Hormonal Metabolic Integration

Insulin

Insulin is a peptide hormone (51 amino acids, two chains linked by disulfide bonds) synthesized in pancreatic β-cells as preproinsulin → proinsulin (with C-peptide) → mature insulin + C-peptide. Secretion is stimulated primarily by elevated blood glucose (>5 mM): glucose enters β-cells via GLUT2 (constitutively present), is phosphorylated by glucokinase (high Km, acts as a glucose sensor), and enters glycolysis/TCA, raising ATP levels. Elevated ATP closes ATP-sensitive K+ channels (K_ATP; SUR1/Kir6.2), depolarizing the membrane, opening voltage-gated Ca2+ channels, and triggering Ca2+-mediated exocytosis of insulin granules. Amino acids (especially arginine and leucine) and incretins (GLP-1, GIP) also stimulate secretion. Insulin signals through a receptor tyrosine kinase (RTK): insulin binds the α-subunits of its receptor → autophosphorylation of β-subunit tyrosine residues → recruitment and phosphorylation of IRS-1 (insulin receptor substrate-1) → PI3K activation → PIP2 → PIP3 → PDK1 and Akt (PKB) activation. Akt phosphorylates multiple targets: (1) AS160 → GLUT4 translocation to membrane in muscle and adipose (increasing glucose uptake); (2) GSK-3β inactivation → glycogen synthase dephosphorylation → glycogen synthesis; (3) PFK-2 activation (dephosphorylated state) → increased F2,6BP → activation of PFK-1 → glycolysis; (4) activation of acetyl-CoA carboxylase → fatty acid synthesis in liver and adipose; (5) mTORC1 activation → protein synthesis. In the liver, insulin stimulates glucokinase gene expression, glycogen synthesis, glycolysis, and fatty acid synthesis, while repressing PEPCK and G6Pase (gluconeogenesis enzymes). In adipose, insulin promotes glucose uptake (GLUT4), glycolysis, and lipogenesis (via activation of lipoprotein lipase and ACC). In muscle, insulin increases GLUT4-mediated glucose uptake and glycogen synthesis. C-peptide, co-secreted in equimolar amounts with insulin, serves as a clinical marker of endogenous insulin production (useful for distinguishing type 1 vs. type 2 diabetes). Type 1 diabetes: autoimmune β-cell destruction → no insulin → hyperglycemia, ketoacidosis (unrestrained lipolysis → excess ketone bodies). Type 2 diabetes: insulin resistance → compensatory hyperinsulinemia → eventual β-cell exhaustion → hyperglycemia.

Glucagon

Glucagon is a 29-amino-acid peptide hormone synthesized in pancreatic α-cells. It is secreted in response to low blood glucose (<4 mM), elevated amino acids (particularly after a protein meal—prevents hypoglycemia from insulin co-secretion), and sympathetic stimulation (β-adrenergic). Insulin directly suppresses glucagon secretion from neighboring α-cells (paracrine inhibition) via intra-islet blood flow. Glucagon signals through a Gαs-coupled GPCR: glucagon binds its receptor → Gαs activates adenylyl cyclase → cAMP synthesis → PKA activation. PKA phosphorylates and activates key catabolic enzymes: (1) phosphorylase kinase → glycogen phosphorylase → glycogenolysis in liver (NOT muscle—muscle lacks glucagon receptors); (2) PFK-2/FBPase-2 bifunctional enzyme (phosphorylation inactivates PFK-2 and activates FBPase-2) → F2,6BP levels drop → PFK-1 activity decreases, FBPase-1 activity increases → glycolysis suppressed, gluconeogenesis favored; (3) hormone-sensitive lipase (HSL) in adipose → lipolysis → FFA and glycerol released; (4) acetyl-CoA carboxylase inhibition (via PKA phosphorylation) → malonyl-CoA levels drop → CPT-1 disinhibited → fatty acids enter mitochondria for β-oxidation → acetyl-CoA → ketone body synthesis in liver. Glucagon also increases transcription of PEPCK and G6Pase (rate-limiting enzymes of gluconeogenesis) via CREB (cAMP response element-binding protein). The net effect: liver releases glucose (glycogenolysis early, gluconeogenesis sustained), adipose releases FFA, and the liver converts FFA-derived acetyl-CoA to ketone bodies (acetoacetate, β-hydroxybutyrate) for export to brain and muscle. The glucagon receptor is NOT expressed on skeletal muscle—muscle glycogen is mobilized only by epinephrine, not glucagon. This tissue specificity is a high-yield MCAT distinction: glucagon acts on liver and adipose; epinephrine acts on liver, muscle, and adipose.

Epinephrine

Epinephrine (adrenaline) is a catecholamine synthesized from tyrosine in the adrenal medulla and released during fight-or-flight response, exercise, and hypoglycemia. It signals through β-adrenergic receptors (Gαs-coupled GPCR → cAMP → PKA) and α1-adrenergic receptors (Gαq-coupled → IP3/Ca2+ → PKC). The β-adrenergic/cAMP/PKA cascade in liver mirrors glucagon signaling: glycogen phosphorylase activated → glycogenolysis; PFK-2/FBPase-2 phosphorylated (inactivates glycolysis, activates gluconeogenesis). In skeletal muscle, epinephrine (via β-receptors) activates glycogenolysis (glycogen phosphorylase) but ALSO activates glycolysis (via Ca2+-calmodulin and AMP allosteric activation of PFK-1)—unlike in liver, muscle lacks G6Pase and cannot export free glucose; instead, muscle glycogen is broken down to G6P, which enters glycolysis to produce ATP locally for contraction. The resulting pyruvate can be reduced to lactate (anaerobic) and exported to liver via the Cori cycle. In adipose tissue, epinephrine (via β-receptors) activates hormone-sensitive lipase → lipolysis → FFA and glycerol released. The key distinction from glucagon: epinephrine acts on ALL THREE tissues (liver, muscle, adipose), while glucagon acts only on liver and adipose (no glucagon receptors on muscle). Epinephrine also has α1-adrenergic effects in liver, activating glycogenolysis via IP3/Ca2+ (distinct from the cAMP pathway), providing a second mechanism for rapid glucose release. In muscle, the Ca2+ released during excitation-contraction coupling directly activates glycogen phosphorylase kinase (calmodulin subunit), linking metabolic rate to contractile activity. Epinephrine's net effect: rapidly mobilize glucose (liver glycogen) and FFA (adipose), provide ATP for muscle contraction (muscle glycogen), and inhibit insulin secretion (α2-adrenergic on β-cells) while stimulating glucagon secretion (β-adrenergic on α-cells)—reinforcing the catabolic state.

Cortisol

Cortisol is a steroid hormone (derived from cholesterol) synthesized in the adrenal cortex (zona fasciculata), released in response to ACTH (from anterior pituitary) under hypothalamic CRH control (HPA axis). It follows a diurnal rhythm (peak in early morning) and is elevated during chronic stress, starvation, and illness. As a steroid hormone, cortisol diffuses through the plasma membrane and binds an intracellular glucocorticoid receptor (GR) in the cytoplasm. Upon cortisol binding, the GR dissociates from Hsp90 chaperones, dimerizes, translocates to the nucleus, and binds glucocorticoid response elements (GREs) in promoter regions of target genes—acting as a transcription factor (genomic effect; slow onset, sustained). Cortisol has permissive effects: it is required for glucagon and epinephrine to exert full catabolic effects; without cortisol, catecholamines have blunted metabolic responses. Cortisol promotes: (1) gluconeogenesis in liver—increases transcription of PEPCK, G6Pase, and other gluconeogenic enzymes and provides substrates by stimulating protein degradation in peripheral tissues (muscle, skin, lymphoid) → amino acids (especially alanine) released into circulation → hepatic gluconeogenesis; (2) lipolysis in adipose (permissive effect on epinephrine/glucagon) → FFA for β-oxidation; (3) protein catabolism in muscle → negative nitrogen balance (chronic excess → muscle wasting); (4) insulin antagonism—cortisol induces insulin resistance, raising blood glucose. Chronic cortisol excess (Cushing's syndrome) produces hyperglycemia, central obesity, muscle wasting, and immunosuppression. Cortisol also suppresses the immune system (inhibits NF-κB, reduces inflammatory cytokines), which is why synthetic glucocorticoids (prednisone, dexamethasone) are used as anti-inflammatory drugs. The MCAT expects you to distinguish rapid (nongenomic) vs. slow (genomic) hormone action: peptide hormones (insulin, glucagon, epinephrine) act rapidly via cell-surface receptors and second messengers; steroid hormones (cortisol) act slowly via intracellular receptors and gene transcription, but their effects are sustained.

Fed State

The fed (absorptive) state occurs after a meal when nutrients are being absorbed from the gut. The insulin-to-glucagon ratio is HIGH (insulin elevated, glucagon suppressed). Blood glucose rises → insulin secretion → glucose disposal into tissues. Metabolic priorities: (1) oxidize glucose for immediate energy, (2) store excess as glycogen, (3) convert remaining excess to fat. In the liver: glucose enters via GLUT2 (high Km, insulin-independent) and is phosphorylated by glucokinase (induced by insulin) → G6P. G6P is channeled to glycogen synthesis (glycogen synthase activated by insulin via GSK-3β inhibition), glycolysis (PFK-1 activated via F2,6BP from insulin-activated PFK-2), and the pentose phosphate pathway (G6PD produces NADPH for fatty acid synthesis). Excess acetyl-CoA from glycolysis/TCA is used for fatty acid synthesis (ACC activated, malonyl-CoA ↑, CPT-1 inhibited—preventing newly synthesized fatty acids from being oxidized). TAGs are packaged into VLDL and exported to adipose. In adipose tissue: insulin stimulates GLUT4 translocation → glucose uptake → glycolysis → glycerol-3-phosphate and acetyl-CoA → TAG synthesis. Insulin also activates lipoprotein lipase (LPL) on capillary endothelium, releasing FFA from chylomicrons and VLDL for adipocyte uptake. In muscle: insulin stimulates GLUT4 translocation → glucose uptake → glycogen synthesis (primary) and glycolysis. Muscle glycogen is the major glucose storage depot (~400 g vs. liver ~100 g) but is used locally—only liver glycogen contributes to blood glucose maintenance. In the brain: glucose uptake is insulin-independent (GLUT1/GLUT3)—the brain takes up glucose constitutively. Key regulatory point: PFK-2/FBPase-2 is a bifunctional enzyme whose phosphorylation state controls F2,6BP levels. Insulin activates a phosphatase that dephosphorylates PFK-2/FBPase-2 → PFK-2 active, FBPase-2 inactive → F2,6BP rises → PFK-1 activated, FBPase-1 inhibited → glycolysis ON, gluconeogenesis OFF. This is the molecular basis of the insulin/glucagon reciprocal switch.

Fasting State

The fasting (post-absorptive) state begins ~4-6 hours after a meal when absorption is complete and blood glucose begins to fall. The insulin-to-glucagon ratio is LOW (insulin falls, glucagon rises). Metabolic priorities shift from storage to mobilization: maintain blood glucose for brain and RBCs, mobilize FFA for other tissues. Phase 1—early fasting (up to ~24 hours): Liver glycogenolysis provides glucose (glycogen phosphorylase activated by glucagon via cAMP/PKA cascade). Muscle uses FFA from adipose lipolysis, sparing glucose for brain. Adipose: glucagon (and falling insulin) activates HSL → lipolysis → FFA and glycerol. Glycerol enters gluconeogenesis in liver. Phase 2—sustained fasting (24 hours to ~3 days): Liver glycogen is depleted (~12-24 hours for hepatic glycogen). Gluconeogenesis becomes the primary source of blood glucose. Substrates: lactate (RBCs + muscle via Cori cycle), alanine (muscle proteolysis → alanine-glucose cycle), and glycerol (adipose lipolysis). Glucagon activates PEPCK and G6Pase transcription via CREB. Cortisol rises, providing permissive support and mobilizing amino acids from muscle. β-oxidation of FFA in liver provides acetyl-CoA and NADH/ATP to drive gluconeogenesis; excess acetyl-CoA → ketone bodies (acetoacetate, β-hydroxybutyrate) exported to brain and muscle. Phase 3—starvation (beyond ~3 days): Brain adapts to ketone bodies as primary fuel (~60-70% of brain energy from ketones after several days of starvation), reducing the demand for gluconeogenesis and thus sparing muscle protein. This is an evolutionary adaptation allowing survival during prolonged food deprivation. Key regulatory enzymes during fasting: (1) PFK-2/FBPase-2 phosphorylated by PKA → PFK-2 inactive, FBPase-2 active → F2,6BP levels plummet → PFK-1 inhibited, FBPase-1 activated → glycolysis OFF, gluconeogenesis ON; (2) glycogen phosphorylase phosphorylated (active); (3) glycogen synthase phosphorylated (inactive)—reciprocal regulation; (4) ACC phosphorylated and inhibited (low malonyl-CoA → CPT-1 active → β-oxidation ON); (5) HSL phosphorylated (active → lipolysis ON). The Cori cycle (lactate → glucose) and glucose-alanine cycle (alanine → glucose) are critical inter-organ shuttles: RBCs lack mitochondria and export lactate; muscle under anaerobic conditions exports lactate; muscle proteolysis releases alanine (transamination of pyruvate). Both lactate and alanine travel to liver for gluconeogenesis, and glucose returns to peripheral tissues.

Tissue-Specific Fuel Use

Each tissue has a characteristic fuel preference determined by its transporter repertoire, metabolic enzyme expression, and hormonal responsiveness—the MCAT frequently tests which tissue uses which fuel in which state. Brain: Obligate glucose consumer under normal conditions (~120 g/day, ~60% of total body glucose utilization). Glucose uptake via GLUT1 (BBB) and GLUT3 (neurons) is insulin-independent. Cannot oxidize fatty acids (FFA do not cross the BBB efficiently). In prolonged starvation (>2-3 days), brain adapts to ketone bodies (β-hydroxybutyrate, acetoacetate), which are transported across the BBB via monocarboxylate transporters—this adaptation spares muscle protein. Red blood cells (erythrocytes): Lack mitochondria entirely—rely exclusively on anaerobic glycolysis for ATP. Glucose uptake via GLUT1 is constitutive. Lactate is the end product, exported to liver (Cori cycle). Cannot use FFA, ketone bodies, or oxidative phosphorylation. This means RBCs are obligate glucose consumers under ALL conditions. Skeletal muscle: Flexible fuel use. At rest, in the fed state: glucose uptake (GLUT4, insulin-dependent) → glycogen synthesis. In fasting: switches to FFA oxidation; GLUT4 not translocated to membrane (low insulin). During exercise: initially uses muscle glycogen (glycogenolysis, epinephrine and Ca2+-stimulated), then blood glucose, and finally FFA as exercise continues. Muscle lacks G6Pase—cannot export free glucose to blood; muscle glycogen is fuel for muscle only. Muscle also lacks glucagon receptors—only epinephrine mobilizes muscle glycogen. Cardiac muscle: Preferential FFA oxidation (60-70% of energy at rest)—the heart is an obligate aerobic tissue rich in mitochondria. Can also use glucose, lactate, and ketone bodies. The heart's metabolic flexibility is high-yield: it oxidizes whatever fuel is abundant in blood. Liver: The metabolic hub—processes and distributes nutrients. Fed state: takes up glucose (GLUT2, high Km, insulin-independent), converts to glycogen and fat. Fasting state: produces glucose (glycogenolysis → gluconeogenesis) and ketone bodies for export. The liver expresses G6Pase (unlike muscle), allowing it to release free glucose into blood. The liver also expresses glucokinase (high Km in fed state, induced by insulin) and is uniquely capable of ketogenesis (HMG-CoA synthase, mitochondrial isoform). Adipose tissue: Stores TAG in the fed state (LPL releases FFA from lipoproteins; insulin stimulates GLUT4 → glycerol-3-P for TAG synthesis). In fasting: HSL activated → lipolysis → FFA and glycerol released. FFA travel bound to albumin in blood. Glycerol goes to liver for gluconeogenesis. Brown adipose tissue (BAT) expresses uncoupling protein-1 (UCP1, thermogenin), which dissipates the proton gradient to generate heat instead of ATP—important in thermogenesis (newborns, hibernating animals). Kidney: Similar to liver in fasting—capable of gluconeogenesis (minor contribution, ~10-20% of total glucose production in prolonged fasting).

How it works

Hormonal metabolic integration operates through a master switch: the insulin-to-glucagon ratio. When this ratio is high (fed state), insulin's signaling cascade (RTK → IRS-1 → PI3K → Akt) activates anabolic pathways—GLUT4 translocation, glycogen synthesis, glycolysis, lipogenesis—while simultaneously inhibiting catabolic enzymes via dephosphorylation. PFK-2 is the critical node: insulin-activated phosphatase dephosphorylates PFK-2/FBPase-2, favoring PFK-2 activity → F2,6BP production → PFK-1 activation → glycolysis ON. When the insulin/glucagon ratio is low (fasting), glucagon (and epinephrine) activate PKA via cAMP, phosphorylating and reversing every step: PFK-2/FBPase-2 is phosphorylated → F2,6BP drops → PFK-1 OFF, FBPase-1 ON → gluconeogenesis dominates. The same cAMP/PKA cascade activates glycogen phosphorylase and hormone-sensitive lipase while inactivating glycogen synthase and acetyl-CoA carboxylase—complete metabolic reversal. Cortisol adds a sustained genomic layer, upregulating gluconeogenic enzymes and providing amino acid substrates. The tissue-specific responses are wired by receptor distribution: glucagon receptors on liver and adipose (not muscle), epinephrine receptors on all three, insulin-dependent GLUT4 on muscle and adipose (but not liver or brain). This architecture ensures coordinated fuel distribution: the brain always gets glucose (or ketones), muscle switches between glucose and FFA, and the liver is the processing hub that either stores or produces fuel depending on the hormonal signal.

How it works

Hormonal metabolic integration operates through a master switch: the insulin-to-glucagon ratio. When this ratio is high (fed state), insulin's signaling cascade (RTK → IRS-1 → PI3K → Akt) activates anabolic pathways—GLUT4 translocation, glycogen synthesis, glycolysis, lipogenesis—while simultaneously inhibiting catabolic enzymes via dephosphorylation. PFK-2 is the critical node: insulin-activated phosphatase dephosphorylates PFK-2/FBPase-2, favoring PFK-2 activity → F2,6BP production → PFK-1 activation → glycolysis ON. When the insulin/glucagon ratio is low (fasting), glucagon (and epinephrine) activate PKA via cAMP, phosphorylating and reversing every step: PFK-2/FBPase-2 is phosphorylated → F2,6BP drops → PFK-1 OFF, FBPase-1 ON → gluconeogenesis dominates. The same cAMP/PKA cascade activates glycogen phosphorylase and hormone-sensitive lipase while inactivating glycogen synthase and acetyl-CoA carboxylase—complete metabolic reversal. Cortisol adds a sustained genomic layer, upregulating gluconeogenic enzymes and providing amino acid substrates. The tissue-specific responses are wired by receptor distribution: glucagon receptors on liver and adipose (not muscle), epinephrine receptors on all three, insulin-dependent GLUT4 on muscle and adipose (but not liver or brain). This architecture ensures coordinated fuel distribution: the brain always gets glucose (or ketones), muscle switches between glucose and FFA, and the liver is the processing hub that either stores or produces fuel depending on the hormonal signal.

Comparisons

• B/B (Insulin signaling): The insulin RTK cascade is the single most-tested signaling pathway. Know: insulin → RTK → IRS-1 → PI3K → PIP3 → Akt → GLUT4 translocation + GSK-3β inhibition. MCAT passages often tie this to diabetes pathophysiology (type 1: no insulin; type 2: insulin resistance).
• B/B (cAMP/PKA cascade): Glucagon and epinephrine use the same GPCR/cAMP/PKA cascade. Know the phosphorylation targets: phosphorylase kinase → glycogen phosphorylase, PFK-2/FBPase-2, HSL, ACC. Distinguish liver vs. muscle effects.
• B/B (PFK-2/FBPase-2): This bifunctional enzyme and its control of F2,6BP is the single most important regulatory mechanism tested in metabolic integration. Know: insulin dephosphorylates → PFK-2 active; glucagon phosphorylates → FBPase-2 active.
• C/P (Second messengers): cAMP, IP3/Ca2+, and PIP3/Akt as second-messenger systems tie into General Chemistry kinetics and equilibrium concepts.
• B/B (Cori and glucose-alanine cycles): Inter-organ metabolite shuttling is a recurring passage topic—RBCs and muscle produce lactate; muscle releases alanine; liver uses both for gluconeogenesis.
• B/B (Tissue-specific metabolism): Passages that ask 'which tissue uses which fuel' test your understanding of transporter distribution (GLUT1-4), receptor expression (glucagon only on liver/adipose), and metabolic capability (RBCs no mitochondria, brain no FFA oxidation, liver has G6Pase, muscle does not).

Common confusions

• Confusing which hormone acts on which tissue. Glucagon acts on LIVER and ADIPOSE—NOT muscle (no glucagon receptors on skeletal muscle). Epinephrine acts on liver, muscle, AND adipose. Insulin acts on liver, muscle, and adipose.
• Assuming muscle glycogen contributes to blood glucose. Muscle lacks G6Pase and cannot export free glucose. Muscle glycogen is for local ATP production. Only LIVER glycogen maintains blood glucose (liver has G6Pase).
• Forgetting that the brain cannot oxidize fatty acids. FFA do not cross the BBB efficiently. The brain is an obligate glucose consumer (switching to ketone bodies only in prolonged starvation). Passages testing this are common.
• Mixing up PFK-2 phosphorylation states. Insulin → dephosphorylation → PFK-2 active → F2,6BP HIGH → glycolysis ON. Glucagon → phosphorylation → FBPase-2 active → F2,6BP LOW → gluconeogenesis ON. This is the most common metabolic regulation trap on the MCAT.
• Thinking RBCs can switch fuels. RBCs lack mitochondria—they rely exclusively on anaerobic glycolysis and produce lactate regardless of nutritional state. No fatty acid oxidation, no ketone body use, no TCA cycle.
• Confusing C-peptide and insulin function. C-peptide is a cleavage product with no known biological function but serves as a clinical marker of endogenous insulin production. Insulin secreted with C-peptide = endogenous; insulin without C-peptide = exogenous (injected).
• Assuming epinephrine and glucagon are identical. While both use cAMP/PKA, epinephrine stimulates glycolysis in muscle (providing ATP for contraction via Ca2+ and AMP activation of PFK-1), while glucagon has no effect on muscle at all.
• Not accounting for cortisol's permissive role. Cortisol is required for glucagon and epinephrine to achieve full catabolic effect. Without cortisol, catecholamine responses are blunted—this is tested in adrenal insufficiency (Addison's disease) passages.
• Forgetting the insulin/glucagon ratio concept. It is not absolute hormone levels but the RATIO that determines metabolic state. A high-protein meal raises both insulin and glucagon—the net effect depends on their ratio.

Quick review

• Fed state = HIGH insulin/glucagon ratio. Fasting state = LOW insulin/glucagon ratio. This ratio is the master metabolic switch.
• Insulin: peptide hormone, β-cells, RTK → IRS-1 → PI3K → Akt. Effects: ↑ GLUT4 translocation, ↑ glycogen synthesis, ↑ glycolysis, ↑ lipogenesis, ↓ gluconeogenesis, ↓ lipolysis.
• Glucagon: peptide hormone, α-cells, GPCR → Gαs → cAMP → PKA. Effects: ↑ glycogenolysis (liver only), ↑ gluconeogenesis, ↑ lipolysis, ↑ ketogenesis. NO receptors on muscle.
• Epinephrine: catecholamine, adrenal medulla, β-adrenergic GPCR → cAMP → PKA. Acts on LIVER, MUSCLE, and ADIPOSE. In muscle: ↑ glycogenolysis AND ↑ glycolysis (local ATP).
• Cortisol: steroid hormone, zona fasciculata, intracellular GR → gene transcription. ↑ gluconeogenesis, ↑ protein catabolism, ↑ lipolysis (permissive). Insulin antagonist.
• PFK-2/FBPase-2 control of F2,6BP: insulin dephosphorylates → PFK-2 active → F2,6BP HIGH → PFK-1 ON, glycolysis ON. Glucagon phosphorylates → FBPase-2 active → F2,6BP LOW → FBPase-1 ON, gluconeogenesis ON.
• Liver: metabolic hub. HAS G6Pase → exports glucose. HAS glucagon receptors. Ketogenesis ONLY in liver mitochondria (HMG-CoA synthase). GLUT2 (insulin-independent uptake).
• Muscle: NO G6Pase → cannot export glucose to blood. NO glucagon receptors. GLUT4 (insulin-dependent). Glycogen for local use only. Switches to FFA in fasting.
• Brain: obligate glucose consumer (GLUT1/GLUT3, insulin-independent). Cannot oxidize FFA. Adapts to ketone bodies in prolonged starvation (>2-3 days).
• RBCs: NO mitochondria → anaerobic glycolysis ONLY. Always produce lactate. Cannot use FFA or ketones. Cori cycle: lactate → liver → glucose.
• Adipose: stores TAG (fed), releases FFA + glycerol (fasting, via HSL). GLUT4 for glucose uptake. Glycerol → liver for gluconeogenesis.
• Hormone-sensitive lipase (HSL): activated by PKA phosphorylation (glucagon, epinephrine). Insulin inhibits HSL via dephosphorylation. Rate-limiting enzyme of lipolysis.
• Cori cycle: muscle/RBC lactate → blood → liver gluconeogenesis → glucose → blood → muscle/RBC. Glucose-alanine cycle: muscle alanine → liver gluconeogenesis → glucose.
• Type 1 DM: no insulin → hyperglycemia + ketoacidosis. Type 2 DM: insulin resistance → compensatory hyperinsulinemia → eventual β-cell failure.