Blood Glucose Levels During the Fed and Fasting

States, Exercise and Diabetes

Key Concepts:
• during an overnight fast blood glucose levels are
maintained by both glycogenolysis and
gluconeogenesis
• hormones tightly regulate these pathways (mostly)
• 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.

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 WHAT YOU NEED TO KNOW!!

• 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

Glucose homeostasis

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 Blood glucose,
insulin and glucagon
levels after a high
carbohydrate meal.

Human endocrine glands

Secretes
hormones into
the bloodstream

The endocrine
organ that
maintains blood THE PANCREAS
glucose level
(BGL) is…….

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 The pancreas is neuroendocrine in origin

Exocrine (secretes digestive enzymes)

Endocrine Islet of
Langerhans
(secretes
hormones)

The pancreas has neuroendocrine origins, parts of the gut are considered
an enteric brain!
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 Mouse pancreatic
islet, a spherical
group of hormone-
producing cells.

Insulin is labelled
here in green,
glucagon in red,
nuclei in blue.

Heller R.S. (2015) The Comparative Anatomy of Islets. In: Islam M. (eds) Islets of
Langerhans. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6686-0_2

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 Glucagon
Glucagon is a 29aa polypeptide

α-cells produce glucagon in response to LOW

BGL

RAISES blood glucose levels by:

- stimulating glycogen break down (&
stopping glycogen synthesis)
- signaling the liver cells to hydrolyse glycogen
releasing glucose into the blood

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Insulin
Insulin is a 51aa polypeptide

β-cells produce insulin in response to HIGH

blood glucose levels
Insulin LOWERS BGL levels by:
- Stimulating all body cells (except brain cells) to
take up glucose

Has numerous other effects such as:

- Stimulating glycogen synthesis
- Promoting storage of fuel e.g. glycogen, muscle
growth and fat

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 Fig. 8.2 Maintenance of glucose homeostasis by insulin
Glucose homeostasis
and glucagon

High blood
glucose
Insulin

Insulin
decreases Low blood
glucagon glucose
secretion Glucagon

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Constant glucose management

Insulin Insulin Insulin Insulin

9
7
Glucose mM

5
3
1

Glucagon Glucagon Glucagon

Glucagon
0

Time
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Post high carbohydrate glucose management

Glucose 10 mM

5 mM

Insulin 120 uU/ml

40 uU/ml

Glucagon 120 pg/ml

80 pg/ml

0 20 40 60 80 100 120 mins

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 So what does insulin do?
• Many things
• In the case for the exam, it drives
glucose uptake in tissues, importantly
into the skeletal muscle and the liver!
• But insulin also promotes fat deposition,
glycogen storage, growth
• Insulin is part of a broad hormone family
that are generally anabolic

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Insulin history, discovery and

mechanisms

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 51 aa protein when cleaved

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Insulin is a growth factor

It drives biosynthesis and storage

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 GLUT1 is ubiquitous, highly conserved, but GLUT2 is
found in the pancreas beta-cells, liver and gut
GLUT2

Pancreatic islet b-cell

GLUT2 has high Km (low affinity) glucose enters when the concentration is
high (GLUT1 Km = 1 mM, GLUT2 Km = 15-20 mM)

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Glucose uptake stimulates cell metabolism in

the pancreas b-cells

GLUT2

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Glucose uptake stimulates cell metabolism in
the pancreas b-cells

ATP
ATP ATP
ATP
ATP

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Glucose uptake stimulates cell metabolism in

the pancreas b-cells

Insulin
containing
vesicles move to KATP sensitive channel
membrane

ATP
ATP ATP
ATP
ATP

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Glucose uptake stimulates cell metabolism in
the pancreas b-cells

ATP ATP
ATP
ATP
ATP

So high glucose (which = high energy) uses metabolic flow/flux

to signal a global regulator of energy levels (glucose)
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Metformin
Is a sulfonylurea

It is actually a tad more complicated

Not just glucose triggers insulin release,
Back to the brain thing, β-cell works like a neuron
Diabetes Res Clin Pract. 2011 Aug;93 Suppl 1:S27-31. doi: 10.1016/S0168-8227(11)70010-9.

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 Back to insulin

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Insulin mediated
glycogenesis
many tissues Glucose

Stimulation of Insulin
receptor
glycogen
synthesis Insulin

Fats

Mitochondria

Glucose
transporter

PI-3K & IRS1

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 DIABETES MELLITUS.

Diabetes -to straddle legs apart- -siphon

Mellitus -sweet (honey) tasting

Hyperglycaemic- excess glucose in blood

appears in urine.

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16 (mmol/l)

Normal fasted blood

glucose = 4.5-5 mM
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Diabetic > 11 mM
(or frequent fasted levels
of > 7 mM)
8
4
0

0 1 2 3 4
Hours following glucose bolus

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 Diabetic complications
Cardiomyopathy
~80% of diabetics die from heart failure
Nephropathy –kidney failure
Retinopathy –visual issues
Neuropathy –peripheral nerve damage
Peripheral circulation issues-gangrene ulcers
Glycation of hemoglobin

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DIABETES
Two main types:

Insulin dependent, common in juveniles,

Sometimes in adults viral infection triggers
Type 1:
loss of b cells.
Loss of Insulin production.

Non – Insulin dependent, common in older people

Type 2: (90%), obesity, stress, variable insulin levels, it starts
high then drops
Insulin insensitivity  no insulin

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 Type I diabetes

Type I diabetes mellitus (insulin-dependent diabetes)

- Autoimmune disorder

- Usually appears in childhood

- Treatment: insulin injections

Normal pancreas Diabetic pancreas

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Type 1

Pancreas beta cells

destroyed

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 A closer look

Pancreas

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Type 1 DM
No insulin

No insulin, no
glucose uptake
Must inject insulin

Complicated

Insulin is not the only

hormone involved
and it is a growth
hormone

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 Type II diabetes

Type II diabetes mellitus (non-insulin dependent)

- Usually due to target cells having a decreased

responsiveness to insulin

- Usually occurs after age 40 – risk increases with age

- Accounts for over 90% of diabetes cases

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Type 2 Diabetes
Generally mediated by obesity

Bodies cells Beta cells also work

desensitised to harder to supply
insulin, blood larger body mass
glucose levels rise with insulin, cells fail
Note this is grossly simplified, there
Glucose uptake and are many things occurring and
disposal impaired T2DM can occur through extreme
stress, genetic mutation and
evolutionary background….

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Type 2 Diabetes
Generally mediated by obesity

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Insulin insensitivity

High fat content of the

blood may alter
signalling, and or
glucose metabolism

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 Type II
Reactive oxygen
species, and Too much fuel
Maternally inherited Too few mitochondria
DM Free radicals
released by mitos

The cell responds

and protects the cell
by decreasing GLUT

Blood glucose rises

Mitochondrial DNA
mutations can also
impair glucose uptake

It is thought that this process may be the cell protecting

itself from elevated glucose and holding it outside the cell

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Fit Unfit

In almost all cases exercise improves if not eradicates type II diabetes

(also extends life marginally, improves life quality, mental capacity,
requires no drugs).

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