Glucose Homeostasis &

Diabetes
Dr Harprit Singh

Learning Outcomes
Understand normal range of blood glucose
level
Explore the mechanism of how glucose
homeostasis is maintained
Mechanism of insulin release from islets
Action of insulin
Action of glucagon

Explore the two types of Diabetes

Signs and symptoms
Aetiology
Complications

Blood glucose is tightly

regulated
Normal range between 4-7.8 mmol/L
This range is tightly controlled by the two
endocrine pancreatic hormones
Excess glucose must be used or stored
Insulin
Glucose needs to be released from stores
during fasting
Glucagon

The islets of Langerhans

perform the endocrine
function of the pancreas

~ 1 million islets
Clusters of well vascularised cells
4 cell types: , , , pp
4 hormones:
1.Insulin
2.Glucagon
3.Somatostatin
4.Pancreatic polypeptide

Islet of Langerhans

Pancreas, H&E., BIOM2003 2010.

IHC showing glucagon and insulin

Glucose homeostasis

Creative commons

Insulin Secretion and

Action

After a meal, blood glucose

exceeds metabolic demand
Interstitial fluid

Glucose

Glucose

Glycolysis

Glycogenesis

(Glucokinase)

Glucose-6-phosphate
(Glycogen
synthase)

Pyruvate
Glycogen

Storage

Acetyl CoA*

ADP

Krebs cycle

ATP

*mitochondria

Glucose enters cells via

Glucose Transporters

Glucose

GLUT1 ubiquitous (i.e. RBC)

cell membrane

GLUT2 - pancreas, liver, small intestine, kidney

GLUT3 - ubiquitous
GLUT4 - skeletal muscle, adipocytes, heart
GLUT5 - kidney tubules, jejunum, intestine
Cells can express a variety of transporters: e.g. Liver
normally expresses GLUT 2, but GLUT 1 and 3 during
starvation

Insulin is a -cell polypeptide

hormone
C-peptide
3 kDa

-chain

-COOH

-COOH

S
S

NH+

Pro-insulin
9 kDa

NH+

Insulin
6 kDa

S
S

-chain*

*Human - pig:
Thr30-Ala

C-peptide is used as an indicator

of beta cell function

C-peptide is cleaved from pro-insulin

Equimolar secretion to insulin
Much lower hepatic clearance
More accurate indicator of beta cell
function

How is Insulin secreted from beta

cells?
Glucose
5mM

Resting potential =
-70 mV

Glut 2
Low ATP:ADP ratio

K+
(open)

Ca2+
=closed)

Ca2+ Ca2+
Ca2+Ca2+
Ca2+ Ca2+

Blood

Insulin secretion is stimulated

by -cell depolarisation
Glucose (>
10 mM)

ADP

Glucose

ATP

(Glucokinase)

K+
(ATP=Close)

Glucose-6-phosphate
Glycogen

Pyruvate
Ca2+
(increase

Ca2+ Ca2+
Ca2+Ca2+
Ca2+ Ca2+

Blood

voltage
=open)

Insulin secretion is
stimulated by -cell
depolarisation
Transporters facilitate glucose diffusion
into cells
Glucokinase acts as a glucose sensor
During glucose oxidation, [ATP]
KATP channels close, K+ efflux is suppressed
Depolarisation
Ca2+ influx activates secretory granule
movement
Exocytosis of insulin

induced
InGlucose
which individual
will insulin be
Hormonal-Incretin
secreted
more? (GLP-1) response to
nutrients in digestive tract
Nutrients

A) In a person given glucose

Insulin
intravenously
Incretins
Glucagon

Pancreas
Digestive
tract

B) In a person given the same

amount of glucose orally

Blood sugar

Four stimulants of insulin release

-

Glucose
Fatty acids
Amino acids
GIT hormones (GLP-1, )
- Oral glucose leads to a greater insulin response
than i.v. infusion

Action of insulin on liver,

muscle and adipose
Entry into cells (Glut transporters)
Glycogen storage & synthesis
(Glycogenesis)
Glycolysis
Glycogenolysis
Gluconeogenesis
Lipogenesis
Lipolysis
Amino acid uptake
Protein synthesis

Insulin signalling

Insulin
Receptor
Substrate

Degraded, stored
or recycled

GLUT4 re-localisation
Glut4 transporters are located
deep within the cytoplasm
contained in vesicles
Insulin

Glut4 transporters are

incorporated into the cell
membrane
Immunoflourescent labelling of
GLUT4

Action of Glucagon

During fasting, glucose is

mobilised and alternative
energy sources may be required
Interstitial fluid

Glucose

FFA

Amino
acids

Gluconeogenesis

Glycogenolysis

Glucose
(Glucokinase)

Glucose-6-phosphate

Pyruvate
Glycogen

Citrate
Acetyl CoA*

Storage

Krebs cycle

Ketones

Glucagon
In almost all respects, the actions of
glucagon are opposite to insulin.
29 amino acids, 3 kDa
Mobilises glucose, triglycerides and amino
acids.

The primary target of glucagon is

the liver, where it promotes:
Glycogenolysis
Gluconeogenesis

Glucose made available = blood

glucose

Glucag
on

Glucagon Mode of A

Liver
ATP

Gs

AC

Glucose

cAMP

Glycogenolysi
s;

PKA

Lipolysi
s
Glycolys
is

Diabetes

Diabetes:

Type 1 diabetes can develop quickly

Type 2 diabetes can go undetected for
years

Two Classifications of Diabetes

Type 1: Insulin dependent
Auto-immune disorder
Islet -cell destruction
Type 2: Non-insulin dependent
Life style related
Insulin resistance
Leading to a progressive loss of insulin
Many eventually require insulin treatment
Two very different aetiologies with the
same clinical consequences!

Type 1
synonym

IDDM
Young onset

prevalence

Type 2
NIDDM
Mature onset

10-20%
80-90%
Prevalence

onset

childhood, puberty

defect
nutrition

cell destroyed
insulin resist.
cell dysfunc.
undernourished
obese

genetics

moderate

ketosis

common

>35yrs

strong
rare

Type 1
Onset

rapid

lipids

normal

plasma insulin
C-peptide

Type 2
gradual
TG high

low/absent

absent

Auto-antibodies present

normal/high
normal/high
rare

Diabetic Complications

QUESTIONS