Why blood glucose does not exceed the normal level after meal and many more answers of mysteries............

1. GLUCAGON and ITS METABOLIC
EFFECTS
BY:
Khuram Aziz
M.Phill Biochemistry
Scientist by IBC Life Sciences
Member of Pakistan Young Scientist Association

2. OUTLINE
• Glucose homeostasis
• Sources of glucose
• Glucagon
• Metabolic effects
• Stimulation of Glucagon
• Physiological actions
• Regulation
• Mechanism of glucagon

3. Glucose Equilibrium – A Wonder !!
• Normal Blood Glucose
– Fasting state : 60 to 100 mg%
– Postprandial : 100 to 140 mg %
Let us grasp some blood glucose in such a
• What keeps the of the fascinating answers !!
narrow range?
• Why are we not becoming hypoglycemic when
we fast?
• Why is our blood sugar not shooting up to very
high levels after a rich meal ?
• What are the regulatory and counter
regulatory hormones ?
3

4. Hormonal Regulation of Metabolism
• Balance
between
anabolism and
catabolism
depends on
levels of
insulin,
glucagon, GH,
thyroxine, and
others
19-35

5. Insulin and Glucagon Secretion
• Normal fasting
glucose level is 60–
100 mg/dl
– Insulin and glucagon
normally prevent
levels from rising
above 170mg/dl
after meals or falling
below 50mg/dl
between meals
19-40

6. Glucose Homeostasis
Lower Blood Glucose Between meals
-cells release -cells release
Glucagon insulin
stimulate glycogen stimulate glucose
breakdown and uptake by
gluconeogenesis peripheral tissues
Higher Blood Glucose
Food
6

7. Homeostasis of Glucose
Counter Regulation Mechanisms
• A steady maintenance of blood glucose with in a narrow range
• Fasting state and fed states – their effects on BG
• Rate of glucose appearance Ra
• Rate of disappearance Rd must be in balance
• Blood Glucose (BG) = Ra - Rd
• Control systems
– Glucose Receptors, GLUT 1-14
– Controlling Hormones, Insulin, Glucagon, Cortisol, Epinephrine etc.,
– Insulin Signaling sequences, Glucagon signaling
– Effector Cells – Muscles, Liver, Brain, Heart and Adipose tissue
– Feedback loops
• Negative feedback
• Positive feedback
7

8. Sources of Glucose in to blood
• Glucose is derived from 3 sources
• Intestinal absorption of dietary carbohydrates
• Glycogen breakdown in liver and in the kidney.
• Only liver and kidney have glucose-6-phosphatase.
• Liver stores 25-138 grams of glycogen, a 3 to 8 hour supply.
• Gluconeogenesis, the formation of glucose from precursors
• These include lactate and pyruvate, amino acids (alanine and
glutamine), and to a lesser degree, from glycerol
8

9. Fasting State
• Short fast
– Utilizes free glucose (15-20%)
– Break down of glycogen (75%)
• Overnight fast
– Glycogen breakdown (75%)
– Gluconeogenesis (25%)
• Prolonged fast
– Only 10 grams or less of liver glycogen remains.
– Gluconeogenesis becomes sole source of glucose
– Muscle protein is degraded for amino acids.
– Lipolysis generates ketones for additional fuel.
9

10. Counter Regulatory Hormones
• Glucagon
We will discuss in detail
• GLP-1 (Glucagon Like Peptide -1)
– The most potent known insulin Secretagogue
– It is made in the intestine by alternative
processing of the same precursor
• Intracellular actions
10

11. Responses to decreasing Glucose levels
Response Glycemic Physiological Role in counter
theshhold effects regulation
↓ Insulin 80 - 85 mg% ↑ Ra (↓ Rd) Primary
First Defense
↑ Glucagon 65 - 70 mg% ↑ Ra Primary
Second Defense
↑ Epinephrine 65 - 70 mg% ↑ Ra ↓ Rd Critical
Third Defense
↑ Cortisol, GH 65 - 70 mg% ↑ R a ↓ Rd Not Critical
↑ Food ingestion 50 - 55 mg% ↑ Exogenous < 50mg% no
Glucose cognitive change
11

12. Glucagon
• It is a peptide hormone.
• Consists of a single chain of 29 amino acids.
• Secreted by alpha cells of pancreatic islets of
langerhans.
• Its main action is on the liver.
• It tends to increase the blood glucose level.
• Known as hyperglycemic hormone.

13. Glucagon Secretion
Stimulation of Glucagon secretion
– Blood glucose < 70 mg/dL
– High levels of circulating amino acids
– Especially arginine and alanine
– Sympathetic and parasympathetic stimulation
– Catecholamines
– Cholecystokinin, Gastrin
– Glucocorticoids
13

14. Role of Glucagon
• Metabolic Effects of Glucagon
– Increases hepatic glycogenolysis
– Increases gluconeogenesis
– Increases amino acid transport
– Increases fatty acid metabolism (ketogenesis)
14

15. Metabolic Effects of Glucagon
15

16. Role of Glucagon
• Metabolic Effects of Glucagon
Clinical Pearl
– Increases hepatic glycogenolysis
1. Glucagon is the treatment for hypoglycemia
– Increases gluconeogenesis
2. Glucagon Kit – 1 mg s/c or IM or IV injection –
– Increases amino acid transport
3. In 2 to 3 minutes recovery
– Increases fatty acid metabolism (ketogenesis)
16

17. Physiological actions
Glucagon
On glucose On fats On insulin
Increases Stimulates
Decreases
Blood glucose Insulin
lipogenesis
level secretion

18. Physiological actions
Glucagon increases
Blood glucose level
Inhibiting Increases
Glycogenolysis glycogen liver
synthesis gluconeogenesis
Increases
Inhibits
stimulate hepatic
glycogen
phosphorylase Production of
synthase
glucose

19. Physiological actions
Glucagon
Increase
Decreases Increases Hepatic
lipogenesis lipolysis utilization of
fats
stimulates
Ketogenesis
Inhibits Hormone
Increase
Acetyl CoA Sensitive
Formation of
carboxylase Lipase in
ketones
liver
Increase
Free fatty
acid

20. Physiological actions
High levels
Of glucagon
Increases Inhibits
Increases
blood flow in Increases bile
Strength of
some tissues
Gastric acid
secretion
The heart secretion
e.g the kidneys

21. Cell
ATP sensitive
K+ channel Voltage dependent
Ca+ channel
ATP
Metabolism
Glucokinase
GLUCOSE INSULIN

22. Somatostatin inhibits glucagon and insulin secretion
• somatostatin secretion is increased by the following;.
1-increased blood glucose
2-increased amino acids
3-increased fatty acids
4- increased concentrations of several of the gastrointestinal hormones
released from the upper gastrointestinal tract in response to food
uptake
• In turn somatostatin has multiple inhibitory effects as follow:
1-acts locally within the islets of langerhans themselves to depress the
secretion of both insulin and glucagon
2-decreases both secretion and absorption in the gastrointestinal tract
3-decrease the motility of the stomach ,duodenum, and gallbladder

23. Somatostatin
Somatostatin
-From delta cells
-Inhibitory hormone
Increase blood Increased amino
glucose acids
Increased fatty Upper
acids GI-hormones
Inhibts Decreases the Decreases both
secretion Motility of stomach Secretion &
Of insulin & Duodenum absorption in
glucaon Gall bladder GIT

24. Regulation of glucagon secretion
- Increased blood glucose inhibits glucagon secretion :
- increase blood amino acids stimulate glucagon secretion
:
High concentrations of amino acids as occur in the blood
after protein meals stimulate the secretion of glucagon .this
is the same effect that amino acids have in stimulating
insulin secretion.
Thus in this instance the glucagon and insulin responses are
not opposite.
- exercise stimulates glucagon secretion.

25. -exercise stimulates glucagon secretion :
In exhaustive exercise, the blood concentration of glucagon
often increases fourfold to fivefold. A beneficial effect of
the glucagon is that to prevents a decrease in blood
glucose
One of the factors that might increase glucagon secretion in
exercise is increased circulating amino acids .other
factors such as beta –adrenergic stimulation of the islets
of langerhans ,may also play a role .

26. Regulation of blood glucose
Regulation of
Blood glucose
Severe Prolonged
Hyperglycemia Hypoglycemia
hypoglycemia hypoglycemia
Release
Release of Release of Catecholamine
of GH
insulin glucagon release
& cortisol
Glycogenesis Release of
Glycogenolysis
Glucose glucose Gluconeogenesis
storage By the From fat
Gluconeogenesis
In liver liver
Decreased Increased
blood blood
Glucose level Glucose level

28. GlucagonMechanism of action
Binds to receptors
On hepatocytes
Stimulation
Of adenyl cyclase
ATP
cAMP
Activates protein
kinases
Desired action

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17-29

30. cAMP and activation of PKA
Glucagon or
epinephrine
Liver cell
ATP inactive
active
cAMP adenylyl
cyclase
p
inactive
active
cAMP inactive
active glycogen
inactive
active phosphorylase p phosphorylase
protein kinase
kinase A
glycogen glucose-1-phosphate
amplification cascade

31. THANKS
BEST OF LUCK