Core Topics: Metabolic States

How to Use This Resource

Each metabolic state section includes: Hormonal Regulation (insulin/glucagon balance), Tissue-Specific Responses (liver, muscle, adipose), and High-Yield Facts (clinical correlations, diabetic emergencies). Use for active recall, spaced repetition, and integration with clinical cases.

Fed State (Absorptive State)

Post-prandial period (2-4 hours) focused on energy storage and anabolism

Definition & Hormones

Definition: Period after meal (2-4 hours) when nutrients are absorbed and stored
Dominant Hormone: Insulin (from pancreatic β-cells)
Metabolic Goals: Store energy, build macromolecules, promote anabolism
Insulin Release Stimuli: ↑Blood glucose, amino acids (leucine, arginine), GLP-1, GIP, vagal stimulation
Insulin Release Mechanism: Glucose → GLUT2 → glycolysis → ↑ATP → closes K-ATP channels → depolarization → Ca²⁺ influx → insulin exocytosis

Insulin Receptor & Signaling

Receptor Type: Tyrosine kinase receptor
Signaling Cascade: Insulin binding → IRS-1 phosphorylation → PI3K/Akt pathway
Key Effects:
- GLUT4 translocation (muscle/adipose)
- Enzyme regulation (glycogen synthase activation, glycogen phosphorylase inhibition)
- Gene transcription changes
- ↑K⁺ uptake (Na⁺/K⁺-ATPase activation)

Tissue-Specific Responses

Tissue	Key Fed State Responses
Liver	↑Glycogenesis, ↑glycolysis, ↑FA synthesis, ↑protein synthesis, ↓gluconeogenesis, ↓glycogenolysis
Muscle	↑Glucose uptake (GLUT4), ↑glycogenesis, ↑protein synthesis, ↑amino acid uptake
Adipose	↑Glucose uptake (GLUT4), ↑lipogenesis, ↑LPL activity, ↓lipolysis (HSL inhibited)

High-Yield: Fed State

Insulin Mechanism

Insulin receptor = tyrosine kinase; activates PI3K/Akt → GLUT4 translocation in muscle/adipose (NOT liver, which uses GLUT2)

Key Enzymes Activated

Glycogen synthase (glycogenesis), PFK-1 (glycolysis), acetyl-CoA carboxylase (FA synthesis), LPL (FA uptake)

Key Enzymes Inhibited

Glycogen phosphorylase (glycogenolysis), PEPCK/F-1,6-BPase (gluconeogenesis), HSL (lipolysis)

Potassium Shift

Insulin drives K⁺ into cells (Na⁺/K⁺-ATPase); used clinically to treat hyperkalemia (with glucose to prevent hypoglycemia)

Fasting State (Post-Absorptive)

Inter-meal period (4-12 hours) focused on glucose maintenance and fuel mobilization

Definition & Hormones

Definition: Period between meals (4-12 hours) when stored fuels are mobilized
Dominant Hormones: Glucagon (α-cells), catecholamines, cortisol
Metabolic Goals: Maintain blood glucose, mobilize stored energy
Glucagon Release Stimuli: ↓Blood glucose, amino acids (arginine, alanine), sympathetic activation
Glucagon Receptor: GPCR → Gs → adenylyl cyclase → ↑cAMP → PKA activation
Primary Target: Liver (muscle lacks glucagon receptors)

Tissue-Specific Responses

Tissue	Key Fasting State Responses
Liver	↑Glycogenolysis, ↑gluconeogenesis, ↑FA oxidation, ↑ketogenesis (prolonged), ↓glycolysis, ↓glycogenesis
Muscle	↑Glycogenolysis (local use only), ↑FA oxidation, ↑protein degradation, ↓glucose uptake
Adipose	↑Lipolysis (HSL activated by PKA), release of FFAs + glycerol, ↓lipogenesis

Glucagon vs Insulin

Insulin:Glucagon Ratio

Fed: High insulin:glucagon → anabolism, storage; Fasting: Low insulin:glucagon → catabolism, mobilization

High-Yield: Fasting State

Muscle Glucagon

Muscle lacks glucagon receptors; glucagon acts primarily on liver; muscle glycogenolysis stimulated by epinephrine/Ca²⁺

Gluconeogenesis Substrates

Lactate (Cori cycle), alanine (glucose-alanine cycle), glycerol (from adipose lipolysis)

Hormone-Sensitive Lipase

HSL activated by PKA phosphorylation (glucagon/epinephrine); inhibited by insulin (dephosphorylation)

Glycogen Depletion

Liver glycogen depleted in ~24 hours of fasting; gluconeogenesis becomes primary glucose source thereafter

Prolonged Fasting/Starvation

Metabolic adaptations beyond 24 hours with shift to ketone utilization

Timeline of Adaptations

Early Fasting (12-24 hours)

Liver glycogen depleted; gluconeogenesis becomes primary glucose source (lactate, alanine, glycerol)

Prolonged Fasting (>24 hours)

↑Ketogenesis (acetoacetate, β-hydroxybutyrate, acetone); brain adapts to ketones (↓glucose requirement by ~75%)

Extended Starvation (weeks)

Ketones = primary brain fuel; muscle proteolysis minimized; metabolic rate decreases

Tissue Fuel Adaptations

Tissue	Normal	Prolonged Fasting
Brain	Glucose only	Ketone bodies (up to 75%)
Muscle	Glucose/FA	FA → ketones (protein-sparing)
RBCs	Glucose only	Glucose only (no mitochondria)
Renal Medulla	Glucose only	Glucose only (anaerobic)

Key Adaptations

Protein-Sparing Effect: Ketone utilization by brain reduces need for gluconeogenic amino acids → ↓muscle proteolysis
Metabolic Rate: Decreases to conserve energy (↓T3, ↑reverse T3)
Obligate Glucose Users: RBCs (no mitochondria), renal medulla, lens, cornea, WBCs, bone marrow, testes
Ketone Transport: Ketones cross BBB via monocarboxylate transporters (MCTs)

High-Yield: Prolonged Fasting

Brain Adaptation

Brain adapts to ketones after 2-3 days of fasting; reduces glucose requirement from ~120g/day to ~30g/day

Obligate Glucose

RBCs always require glucose (no mitochondria → obligate glycolysis → lactate); renal medulla also obligate glucose user

Ketone Bodies

Acetoacetate, β-hydroxybutyrate (major in DKA), acetone (exhaled, fruity breath); synthesized in liver, used by extrahepatic tissues

Liver Ketone Use

Liver cannot use ketones (lacks thiophorase/succinyl-CoA:acetoacetate CoA transferase); produces but doesn't consume

Hormonal Regulation of Metabolism

Key metabolic hormones and their tissue-specific effects

Insulin (Anabolic)

Source: Pancreatic β-cells
Stimuli: ↑Glucose, amino acids, GLP-1, GIP, vagal
Inhibitors: Somatostatin, sympathetic, hypokalemia
Actions: ↑Glucose uptake (GLUT4), ↑glycogenesis, ↑glycolysis, ↑lipogenesis, ↑protein synthesis, ↑K⁺ uptake
Mechanism: Tyrosine kinase → IRS → PI3K → Akt → GLUT4 translocation

Glucagon (Catabolic)

Source: Pancreatic α-cells
Stimuli: ↓Glucose, amino acids (arginine, alanine), sympathetic
Inhibitors: Insulin, somatostatin, GLP-1
Actions: ↑Glycogenolysis, ↑gluconeogenesis, ↑FA oxidation, ↑ketogenesis (liver only)
Mechanism: GPCR → Gs → ↑cAMP → PKA activation

Catecholamines

Source: Adrenal medulla (Epi), sympathetic nerves (NE)
Liver: ↑Glycogenolysis, ↑gluconeogenesis (β₂, α₁)
Muscle: ↑Glycogenolysis (β₂)
Adipose: ↑Lipolysis (β₃)
Pancreas: ↓Insulin (α₂), ↑glucagon (β₂)

Cortisol

Source: Adrenal cortex (zona fasciculata)
Actions: ↑Gluconeogenesis (induces PEPCK, G-6-Pase), ↑proteolysis, ↑lipolysis, ↓peripheral glucose uptake
Effects: Permissive for glucagon/epinephrine; anti-inflammatory
Clinical: Cushing syndrome → hyperglycemia, central obesity, muscle wasting

Growth Hormone

Source: Anterior pituitary
Actions: ↑Lipolysis, ↓glucose uptake (diabetogenic), ↑protein synthesis, ↑IGF-1 (from liver)
Net Effect: Insulin antagonist; promotes growth while maintaining glucose

Thyroid Hormones

Forms: T3 (active), T4 (prohormone)
Actions: ↑BMR, ↑glucose absorption, ↑glycogenolysis, ↑gluconeogenesis, ↑lipolysis, ↑protein turnover
Net Effect: Calorigenic; increases metabolic rate of all tissues

High-Yield: Hormonal Regulation

Insulin Receptor

Tyrosine kinase (intrinsic activity); glucagon/epinephrine = GPCR (Gs → cAMP → PKA)

Cortisol Timing

Cortisol has circadian rhythm (peak 6-8 AM); permissive effect allows glucagon/epinephrine to work effectively

GH Diabetogenic

GH ↓glucose uptake → insulin resistance; chronic excess → secondary diabetes; stimulates IGF-1 from liver

Thyroid & Metabolism

T3/T4 ↑Na⁺/K⁺-ATPase activity → ↑O₂ consumption → ↑BMR; hyperthyroid → weight loss despite ↑appetite

Tissue-Specific Metabolism

Unique metabolic capabilities and fuel preferences of major tissues

Liver

Glucokinase (high Km, not inhibited by G-6-P)
Glucose-6-phosphatase (releases free glucose)
Complete urea cycle, ketogenesis
VLDL synthesis/secretion
Fed: Glycogenesis, lipogenesis; Fasting: Glycogenolysis, gluconeogenesis, ketogenesis

Skeletal Muscle

Hexokinase (low Km, inhibited by G-6-P)
No G-6-Pase (cannot release glucose)
Glycogen for local use only
BCAA metabolism, creatine phosphate
Fed: Glucose uptake, glycogenesis; Fasting: FA oxidation, proteolysis

Cardiac Muscle

Highly aerobic (many mitochondria)
Prefers fatty acids (60-70% ATP)
Can use ketones, lactate, glucose
Continuous energy demand
Fuel preference: FA > lactate > glucose > ketones

Brain

Obligate glucose user (normally)
No significant fuel storage
BBB limits fuel access
Adapts to ketones in prolonged fasting
Cannot use: Fatty acids (don't cross BBB)

Adipose Tissue

LPL on capillary endothelium
HSL intracellular
Stores triglycerides
Releases FFAs + glycerol
Fed: Lipogenesis (LPL active); Fasting: Lipolysis (HSL active)

Red Blood Cells

No mitochondria → obligate glycolysis
No nucleus → cannot synthesize proteins
2,3-BPG for O₂ delivery regulation
PPP for NADPH (glutathione)
Fuel: Glucose only (anaerobic → lactate)

High-Yield: Tissue Metabolism

Liver Uniqueness

Only tissue with glucose-6-phosphatase (releases free glucose); only tissue with complete urea cycle; only tissue that performs ketogenesis

Muscle Limitations

Muscle cannot release glucose (no G-6-Pase); glycogen for local use only; lacks glucagon receptors

Brain Fuel

Brain cannot use fatty acids (don't cross BBB); adapts to ketones after 2-3 days fasting; RBCs always need glucose

Heart Preference

Cardiac muscle prefers fatty acids (60-70% ATP); highly efficient aerobic metabolism; can use lactate (Cori cycle product)

Metabolic Syndrome & Diabetes

Pathophysiology, diagnosis, and acute complications of glucose metabolism disorders

Metabolic Syndrome (ATP III)

Definition: ≥3 of 5 criteria:
Waist: >102 cm (men), >88 cm (women)
TG: ≥150 mg/dL
HDL: <40 mg/dL (men), <50 mg/dL (women)
BP: ≥130/85 mmHg
Fasting glucose: ≥100 mg/dL
Pathophysiology: Central obesity → ↑FFAs → insulin resistance → compensatory hyperinsulinemia

Adipose Dysfunction

Pro-inflammatory: ↑TNF-α, IL-6 (promote insulin resistance)
Adipokines: ↓Adiponectin (insulin-sensitizing), ↑resistin, ↑leptin (leptin resistance)
Atherogenic Dyslipidemia: ↑TG, ↓HDL, ↑small dense LDL (most atherogenic)
Clinical Consequences: Type 2 DM, CVD, NAFLD, PCOS, sleep apnea

Type 1 vs Type 2 Diabetes

Feature	Type 1 DM	Type 2 DM
Pathophysiology	Autoimmune β-cell destruction	Insulin resistance + relative deficiency
Antibodies	Anti-GAD65, anti-islet, anti-insulin	None
Age	Usually <30 years	Usually >40 years (changing)
Body Habitus	Thin/normal	Obese (80-90%)
Ketosis	Common (DKA)	Rare (HHS instead)
Treatment	Insulin required	Lifestyle, oral agents, ±insulin

Diabetic Ketoacidosis (DKA)

Pathophysiology: Insulin deficiency + glucagon excess → ↑lipolysis → ↑FFAs → hepatic ketogenesis
Triggers: Infection, non-compliance, new diagnosis, MI, drugs
Labs: Glucose >250 mg/dL, anion gap metabolic acidosis, ↑ketones, ↓pH, ↓HCO₃⁻, ↑K⁺ (initially)
Management: IV fluids, insulin, K⁺ replacement, treat underlying cause

Hyperosmolar Hyperglycemic State (HHS)

Pathophysiology: Severe hyperglycemia WITHOUT significant ketosis (enough insulin to prevent lipolysis)
Typical Patient: Elderly with Type 2 DM
Labs: Glucose >600 mg/dL, osmolality >320 mOsm/kg, minimal ketosis, no significant acidosis
Management: Aggressive IV fluids, insulin, electrolyte replacement

High-Yield: Metabolic Syndrome & Diabetes

DKA vs HHS

DKA: Type 1, ketosis, acidosis, younger; HHS: Type 2, no ketosis, higher glucose/osmolality, elderly, higher mortality

Potassium in DKA

Serum K⁺ normal/high initially (acidosis shifts K⁺ out of cells) but total body K⁺ depleted; replace K⁺ before/during insulin

Small Dense LDL

Metabolic syndrome → ↑small dense LDL particles (most atherogenic); penetrate endothelium easily, oxidize readily

Metformin

First-line for Type 2 DM; ↓hepatic gluconeogenesis, ↑insulin sensitivity; risk of lactic acidosis (avoid in renal failure)

Metabolic Pathway Integration

Inter-organ cycles that coordinate metabolism across tissues

Cori Cycle (Lactate Cycle)

Muscle (Anaerobic)

Glucose → pyruvate → lactate (glycolysis); lactate released to blood

Liver (Aerobic)

Lactate → pyruvate → glucose (gluconeogenesis); glucose released to blood

Purpose: Recycles lactate, shifts metabolic burden to liver
Energy Cost: 6 ATP (liver) - 2 ATP (muscle) = net -4 ATP

Glucose-Alanine Cycle (Cahill)

Muscle

Amino acid catabolism → amino groups transferred to pyruvate → alanine

Liver

Alanine → pyruvate (transamination) + NH₄⁺ → urea; pyruvate → glucose

Purpose: Transports nitrogen from muscle to liver for urea synthesis; provides gluconeogenic substrate
Key Enzyme: ALT (alanine aminotransferase)

Fed-Fast Cycle Integration

State	Hormones	Liver	Muscle	Adipose
Carb Meal	↑Insulin, ↓Glucagon	↑Glycogenesis, ↑glycolysis	↑Glucose uptake, ↑glycogenesis	↑Lipogenesis, ↑LPL
Protein Meal	↑Insulin + ↑Glucagon	↑Protein synthesis, ↑urea	↑Protein synthesis	Minimal change
Fasting	↓Insulin, ↑Glucagon	↑Glycogenolysis → ↑GNG → ↑Ketones	↑FA oxidation, ↑proteolysis	↑Lipolysis
Exercise	↑Epi, ↑Glucagon, ↓Insulin	↑Glycogenolysis, ↑GNG	↑Glycogenolysis, ↑FA oxidation	↑Lipolysis

High-Yield: Pathway Integration

Cori Cycle Energy

Net cost of 4 ATP per cycle (6 ATP in liver gluconeogenesis - 2 ATP from muscle glycolysis); shifts lactate burden to liver

Alanine Cycle

Transports nitrogen (as alanine) from muscle to liver; alanine is major gluconeogenic amino acid; ALT/AST elevated in liver disease

Protein Meal

Amino acids stimulate both insulin AND glucagon; glucagon prevents hypoglycemia despite insulin release

Exercise Metabolism

↑Epinephrine → muscle glycogenolysis (local use); liver glycogenolysis maintains blood glucose; lactate produced enters Cori cycle

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Evidence & Further Reading

Berg JM et al. Biochemistry. 9th ed. W.H. Freeman; 2019.
Nelson DL, Cox MM. Lehninger Principles of Biochemistry. 8th ed. W.H. Freeman; 2021.
USMLE Content Outline 2025. Federation of State Medical Boards & NBME.
Kahn SE et al. Pathophysiology of type 2 diabetes. Diabetes Care. 2014;37(1):S2-S8.
American Diabetes Association. Standards of Medical Care in Diabetes. Diabetes Care. 2024;47(Suppl 1).
Grundy SM et al. Metabolic syndrome. Circulation. 2005;112(17):2735-2752.

Core Topics: Metabolic States & Integration

How to Use This Resource

Fed State (Absorptive State)

Fasting State (Post-Absorptive)

Prolonged Fasting/Starvation

Hormonal Regulation of Metabolism

Tissue-Specific Metabolism

Liver

Skeletal Muscle

Cardiac Muscle

Brain

Adipose Tissue

Red Blood Cells

Metabolic Syndrome & Diabetes

Diabetic Ketoacidosis (DKA)

Hyperosmolar Hyperglycemic State (HHS)

Metabolic Pathway Integration

Evidence & Further Reading