Glucose homeostasis

The Pancreas

Pancreatic Hormones, Insulin & Glucagon Regulate Metabolism

Actions of insulin and glucagon

Insulin

Signal of feeding.

Target tissues:

liver, adipose

skeletal muscle

Affects metabolism of:

carbohydrates, lipidsproteins

Actions are anabolic

Glucagon

Signal of fasting.

Target tissues:

liver, adipose

Affects metabolism of:

carbohydrates, lipids

Actions are catabolic

Why keep blood glucose concentration constant?

Some tissues only metabolise glucose:

CNS, PNS, red blood cells, kidney, eye

Metabolise glucose at constant rate.

Rate of glucose uptake determined by blood [glucose].

Keep blood [glucose] constant to enable metabolism to proceed

at constant rate.

Control of insulin & glucagon secretion

Factor Insulin Glucagon

Nutrients:

glucose 5mM + -

glucose 5mM - +

amino acids + +

fatty acids + 0

Hormones/neurotransmitters:

GI tract + 0

adrenaline - +

noradrenaline - +

110aa

Preproglucagon

PreproinsulinA|F1 KTRR|E33 KR|G66

Ins B-chain

C-peptide

Ins A-Chain

180aaQ|R1 KR|H33

KR|N64

KR|H72

R|H78

RGRR|D111

GRR|H125

RK160

Glicentin Glucagon

Oxyntomodulin GLP-1 GLP-2

GLP-1 (7-37amide)

116aa

PreprosomatostatinG|A25

F|L34

Q|R89

Antrin ?

SS-14

Somatostatin 28

RERK|A103

95 aa

Prepro Pancreatic polypeptideE|P33 RPRYGKR|H69

Pancreatic polypeptide

Islet Prohormones

Synthesis of insulin - 1

ESR10-07

S

S

S

S

HOOC

SS

NH2

Preproinsulin (110aa)

Synthesis of insulin - 2

ESR10-08

S

S

S

S

HOOC

SS

NH2

Proinsulin (86aa)

Synthesis of insulin - 3

ESR10-09

S

S

S

S

HOOC

SS

NH2

Insulin (21 + 30aa)HOOC

NH2

- chain

- chain

C - peptide (35aa)

Regulation of glucose transport by insulin

Binding of insulin to cell-surface receptorsIntracellular vesicles containing membrane-imbedded GLUT4 transporters fuse with the plasma membraneGLUT4 transporters in muscle or adipose cell surface increases capacity of the cell to transport glucose.

Basal levels of glucose transport are maintained by GLUT1 and GLUT3 forms of the glucose transporter (in most tissues).

Activation of glycogen synthase and inactivation of glycogen phosphorylase

Binding of insulin by the liver or muscle cell leads to stimulation of protein phosphatase-1

Hydrolysis of phosphate catalyzed by protein phosphatase-1 increases the activity of glycogen synthase but deactivates glycogen phosphorylase.

Insulin switches ON glycogen synthetase (GS)

ESR10-26

GSGS

ActiveInactive

Pi

ATPADP

Phosphoprotein phosphatase

cAMP-INDEPENDENT

kinase

Insulin

( + )

Insulin

( - )GSK3

Insulin Inhibition of TAG Degradation in Adipose

In high insulin/low glucagon state:cAMP falls in adiposeHSL is not phosporylated and is inactiveRemember: epinephrine as shown here is a counterregulatory hormone

Insulin Action on Cells: Dominates in Fed State Metabolism

Stimulation - insulin secretion

ESR10-12

• Increased [ glucose ]

• Increased [ free aa ]

• Increased [ GI hormones ]

(gastrin, secretin, CCK, GIP)

MixedMeal

• Increased [ glucagon ]

• Noradrenaline

(low [ ]; α-adrenergic receptors)

• Acetylcholine

Inhibition - insulin secretion

ESR10-13

• Decreased [ glucose ]

• Increased [ somatostatin ]

(pancreatic + gastric)

• Noradrenaline

(high [ ]; β-adrenergic receptors)

• Adrenaline

(β-adrenergic receptors)

Hypoglycaemia

Blood glucose < 3.0mM

Uptake of glucose by glucose-dependent tissues not adequate to maintain tissue function.

CNS very sensitive:

Impaired vision, slurred speech, staggered walk

Mood change – aggressive

Confusion, coma, death

Stress response (release of adrenaline):

Pale

Sweating – clammy

Diabetes Mellitus

Group of metabolic diseases.

Affect 1-2% of population in UK.

Characterised by: • chronic hyperglycaemia (prolonged elevation of blood glucose)• leading to long-term clinical complications

Caused by:• Insulin deficiency – failure to secrete adequate amounts of

insulin from -cells.

and/or• Insulin resistance – tissues become insensitive to insulin.

Classification of Diabetes

Two major types recognised clinically

Type 1 – absolute insulin deficiency (loss of -cells).

Type 2 – relative insulin deficiency and/or insulin resistance.

Also Gestational Diabetes (only occurs during pregnancy).

Other pancreatic hormones

ESR10-10

Glucagon (29aa) - synthesised from preproglucagon

• Zn not required for secretion

• metal ions decrease clearance

Somatostatin (14aa)

• physiological role unclear

• can suppress insulin and glucagon

Stimulation - glucagon secretion

ESR10-14

• Decreased [ glucose ]

• Increased [ free aa ]*

• Adrenaline

Inhibition - glucagon secretion

• Increased [ glucose ]

Activation of glycogen phosphorylase and inactivation of glycogen synthase

Glucagon as a signal of hunger. In its presence, the liver carries out glycogenolysis to provide glucose to the bloodstream and the rest of the body.Epinephrine is a signal of stress. Stimulates muscle glycogenolysis to provide glucose to support contraction and movement

6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2/F-2,6-P2ase)

Fructose-6-P

Fructose-1,6-P2

Fructose-2,6-P2

PFK-1F-1,6-P2ase

+-

ActiveF-2,6-Pase

InactiveF-2,6-Pase

InactivePFK-2

ActivePFK-2

cAMP-DependentProtein Kinase

ProteinPhosphatase-2

P-Glucagon

Glycolysis Gluconeogenesis

Glucagon switches OFF glycogen synthetase (GS)

ESR10-25

GSGS

ActiveInactive

Pi

ATPADP

Phosphoprotein phosphatase

cAMP-dependent

kinase

Glucagon

Glycogenphosphorylase a

( - )

( + )Glucagon

( + )

HSL and futile cycling

ESR10-32

CytosolicAcetyl CoA

MitochondrialAcetyl CoA

FA TAG

Glycerol

GlycerolHSL Insulin

( - )

cAMP-dependent

kinaseGlucagon

( + )

( + )( + )

Glucocorticoids

Somatostatin (somatotropin release-inhibiting factor,

SRIF)

• Chemistry:

Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys

S S

A single peptide of 14 amino acids

A 28-amino acid form is found in the gut

• Secreted by hypothalamic anterior periventricular region and by cells of the pancreatic islets• Secretion by GH, IGF-I, thyroid hormones

Stimulation - somatostatin secretion

ESR10-15

• Carbohydrates

• Proteins

• Fats

MixedMeal

• Decreased pH in duodenum

(by gastric acid - bulbogastrone

mechanism)

Somatostatin • Actions: • Inhibits GH secretion but not its synthesis• Inhibits basal and TRH-stimulated TSH secretion• Inhibits secretion of GI peptide hormones:• insulin, glucagon, VIP, gastrin, and others

• Mechanism of action: • Gi protein-coupled receptors with tissue-specific

expression• Reduces cAMP production and Ca2+