Section V. Carbohydrate metabolism
V. Glucose is central to all metabolism
• 3 major paths: glycolysis, glycogen synthesis and
pentose phosphate (generates NADPH, 5-C sugars) (V.2)
• Major diet carbohydrates (starch, sucrose, lactose)
are digested to glucose, fructose and galactose (V.1)
• Fructose and galactose are converted to
intermediates in glucose metabolism (V.3)
• Glycolysis plus TCA, ETC; anerobic glycolysis (V.4)
• Intermediates in glycolysis, TCA serve biosynthesis
of amino acids, fatty acids, glycerol (V.5)
Section V cont.
• Pentose phosphate path takes glucose to pyruvate:
forms NADPH (use for biosynthesis, antioxidant)
forms 5-C sugars used for nucleotides (v.6)
• UDP-glucose is used in synthesis of glycogen, UDPgalactose, also glycoproteins, glycolipids (V.7)
• Glycogenolysis degrades glycogen → glucose
• Gluconeogenesis → glucose from glycerol (V.8)
• Overview of major paths of glucose metabolism (V.9)
• Hormonal control: glucagon vs. insulin to maintain
glucose homeostasis (V.10)
Insulin vs. glucagon V.10
V.10 Pathways regulated by glucagon vs. insulin
in response to blood glucose (tissue-specific also)
Blood glucose decrease → Glucagon release →
↑glycogenolysis ↑gluconeogenesis
↑lipolysis ↓liver glycolysis
Blood glucose increase → Insulin release →
↑glycogen synthesis ↑fatty acid synthesis
↑triglyceride synthesis ↑liver glycolysis
Chapt. 26 hormone regulation
Ch. 26 Regulation by Insulin,
glucagon and other hormones
Student Learning Outcomes:
• Describe mechanisms of major hormones insulin and
glucagon to control glucose homeostasis
• Explain that Homeostasis is balance of fuel mobility
and storage: keep glucose 80-100 mg/dL (~5 mM)
• Regulate carbohydrate, lipid, aa metabolism
• Describe counteracting influences of insulin and
glucagon and other counter-regulatory hormones
Insulin vs glucagon and others
Homeostasis requires glucose control:
Insulin is anabolic hormone:
• from b-cells of pancreas
• Glucose entry into tissues
• Glucose storage, growth
Glucagon counters:
• Degradation of glycogen
• Gluconeogeneis
• Mobilize fatty acids
• Stress hormones counter:
•
•
Epinephrine,
Cortisol (glucocorticoid)
Fig. 2
Glucagon mobilizes glucose from tissues
Glucagon activates pathways for
glucose mobilization:
• Counteracts insulin
• Pancreas a-cell
• Acts via G-proteincoupled receptor,
cAMP, PKA
Fig. 1, 3
Fuel homeostasis
Fuel homeostasis requires balance:
• Substrate availability and need
• Concentration nutrients in blood affects storage
• Hormonal messages to target tissue
• Neuronal signals
Fig. 4
homoeostatis
Glucose homeostasis is critical:
• Multiple signals
• Insulin vs. glucagon
• Stress hormones
• Epinephrine
• Cortisol
Fig. 5
Insulin is anabolic
Insulin is major anabolic hormone for fuel storage:
• Storage as glycogen
• Synthesis of fatty acids
• Triacylglycerol storage
• Protein synthesis
• Tissues of action
Fig. 6; + stimulated by
insulin; -, inhibited
Glucagon is fuel metabolism
Glucagon is major hormone for fuel metabolism:
• Maintain fuel in absence of dietary glucose
• Glycogenolysis in liver
• Gluconeogenesis in liver
• Fatty acids from adipocytes
• Tissues of action
Fig. 7; + stimulated by
glucagon; -, inhibited
Pancreas
Pancreas has a and b cells
a cells make insulin; b cells make glucagon
High-carbohydrate meal
High-carbohydrate meal:
• Rapid increase of glucose
• 80 → >120 mg/dL
• Rapid increase of insulin
• 5 → >120 mU/mL
• Decrease of glucagon
• 110 → 90 pg/mL
Fig. 8 Blood levels after meal
Table 1 Insulin and counterregulatory hormones
Hormone functions major metabolic paths
Insulin
promotes storage
promotes growth
Glucagon
mobilizes fuels
maintains blood
glucose in fasting
Epinphrine mobilizes fuels
in acute stress
Cortisol
stimulate glucose storage in
muscle, liver
stimulates protein synthesis,
fatty acid synthesis
activates gluconeogenesis
and glycogenolysis
activates fatty acid release
stimulate glycogenolysis
stimulate fatty acid release
changing long term amino acid mobilization
gluconeogenesis
Insulin counterregulatory hormones
Major insulin counterregulatory hormones:
Stress of low glucose:
• Neuronal signals release hormones:
• ACTH from pituitary→
• Cortisol from adrenal cortex
• Epinephrine from adrenal medulla
• Norepinephrine from nerves
• Minor role release glucagon
Fig. 9
III. Synthesis and release of insulin and glucagon
Insulin is polypeptide of 51 amino acids:
• a and b chains, cross-linked
•
•
•
•
Synthesized as preproinsulin, cleaved in RER to proinsulin
Passed through Golgi, into storage vesicles (also Zinc)
Final protease cleavages forms active insulin
Exocytosis into blood is stimulated
by increased glucose in blood
around b-cells
Fig. 10
insulin
Release of insulin by b-cells
Release of insulin by b-cells:
•
•
•
•
•
•
•
Stimulated by increased glucose in blood around b-cells
Glucose enters through transporters (GLUT 2)
Hexokinase phosphorylates, TCA, ETC
ATP ↑; inhibit ATP-dep K+ channel
Membrane depolarization
Ca2+ channel opens
[Ca2+] stimulate vesicle fusion
Fig. 11 release of insulin in response
to increased blood glucose
Table 26.2 Regulators of insulin release
Regulators of insulin release:
Major regulators:
Glucose
Effect:
+
threshhold ~80 mg/dL, increase proportional to ~300 mg/dL
Insulin is removed from blood and degraded in liver
New synthesis of insulin occurs in b-cells after release
Minor regulators:
Amino acids
Neural input
Gut hormones
+
+
+ (chapt. 43)
Table 26.3 Regulators of Glucagon release
Regulators of glucagon release:
Major regulators:
Effect:
Glucose
Insulin
Amino acids
+
Minor regulators:
Cortisol
Neural input (stress)
Epinephrine
+
+
+
Glucagon is 160-aa preproglucagon in a-cells; converted to
proglucagon in RER; mature 29-aa glucagon in vesicles;
Rapid half-life of glucagon in plasma
Effect of high-protein meal
High-protein meal:
• Stimulates glucagon release
• Not much insulin
• Blood glucose not change
Mixed meals:
get some of each hormone
Fig. 12 high protein meal
Mechanisms of hormone actions
IV. Mechanisms of hormone actions
Recall from Chapt. 11, that hormones can affect
activities of enzymes or transport proteins:
• Change conformation of enzyme (as phosphorylation),
Change amount of protein (induce or repress synthesis),
Change allosteric effector concentration
• Signal transduction pathways of hormones:
• Intracellular receptors (cortisol, thyroid hormone)
• Plasma membrane receptors:
• G-protein coupled receptors (adenylyl cyclase, cAMP)
• Receptor tyrosine kinases and Ras/Raf, MAPK
• PIP2, DAG signaling from both
Plasma membrane hormone receptors
2 major plasma membrane hormone receptors:
• G-protein coupled heptahelical - glucagon
• Tyrosine kinase receptors - insulin
Figs. 11.9, 11.10
RTK Insulin receptor has several signaling paths
* Insulin receptor signals through several paths:
• Binding of hormone causes autophosphorylation
• Binds IRS (insulin receptor substrates), PO4 those:
• Grb2 can signal through Ras and MAPK path
•Other proteins bind, interact with PIPs in membrane
Fig. 11.13 Insulin
signaling:
PLC - phospholipase
PIP – phosphatidyl
inositol forms
PI 3-kinase signals
through protein
kinase B (Fig. 11.14)
Signal transduction by insulin
Signal transduction by insulin:
5 categories of tissue specific responses:
• Reverses glucagon-stimulated phosphorylation
• Phosphorylation cascade stimulates
phosphorylation of several enzymes
• Induces and represses synthesis of some enzymes
• Growth factor, stimulation of protein synthesis
• Stimulates glucose and amino acid transport into
cells
Signal transduction by glucagon
Signal transduction by glucagon:
• Glucagon receptor is G-protein coupled (Gs)
• Activate adenylyl cyclase → cAMP → activate PKA
• PKA phosphorylates enzymes on ser:
• Activates some enzymes, inhibits others
• Especially affects kinases, phosphatases
• cAMP rapidly degraded to AMP
• Hormone signal terminated by phosphatases remove
the PO4 from enzymes
• Skeletal muscle does not have glucagon receptor,
but liver and other tissues do
Signal transduction by cortisol, intracellular receptors
Cortisol and thyroid hormone
bind intracellular receptors:
• Binding of hormone causes
hormone-receptor complex to bind
specific DNA sequences, increase
transcription from target genes.
Figs. 11.7,8
Signal transduction by epinephrine, norepinephrine
Epinephrine, norepinephrine are catecholamines
• Neurotransmitters or hormones
• Stress hormones increase fuel mobilization
• Adrenergic receptors (autonomic)
• 9 different receptors: 6a, 3 b:
b receptors work through G-protein
coupled, adenylyl cyclase, cAMP, PKA
• Different receptors on tissues
• Mobilize fuels
• Stimulate muscle contractions
Fig. 13
Key concepts
Key concepts:
• Glucose homeostasis maintains blood glucose levels
• Insulin and glucagon are two major hormones regulating
levels of glucose – opposing effects
• Excess fuel is stored as glycogen or fat; stored fuels are
mobilized when demanded
• Insulin promote glucose utilization, storage; secretion
regulated by blood glucose levels
• Insulin binds to RTK receptor
• Glucagon promotes glucose production, mobilization of
glycogen, gluconeogenesis
• Glucagon binds G-protein coupled receptor, cAMP
Review questions
Review question:
2. Caffeine is a potent inhibitor of the enzyme cAMP
phosphodiesterase. Which of the following consequences
would you expect to occur in the liver after drinking two cups
of strong espresso coffee?
a. A prolonged response to insulin
b. A prolonged response to glucagon
c. An inhibition of protein kinase A
d. An enhancement of glycolytic activity
e. A reduced rate of glucose export to circulation