LECTURE 8: Blood Glucose Levels During the Fed

and Fasting States, Exercise and Diabetes.

Key Concepts:
during an overnight fast blood glucose levels are
maintained by switching between glycogenesis,
glycogenolysis and gluconeogenesis
hormones tightly regulate these pathways
insulin and glucagon are the major hormones
regulating the switch from the fed to the fasting state
muscle glycogen serves as an energy source during
exercise.

WHAT YOU NEED TO KNOW!! You should:

understand the roles of insulin and glucagon to

regulate blood glucose levels
understand how glucagon stimulates glycogen
breakdown and glucose synthesis
be familiar with the roles of different energy sources
during the fed and starved state and exercise

Fig 8.1 Blood glucose,

insulin and glucagon
levels after a high
carbohydrate meal.

Exocrine (secretes digestive enzymes)

Endocrine Islet of
Langerhans
(secretes
hormones)
The pancreas has neuroendocrine origins, parts of the guts are considered and
enteric brain!

Mouse pancreatic islet,

an often spherical group
of hormone-producing
cells. Insulin is labelled
here in green, glucagon
in red, and the nuclei in
blue.

Fig. 8.2 Maintenance of glucose homeostasis by insulin

and glucagon

High blood
Glucose Insulin

Low blood
Glucose
Glucagon

Fig 8.1 Blood glucose,

insulin and glucagon
levels after a high
carbohydrate meal.

Insulins 400,000,000 years divergence 61% at aa level

Crystal structure (or shape) is almost identical
Most potent anabolic hormone
Insulin is a growth hormone first and foremost

Banting & Macleod 1923

Nobel Laureates

Banting and Best

1921 treat dog

Macleod

51 aa protein when cleaved

How does glucose trigger insulin

release?
GLUT1,2,3 or 4

Cell

GLUT1 is ubiquitous, highly conserved, but GLUT2

is found in the pancreas beta-cells, liver and gut
GLUT2

Pancreatic islet -cell

GLUT2 has high Km (low affinity) glucose enters when the

concentration is high (GLUT1 Km = 1 mM, GLUT2 Km = 15-20 mM)

Glucose uptake stimulates cell metabolism in the

pancreas -cells ATP is formed
GLUT2

GLUT2 has high Km (low affinity) glucose enters when the

concentration is high (GLUT1 Km = 1 mM, GLUT2 Km = 15-20 mM)

ATP triggers and ATP sensitive K channels

depolarising the cell, insulin vesicles fuse with the
cell membrane

ATP
ATP
ATP

ATP
ATP

GLUT2 has high Km (low affinity) glucose enters when the

concentration is high (GLUT1 Km = 1 mM, GLUT2 Km = 15-20 mM)

ATP triggers and ATP sensitive K channels

depolarising the cell, insulin vesicles fuse with the
cell membrane

ATP
ATP
ATP

ATP
ATP

Insulin is secreted

ATP

ATP

ATP
ATP

ATP

So high glucose (which = high energy) uses metabolism to signal a

global regulator of energy (glucose)

It is actually a tad more complicated

Diabetes Res Clin Pract. 2011 Aug;93 Suppl 1:S27-31. doi: 10.1016/S0168-8227(11)70010-9.

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So what does insulin do?

Many things
In the case for the exam, it drives glucose
uptake in tissues, importantly skeletal
muscle and the liver!
Insulin also promotes fat deposition,
glycogen storage, growth
Insulin is part of a broad family that are
generally anabolic

Insulin mediated
glucose uptake in
health

Glucose
Insulin
receptor
Insulin
Fats
Mitochondria
Glucose
transporter
PI-3K & IRS1

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Diabetes
mellitus?
Hypoinsulinism?

Normal fasted blood glucose = 4.5-5 mM

Diabetic > 11 mM
(or frequent fasted levels of > 7 mM)

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DIABETES MELLITUS.
Diabetes -to straddle legs apart- -siphon
Mellitus -sweet (honey) tasting
Typically hyperglycaemic- excess glucose in blood
appears in urine.
1553 B.C. Polyuria mentioned by Hensy-Ra (Eygpt)
Arateus 100 AD 'the melting down of flesh and limbs
into urine.'
Sweet tasting!
Wee tasters 11 Century
Dream job?

Diabetic

Time

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Cardiomypoathy

~80% of diabetics die from heart failure

Nephropathy

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Retinopathy

Elevated glucose results in uncontrolled uptake

in some cells (epithelial cells of blood vessels)

Issues with peripheral circulation

Gangrene amputation

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Hba1c

http://www.indiana.edu/~k562/diab.html

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DIABETES
Typically hyperglycaemic- excess glucose in blood
appears in urine.
Two main types:
Type 1:

Insulin dependent, common in juveniles,

Sometimes in adults viral infection triggers
loss of cells.
Loss of Insulin production.

Type 2: Non Insulin dependent, common in older people

(90%), obesity, stress,
variable insulin levels, start high then drops
Insulin insensitivity no insulin

Type 1

Pancreas beta cells

destroyed

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Type 2 Diabetes mediated obesity?

Bodies cells
desensitised to
insulin, blood
glucose levels rise

Beta cells work

harder to supply
larger body mass
with insulin, cells fail

Glucose uptake and

disposal impaired

Note this is grossly simplified, there

are many things occurring and
T2DM can occur through extreme
stress, genetic mutation and
evolutionary background.

A closer look

Pancreas

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Type 1 DM
No insulin
No insulin, no
glucose uptake
Inject insulin and
glucose is taken up
The issues are
control is hard to get
right
Insulin is not the only
hormone involved
and it is a growth
hormone

Muscle cells

Insulin insensitivity

High fat content of the

blood may alter
signalling, and or
glucose metabolism

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Oxidative stress, and

Maternally inherited
DM

Too much fuel to too

few mitochondria
drive the release of
excess free radicals
The cell responds
and protects the cell
by decreasing GLUT
Blood glucose rises
Mitochondrial DNA
mutations can also
impair glucose uptake

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21

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Birdshavemuchhigherrestingbloodglucose

16mM
5.5mM

Notehyperglycemiaisnotcoincidentwithhyperlipidemia
Bluecircle=batsandstressedmammals

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Fit

Unfit

In almost all cases exercise (~2-hrs/week) improves if not eradicates

diabetes (also extends life marginally, improves life quality, mental
capacity, requires no drugs). Also a healthy balanced diet.

Endurance animals
have fat stores near
mitochondria and
many mitochondria

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Starvation

Figure 8.3b
The five
phases of
glucose
homeostasis
in humans

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Fig. 8.3a Fuel choice during starvation

Fuel switching with starvation

The brain requires glucose
However it can use Ketone bodies
(smell of acetone), also used by heart

Made but not used,

Is expired (breathed off)

Ketone Bodies

acetoacetate

acetone

-hydroxybutyrate

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Why Ketone Bodies?

I dunno?

Ketone Bodies Starvation

Brain cannot use fat
After 3 days starvation, 30% of brains energy
is from ketone bodies.
After ~ 40 days, ~70% ketones & glucose
use drops from ~120 to ~40g/day.
Acetoacetate and -hydroxybutyrate are
acidic, pH of the blood drops, resulting in
ketoacidosis.

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Fats

Acetyl-CoA

Ketoacidosis
untreated Type I diabetes and binge
drinking alcoholics (alcohol-induced
impairment of liver gluconeogenesis).

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Exercise

Fig. 8.4: Classification of

physical activity on the basis
of duration of all-out exercise
and the corresponding
intracellular energy pathways

From: Exercise Physiology 5th

Edition.. McArdle et al

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Human variation

Kenyan
Endurance

Jamaican, West African Descent

Speed

ATP use in muscle

With exercise ATP levels remain the relatively
stable (In health)!
ATP is used but..it is replaced by creatine
phosphate almost immediately (~ 15 secs
reserve of CP reserves)
If ATP stores decline cells die by necrosis!

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25

20

mM

15

10

0
phospho-creatine ATP pre exercise phospho-creatine ATP post-exercise
pre-exercise
post-exercise

Creatine phosphate stores

CP
CP

CP
CP CP CP

CK = creatine kinase

ATP
CK

CP
ATP

ATPases

ADP

= 211 g/mole
= 518 g/mole

ATP is bulky and charged (binds metals e.g. Ca2+)

Contractile machinery

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Fig. 8.5 : Fuel use during exercise

Fig 8.6: Fuel sources for muscle contraction

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Why use anaerobic

pathways?
Creatine phosphate and glycogen
(glucose) are self contained within cells
Oxygen dependent pathways
(respiration) dependent on transport of
oxygen, this takes time, organ
coordination and many more reactions

In other animals things are different

Insect flight muscles cannot go anaerobic, no LDH expressed

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Some turtles can survive anoxia (no O2) for 4 months!

Metabolic extremes

Honey bee gets the equivalent of 2,015,301 km/l petrol

(50 x around the world)

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