Download ILA: DIABETES

ILA: DIABETES
Ass Prof Dr. Gihan Sharara
• Questions (Based on basic biochemistry)
• What is hyperglycemia?
• Why was there hyperglycemia in this patient?
• Explain why there is increased urination (polyuria) with
this high blood glucose?
• Why Hoda had increased appetite (polyphagia) despite
high glucose levels?
• Discuss normal glucose metabolism
• Suggest the possible alterations in glucose storage
and break down that might occur in this clinical
problem.
What is hyperglycemia?
• Hyperglycemia is the elevation of blood
glucose levels above the normal range.
• Normal fasting blood glucose:
• 70 – 100mg/dl
Why was there hyperglycemia in this
patient?
•
INSULIN DEFICIENCY:
1. decreases uptake of glucose by cells.
2. insulin dependent enzymes are less active
•
Net effect:
A. inhibition of glycolysis
B. Inhibition of glycogenesis (glycogen synthesis)
C. stimulation of gluconeogenesis
D. Stimulation of glycogenolysis (glycogen
degradation)
MAJOR METABOLIC EVENTS THAT
LEAD TO HYPERGLYCEMIA
INSULIN
Glucose uptake
by the tissues
GLUCAGON
Breakdown of
tissue proteins
Glycogenolysis
Gluconeogenesis
Hepatic output
Of glucose
HYPERGLYCEMIA
• Explain why there is increased
urination (polyuria) with this high blood
glucose?
• When the blood glucose levels exceed
the renal sugar threshold
glucose
is excreted in urine (glucosuria)
• Due to the osmotic effect of glucose,
more water accompanies glucose
excretion
Polyuria (increase in
volume of urine excretion)
When the blood
glucose levels
exceed the renal
sugar threshold
glucose is excreted in
urine (glucosuria)
osmotic effect of
glucose
Polyuria
(increase in volume
of urine excretion)
water accompanies
glucose excretion
• To compensate for the water loss
• Thirst centre is stimulated
• More water is is taken (polydepsia:
always thirsty, drinks a lot)
• Why Hoda had increased appetite
(polyphagia) despite high glucose
levels?
• Although the blood glucose level is
high but glucose is not taken up by the
cells due to insulin deficiency therefore
the cells are starved
• The patient will take more food
(polyphagia) to compensate for the loss
of glucose and also loss of protein
Although the
blood glucose
level is high
BUT
BUT glucose is NOT
taken up by the cells
due to insulin
deficiency
the cells are starved
The patient will take more food (polyphagia)
to compensate for the decrease of glucose
and ATP intracellulary
• Discuss normal glucose metabolism
GLUCOSE
GLUCOSE
+
Insulin
glycolysis
+
+
Pyruvate
PDH
ACETYL COA
MITOCHONDRIA
CITRIC ACID
CYCLE
ATP
GLUCOSE -6- PHOSPHATE
1)OXIDATION
a) For energy
production
(glycolysis &
Krebs cycle)
b) For production
of pentose P
and NADPH (HMS)
2) Conversion to
other hexoses:
Fructose,
galactose
3)Conversion to
non essential
amino acids.
4)Storage in the
form of
glycogen or fats.
c) For production
of uronic acid.
Biological effects of insulin
PATHWAY
Key
enzyme
Glycolysis
Glucokinse Stimulation
dephosphorylation
PFK-1
of the enzymes
Pyruvate
kinase
*Pyruvate
Inhibition
Gluconeogenesis
Action of
insulin on the
enzyme
carboxylase
*PEPCK
Dephosphorylation
*F1,6
diphosphatase of the enzymes
*Glucose 6
phosphatase
Direct Overall
effect effect
Hypoglycemia
Hypoglycemia
Biological effects of insulin
PATHWAY
Key
enzyme
Action of
insulin on the
enzyme
Glycogen
synthesis
Glycogen
synthase
Activation
Direct
effect
Overall
effect
Glycogen Hypoglycemia
dephosphorylation storage
of the enzymes
Glycogen
degradation
Glycogen
phosphorylase
Glycogen Hypoglycemia
dephosphorylation storage
Inactivation
of the enzymes
•
•
•
•
In Diabetes Mellitus all these effects are
reversed because
INSULIN
GLUCAGON
A. inhibition of glycolysis
B. Inhibition of glycogenesis (glycogen
synthesis)
C. stimulation of gluconeogenesis
D. Stimulation of glycogenolysis (glycogen
degradation)
•
Suggest the possible alterations in
glucose storage and break down that
might occur in this clinical problem.
A. Inhibition of glycogenesis (glycogen
synthesis)
B. Stimulation of glycogenolysis
(glycogen degradation)
GLUCAGON in liver
ACTIVE
Glycogen Synthase
ATP
Hormone receptor complex
ADP
P
Adenyl Cyclase
cAMP
ATP
Inactive
protein
kinase
INACTIVE
Glycogen Synthase
INHIBITION OF
GLYCOGEN SYNTHESIS
ACTIVE
protein
kinase
Inactive
phosphorylase
kinase
ATP
ACTIVATION OF
GLYCOGEN BREAKDOWN
ACTIVE
phosphorylase
kinase
ADP
ACTIVE
Inactive
phosphorylase
ATP
phosphorylase
ADP
P
ATP
cAMP
PHOSPHODIESTERASE
+
ACTIVE
protein
kinase
Inactive
protein
kinase
AMP
INSULIN
Insulin
ACTIVE
Inactive
dephosphorylates
phosphorylase
phosphorylase
kinase
and inactivates
kinase
ADP
phosphorylase andATP
ACTIVE
Inactive
inhibits
phosphorylase
phosphorylase
glycogenolysis
ATP
+
ADP
PROTEIN
PHOSPHATASE
INSULIN
Pi
H2O
P
ATP
cAMP
AMP
PHOSPHODIESTERASE
Inactive
protein
kinase
+
ACTIVE
protein
kinase
INSULIN
INACTIVE
Glycogen Synthase
ACTIVE
Glycogen Synthase
ATP
Insulin
dephosphorylates
and activates
Glycogen synthase
and activates
glycogenesis
Pi
ADP
PROTEIN
PHOSPHATASE
H2O
+
INSULIN
P
Therefore, in DM
when insulin is
deficient
No activation of
PHOSPHODIESTERASE
PROTEIN
PHOSPHATASE
cAMP
Phosphorylation of the key enzymes of
glycogenolysis and glycogenesis
ACTIVE
INACTIVE
Glycogen Synthase
phosphorylase
INHIBITION OF
GLYCOGEN SYNTHESIS
ACTIVATION OF
GLYCOGEN BREAKDOWN