Carbohydrate Digestion and Metabolism

Carbohydrate Digestion

• Digestion starts in the mouth with salivary amylase which acts on cooked starch and glycogen.
• Pancreatic amylase acts in the small intestine at pH 7.1, breaking down cooked and uncooked starch.
• Final digestion is completed by intestinal enzymes: lactase, maltase, sucrase, and dextrinase.
• Cellulose is not digested by humans due to the lack of the enzyme cellulase.

Fate of Absorbed Sugar

• Absorbed sugar is primarily taken up by the liver where galactose and fructose are converted to glucose.
• Glucose can be utilized by tissues through oxidation, storage, or conversion.
• Oxidation: Glucose is oxidized for ATP production through glycolysis and the Krebs cycle. The hexose monophosphate (HMP) shunt also utilizes glucose to produce ribose, NADPH, and glucuronic acid.
• Storage: Glucose can be stored as glycogen through glycogenesis or converted to fat (lipogenesis).
• Conversion: Glucose can be converted to ribose and deoxyribose for DNA and RNA synthesis, lactose for milk, and various other compounds.

Glucose Oxidation

• All carbohydrate metabolic pathways occur in the cytoplasm except for the Krebs cycle, which takes place in the mitochondria.
• Complete glucose oxidation to CO2 and H2O involves both glycolysis (cytoplasm) and the Krebs cycle (mitochondria).
• Anaerobic glycolysis occurs in the absence of mitochondria (RBCs) or during oxygen deprivation (muscle exercise).

Glycolysis

• Also known as the Embden-Meyerhof pathway, glycolysis is the anaerobic phase of glucose oxidation.
• Site: Cytoplasm of all tissues but especially important in muscle during exercise due to oxygen lack and in RBCs due to the absence of mitochondria.

Function of Glycolysis

• It is the primary source of energy for muscle contraction and for red blood cells.
• Produces 8 or 6 ATP in the presence of oxygen.
• Generates 2,3-bisphosphoglycerate (BPG) which reduces hemoglobin's affinity for oxygen, facilitating oxygen delivery to tissues.
• Produces pyruvate, which can enter the Krebs cycle.
• DHAP can be converted to glycerol-3-phosphate, crucial for lipogenesis.
• Produces two amino acids: serine (from 3-phosphoglycerate) and alanine (from pyruvate).

Mitochondrial Pathway for Glucose Oxidation

• The complete oxidation of glucose to CO2 and H2O involves both glycolysis (cytoplasm) and the Krebs cycle (mitochondria).
• First stage: Oxidative decarboxylation of pyruvate to acetyl CoA.
• Second stage: Krebs cycle.

Oxidative Decarboxylation of Pyruvate to Acetyl CoA

• Catalyzed by the pyruvate dehydrogenase complex (PDC).
• Requires five coenzymes: TPP (thiamin pyrophosphate), lipoic acid, CoASH, FAD, and NAD.
• Pyruvate is converted into acetyl-CoA.

Citric Acid Cycle (CAC), Krebs Cycle or Tricarboxylic Acid Cycle (TCA)

• Site: Mitochondria
• Amphibolic role: Involved in both anabolic and catabolic reactions.
• Catabolic role: Produces 12 ATP for each acetyl-CoA. Involved in the complete oxidation of carbohydrates, lipids, and proteins.
• Anabolic role: Involved in heme synthesis (succinyl CoA + glycine), amino acid synthesis through transamination (glutamate to α-ketoglutarate and aspartate to oxaloacetate), fatty acid synthesis, gluconeogenesis, and the production of CO2 for various biosynthetic pathways.

Hexose Monophosphate Shunt (HMP Shunt), Pentose Shunt

• Site: Cytoplasm of the liver.
• Functions:
  • Production of pentoses (required for DNA and RNA synthesis).
  • Production of NADPH (required for fatty acid and cholesterol synthesis, sphingosine and galactolipid synthesis, glucuronic acid synthesis, non-essential amino acid synthesis, and reduction of glutathione).

Favism

• Deficiency in glucose-6-phosphate dehydrogenase (G6PD) leads to hemolysis of red blood cells, especially following the intake of fava beans.
• Mechanism: Reduced G6PD leads to decreased NADPH production, resulting in a reduced ability to reduce glutathione. This leaves the cells vulnerable to oxidative stress, causing hemolysis.

Blood Glucose

• Fasting blood glucose levels: 70-110 mg/dl.
• One hour after a meal: 120-150 mg/dl.
• Regulation of blood glucose involves hormonal and hepatic mechanisms.

Hormonal Regulation of Blood Glucose

• Insulin: Secreted by beta cells of the pancreas. Decreases blood glucose by:

  • Facilitating glucose uptake into cells.
  • Stimulating glycolysis (activation of hexokinase, PFK1, pyruvate kinase).
  • Stimulating glycogenesis.
  • Inhibiting glycogenolysis.
  • Inhibiting gluconeogenesis.
  • Stimulating lipogenesis.
  • Stimulating protein synthesis.

• Anti-Insulin Hormones:

  • Glucagon (secreted from alpha cells of pancreas): Increases blood glucose by stimulating glycogenolysis and gluconeogenesis.
  • Catecholamines (epinephrine and norepinephrine): Stimulate glycogenolysis and inhibit glucose uptake by the liver.
  • Corticosteroids (glucocorticoids): Stimulate gluconeogenesis and inhibit glucose uptake by tissues.
  • Growth hormone: Inhibits glucose uptake and reduces insulin sensitivity.
  • Thyroid hormone: Decreases insulin sensitivity and stimulates glycogenolysis.

Hepatic Regulation of Blood Glucose

• Fasting: Glycogenolysis and gluconeogenesis dominate.
• After a meal: Glycogenesis and lipogenesis are favored.

Renal Regulation of Blood Glucose

• Renal Threshold: The blood glucose level above which glucose appears in urine (180 mg/dl).
• Abnormal Low Renal Threshold: Occurs when glucose appears in urine even with normal insulin levels due to kidney disease (e.g., 25% of pregnancies).
• Abnormal High Renal Threshold: Glucose does not appear in urine even in diabetic patients (e.g., older individuals).

Variation in Blood Glucose

• Hyperglycemia: Elevated blood glucose levels (fasting >126 mg/dl, 1 hour after meal >200 mg/dl).
  • Causes: Decreased insulin (diabetes mellitus or surgical removal of pancreas), increased anti-insulin hormones (adrenaline, cortisone, thyroid hormone, growth hormone).
• Hypoglycemia: Low blood glucose level (< 40 mg/dl). More dangerous than hyperglycemia as the brain relies on glucose.
  • Symptoms: confusion, dizziness, tremors, weakness, tachycardia, coma if untreated.
  • Causes: Increased insulin (excessive insulin dosage, missed meals, insulinoma), decreased anti-insulin hormones (glucocorticoid deficiency, pituitary hormone deficiency, glycogen storage diseases, fructosemia, and galactosemia).

Diabetes Mellitus

• Definiton: Hyperglycemia and glucosuria.
• Type 1: Insulin-dependent diabetes mellitus (IDDM). Often diagnosed during childhood. Usually underweight. Has an autoimmune component. Insufficient insulin production. Requires insulin therapy. More prone to ketoacidosis.
• Type 2: Non-insulin dependent diabetes mellitus (NIDDM). Diagnosed after 35 years. Usually obese. Moderate genetic predisposition. May have normal insulin levels but exhibit insulin resistance. Oral drugs may be effective. Insulin therapy may not be required. Less prone to ketoacidosis.

Manifestation of Diabetes Mellitus

• Carbohydrate Metabolism:

  • Decreased insulin leads to decreased glucose uptake by cells, resulting in polyphagia (excessive eating)
  • Hyperglycemia (due to decreased glucose oxidation and increased gluconeogenesis) leads to increased blood osmolarity, resulting in dehydration and polydipsia (excessive drinking).
  • Glucosuria (due to hyperglycemia) leads to increased osmotic diuresis, causing polyuria (excessive urination) and loss of water-soluble vitamins.

• Protein Metabolism:

  • Decreased insulin leads to increased protein catabolism, resulting in muscle wasting, decreased antibody formation, increased susceptibility to infections, and poor wound healing.

• Lipid Metabolism:

  • Decreased insulin increases lipolysis in adipose tissue, resulting in weight loss, fatty liver, increased free fatty acids, hypercholesterolemia, and atherosclerosis.

• Microangiopathy: Degeneration of small blood vessels.

  • Retinopathy: Affects the retina, leading to blindness.
  • Nephropathy: Affects the kidney, leading to renal failure.

Most Frequent Symptoms of Diabetes

• Polyphagia (excessive hunger)
• Polyuria (excessive urination)
• Polydipsia (excessive thirst)

Difference Between Hypoglycemia and Hyperglycemic Coma

Diagnosis of Diabetes Mellitus