BSCI Lecture 9: Notes on Regulation of Metabolism and Glucose Fate

Regulation of metabolism

• Topic overview: how cells obtain energy from food, with focus on regulation by insulin and glucagon and how this controls storage vs. oxidation of glucose. Excerpts referenced from Chapter 13 (How cells obtain energy from food) and Chapter 14 (Energy generation in mitochondria and chloroplasts);
• Semaglutide (GLP-1 receptor agonist) stimulates insulin secretion which regulates metabolism by promoting glucose storage and reducing blood glucose; also influences appetite; relevant to treatment of T2D and obesity.

Blood glucose: sources and regulation

• Glucose from food is absorbed in the gut and reaches the liver first via the bloodstream, then distributes to other organs.
• Glucose can be oxidized to generate ATP or stored as glycogen in the liver and skeletal muscle when in excess.
• Primary hormonal regulators of blood glucose are insulin and glucagon, maintaining glucose within a narrow range.
• Key ideas:
  • Insulin promotes storage and utilization that lowers blood glucose.
  • Glucagon promotes glucose release during fasting.

Blood glucose concentrations and regulation (normal ranges)

• Fasting blood glucose ranges:
  • Normal: $70-110\,\mathrm{mg/dl}$
  • Hypoglycemia: <70\,\mathrm{mg/dl}
  • Type 2 Diabetes (T2D): >126\,\mathrm{mg/dl}
• Blood glucose is kept within a narrow band largely through regulation by insulin and glucagon.

Liver glucose fate and regulation (overview)

• In liver cells (hepatocytes), glucose fate depends on:
  • Energy status: AMP/ADP:ATP ratio
  • Hormonal state: insulin:glucagon ratio
• Core fates in the liver include:
  • Glycogenolysis: breakdown of glycogen to release glucose during early fasting (12–18 h)
  • Gluconeogenesis: synthesis of glucose from non-carbohydrate sources (amino acids, lactate) during prolonged fasting (>18 h)
  • Glycogen synthesis: storage of glucose as glycogen (occurs in liver and skeletal muscle)
  • Lipogenesis: conversion of glucose to fats (acetyl-CoA to fatty acids) and storage as fat
  • Oxidation: oxidation of glucose to generate ATP for immediate energy needs
• Insulin promotes storage and energy storage, while glucagon promotes mobilization of stored glucose.

AMP/ADP : ATP and insulin : glucagon control of hepatic glucose fate

• When AMP/ADP ratios are high and ATP is low (low energy state):
  • Glucose oxidation is favored.
  • Activation of PFK (phosphofructokinase) promotes glycolysis.
  • Glycogen synthase is inhibited (less glycogen synthesis).
  • Glycogen phosphorylase is activated (glycogen breakdown).
  • Insulin effect is minimal or opposing in this specific energy-deprived state; the main driver is energy charge and glucagon signaling.
  • Key enzymes/products involved include: DHAP, G3P, BPG, NAD+, NADH, PEP, G6P, F6P, F-1,6-bisP, ATP/ADP, AMP/ADP.
• When ATP is high and insulin is present (fed/high-energy state with insulin signaling):
  • Glycogen synthesis is favored.
  • Inhibition of PFK reduces glycolytic flux toward oxidation.
  • Activation of glycogen synthase promotes glycogen formation.
  • Inhibition of glycogen phosphorylase reduces glycogenolysis.
  • Overall tendency is storage of glucose as glycogen rather than immediate oxidation.
• Enzymes mentioned:
  • PFK = phosphofructokinase
  • Glycogen synthase
  • Glycogen phosphorylase
• Metabolite flow (general hepatocyte pathway):
  • Glucose → G6P → F6P → F-1,6-bisP → DHAP + G3P → 3PG → 2PG → PEP → Pyruvate
  • Intermediates linked to glycogen metabolism and lipid synthesis via acetyl-CoA
• Note on insulin’s broader effects: insulin promotes glycogen synthesis and fat storage, and promotes glucose uptake into tissues.

Practical: Interpretive practice (Predict questions)

• Practice 1 (from the activity): Predict outcomes for two conditions:
  • Condition 1: High blood glucose and low ATP in the liver
  • Condition 2: High blood glucose and high ATP in the liver
• Options to match (A–F):
  • A. Glucose oxidation
  • B. Glycogen synthesis
  • C. Glucose uptake
  • D. Gluconeogenesis
  • E. Glycogenolysis
  • F. Fat synthesis
• Answers provided by the transcript for these two conditions (Page 6):
  • Condition 1 (High glucose, low ATP): matches A and E
  • Condition 2 (High glucose, high ATP): matches B and C
• Additional predict-and-match exercises (for self-check):
  • Page 9: 1) High blood glucose and low ATP in liver — A, C, E; 2) High blood glucose and high ATP in liver — B, C
  • Page 14: 1) Low blood glucose and sufficient ATP in liver — D, E
• Summary of these exercises: they reinforce how energy charge and hormonal signals shift liver metabolism toward oxidation, storage, uptake, or gluconeogenesis depending on state.

Hepatic glucose handling in fed/fasting states (detailed flow)

• Glucose uptake into hepatocytes:
  • Occurs by passive transport in a concentration-dependent manner.
  • Fate depends on energy charge and hormone signals (AMP/ADP:ATP and insulin:glucagon).
• Key metabolic map (liver):
  • Glucose → G6P → F6P → F-1,6-bisP → DHAP + G3P → BPG → NAD+ / Pi → NADH → 3PG → 2PG → ADP / ATP → PEP → Pyruvate
  • Parallel branches: glycogen (glycogen synthase for storage) and glycolytic branch (PFK governs glycolysis), and gluconeogenic branch in liver for glucose production when needed.
• Regulatory node: PFK (phosphofructokinase) is a major control point; its activity is modulated by energy state (AMP/ADP and ATP) and insulin/glucagon signals.
• Key points on enzyme regulation in fed vs. fasted states:
  • ATP-rich, insulin-present state: promotion of glycogen synthesis; inhibition of PFK; inhibition of glycogen phosphorylase.
  • Low-energy state (high AMP/ADP): activation of PFK; glycogen breakdown via glycogen phosphorylase; gluconeogenesis upregulation when needed (via glucagon).

Cori cycle (anaerobic glycolysis and lactate shuttle)

• The Cori cycle describes lactate production in skeletal muscle under anaerobic conditions, which is transported to the liver and converted back to glucose.
• Benefits:
  • Recycling of lactic acid during intensive muscle activity.
  • Provides a continuous glucose supply to fuel muscle activity when oxygen is limited.
• Cycle outline (simplified):
  • Muscle performs anaerobic glycolysis → lactate produced → lactate travels to liver → liver converts lactate to glucose (gluconeogenesis) → glucose released back to bloodstream → muscle uptake for energy.

Lipogenesis and fat deposition from excess sugars

• When fuel is plentiful and glycogen stores are replenished, excess acetyl-CoA from glucose metabolism is diverted to fat synthesis (lipogenesis).
• Liver-centric flow:
  • Glucose → G6P → F6P → F-1,6-bisP → DHAP + G3P → glycerol backbone formation → acetyl-CoA → fatty acid synthesis → fats packaged as VLDL (Very Low Density Lipoprotein) for transport to other tissues.
• Key fatty-acid packaging: VLDL particles deliver triglycerides and cholesterol to tissues as needed.

Fructose metabolism and its lipogenic potential

• Fructose metabolism in the liver differs from glucose metabolism:
  • In most tissues, glucose and fructose are phosphorylated by hexokinase; in the liver, fructose is phosphorylated by a specific enzyme (fructokinase).
  • Fructose enters glycolysis downstream of the main regulatory point (bypassing PFK-1 control), which can promote unregulated flux toward acetyl-CoA and fat synthesis.
  • Fructose uptake is liver-dominant due to specific transporters and enzymes expressed in hepatocytes.
• Consequences: high fructose intake is more closely linked to fat deposition (lipogenesis) than equivalent glucose intake under some conditions.
• Pathway outline (hepatic):
  • Fructose → fructose-1-phosphate (via fructokinase) → intermediates feed into glycolysis downstream of PFK-1 → glycerol and acetyl-CoA production → fatty acid synthesis → fats packaged as VLDL.
• Additional note from slide: Fructose and sucrose metabolism involve distinct enzymes (fructo-kinase and gluco-kinase) with fructose metabolism leaning toward lipogenesis in liver.

Semaglutide: clinical relevance to T2D and obesity

• Semaglutide is used to treat both T2D and obesity.
  • T2D: characterized by high blood glucose; Semaglutide promotes glucose storage in liver and especially in muscle by stimulating insulin release, thereby reducing blood glucose levels.
  • Appetite regulation: Semaglutide also modulates appetite, addressing root causes of obesity and insulin resistance.
• Clinical implications:
  • By increasing insulin secretion, hepatic and muscle glucose storage is enhanced, lowering circulating glucose.
  • Appetite suppression contributes to weight loss, reducing insulin resistance and metabolic burden.

Obesity, Type 2 diabetes, and metabolic regulation (context)

• High-sugar and high-fat diets coupled with limited physical activity contribute to rising obesity rates.
• Obesity is linked to increased prevalence of Type 2 diabetes due to insulin resistance and dysregulated glucose metabolism.
• This regulatory framework helps explain why therapies like semaglutide can improve both glycemic control and weight management.

Learning objectives (checklist)

• Describe sources of blood glucose and how each interacts with insulin and glucagon.
• Explain regulation of the fate of glucose in liver cells, considering the roles of AMP/ADP : ATP and insulin : glucagon in controlling:
  • phosphofructokinase (PFK)
  • glycogen synthase
  • glycogen phosphorylase
  • the gluconeogenesis pathway
• Describe the Cori cycle and its metabolic significance.
• Explain how excess sugars can lead to fat deposition via lipogenesis and VLDL packaging.
• Explain why fructose is more prone to fat deposition than glucose.

Quick reference: key definitions and symbols

• Blood glucose target range: $70-110\,\mathrm{mg/dl}$
• Hypoglycemia: <70\,\mathrm{mg/dl}
• T2D threshold: >126\,\mathrm{mg/dl}
• Key metabolic intermediates: $G6P, F6P, \text{F-1,6-bisP}, \text{DHAP}, \text{G3P}, \text{3PG}, \text{2PG}, \text{PEP}, \text{pyruvate}$
• Major enzymes: $PFK\;\text{(phosphofructokinase)}$, glycogen synthase, glycogen phosphorylase, glucagon, insulin
• Major energy carriers: $ATP, ADP, AMP, NAD^+, NADH, Pi$
• Major lipoprotein for fat transport: $VLDL$
• Major acetyl-CoA contributor to lipogenesis: $\text{AcCoA}$
• Lactate shuttle: Cori cycle between muscle and liver