Glucose Metabolism: Glycogenesis, Glycogenolysis

Glucose Metabolism

• Glycogenesis is the creation of glycogen, the only stored carbohydrate in humans.
• Insulin stimulates hepatocytes and skeletal muscle cells to synthesize glycogen, acting as a storage hormone.
• The body can store about 500g of glycogen, with 75% stored in skeletal muscle.

Glycogenolysis

• Glycogenolysis is the breakdown of glycogen into glucose, which occurs in hepatocytes and is released into the blood.
• Glycogen stored in muscle is converted to glucose-6-phosphate and enters glycolysis because skeletal muscle lacks the enzyme to cleave the final phosphate.
• Glucagon and epinephrine stimulate glycogenolysis, with glucagon increasing blood sugar and epinephrine triggered by stress.
• Any glycogen stored in skeletal muscle needs to be used by skeletal muscle.

Gluconeogenesis

• Gluconeogenesis is the formation of glucose from noncarbohydrate sources like glycerol, lactic acid, and most amino acids, occurring in the liver.
• Gluconeogenesis is stimulated by cortisol and glucagon, which are released during stress and when blood sugar needs to be increased, respectively.
• Carbon, hydrogen, and oxygen are the 3 ingredients to create carbohydrates.

Lipid Transport

• Lipids, being mostly nonpolar and hydrophobic, are transported by lipoproteins after being made more water-soluble through combination with proteins.
• Lipoproteins are spherical, with an outer shell of proteins, phospholipids, and cholesterol surrounding fats.
• Proteins in the outer shell, called apoproteins, have specific functions as transport vehicles.

Lipoproteins

• Lipoproteins are categorized by density, with high density indicating more proteins.
• Chylomicrons transport dietary fats from the small intestine to skeletal muscle, cardiac muscle, adipose tissue, and the liver.
• Very low-density lipoproteins (VLDLs) are formed in hepatocytes and transport triglycerides to adipocytes, becoming LDLs after triglycerides are removed.
• Low-density lipoproteins (LDLs) carry 75% of total cholesterol in blood, delivering it to body cells for repair and steroid hormone synthesis. Excess LDL can deposit cholesterol in arteries, increasing the risk of coronary artery disease.
• High-density lipoproteins (HDLs) remove excess cholesterol from body cells and blood, delivering it to the liver for elimination and preventing cholesterol accumulation in the blood.

Cholesterol

• Cholesterol has 2 sources: dietary intake and endogenous production in the liver.
• Trans fats and saturated fats have the biggest impact on circulating cholesterol.

Health Applications

• Indicators of potential cardiovascular problems include total cholesterol above 200 mg/dL and a high LDL:HDL ratio.
• Excess cholesterol can accumulate as plaques in blood vessels, causing hypertension, heart attacks, and strokes.

Lipid Catabolism: Lipolysis

• Lipolysis is the breakdown of lipids into pieces that can be converted to pyruvate or channeled directly into the citric acid cycle to generate ATP.
• Triglycerides consist of glycerol and 3 fatty acids, both of which can generate ATP after breakdown that is enhanced by epinephrine, norepinephrine, cortisol, and thyroid hormones, while insulin inhibits lipolysis.
• Glycerol is converted to glyceraldehyde 3-phosphate (glycolysis intermediate) and eventually pyruvate, yielding 2 ATP.
• Fatty acids are catabolized to acetyl-CoA through beta-oxidation in the mitochondrial matrix, producing more ATP per carbon than glucose.
• For each step in beta-oxidation, the cell gains 13 ATP.
• Excessive beta oxidation, with a lack of glucose, results in the formation of ketones in the liver.
• Heart, brain, and RBCs can use ketone bodies to generate ATP, since brain and RBCs cannot use beta oxidation.
• Excessive ketones can lead to ketosis and/or ketoacidosis, of which the latter damages tissue.

Lipid Anabolism: Lipogenesis

• Lipogenesis, the synthesis of lipids, occurs in liver and adipose cells, beginning with acetyl-CoA derived from almost any organic substrate.
• Excess dietary carbs, proteins, and fats are all converted to triglycerides.
• Essential fatty acids, like omega-3 and omega-6, cannot be synthesized and must be obtained from the diet.

Metabolism of Proteins

• Amino acids are either oxidized to produce ATP or used to synthesize new proteins.
• Excess dietary amino acids are converted into glucose (gluconeogenesis) or triglycerides (lipogenesis).

Protein Catabolism

• Protein from worn out cells are recycled or can be converted to other amino acids and reformed to make new proteins or enter the citric acid cycle.
• Before entering the citric acid cycle, the amine group must be removed through deamination in hepatocytes, producing ammonia that the liver converts to urea for excretion in urine.

Protein Anabolism

• Protein synthesis is carried out using ribosomes (translation) using free amino acids.
• Essential amino acids cannot be synthesized in the body and must be acquired through diet.
• There are 9 essential amino acids for humans.
• Nonessential amino acids can be synthesized by body cells using amination and transamination.
• Transamination is the transfer of an amine group from one amino acid to a ketoacid to form a new amino acid.
• There are 11 nonessential amino acids.

Metabolic Adaptations

• There are two general patterns of metabolic activity: the absorptive state and the postabsorptive state.
• During the absorptive state, ingested nutrients enter the blood stream and glucose is readily available for ATP production, dominated by the effects of insulin.
• During the postabsorptive state, absorption of nutrients from the GI tract is complete and energy needs are met by stored fuels in the body, with maintaining steady blood glucose critical for the nervous system and red blood cells.

Absorptive State

• Absorptive state typically continues for ~4 hours and is the time following a meal, when nutrient absorption is occurring.
• Insulin stimulates glucose uptake and glycogenesis, amino acid uptake and protein synthesis, and triglyceride synthesis.
• Glycolysis and aerobic metabolism provide the ATP needed to power cellular activities as well as the synthesis of lipids and proteins.
• Also, storage of excess fuel molecules in hepatocytes, adipocytes, and skeletal muscle cells.

Postabsorptive State

• About 4 hours after the last meal, absorption in small intestine nearly complete.
• Blood glucose levels start to fall – main purpose is to maintain blood sugar.
• Metabolic activity is focused on mobilizing energy reserves and blood glucose.
• This activity is coordinated by hormones like glucagon, epinephrine, and glucocorticoids.
• Glucocorticoids stimulate the mobilization of lipid and protein reserves; these effects are enhanced by growth hormone.
• Glucagon stimulates glycogenolysis and gluconeogenesis, primarily in the liver.
• The release of glucose by the liver and the shift away from glucose metabolism by other tissues stabilizes blood glucose levels.
• Epinephrine is important in stimulating glycogenolysis in skeletal and cardiac muscle, and lipolysis in adipocytes.

During the Postabsorptive State...

• Production of glucose is increased by:

  • Breakdown of liver glycogen.
  • Lipolysis.
  • Gluconeogenesis using lactic acid, glycerol and/or amino acids.

• Blood glucose is conserved by:

  • Oxidation of fatty acids, lactic acid, amino acids, ketone bodies.
  • Breakdown of muscle glycogen.

• Blood lipid levels decrease, which triggers a response in release of fatty acids by adipocytes.

• Blood amino acid levels decrease, which triggers a response in amino acid release by skeletal muscles and other tissues.

• Blood glucose levels decrease, which triggers a response in glucose release by liver.

• Catabolism of lipids and amino acids in liver produce acetyl-CoA, which leads to the formation of ketone bodies. These diffuse into blood and are used by other cells as energy source.

Fasting and Starvation

• Fasting is going without food for many hours or a few days.
• Starvation implies weeks or months of food deprivation or inadequate food intake.
• During these times, nervous tissue and RBC's continue to use glucose for ATP production.
• The most dramatic metabolic change that occurs is the increase in formation of ketone bodies by hepatocytes from excess fatty acid metabolism. These can be used as an alternative fuel source.