Glucose Metabolism: Glycogenesis and More

Glucose Metabolism: Glycogenesis

• Glycogenesis is the creation of glycogen and, glycogen is a polysaccharide and the only stored carbohydrate in humans.
• Insulin stimulates hepatocytes and skeletal muscle cells to synthesize glycogen and is a storage hormone.
• About 500g of glycogen can be stored in the body, with 75% in skeletal muscle.
• Hepatocytes and skeletal muscle store glycogen, with the majority in skeletal muscle.

Glucose Metabolism: Glycogenolysis

• Glycogenolysis is the breakdown of glycogen.
• Glycogen stored in hepatocytes is broken into glucose and released into the blood.
• Glycogen stored in muscle is converted to glucose-6-phosphate and enters glycolysis; skeletal muscle lacks the enzyme to cleave the final phosphate.
• Glycogenolysis is stimulated by glucagon and epinephrine.

Glucose Metabolism: Gluconeogenesis

• Gluconeogenesis is glucose formation from noncarbohydrate sources like glycerol, lactic acid, and most amino acids.
• Gluconeogenesis occurs in the liver and is stimulated by cortisol and glucagon.
• Carbon, hydrogen, and oxygen are the 3 ingredients to create carbohydrates

Metabolism of Lipids: Lipoproteins

• Lipids are transported by lipoproteins because most lipids are nonpolar and hydrophobic.
• Lipoproteins are spherical with an outer shell of proteins, phospholipids, and cholesterol surrounding fats, making them more water-soluble.
• Proteins in the outer shell are called apoproteins, each with specific functions.
• Lipoproteins are categorized by density (ratio of lipids to proteins); high density means more proteins.
• Examples of lipoproteins: chylomicrons, very low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), high-density lipoproteins (HDLs).

Metabolism of Lipids: Lipoproteins - Chylomicrons

• Chylomicrons are formed in small intestine mucosal epithelial cells and transport dietary fats.
• They enter villi, then lacteals, and are carried by lymph into venous blood.
• Chylomicrons transport dietary lipids to skeletal muscle, cardiac muscle, adipose tissue, and the liver.

Metabolism of Lipids: Lipoproteins - VLDLs

• VLDLs are formed in hepatocytes and transport triglycerides to adipocytes.
• VLDLs become LDLs once triglycerides are removed.

Metabolism of Lipids: Lipoproteins - LDLs

• LDLs are "bad cholesterol" and carry 75% of total cholesterol in the blood.
• LDLs deliver cholesterol to body cells for cell membrane repair and synthesis of steroid hormones.
• Excess LDL deposits cholesterol in arteries, forming plaques that increase the risk of coronary artery disease.
• The primary function is transporting cholesterol.

Metabolism of Lipids: Lipoproteins - HDLs

• HDLs are "good cholesterol" that remove excess cholesterol from body cells and blood.
• HDLs act as a cholesterol scavenger, delivering it to the liver for elimination in bile salts.
• High HDL levels are associated with a decreased risk of coronary artery disease.

Metabolism of Lipids: Cholesterol

• Cholesterol comes from two sources: present in foods and endogenous cholesterol made in the liver.
• Trans and saturated fats have the biggest impact on circulating cholesterol.
• Total cholesterol above 200 mg/dL and a high LDL:HDL ratio are indicators of potential cardiovascular problems.
• Excess cholesterol can accumulate as plaques in blood vessels, causing hypertension, heart attacks, and strokes.

Metabolism of Lipids: Lipid Catabolism - Lipolysis

• Lipolysis breaks down lipids into pieces that can be converted to pyruvate or channeled into the citric acid cycle.
• Either route of lipolysis can generate ATP.
• If energy demand is low, triglycerides are stored in adipocytes.
• Triglycerides consist of glycerol and 3 fatty acids, both of which generate ATP.
• Lipolysis is enhanced by epinephrine, norepinephrine, cortisol, and thyroid hormones and inhibited by insulin.

Metabolism of Lipids: Lipid Catabolism - Glycerol and Fatty Acids

• Glycerol is converted to glyceraldehyde 3-phosphate (a glycolysis intermediate) and eventually pyruvate, yielding 2 ATP.
• Fatty acids are catabolized to acetyl-CoA through beta-oxidation in the mitochondrial matrix.
• Beta-oxidation involves chopping 2 carbons off at a time and converting to acetyl-CoA, gaining 13 ATP per step.
• Pyruvate (from glycerol) and acetyl-CoA (from fatty acids) can enter the Citric Acid Cycle.

Metabolism of Lipids: Lipid Catabolism - Ketones

• Excessive beta-oxidation with a lack of glucose results in ketone formation in the liver.
• The heart, brain, and RBCs can use ketone bodies to generate ATP, with the brain and RBCs relying heavily on this source.
• Excessive ketones can lead to ketosis and/or ketoacidosis, damaging tissue.
• Beta-oxidation is very efficient, and excess lipids can be easily stored as triglycerides.
• Lipid catabolism is well-suited for chronic energy demands during stress or starvation.

Metabolism of Lipids: Lipid Anabolism - Lipogenesis

• Lipogenesis involves liver and adipose cells synthesizing lipids, beginning with acetyl-CoA.
• Almost any organic substrate can be converted to acetyl-CoA.
• Lipogenesis occurs when more calories are consumed than needed for ATP production, converting excess carbs, proteins, and fats to triglycerides.
• Essential fatty acids, like omega-3 and omega-6, cannot be synthesized and must be obtained from the diet.

Metabolism of Proteins: Protein Catabolism

• Amino acids are oxidized to produce ATP or used to synthesize new proteins.
• Excess dietary amino acids are converted into glucose (gluconeogenesis) or triglycerides (lipogenesis).
• Protein from worn-out cells is recycled, converted to other amino acids, and reformed to make new proteins or enter the Citric Acid Cycle (CAC).
• Before entering the CAC, the amine group must be removed via deamination, which occurs in hepatocytes.
• Deamination produces ammonia, which the liver converts to urea and excretes in urine.

Metabolism of Proteins: Protein Anabolism

• Protein synthesis is carried out using ribosomes (translation) utilizing free amino acids.
• Essential amino acids cannot be synthesized in the body and must be acquired through diet.
• 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 keto acid to form a new amino acid.
• There are 9 essential amino acids that must be present in the diet because they cannot be synthesized.
• There are 11 nonessential amino acids that can be synthesized by body cells using amination and transamination

Metabolic Adaptations: Absorptive State

• Two general patterns of metabolic activity are the absorptive and postabsorptive states.
• During the absorptive state, ingested nutrients enter the bloodstream.
• During the postabsorptive state, absorption of nutrients from the GI tract is complete, and energy needs are met by stored fuels.
• The nervous system and red blood cells depend on glucose.
• The absorptive state occurs following a meal, typically lasting ~4 hours.
• Insulin stimulates glucose uptake and glycogenesis, amino acid uptake and protein synthesis, and triglyceride synthesis.
• Glycolysis and aerobic metabolism provide ATP needed to power cellular activities and synthesize lipids and proteins.

Metabolic Adaptations: Postabsorptive State

• The postabsorptive state occurs about 4 hours after the last meal, when absorption in the small intestine is nearly complete.
• Blood glucose levels start to fall, and the main purpose is to maintain blood sugar.
• Metabolic activity focuses on mobilizing energy reserves and blood glucose.
• The postabsorptive state is coordinated by glucagon, epinephrine, and glucocorticoids.
• Glucocorticoids stimulate the mobilization of lipid and protein reserves; effects are enhanced by growth hormone.
• Glucagon stimulates glycogenolysis and gluconeogenesis, mainly in the liver.
• Epinephrine stimulates glycogenolysis in skeletal and cardiac muscle and lipolysis in adipocytes.

Metabolic Adaptations: Postabsorptive State - Glucose Production and Conservation

• Glucose production is increased by the breakdown of liver glycogen, lipolysis, and gluconeogenesis.
• Gluconeogenesis uses lactic acid, glycerol, and/or amino acids.
• Blood glucose is conserved by the oxidation of fatty acids, lactic acid, amino acids, ketone bodies, and breakdown of muscle glycogen.
• Blood lipid levels decrease, resulting in the release of fatty acids by adipocytes.
• Blood amino acid levels decrease, resulting in amino acid release by skeletal muscles and other tissues.
• The liver releases glucose into the blood

Metabolic Adaptations: Fasting and Starvation

• Fasting is going without food for many hours or a few days and starvation is weeks or months of food deprivation.
• During fasting and starvation, nervous tissue and RBCs continue to use glucose for ATP production.
• The most dramatic metabolic change is the increase in ketone body formation by hepatocytes from excess fatty acid metabolism.
• Ketone bodies can be used as an alternative fuel source during this time.