactions catalyzed by hexokinase, phosphofructokinase1 and pyruvate kinase are reversed by four key ones.

Four Unique Gluconeogenesis Enzymes:

• Pyruvate carboxylase converts pyruvate to phosphoenolpyruvate, fructose-1,6-bisphosphatase converts fructose-1,6-bisphosphate to fructose-6-P, and glucose-6-phosphatase converts glucose-6-phosphate to glucose

Gluconeogenic Substances

• Glucogenic amino acids form pyruvate or enter the citric acid cycle post-transamination or deamination.
• Lactate is converted to pyruvate by lactate dehydrogenase.
• Propionate produces glucose in ruminants through the succinyl COA cycle.
• Glycerol, derived from lipids, is converted to glycerol-3-phosphate in the liver and kidneys to undergo gluconeogenesis by glycerol kinase.

Gluconeogenesis Regulation

• Insulin decrease the activity of gluconeogenesis and stimulates glycolysis.
• Regulatory hormones (glucagon, epinephrine, glucocorticoids, and growth) increase gluconeogenesis and decrease glycolysis.

Blood Glucose

• Normal Fasting Levels range from 70-110mg/dL, and Post-prandial levels raise to 140mg/dL.

Blood Glucose Sources

• Blood Glucose comes from dietary carbohydrates, gluconeogenic compounds, and liver glycogen.

Blood Glucose Concentration Regulation

• Regulation occurs via metabolic and hormonal mechanisms.
• Liver and extrahepatic tissues regulate the concentration of glucose.
• Rate of glucose uptake depends on blood glucose concentration because liver cells are freely permeable to said glucose, while other tissues are impermeable.

Hormones That Lower Blood Glucose

• Insulin secretion (beta-cells of islets of langerhan) increases when glucose increases and lowers glucose, increases glucose, enhancing glucose uptake by controlling glycolysis/genesis, inhibiting gluconeogenesis/glycogenolysis, stimulating glycolysis, glycogenesis, and lipogenesis.

Hormones That Increase Blood Glucose

• Glucagon production increases because of concentration decrease, activating glycogenolysis that enhances gluconeogenesis.
• Hormones (anterior pituitary/growth hormone/ACTH), are antagonists to insulin and cause glucose to rise.
• Glucocorticoid hormones increase gluconeogenesis while inhibiting glucose use.
• Epinephrine is secreted during stress causing glycogenolysis, where glucose is created and diffuses from the liver, increasing glucose.
• Thyroid Hormones produce hyperglycemia as well.

Abnormalities Relating to Blood Glucose

Diabetes Mellitus

• Hyperglycemia is a result, and symptoms include glucosuria, polyuria, thirst, polyphagia loss of weight, as well as delayed healing.
• DM is caused due to a metabolic disease from reduced insulin/resistance.

Idiopathic vs. Secondary Complications

• DM can be classified as idiopathic or secondary.
• Idiopathic can be broken into 2 types.

Type I vs Type II Diabetes

• IDDM: 10% chance, before 20 years, rapid, as a result of autoimmune disease causing destruction, and can be fixed via Insulin and IDDM: 90% chance, after 40 years, slow, as a result of insulin deficiencies, can be fixed via lifestyle changes, and insulin.

Secondary Diabetes

• Result of other diseases increasing the anti-insulin system.
• Endocrine disorders, pancreatic disease, or drug usage.

Diabetes Metabolic Changes

• Reduced glucose, reduced oxidation, increased gluconeogenesis, resulting in hyperglycemia and dehydration
• Reduced lipogenesis and increased lipolysis, which leads to weight loss, increased free fatty acids, leading to hypercholesterolemia and ketosis
• Reduces protein and synthesis, resulting in healing sensitivity.

Diabetes Diagnosis

• Patient Symptoms, urine glucose via measurements, blood glucose lab tests, with the need to confirm diabetes via oral test , or glycosylated measurements..
• Normal Fasting: 70-110 Normal 2hr: Lower than 140, impaired with Fasting at 111-126 and Normal 2hr at 140-200.

Diabetes Complications

• Macrovascular issues.
• Microvascular.
• Coma incidents.

Diabetic Coma

• From insulin deficiency leading to a chain reaction.
• Marked hyper/osmotic water loss, leading to an increase in ketone bodies
• Medical intervention is needed, fluids, potassium, insulin, and bicarbonate.
• Hyper is in high amount, and hypo would lead to low amounts.

Diabetes Treatments

• Manage your diet.
• Oral drugs.
• Insuline injections.

Hypoglycemia

• When concentration is lower than 60, this causes faintness, lethal symptoms over time.

Hypoglycemia Causes

• Stimulating: drugs such as overdoses, inborn errors, alcohol consumption
• Fasting : when you can not normally regulate the balance due to exhaustion and urine diseases.
• Enhanced use as well as defective production.

Glucosuria

• Normal threshold should have glucose reabsorbed, but when it is not and venous levels exceed, that means glucose is present.
• Caused either by : Diabetes issues or kidney issues.