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Intermediary Metabolism
• GLUCOSE AND ENDOCRINE PANCREAS
23
• Introduction to the pancreas, its cell types,
its hormones, its functional organization, its
venous output to liver and its regulation
• Overview of intermediary metabolism and
enzyme sites of major actions of insulin and
glucagon
• Pancreatic hormones, insulin, glucagon, SS
and PPY. Their structure, synthesis, related
peptides, secretion, regulation, receptors and
effects. Effect of exercise on insulin and on
its counter-regulatory hormones
• Regulation of pancreatic hormones, Diabetes
Mellitus, hypoglycemia, fasting, NIDDM
Intermediary Metabolism
GLUCOCORTICOIDS & GLUCOSE CONTROL
Glucose
metabolism
22
• Introduction to steroids in general:
synthesis, regulation, mechanisms
of action, development, physiology
and related - diseases
• Adrenal gland: anatomy, histology,
hormones, effects, feedback.
Cortisol secretion, receptors,
mechanism of action and effects
• Cortisol: effects on glucose metabolism,
anti-inflamatory action, regulation,
synthetic cortisol, the stress
response
• Cortisol related pathologies: Addison's
disease and Cushing's syndrome
Page 1
Glucose
metabolism
Intermediary Metabolism Control
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glycogen
glycogen phosphorilase
glycogen synthetase
G-1-P
G-6-Pase
glucose
hexokinase
glucose
G-6-P
F-6-P
PFK
F-1,6-diPase
F - 1,6 -diP
transaminases
insulin
glucagon
epinephrine
glucocorticoids
triose
amino acids
pyruvate
proteins
Krebs
cycle
acetyl CoA
fats
Pancreas and the main “story lines” controlling metabolism
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glucose
gluconeogenesis
glycogen
Plasma levels of glucose and insulin in relation to meal intake, and the time
course of blood glucose related to the origin of glucose under fasting conditions
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FUEL METABOLISM IN ANABOLIC AND CATABOLIC PHASES
State
anabolism
Hormones
insulin
Fuel Source
diet
glycogen synth.
triglycerid synth.
protein synth.
storage
depots
glycogenolysis
lipolysis
proteolysis
ketogenesis
glucagon
catabolism
insulin
glucagon
Process
Quantitative turnover of substrates in the basal state after fasting for 24 hours.
The opposite direction of plasma insulin and glucagon define metabolic state.
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Some associations to remember for an endocrine regulatory
viewpoint. Remember hormones act on enzymes and channels
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Some associations to remember for an endocrine regulatory
viewpoint. Remember hormones act on enzymes and channels
Page 4
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An overview of the factors affecting insulin
signalling
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An overview of blood glucose stimulation of insulin secretion
and effect
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An overview of blood glucose stimulation of insulin secretion
and effect. Insulin’s main effect is on Glut-4 transporters
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Organ
liver
Net effect
glycogenolysis
gluconeogenesis
ketogenesis
glycogen synthesis
fatty acid synthesis
Chief mechanism
phosphorylase (glucose-dependent de-P)
PEPCK (transcriptional regulation)
FDPase-2 (enzyme dephosphorylation)
substrate (alanine) delivery from muscle
substrate (FFA) delivery from fat
glycogen synthase (enzyme de-P)
acetyl CoA carboxylase (transcription)
fatty acid synthase
muscle proteolysis
protein synthesis
glucose uptake
glycogen synthesis
multiple mechanisms
activity at multiple steps
recruit glucose transporter to cell surface
glucose uptake
glycogen synthase (enzyme de-P)
fat
hormone sensitive lipase (enzyme de-P)
delivery of tryglyceride from liver
lipoprotein lipase
lipolysis
triglyceride synthesis
The effect of insulin on the Glut - 4 transporter and on the main
enzymes involved in intermediary metabolism
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The effect of insulin on the enzymes glycogen synthetase and 6 –
phosphofructokinase (PFK), two of the main metabolic switches
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Glucagon secreted by the pancreatic alpha-cells increase blood
glucose levels, acting through a cAMP mediated mechanism
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Organ
liver
Net effect
Chief mechanism
glycogenolysis
glycogen phosphorylase (cAMP-dep- P)
glycogenesis
glycogen synthase
(phosphorylation)
F - 1,6 - diPase
(phosphorylation)
pyruvate kinase
(phosphorylation)
substrate delivery, releasing inhibition of
carnitine palmytoil transferase, allowing
mitochondrial transfer and FA oxidation
gluconeogenesis
glycolysis
ketogenesis
Main actions of glucagon on metabolic pathways and the effect of
a meal or arginine infusion on blood glucose, insulin & glucagon
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A good example of “pushing the regulatory feedback envelope”
in endocrinology is Diabetes Mellitus (both type 1 and type 2)
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Pathologies of the endocrine pancreas
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HPA axis and its “story
lines”
Hypothalamic - pituitary - adrenal axis (HPA axis) is
control predominantly by cortisol negative feedback
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The main stimulus for ACTH secretion is hypothalamic CRH acting through AC
and PLC mediated mechanisms. ACTH increases Pregnenolone through cAMP
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The secretion of ACTH and adrenal steroids to plasma has a circadian rhythm.
Secretion of these ligands is also affected by stress, such as insulin injection.
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The main metabolic effect of cortisol on metabolism is gluconegenesis
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structure
a)
b)
Which, increase
or decrease?
function
How do
you know?
c)
Parts to total?
d)
Two feedbacks and
an absolute
requirement?
Next week question
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