GLUCAGON

GLUCAGON

• Glucagon: is secreted when “Glucose is GONE”• Peptide hormone made of 29 amino acids.• MW: 3485• Has several functions that are dramatically

opposite to Insulin• One injection of purified glucagon can have profound Hyperglycemic effects! Therefore, it is also called the HYPERGLYCEMIC HORMONE!

GLUCAGON

SYNTHESIS: in the alpha cells of the Islets of Langerhans.

Preproglucagon (158 AA)↓

Glucagon + Major proglucagon fragment(in the alpha cells)

GLUCAGON METABOLISM

• Circulates without binding to carrier proteins.• Plasma half-life: 5 minutes• 25% of the Glucagon is destroyed during

passage through the Liver.• Glucagon also degraded by the kidneys & the

plasma peptides.

ACTIONS OF GLUCAGON

The physiological role of Glucagon is to stimulate hepatic production & secretion of glucose. It

accomplishes this by:1. Glycogenolysis

2. Increased Gluconeogenesis

NOTE: Muscle DOES NOT respond to Glucagon. It exerts its effects on the Liver and Adipose tissues.

Mechanism of GlycogenolysisGlucagon activates adenylyl cyclase in the hepatic cell membrane

↓Formation of cyclic adenosine monophosphate (cAMP)

↓Protein kinase regulator protein is activated

↓Protien kinase is activated

↓Phosphorylase b kinase is activated

↓Phosphorylase b is converted into phosphorylase a

↓Promotes degradation of Glycogen into Glucose-1-phosphate

↓Glucose-1-phosphate is dephosphorylated

↓Glucose is released from the liver

MECHANISM OF GLUCONEOGENESIS

• It increases the rate of amino acid uptake by the liver cells.

• It then stimulates the conversion of many amino acids to Glucose.

↓This is achieved by activating many enzymes required for AA transport & gluconeogenesis.

OTHER EFFECTS:

• It activates adipose cell lipase→ increased quantities of fatty acids are made available.

• It inhibits storage of TG in the liver → this prevents the liver from removing fatty acids from the blood!

• It increases the blood flow in some tissues such as kidneys.

• Enhances bile secretion.• Inhibits gastric acid secretion.

REGULATION OF GLUCAGON SECRETION

• Increased blood glucose concentration is the most potent factor: It INHIBITS Glucagon secretion

• Increased amino acids stimulate Glucagon secretion (same effect as on INSULIN!)

• Decrease in fatty acid levels stimulate Glucagon secretion (opposite to the effect on Insulin).

• Somatostatin inhibits Glucagon & Insulin secretion

• Exhaustive exercise stimulates Glucagon secretion

What happens when you take a protein only diet?

Glucagon release is stimulated by plasma amino acids. This pathway prevents hypoglycemia after ingestion of a pure protein meal.

If a meal contains protein but no carbohydrate, amino acids absorbed from the food cause insulin secretion. Even though no glucose has been absorbed, insulin-stimulated glucose uptake increases, and plasma glucose concentrations fall.

Unless something counteracts this process, the brain’s fuel supply is threatened by hypoglycemia. Co-secretion of glucagon in this situation prevents hypoglycemia by stimulating hepatic glucose output.

As a result, although only amino acids were ingested, both glucose and amino acids are made available to peripheral tissues.

Glucagon Dominates in Fasting State Metabolism

Figure 21-14: Endocrine response to hypoglycemia

The Balance b/w insulin & Glucagon

• Over-riding concern is glucose homeostasis :– must maintain sufficient levels for use by brain – other tissues adjust to other energy sources as

necessary.

Insulin is known as the “Hormone of Feasting”, while Glucagon is known as the “Hormone of

Fasting”.

Glycogen Glucose Pyruvate

Muscle: Fed State

Glucose from circulation

(Active muscle)

(Inactive muscle)

Glycogen Glucose Pyruvate

Muscle: Fasting State

Acetyl CoAFatty Acids and Ketone Bodiesfrom Circulation

1st uses own glycogen stores2nd absorbs fatty acids and ketone bodies

Glycogen Glucose Pyruvate

Liver: Fed State

Glucose from circulation

Acetyl CoAFatty Acids released to Circulation

Glycogen Glucose Pyruvate

Adipose: Fed State

Glucose from circulation

Acetyl CoAFatty Acids

Fatty Acids fromCirculation

Triacylglycerol(Fat)

Glycogen Glucose Pyruvate

Adipose: Fasting State

Acetyl CoAFatty Acidsand glycerol

Fatty Acids and glycerolreleased to circulation

Triacylglycerol(Fat)

SOMATOSTATIN

SOMATOSTATIN• Secreted by the Delta cells of Islets of Langerhans• Polypeptide containing only 14 AA• Extremely short half life of 3 minutes• All matters related to food ingestion increase its

secretion:-increased blood Glucose-increased fatty acids-increased amino acids-increased concentrations of GI hormones

ACTIONS OF SOMATOSTATIN It has paracrine function locally within the Islets of

langerhans where it depresses the secretion of both Insulin & Glucagon

It decreases the motility of stomach, duodenum & gall bladder

It decreases both secretion & absorption in the GIT

Principal role is to extend the period of time over which the food nutrients are absorbed into the blood by

slowing its passage through the GIT!