Download Blood Glucose Concentration

MedSci 7
2/24/09
Slide 1
LECTURE 7
Liver — Blood Glucose
(Sherwood 704-715)
Diabetes mellitus
• Inputs and Outputs
• Fed
• Fasting
• Types 1 & 2
– Effects
• Long-term
• Short-term
• Regulation
– Insulin
– Glucagon
• Food intake
Dr Alan Tuffery — Physiology
•
•
•
•
Diabetic Coma
Types
Causes
Symptoms
Treatment.
Medical Science 2008/09
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Sole fuel for CNS function
Slide 2
Blood Glucose Concentration
Sherwood Fig. 19-14
Essence: to understand how all these inputs/outputs are
affected in feed/fasting states.
Dr Alan Tuffery — Physiology
Medical Science 2008/09
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2/24/09
‘Aim’: to maintain glucose[blood]
Slide 3
Glucose [blood]
(Biochemical reactions in Liver)
Increases Glucose [blood]
1. Glycogenolysis
–
Breakdown of glycogen
•
Liver, muscle
Contributory reactions
‘new’ glucose from
amino acids
Dr Alan Tuffery — Physiology
• Glycogen synthesis
• From circulating glucose
AND Switch off production
2. Gluconeogenesis
–
Decreases Glucose [blood]
FEEDING
FASTING
Proteins
Amino Acids
Triglycerides
Fatty acids.
Medical Science 2008/09
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Slide 4
Feeding & Fasting — CHO
Fasting
Fed
• Glucose freely available
Maintaining blood glucose for CNS
– major energy source
• Form glucose (increased supply)
– Glycogenolysis
• Glycogen
synthesis/storage
• Excess to fat
Dr Alan Tuffery — Physiology
• glycogen to glucose
– Gluconeogenesis
• forms new glucose from Amino
Acids (AA)
• Glucose Sparing (reduced demand)
– tissues switch from glucose to
Free Fatty Acids and Amino
Acids.
Medical Science 2008/09
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Slide 5
Amino acid homeostasis
Fasting
Fed (high [AA]blood)
• All cells
(low [AA]blood)
• Muscle
– AA to Protein
synthesis
– Proteins to AA
• Liver
– AA to keto-acids for
energy or triglyceride
synthesis
which in
• Liver
– Gluconeogenesis
• Triglycerides to
adipose tissue
Dr Alan Tuffery — Physiology
• i.e. forms glucose.
Medical Science 2008/09
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Slide 6
Lipid homeostasis
Fed
Fasting (low [fat]blood)
(high [fat]blood)
• Fat cells
• Fat cells (adipocytes)
– Triglycerides to FFA +
glycerol
– via blood to…
– Fats, protein +
glucose form
triglycerides (TG)
• …Most cells
– Fats to energy
• Liver
• …Liver
– FFA to ketones*
– triglyceride synthesis
• Alt. energy source for CNS.
• to adipose tissue
Dr Alan Tuffery — Physiology
Medical Science 2008/09
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GIP release stim by glucose in duodenum — ‘anticipatory’
Slide 7
Insulin Secretion
• Rise in [Glucose]blood is
main stim of secretion
and release
(endocrine pancreas)
Esp. GIP
• Acts to damp rise in
glucose following
digestion/absorption
• Main effect is to
increase glucose
uptake by all cells
‘Fight/flight’.
– There are other insulin
responses leading to a
fall in [glucose]blood
Sherwood Fig. 19-15
Dr Alan Tuffery — Physiology
Slide 8
Medical Science 2008/09
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Think: inputs and outputs of [glucose]blood
Insulin — acts to reduce [glucose]blood
Carbohydrate
1. Remove glucose from blood [primary and unique effect of insulin]
•
•
Increases cellular uptake (via GLUT-4 transporter recruitment)
Promotes hepatic phosphorylation of glucose
– Increases glucose gradient into hepatocytes
•
Promotes glycogenesis
– Stores glucose in liver as glycogen
2. Decreases supply of glucose
• Inhibits gluconeogenesis (blocks enzymes, reduces protein
breakdown)
•
Inhibits glycogenolysis.
Dr Alan Tuffery — Physiology
Medical Science 2008/09
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Slide 9
Insulin acts to reduce fat/protein in blood
Insulin actions (contd)
Fat
Protein
1. Remove fat from blood
• Promotes glucose entry to cells
•
Promotes formation of Fatty
Acids from glucose
Promotes entry of Fatty Acids
to cells
•
1. Remove protein from blood
•
Promotes (active) Amino Acid
entry to cells
•
Promotes protein synthesis
2. Reduce Amino Acid addition
•
Inhibits protein breakdown
–
2. Reduce fat formation
• Inhibits lipolysis
Dr Alan Tuffery — Physiology
See gluconeogenesis.
Medical Science 2008/09
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Slide 10
Insulin and Glucagon
• Opposite effects:
– Insulin reduces
[glucose]blood
– Glucagon increases
[glucose]blood
• Combined effect:
– Maintains [glucose]blood
within 70-110 mg/dl [mg/100 ml]
Dr Alan Tuffery — Physiology
Medical Science 2008/09
Sherwood Fig. 19-17
– Hyperglycaemia >120 mg/dl
– Hypoglycaemia <60 mg/dl.
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Slide 11
Diabetes mellitus
Type 1 (IDDM)
Type 2 (NIDDM)
• Insulin-dependent
– Impaired insulin production
(beta cells)
• Auto-immune
• Non-insulin-dependent
• Impaired target-cell
responsiveness to insulin
• adult onset
• 85-90% cases
• 80% are obese
• juvenile onset
• 10-15% cases
• Insulin replacement
– Weight control
– Exercise.
– (islet-cell implant etc)
• Monitor [glucose]blood
Dr Alan Tuffery — Physiology
Medical Science 2008/09
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Slide 12
Type 1 (IDDM) — possible effects
• Lipolysis increased:
–
–
–
–
Blood [FFA] up:
ketosis
metabolic acidosis
CNS (coma, death)
Stanfield & Germann p 617
• Protein synthesis inhibited
– Impaired
growth/repair/muscle
weakness.
Dr Alan Tuffery — Physiology
Medical Science 2008/09
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Slide 13
Diabetes — other effects
(Sherwood, Fig. 19-16)
Glucosuria
• Urine volume increased (osmotic)
– Dehydration
– Blood volume (BP) down
(collapse, death)
Damage to blood vessels
– Atherosclerosis (reduced flow)
– Stroke, heart disease, renal
failure
– Impaired repair (gangrene)
– Diabetic retinopathy.
Dr Alan Tuffery — Physiology
http://www2.warwick.ac.uk/fac/med/research/csri/proteindamage/physi
ology/diabetes/
Medical Science 2008/09
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Slide 14
Paradoxical rise in glucagon (IDMM)
One effect of insulin lack is impaired
permeability of pancreatic alpha cells to glucose
(Increased permeability to glucose is a principal effect of insulin.)
Hence perceived fall in [glucose] and
consequent glucagon production
Exacerbates hyperglycaemia.
Dr Alan Tuffery — Physiology
Medical Science 2008/09
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http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Diabetes_and_coma?OpenDocument
Slide 15
Diabetic Coma
Hyperosmolar
Ketoacidotic
(Type I)
(Type II)
Symptoms
• Xs fat breakdown
• Thirst
• Urination
• Progressive
drowsiness
• ‘Fruity breath’
Treatment
• Fluids (iv)
• Insulin
• Na+ , K+
Symptoms
Hypoglycaemic
Symptoms
• Hypoglycaemia
• Hyperglycaemia
(hyperosmosis)
(<3.5mmol/L; 63 mg/dL)
• Sweating
• Severe dehydration
• Hunger
• Slow onset (days)
• Confusion
Treatment
Treatment
• Fluids (iv)
• Medical emergency
• Insulin
• Glucagon/glucose.
• Na+ , K+
Dr Alan Tuffery — Physiology
Medical Science 2008/09
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Slide 16
Factors Affecting Food Intake
•
•
•
•
•
Short-term
Long Term
Gut distension
Glucose utilisation
Insulin
ATP/ADP turnover
CCK
• Fat stores
(‘lipostat’)…
• Release leptin…
• Signals size of store
to CNS…
• Inhibits feeding
[?Effect of anti-leptin or leptin deficiency]
Dr Alan Tuffery — Physiology
Medical Science 2008/09
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