Glucose Homeostasis

Glucose Homeostasis: Insulin and Glucagon

Production and Utilization of Glucose

blood glucose is maintained between 60-110 mg/dl (5 mM)

Glucose Requirements – 200-250 g/day needed for basal (resting) metabolism – brain uses 45% of this

two sources of fasting glucose, both under minute-to-minute control by insulin:

(1) glycogenolysis – but only 450 grams glycogen total, and of this only 150 grams can be released into blood

both muscle and liver have glycogen, but only liver can release it (muscle has no glucose-6-phosphatase)

(2) gluconeogenesis – use energy from fat (100x daily need) and carbon from protein to make glucose de novo

occurs in kidney and liver – both have glucose-6-phosphatase, so can release glucose

Glucose Transport – glucose does not diffuse efficiently through lipid membranes – requires transporters

muscle/adipose form (GLUT-4) – transport is rate-limiting, so transport rate is proportional to # of receptors
liver (GLUT-2) and brain (GLUT-3) – have much larger K_M, so transport rate is proportional to blood glucose

(2) epithelial Na⁺-coupled transport – high capacity for transport against gradient

reabsorption in kidney – blood glucose must be 3x normal before renal glucose transport is saturated

Regulation of Blood Glucose

primarily involves two polypeptide hormones; both are released directly into portal circulation – liver sees them 1^st and uses 50%

(1) Insulin – secreted in fed state in response to elevated serum glucose

insulin is the major controller of blood glucose – nothing (not even glucagon) can compensate for its loss

Structure – 6 kD peptide – two chains (A and B) linked together by two disulfide bonds

synthesized as single chain – intervening chain (C-peptide) is excised and is a good marker of insulin production

Synthesis – produced exclusively in b cells, which account for 50% of cells in Islets of Langerhans (endocrine pancreas)

Secretion – secretory vesicles fuse with plasma membrane in response to increased glucose use by b cells

cell becomes depolarized, L-type Ca⁺⁺ channels open, and elevated Ca⁺⁺ mediates vesicle release

many things can affect secretion (drugs, amino acids, gastric inhibitory peptide, glucagon-like peptide, etc.)

threshold for secretion is 60 mg/dl glucose, with 10-fold increase after meals; half maximum secretion at 150 mg/dl

although it varies considerably, secretion is never completely turned off (except in pathological states)

Action – three main effects:

(1) increase glucose transport – increase GLUT-4, allowing more glucose uptake into muscle and adipose tissue

GLUT-4 are stored on intracellular vesicles –insulin causes exocytosis, placing GLUT-4 on cell membrane

(2) decrease glucose production – activate glycogen synthesis and deactivate glycogenolysis/gluconeogenesis

(3) increase glucose usage – increase protein and glycogen synthesis; repress protein and triglyceride breakdown

increase glycolysis by activating committed glycolytic enzymes – hexokinase, PFK-1, and pyruvate kinase

Signal Transduction at Insulin Receptor – receptors are found in most tissues

receptor tyrosine kinase – 2 extracellular a -subunits attached to 2 membrane-spanning b -subunits

insulin initiates a signal cascade including ras GTP-binding protein, MAP-kinase, and phosphatidylinositol 3-kinase

fast effects occur through phosphorylation/dephosphorylation (tyr and ser/thr), GLUT-4, and K⁺ channels

slow effects occur through alteration of transcription patterns of various metabolic enzymes

(2) Glucagon – released in fasted state, assists insulin in controlling blood glucose levels

Synthesis – produced in a cells, which account for 20-30% of cells in Islets of Langerhans

Secretion – released from secretory vesicles in response to hypoglycemia and high amino acids

Action – in liver, causes glycogenolysis and gluconeogenesis; in adipose, causes mobilization of triglycerides

activates glucose-6-phosphatase, bisphosphatase, PEPCK, pyruvate carboxylase, glycogen phosphorylase
weakly inhibits insulin-activated enzymes
phosphorylates L-type Ca⁺⁺ receptors, so glucagon paradoxically potentiates insulin secretion

Signal Transduction at Glucagon Receptor – receptors are present only on liver and adipose tissue

G-protein coupled receptor coupled to G_s proteins Þ Ý cAMP Þ PKA activation

PKA regulates via phosphorylation (directly affects enzyme activity) and CREB proteins (affects transcription)