Glucagon - REGULATION OF BLOOD GLUCOSE

DR NILESH KATE

MBBS,MD

ASSOCIATE PROF

DEPT. OF PHYSIOLOGY

GLUCAGON

OBJECTIVES. Source Chemistry Synthesis. Mechanism of action Actions of glucagon. Applied aspects. Blood glucose control

Monday, May 1, 2023

WHERE IS THE PANCREAS?

INTRODUCTION They constitute endocrine

part of pancreas. 1-2 million islets , more in

tail

ISLETS OF LANGERHANS Four types of cells are

present in islets. They are A or alpha cells – secrete

Glucogon B or beta cells – secrete

Insulin D or delta cells – secrete

Somatostatin F or PP cells -- secrete

Pancreatic Polypeptide

ENDOCRINE PANCREAS

ISLETS OF LANGERHANS

Pancreatic Hormones, Insulin & Glucagon Regulate Metabolism

Beta cells produce insulin – cellular uptake of blood glucose

Alpha cells produce glucagon – blood glucose (from cells)

D cells produce somatostatin – gastric secretion

HISTOLOGICAL ORGANIZATION B CELLS, AT THE CORE A/D CELLS, AT THE PERIPHERY

GLUCAGON Source of secretion :

A cells or Alpha cells of pancreas.

Chemistry : Glucagon is a polypeptide with a molecular weight of 3500.

It has 29 amino acid.

SYNTHESIS From Preproglucagon

precursor by islets α cells.

Proglucagon

GLUCAGON.

SECRETION. Stored in dense

granules Released by

Exocytosis. Ca is needed for

exocytosis.

Monday, May 1, 2023

PLASMA LEVELS Circulating Glucagon – Unbound. Basal level in Fasting – 100-150 pg/ml. Half life – 6 min(5-9 min) Secretion Rate 100 -150 μg/day. Degradation – in liver & kidney

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MECHANISM OF ACTION

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ACTIONS OF GLUCAGON Mobilization of

stored nutrients Glucose, fatty acids,

ketoacids. Action exactly

opposite to insulin. Hormone of energy

release.

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ACTIONS OF GLUCAGON Effect of glucagon on carbohydrate

metabolism. Effect of glucagon on protein metabolism Effect of glucagon on fat metabolism. Other actions of glucagon .

EFFECT OF GLUCAGON ON CARBOHYDRATE METABOLISM.

Increases Glycogenolysis in liver and not in muscle.

Glycogen Glucose-1-Phosphate

(inhibit Glycogen Synthetase)

Glucose

EFFECT OF GLUCAGON ON CARBOHYDRATE METABOLISM.

Increases gluconeogenesis in liver.

Formation of Glucose from Lactate, Pyruvate, Glycerol & amino acids.

Monday, May 1, 2023

EFFECT OF GLUCAGON ON FAT METABOLISM.

Increases lipolysis – excess FFA oxidized – energy production -ketogenesis in liver.

Increases release of FFA & Glycerol from adipose tissue and makes it available for peripheral utilization.

Prevents synthesis of triglycerides. Thus Glucagon – Ketogenic & Hyperglycemic

Hormone.

EFFECT OF GLUCAGON ON PROTEIN METABOLISM

Increases Gluconeogenesis by increasing transport of Amino Acids into the liver.

Lowers plasma amino acids.

CALORIGENIC EFFECT Due to increased hepatic deamination of amino

acids

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OTHER ACTIONS OF GLUCAGON:

Inhibit renal tubular Na reabsorption – Natriuresis.

Increases Cardiac force of contraction – activation of myocardial Adenyl cyclase.

Stimulate secretion of growth hormone, insulin & Somatostatin

Regulation of appetite. Increases secretion of bile. Inhibits secretion of gastric juice.

Monday, May 1, 2023

PLASMA GLUCOSE

Pancreatic islet alpha cells

GLUCAGONSECRETION

PLASMA GLUCAGON

Liver GLYCOGENOLYSIS GLUCONEOGENESIS KETONE SYNTHESIS

PLASMA GLUCOSE PLASMA KETONES

-

REGULATION OF GLUCAGON SECRETION

Role of blood levels of Nutrients. Blood Glucose level – BSL

>70mg% stimulate Plasma amino acids-

protein rich meal specially Arginine & Alanine.

Free fatty acids & keto-acids – Negative feedback relationship.

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REGULATION OF GLUCAGON SECRETION

Role of GIT hormones – CCK-PZ, Gastrin, GIP stimulates

Role of Nervous system – sympathetic nerve stimulation – increases Stress, fasting, exercise,

infection – increases Vagal stimulation,

acetylcholine – increases.

Monday, May 1, 2023

STIMULATORS OF GLUCAGON SECRETION

LOW PLASMA [GLUCOSE] AMINO ACIDS (ala, ser, cys, thr) GI HORMONES (CCK, gastrin) CORTISOL, GROWTH HORMONE EXERCISE INFECTIONS, other stresses -ADRENERGIC STIM, Ach

INSULIN/GLUCAGON

INHIBITORS OF GLUCAGON SECRETION

ELEVATED PLASMA [GLUCOSE] SOMATOSTATIN SECRETIN FFA, KETONES INSULIN -ADRNERGIC STIM, GABA

PANCREATIC HORMONES, INSULIN & GLUCAGON REGULATE METABOLISM

Metabolism is controlled by insulin and glucagon

INSULIN VS. GLUCAGON

INSULIN Anabolic (building) hormone Increases glucose transport to

muscles and adipose for use Stores excess glucose in liver

and muscles as glycogen Lowers blood glucose Inhibits gluconeogenesis

(endogenous glucose production)

Promotes growth overall

GLUCAGON Catabolic (breaking down)

hormone Breaks down glycogen to

increase blood glucose level

Promotes gluconeogenesis

REGULATION OF GLUCAGON

REGULATION OF GLUCAGON

HORMONAL REGULATION OF BLOOD GLUCOSE

Normal blood glucose levels & body glucose reserves.

Normal blood glucose levels. – Fasting blood glucose

levels -70-110 mg%. Postprandial – 140mg

%

GLUCOSE TOLERANCE CURVE.

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HORMONAL REGULATION OF BLOOD GLUCOSE

Normal body reserves of glucose. Free glucose –

currency of body 18 gms of free

glucose Enough for basal

energy requirement of body for 1 hour.

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STORED GLUCOSE. In the form of glycogen in liver & muscle Liver – 100 gms

Can provide 40-50 gms of glucose from glycogen

Can produce 125-150 mg of glucose Muscle –contains more glycogen than

liver But degradation does not produce glucose

directly but produce Lactate used for Gluconeogenesis.

Monday, May 1, 2023

SOURCES OF BLOOD GLUCOSE. Dietary sources – Carbohydrates into

Monosaccharide's – into glucose Gluconeogenesis – from Lactate, Glycerol,

Propionate & amino acids Lactate – by degradation of muscle Glycogen. Free Glycerol & propionate by breakdown of fat in

adipose tissue. Amino acids from protein breakdown.

Glycogenolysis. From stored Glycogen in liver.

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UTILIZATION OF BLOOD GLUCOSE.

To provide energy need to body tissue Glycolysis & TCA cycle HMP shunt for pentoses & NADPH Uronic acid pathway

Glycogenesis. Synthesis of other Monosacchrides & amino

acids Synthesis of Fat.

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ROLE OF HORMONES IN REGULATION OF BLOOD GLUCOSE.

Monday, May 1, 2023

PLASMA GLUCOSE

Adrenal medulla EPINEPHRINE SECRETION

PLASMA EPINEPHRINE

ACTIVITY OF SYMPATHETIC NERVESTO ADIPOSE TISSUE AND LIVER

Skeletal muscle GLYCOGENOLYSIS

Liver GLYCOGENOLYSIS GLUCONEOGENESIS

Adipose Tissue LIPOLYSIS

PLASMA GLUCOSE, FATTY ACIDS, GLYCEROL

PREVENTION OF OCCURRENCE OF HYPERGLYCEMIA

Hyperglycemia after a carbohydrate meal or mixed meal is prevented by 4-5 times increase in INSULIN secretion. Increase uptake & utilization as chief fuel Promotes store of glucose as glycogen in liver & TG in

adipose tissue. Inhibit Gluconeogenesis & Glycogenolysis.

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PREVENTION OF OCCURRENCE OF HYPOGLYCEMIA.

There is only one hormone to prevent Hyperglycemia – Insulin

But 4 hormones to prevent Hypoglycemia Glycogen, Growth hormone,

Glucocorticoids & Epinephrine. Organs cannot use any fuel other

than glucose so vulnerable to Hypoglycemia are – Brain, Retina & Germinal Epithelium of gonads.

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PREVENTION OF OCCURRENCE OF HYPOGLYCEMIA.

Role of Glucagon – prevent Hypoglycemia between meals (few hours). Promotes Glycogenolysis & Gluconeogenesis. Lypolysis in adipose tissue& use FFA as chief fuel.

Role of Epinephrine (Many hours) – stimulate sympathetic nervous system through Hypothalamus Supplement actions of Glycogen Increase FFA production by lypolysis.

Role of growth hormones & Glucocorticoids(Few days) – decrease peripheral use of Glucose.

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Thank You

Monday, May 1, 2023