Glucose Metabolism III

Cori cycle

-pyruvate → lactate, lactate goes through blood to liver, lactate → pyruvate, pyruvate goes through gluconeogenesis → glucose

-liver cells can synthesize glucose from pyruvate

glycogen

-stores energy in animals

-glycogen synthase builds glycogen in liver & skeletal muscle; biggest percentage in liver

-stored when glucose in excess; quick energy source when blood glucose is low

-compact and highly branched (α1 → 4 chains with α1-6 branches)

glycogen synthesis

glucose-6-P → glucose-1-P → UDP-glucose → glycogen

-when excess glucose is available and ATP is abundant; stores glucose for later energy needs

-in cytosol of liver & skeletal muscle

glycogenolysis

glycogen phosphorylase removes one glucose at a time from α1 → 4 chains, stopping a few residues from a branch → glucan transferase and debranching enzyme resolve the α1→6 branch point

-glucose-1-P → glucose-6-P

—→ in muscle, → glycolysis

—→ in liver, glucose-6-phosphatase → glucose → blood

-when cell energy is low/blood glucose is low

-in cytosol of liver & skeletal muscle

glucagon (GPCR) control of glycogen

glucagon → PKA (phosphorylation turns glycogen phosphorylase on and glycogen synthase off → glycogen breakdown, glucose exported via GLUT2)

insulin (RTK) control of glycogen

insulin → protein phosphatase-1 (dephosphorylation turns glycogen phosphorylate off and glycogen synthase on → glycogen synthesis)

glucagon signaling in the liver

glucagon binds receptor (GPCR) → G_s activates adenylyl cyclase → cAMP → protein kinase A on → glycogen phosphorylase on, glycogen synthase off → gluconeogenesis up, glycolysis down

-ends when phosphodiesterase breaks down cAMP

insulin secretion from ß cell

glucose enters ß cell (GLUT1 in humans) → glucokinase → glycolysis → mitochondrial oxidation → ATP → rising ATP/ADP closes ATP-sensitive K⁺ channels → less K⁺ leaves, depolarization opens Ca²⁺ channels → Ca²⁺ influx triggers insulin granule exocytosis

insulin acts through its RTK

α₂ß₂ tyrosine kinase receptor, insulin binding triggers ß-subunit autophosphorylation → glycogen phosphorylase off, glycogen synthase on

insulin and glucagon are counter-regulatory

-glucagon: glycogen breakdown & gluconeogenesis in liver

-only liver releases glucose into blood

-skeletal muscle only responds to epinephrine; no glucagon receptor

pancreas

helps liver monitor blood glucose

-fed: insulin from ß cells → glucose storage & oxidation go up

-fasted: glucagon from α cells → glucose release into blood goes up

type 1 diabetes

pancreas failure to produce insulin

type 2 diabetes

cells fail to respond to insulin properly

increased by insulin

-in liver (glycogen synthesis)

-in adipose tissue (glucose uptake)

-in muscle (both glucose uptake & glycogen synthesis)

decreased by insulin

-in liver (gluconeogenesis)

increased by glucagon

-in liver (glycogenolysis, gluconeogenesis)

liver vs skeletal muscle

-takes more for glucose to be converted in liver

-liver: GLUT2 (insulin independent), glucose-6-P exports glucose, gluconeogenesis

-skeletal muscle: GLUT4 (insulin dependent), glucose stays in cell, releases lactate