Endocrine pancreas

1

• Endocrine pancreas the control of energy
  metabolism

2
Endocrine glands
3
Pancreas

• 1 endocrine tissue, 99 exocrine tissue
• Endocrine tissue islets of Langerhans
• 1 million islets per pancreas
• Major cell types in islets
• ?-cells - produce glucagon
• ?-cells - produce insulin

4
Structures of insulin and glucagon

• Insulin
• 51 amino acids
• 2 polypeptide chains
• (A 21, B 30)
• 3 disulphide bridges
• rigid structure
• Synthesis is complex
• proinsulin (86)

• Glucagon
• 29 amino acids
• 1 polypeptide chain
• 0 disulphide bridges
• flexible structure
• Simpler synthesis

5
Proinsulin, insulin and C-peptide

• 
  

6
(No Transcript)
7
Properties of insulin and glucagon

• Water soluble.
• carried dissolved in plasma no special
  transport proteins.
• interact with cell surface receptors on target
  cells.

8
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

9
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 -

10
(No Transcript)
11
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.

12
Fuel homeostasis
GI Tract Blood
Tissues
Food

Storage Interconversion Utilisation
Synthesis Energy Waste
products
Fuels
Fuels

Loss (faeces) Loss (kidney, lungs)

13
Processes affected by insulin glucagon

• Process
• Glucose uptake
• (muscle adipose tissue).
• Gluconeogenesis
• (liver)
• Glycogenesis
• (liver muscle)
• Glycogenolysis
• (liver muscle)

• Insulin Glucagon
• o
• -
• -
• -

14
Processes affected by insulin glucagon

• Process
• Lipogenesis
• (liver adipose tissue)
• Lipolysis.
• (adipose tissue)
• Ketogenesis
• (liver)
• Amino acid uptake
• (muscle)
• Protein synthesis.

• Insulin Glucagon
• -
• -
• -
• o
• o

15
What happens to metabolism when insulin or
glucagon levels are abnormal?

• Insulin
• High hypoglycaemia.
• Low diabetes.
• Glucagon
• High no significant effect.
• Low no significant effect.

16
Hypoglycaemia

• Blood glucose lt 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

17
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.

18
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).

19
Causes of hyperglycaemia

• Insulin deficiency and/or insulin resistance
  affects
• Muscle
• uptake of glucose.
• glycogenesis.
• Adipose tissue
• uptake of glucose.
• lipogenesis and esterification.
• Liver
• glycogenesis glycolysis.
• ? gluconeogenesis.

20
Additional metabolic problems due to insulin
deficiency

• Muscle
• uptake of amino acids protein synthesis (?
  proteolysis).
• Adipose tissue
• esterification (? lipolysis).
• Liver
• gluconeogenesis from muscle amino acids.
• ketogenesis from adipose tissue fatty acids.
• Consequences
• muscle wasting weight loss.
• hyperglycaemia
• ketosis.

21
Clinical consequences of hyperglycaemia

• Acute - metabolic
• glycosuria (exceeds renal threshold).
• polyuria (excess urine production).
• polydipsia (thirst).
• Chronic - microvascular disease
• eye disease including retinopathy.
• kidney (nephropathy).
• peripheral nervous system (neuropathy).
• Chronic - macrovascular disease
• coronary artery disease.
• stroke.
• poor peripheral circulation (feet).

22
Development of the clinical complications of
diabetes

• Hyperglycaemia contributes to development of
  microvascular complications of diabetes. How?
• Tissues affected - peripheral nerve, eye, kidney.
• Uptake of glucose into these tissues
• does not require insulin.
• determined by extracellular glucose.
• During hyperglycaemia ? intracellular glucose
• interacts with proteins (glycosylation).
• metabolised via abnormal pathways (polyol).

23
Protein glycosylation (glycation)

• Covalent attachment of glucose to proteins
• N-terminal free amino group.
• ?-amino group of lysine.
• Non-enzymatic reaction that involves a number of
  reactive intermediates.
• Extent of glycosylation depends on
• glucose.
• half-life of protein.

24
Protein glycosylation (glycation)

• Effects of glycosylation
• changes net charge on protein.
• changes 3-D structure of protein.
• can lead to cross-linking of polypeptide chains.
• Changes protein structure and therefore function.

25
Glycosylated (glycated) haemoglobin

• As erythrocytes age - gradual conversion of
  haemoglobin (HbA) to a series of glycosylated
  forms (HbA1).
• Major component of HbA1 is HbA1c glucose added
  to the N-terminal valine of the ?-chain.
• Amount of HbA1c correlates with the average blood
  glucose concentration over the previous 2 - 3
  months.
• In non-diabetic subjects HbA1c 5 of the
  total HbA.
• In diabetic patients HbA1c give a good indication
  of blood glucose control.

26
Relationship between blood glucose concentration
HbA1c
27
Polyol pathway

• Glucose metabolised via aldose reductase
• Glucose NADPH ? Sorbitol NADP
• Depletes cellular NADPH
• Leads to disulphide bond formation in proteins
• -SH HS- ? -SS-
• -SS- NADPH ? -SH HS- NADP
• Alters protein structure function (lens)
  -cataracts.
• Sorbitol accumulates
• Osmotic effect causes tissue damage (glaucoma
  eye).
• Treatment aldose reductase inhibitors