Sfm: Fed And Fasted States

Front 1

Critical organs

Back 1

Brain – Maintenance of its function (maintaining its supply of metabolic substrate) is absolutely essential.

Liver – The central organ with regard to the conversion of metabolic substrates to their storage forms (synthesis of hepatic glycogen, synthesis of fatty acids).

Adipose tissue – The primary storage depot for meeting long-term needs.

Skeletal muscle – Functions as a storage depot for meeting long-term needs (protein, available for conversion to glucose via hepatic gluconeogenesis); also is the
major repository for “excess” blood glucose.

Front 2

Critical organs communicate through

Back 2

innervation

circulating metabolites (especially glucose)

hormones and cytokines

Front 3

critical hormones

Back 3

Insulin (increased in fed state; regulates most enzymes by their dephosphorylation)

Counterregulatory hormones (increased in the fasted state; cAMP-mediated; regulate most enzymes by their phosphorylation):

o Glucagon (acute regulation; acts almost exclusively on hepatocytes)
o Catecholamines (epinephrine, norepinephrine; acute regulation)
o Growth hormone (involved in long-term adaptation to fasting)
o Glucocorticoids (involved in long-term adaptation to fasting)

Front 4

A Hypothetical 24 Hour Fed-Fasting Cycle

Back 4

In the post-absorptive state, you have
finished absorbing any food that you
ingested. You are therefore in negative
energy balance. That is, you are
consuming more energy than is
available. You are using your energy
stores.

The same is true in the preprandial
state, unless you are eating a meal
before you finished absorbing the
previous meal.

In the postprandial state, you are
absorbing the food you’ve eaten. Your
energy intake is greater than your
energy utilization, so you are in positive
energy balance.

Front 5

When you eat and absorb nutrients,
where is the energy stored:

Back 5

Glycogen (liver and muscle –
and other tissues)

Fat (adipose tissue – and
other tissues)

Protein (predominantly in
muscle)

Front 6

INTERMEDIARY METABOLISM

Back 6

refers to the
metabolic pathways involved in the storing and utilization
of energy and to the use of that energy in cellular
processes.

Front 7

Insulin action in the fed versus fasted state

Back 7

metabolic functions are under the direct regulation of insulin in most organs and tissues.

The major exceptions are brain and heart – two organs
that must function similarly under fed and starved states.

Front 8

Insulin synthesis and secretion

Back 8

fed--hi
fasted--lo

Front 9

Glucose disposal (mostly muscle)

Back 9

fed: hi
fasted: lo

Front 10

Glycogen synthesis (muscle, liver)

Back 10

fed: hi
fasted: lo

Front 11

Glycogenolysis (liver)

Back 11

fed: lo
fasted: hi

Front 12

Gluconeogenesis (liver)

Back 12

fed: lo
fasted: hi

Front 13

Lipogenesis

Back 13

fed: hi
fasted: lo

Front 14

Lipolysis (fat) and ketogenesis (liver)

Back 14

fed: lo
fasted: hi

Front 15

Protein synthesis (all tissues)

Back 15

fed: hi
fasted: lo

Front 16

Proteolysis (all tissues)

Back 16

fed: lo
fasted: hi

Front 17

“Growth” (cell proliferation)

Back 17

fed: stimulated
fasted: inhibited

Front 18

(PRO)INSULIN STRUCTURE

Back 18

Insulin consists of two peptides: A for acidic, B for basic.

MW ca. 6,000.

A and B joined by disulphide bonds with a 3rd disulphide internal to the A chain.

Synthesized as a prohormone, proinsulin.

Proinsulin is converted to insulin by proteolytic removal of a connecting peptide, C-peptide.

clinically: c-peptide of insulin production

C-peptide has no biological function other than to promote the proper folding of proinsulin.

Front 19

THE RELATIONSHIP BETWEEN CIRCULATING
INSULIN AND GLUCOSE

Back 19

As blood glucose rises (after a meal, for example),
insulin release is stimulated. This results in an
insulin-mediated fall in serum glucose (due to
combined stimulation of skeletal muscle glucose
uptake and inhibition of hepatic glucose production).

Front 20

HOW IS INSULIN SYNTHESIS AND SECRETION
BY THE Beta-CELL OF THE PANCREAS
REGULATED?

Back 20

Glucose enters the beta-cell via a non-hormone regulated glucose transporter (GLUT-2). The
Km for this transporter is such that glucose entry will parallel extracellular glucose concentration over the normal physiologic range.

Once in the beta-cell, glucose is phosphorylated by an isoform of glucokinase that has a high
Km. Therefore, glucose phosphorylation is proportional to glucose entry.

After glucose phosphorylation, metabolism proceeds along aerobic pathways. This leads to
an increase in the intracellular ATP:ADP ratio.

The higher ATP:ADP ratio inhibits an ATP-sensitive potassium channel. This leads to depolarization, activation of a voltage-gated calcium channel, calcium influx and activation of
insulin secretion.

Front 21

Mutations in the beta-cell glucokinase

Back 21

can result in a mild form of diabetes
referred to as “Maturity Onset Diabetes of the Young” (MODY). It is inherited in an autosomal
dominant manner.

Front 22

Insulin secretion

Back 22

proportional to glucose metabolism because the generation of ATP from
glucose is the trigger for the membrane depolarization that signals insulin secretion.

Front 23

THE BIOLOGICAL ACTIONS OF INSULIN

Back 23

Insulin is the prototypical anabolic hormone. It stimulates synthesis of glycogen, protein,
fat, DNA and RNA. It inhibits breakdown of glycogen, protein and fat.

Besides increasing uptake of glucose (which decreases blood glucose), what does insulin
do to glucose utilization? It stimulates it in liver, where it also inhibits fatty acid oxidation and
glycogen breakdown.

Insulin is a mitogenic hormone for many cells. That is, it stimulates cell growth and
proliferation.

Front 24

Starved state (lo insulin)

Back 24

decreased exogenous intake

endogenous intake (hepatic, other) remains the same

little/no change in amount of glucose utilization by brain (in order to maintain brain function)

decreased utilization by muscle

other tissues' utilization remains relatively unchanged

Front 25

fed state (hi insulin)

Back 25

increased exogenous intake

decreased endogenous (hepatic, other) intake

no change in utilization: brain, other tissues

main utilization: increase in muscle (stored as glycogen)

Front 26

The effects of insulin on serum glucose are dependent on the balance between:

Back 26

Entry of glucose into the circulation (from intestinal absorption, parenteral administration
[such as by IV infusion], or by endogenous production)

AND

Glucose disposal (mostly by activating transport into skeletal muscle).

Front 27

SUMMARY OF INSULIN SIGNALING

Back 27

The insulin receptor is a protein tyrosine kinase.
That is, it can phosphorylate other proteins on
tyrosine residues. Its kinase activity is activated
when insulin binds – then lots of things happen!

Front 28

HOW INSULIN EFFECTS SERUM GLUCOSE CONCENTRATION

i.e.

Insulin released into the portal circulation lowers circulating glucose concentration by:

Back 28

Decreasing hepatic glucose production (inhibition of glycogenolysis and
gluconeogenesis).

Promoting glucose disposal by stimulating glucose uptake, mostly in skeletal
muscle.

Front 29

INSULIN EFFECTS ON ENZYME SYSTEMS

Back 29

Most, but not all, of insulin's effects result from DEPHOSPHORYLATION of regulatory enzymes.

The enzymes activated by insulin are ANABOLIC (glycogen synthesis, fatty acid synthesis, protein
synthesis).

Key CATABOLIC enzymes are often inactivated in response to dephosphorylation.

Potein phosphatase 1 (PP1): ACCOUNTS FOR THE ABOVE
DEPHOSPHORYLATION EVENTS

Front 30

Adult Onset (Type 2) Diabetes

Back 30

Impaired skeletal muscle glucose transport in response to insulin is the primary
reason for hyperglycemia in Adult Onset (Type 2) Diabetes. The mechanism(s) accounting for
this insulin resistance is not known, but it is not due to a mutation in GLUT4. However, it may be
due to a defect in the mechanism that mediates insulin-stimulated GLUT4 translocation.

Front 31

LIVER –

Back 31

THE NUTRIENT DISTRIBUTION CENTER

Front 32

Hormonal Regulation in LIVER

Back 32

Flux through glycolysis/gluconeogenesis is acutely regulated by the bifunctional enzyme,
phosphofructokinase-2/fructose 2,6-bisphosphatase. This enzyme controls the allosteric
activator, fructose 2,6-bisphosphate, which in turn regulates phosphofructokinase-1 and
fructose 1,6-bisphosphatase.

Fatty acid synthesis/degradation is regulated by acetyl CoA carboxylase. It catalyzes the
formation of malonyl CoA, which is the primary substrate for fatty acid synthesis and which
allosterically inhibits CPT-1.

Glycogen synthesis/degradation is regulated by the coordinated phosphorylation and
dephosphorylation of phosphorylase and glycogen synthase.

All of the key regulatory enzymes described above are dephosphorylated in response to
insulin and phosphorylated in response to glucagon and epinephrine.

Front 33

Regulation in LIVER by Metabolic Substrates

Back 33

In the fed state, excess glucose binds to phosphorylase, thereby inhibiting it. This results in
net synthesis of glycogen in the presence of greater glucose availability.

In the fed state, increased flux through glycolysis results in increased flux through the hexose
monophosphate pathway. The resulting increase in NADPH promotes fatty acid synthesis.

In the fasted state, excess production of acetyl CoA via fatty acid oxidation exceeds the
capacity of the TCA cycle (limited because of reduced glycolytic activity). The excess acetyl
CoA is used for ketone body production.

Front 34

ADIPOSE TISSUE –

Back 34

THE ENERGY STORAGE DEPOT

Front 35

Hormonal Regulation in FAT CELLS

Back 35

The primary regulatory point is hormone-sensitive lipase, which is dephosphorylated and
inactivated in response to insulin, and phosphorylated and activated in response to
catecholamines.

BRAIN: During fasting, glucose continues to be the important metabolic fuel. With longer
periods of fasting, utilization of ketone bodies increases.

MUSCLE: Acts as the major repository for excess glucose in the fed state (insulin-stimulated
glucose uptake). During a prolonged fast, skeletal muscle protein provides the substrate for
gluconeogenesis

Front 36

Hepatocyte metabolism: early starvation

Back 36

glycogen->G6P->glucose

Front 37

hepatocyte metabolism: late starvation

Back 37

no glycogen

gluconeogenesis: skeletal muscle protein->amino acids->pyruvate->G6P->glucose

Fatty acid oxidation: fatty acids->AcCOA->TCA cycle->Ketone bodies

Front 38

familial hyperproinsulinemia

Back 38

presented with glucose intolerance during childhood. Glucose tolerance testing revealed high immunoreactive insulin levels. These were due to elevated circulating levels of proinsulin.

The disorder in this family is due to a point mutation in the insulin gene that altered the primary structure of proinsulin (an aspartic acid in
the 10th position of the B-chain instead of the normal histidine). This change causes a change in the conformation of proinsulin, thereby impeding its conversion to insulin.