C

L5 - Glucose homeostasis

Introduction to Glucose Regulation and Diabetes

  • Type one diabetes: Body can't secrete insulin.
  • Goal: Design cells to secrete insulin for a potential cure.
  • Lecture 1 focus: Control of glucose homeostasis.
  • Feedback loops: Essential for blood glucose regulation.
  • Next lecture: Insulin secretion, beta cell regulation, and glucose sensing.

Diabetes Overview

  • Diabetes: Dysregulation of glucose.
  • Two main types:
    • Type 1: Autoimmune, no insulin secretion.
    • Type 2: Prevalent in the Western world.
      • About 30% of the US population has pre-diabetes (elevated blood sugar).
      • Long-term complications: blindness, amputations.

Feedback Loops

  • Stimulus event: External variable impinging on the body.
  • Detection: Systems (receptors or cells) detect changes.
  • Receptor-mediated: Cells like beta and alpha cells sense changes in blood glucose.
  • Response: Triggered based on change relative to a set point (too high or too low).
  • Responses affect the variable and maintain balance.

Temperature Regulation Example

  • Set point: 37^{\circ}C
  • Increase in body temperature:
    • Triggers nervous system.
    • Leads to sweating, causing evaporation and temperature decrease.
  • Decrease in body temperature:
    • Triggers shivering.
    • Increases body temperature.
  • Blood glucose control uses similar feedback loops with insulin and glucagon.

Lecture Aims

  • Describe mechanisms maintaining blood sugar in the fed state (post-meal).
  • Understand mechanisms maintaining blood sugar during a normal fasting state (between meals).

Importance of Precise Blood Glucose Control

  • Brain's dependence: The brain relies on circulating glucose for energy.
  • No glycogen stores: Unlike skeletal muscle and liver, the brain cannot store much glucose.
  • Alternative fuels: Free fatty acids and ketones can be used, but glucose is primary.
  • Hypoglycemia risk: If blood glucose drops below about 3 mM, the brain is in danger.
    • Can lead to coma and death within minutes.

Normal Blood Glucose Levels

  • Set point: About 5 mM.
  • Mechanisms: Prevent levels from going too high or too low.
  • Effective regulation: Keeps blood sugar within a narrow range despite variations in food intake.

Principles of Glucose Movement

  • Dominance of Diffusion
    • Glucose movement: From gut to blood to target tissues, driven by diffusion.
    • Diffusion: Movement along a concentration gradient from high to low.

Key Tissues Involved in Glucose Handling

  • Skeletal Muscle
    • Major sink: Large mass allows significant glucose absorption from blood.
  • Fat Tissue
    • Substantial absorption: Large volume enables significant glucose uptake.
  • Brain
    • Dependence on glucose: Relies on stable blood glucose levels for energy.
  • Liver
    • Critical organ: The only site for glucose generation.
    • Two-way glucose handling: Absorbs and releases glucose.

Glucose Distribution via Diffusion

  • Post-meal: Glucose moves from gut to blood, raising blood glucose levels.
  • Absorption: Glucose absorbed into skeletal muscle, leveling off blood glucose.
  • Continuous use: Blood glucose gradually decreases as glucose is used.
  • Release from stores: High glucose levels in muscle and fat slow blood glucose decline.
  • Diffusion alone regulates blood glucose levels without active mechanisms.

Types of Glucose Transporters

  • Need for Transporters
    • Membrane crossing: Glucose needs transporters to cross cell membranes.
  • SGLT Transporters (Sodium Glucose Transporters)
    • Co-transport: Move both sodium and glucose.
  • GLUT Transporters
    • Specificity: Only move glucose.
    • Facilitated diffusion: Enhance diffusion without using ATP.

Key Characteristics of GLUT Transporters

  • Bidirectional transport: Facilitate diffusion in either direction based on glucose gradient.
  • High glucose outside: Drive glucose into the cell.
  • High glucose inside: Drive glucose out of the cell.
  • Essential Role: Without GLUT transporters, glucose cannot cross the membrane.

SGLT Transporters

  • Location: Small intestine and kidney.
  • Function: Recover glucose from gut contents and urine.
  • Regulation: Not part of glucose control, operate to maximize glucose recovery.

SGLT2 Inhibitors

  • Mechanism: Block glucose transport in the kidney, causing glucose to be excreted in urine.
  • Therapeutic Use: Effective treatments for type 2 diabetes by lowering blood glucose levels.

GLUT Transporters: GLUT4 and GLUT2

  • Distribution: Muscle and fat cells have GLUT4; liver cells have GLUT2.
  • Functional Differences: GLUT4 and GLUT2 behave differently, critical for their functions.

Need for Regulation

  • Problem with Unregulated System
    • High glucose: Blood glucose would continuously increase with each donut.
    • Low glucose: Blood glucose would plummet during fasting.
  • Importance of Regulation
    • Prevention: Prevent blood glucose from going too high or too low.
    • Maintenance: Keep blood glucose within a narrow range around 5 mM.

Mechanisms for Controlling Blood Glucose

  • Rising Phase: Glucose entering the body is stored in tissues like skeletal muscle and liver as glycogen, limiting the upper glucose level.
  • Declining Phase: Trigger a controlled release of glucose back into the blood when levels are too low, primarily via the liver.

Role of Fed and Fasting States

  • Fed State: Glucose is stored.
  • Fasting State: Glucose is released if levels drop below 5 mM.

Glucose Handling in Muscle Cells

  • Fed State
    • GLUT4 transporters: Glucose uptake into the cell.
    • Glycogen conversion: Glucose is converted to glycogen.
    • Removing glucose: Promotes further glucose diffusion into the cell.
  • Fasting State/Exercise
    • Energy source: Glycogen stores are used for energy.
    • Lactate Production: Via anaerobic exercise.
    • No Glucose Generation: Muscle does not generate glucose.
  • Extreme Fasting
    • Protein breakdown: Triggered by low glucose.
    • Muscle breakdown: Releases amino acids for energy.

Fat Cells

  • Glucose -> Triglycerides: Uses glucose and free fatty acids to generate triglycerides.
  • Same principle: Creates triglycerides to maintain the diffusional gradient and promote glucose entry.

Liver

  • Similar action: Enters in fed state using a transporter.
  • Key difference: It can generate additional glucose for release into the blood, especially during fasting.
  • Other compounds: Can use fatty acids, lactate, amino acids, and glycerol to generate ketone bodies.

Overall Glucose Flux

  • The fed state moves glucose into various tissues.
  • The fasting state releases amino acids and lactate from the muscle, fatty acids, and glycerol from fat.
  • Liver action then generates glucose.

Glucose Control Example

  • The graph shows a person's blood glucose levels within a tight range daily when eating normally.
  • The only notable thing is someone eating poorly on Thursday.

Diabetes Example

  • Taking insulin, but very poorly controlled. The key is cell replacement can cure the patient.
  • Putting beta and alpha cells back in the body allows the patient to have a much smoother glucose level.
  • Driven by research of cell replacements to try to do this.

Regulation and Control

  • Fed State: Insulin is key hormone.
  • Fasting State: Glucagon is key hormone.
  • Homeostasis: Regulated according to set point of 5mM.
  • Beta cells: Sense high glucose to release insulin.
  • Alpha cells: Sense low glucose to release glucagon.
  • Regulation: Important for glucose storage and release.

Insulin and GLUT4 Transporters

  • Targeting GLUT4: Insulin targets the GLUT4 transporter in muscle cells.
  • Weird Mechanism: The protein is present in small vesicles inside muscle cells. When in contact
  • Insulin: The hormone causes the vesicles to fuse with the cell and enter the bloodstream.
  • Normal mechanisms: Typically use phosphorylation/dephosphorylation, modification for activity, or channels/open close, etc..
  • Rest Levels: There is little glucose transport inside these systems, causing less glucose to get into the cells.

Detail of GLUT4 Transporters in Cells

  • Vesicles continuously fuse with the cell membrane and retrieve back into the cell.
  • Insulin action accelerates this cycle.

Fat Cells

  • Regulated by insulin on glut4 transport, creating more glucose in the membrane.

Liver and GLUT2 Transporters

  • GLUT2 transporter: Always present in the liver cell membrane.
  • Glucose entry: Glucose enters through GLUT2.
  • Glycogen conversion: Accelerated by insulin.
  • Glucagon Action: Glucagon converts glycogen back into glucose if glucose is too low.
  • GLUT2 importance: Needs to be there to pump glucose back out.

Summary of Hormone Action

  • Insulin: Targets muscle to promote glucose uptake.
  • Glucagon: Primarily targets the liver to promote glycogen breakdown.

Recap of Lecture Aims

  • Fed state: High production of insulin to secrete the glucose etc.
  • Fasting state: Release of glucagon on the liver is important.