GLUCONEOGENISIS

1. Homeostasis
1
Homeostasis is the maintenance of a stable
internal environment within an organism, and
maintaining a stable internal environment in a
human means having to carefully regulate
many parameters.
Glucose homeostasis reflects a balance between
hepatic glucose production and peripheral
glucose uptake and utilization.

2. Homeostasis Of Blood Glucose
Levels2
 Glucose is an obligate metabolic fuel for the
brain under physiologic conditions.
 The brain cannot synthesize glucose or store it
as glycogen
 Therefore requires a continuous supply of
glucose from the arterial circulation.

3. Plasma glucose concentrations
3
Plasma glucose concentrations are normally
maintained within a relatively narrow range,
roughly 70–110 mg/dL (3.9–6.1 mmol/L) in the
fasting state with transient higher excursions
after a meal, despite wide variations in
exogenous glucose delivery from meals and in
endogenous glucose utilization by, for
example, exercising muscle.

4. Plasma glucose concentrations
4
Between meals and during fasting, plasma
glucose levels are maintained by-
 Endogenous glucose production, hepatic (and
renal) gluconeogenesis,
 Hepatic glycogenolysis.

5. Hepatic glycogen stores
5
Although hepatic glycogen stores are usually
sufficient to maintain plasma glucose levels for
approximately 8 hour.
This time period can be shorter if glucose
demand is increased by exercise or if glycogen
stores are depleted by illness or starvation.

6. Phases of glucose homeostasis
06/03/19Biochemistry for medics- Lecture notes
6
Phase 1 Phase 2 Phase 3 Phase 4
Nutritional
status
Well fed
state
Post- Absorptive
state
Fasting Prolonged
fasting/
Starvation
Source of
glucose
Diet Hepatic glycogen
and
Gluconeogenesis
Hepatic and
Renal
gluconeogenesi
s
Renal and
hepatic
gluconeogenesi
s
Tissues
using
glucose
All All tissues, but in
Liver, muscle and
adipose tissue,
the rate of
utilization is
slowed.
Brain and
RBCs and cells
lacking
mitochondria;
small amount
by muscle.
Brain at a
slower rate,
RBCs normal
rate
Major fuel
of brain
Glucose Glucose Glucose and
ketone bodies
Ketone bodies
and glucose

7. Variations in blood glucose
levels7
A) Hypoglycemia- In a long period of starvation,
adequate amount of glucose is not provided in the
diet, and the blood glucose concentration falls below
the normal, a condition called hypoglycemia.
 A decrease in insulin secretion is the first defense
against hypoglycemia.
 As plasma glucose levels decline just below the
physiologic range, glucose counter regulatory
(plasma glucose–raising) hormones are released.
Among these, pancreatic α cell glucagon, which
stimulates hepatic glycogenolysis, plays a primary
role.
Glucagon is the second defense against
hypoglycemia.

8. A) Hypoglycemia (contd.)
8
 Adreno- medullary epinephrine, which
stimulates hepatic glycogenolysis and
gluconeogenesis (and renal gluconeogenesis),
is not normally critical, however, it becomes
critical when glucagon is deficient.
Epinephrine is the third defense against
hypoglycemia.
 When hypoglycemia is prolonged, cortisol and
growth hormone also support glucose
production and limit glucose utilization.

9. Hypoglycemia
9
 Hypoglycemia is a laboratory ‘diagnosis’ which
is usually considered a blood glucose level
below 60 mg/dL.
 Symptoms begin at plasma glucose levels in
the range of 60 mg/dL and
 Impairment of brain function at approximately
50 mg/dL.

10. B) Hyperglycemia
10
Increase in blood glucose level above the normal
physiological limit is called as Hyperglycemia
Causes of hyperglycemia
Diabetes mellitus
Diseases of pancreas(pancreatitis,
hemochromatosis, carcinoma head of pancreas,
Cystic fibrosis)
Infections and sepsis
Anesthesia
Asphyxia

11. Blood glucose homeostasis
(Summary)11
 Glucose homeostasis reflects a balance between
hepatic glucose production and peripheral glucose
uptake and utilization. Insulin is the most
important regulator of this metabolic equilibrium.
 In the fasting state, low insulin levels increase
glucose production by promoting hepatic
Gluconeogenesis and glycogenolysis and reduce
glucose uptake in insulin-sensitive tissues
 Glucagon, secreted by pancreatic alpha cells
when blood glucose or insulin levels are low,
stimulates glycogenolysis and gluconeogenesis
by the liver and renal medulla.

12. Blood glucose homeostasis
(Summary)12
 Postprandially, the glucose load elicits a rise in
insulin and fall in glucagon, leading to a
reversal of these processes.
 Insulin, an anabolic hormone, promotes the
storage of carbohydrate and fat and protein
synthesis.
 The major portion of postprandial glucose is
utilized by skeletal muscle, an effect of insulin-
stimulated glucose uptake.
 Other tissues, most notably the brain, utilize
glucose in an insulin-independent fashion.

13. 06/03/19Biochemistry for medics- Lecture notes13

14. Gluconeogenesis

15. gluco neo genesis
sugar (re)new make/
create
glycolysis
glucose
pyruvate
lactate
gluconeogenesis

16. Topics: Gluconeogenesis
1. Principles, substrates & relationship to
glycolysis
2. Bypass of irreversible steps in glycolysis
3. Link between liver gluconeogenesis and
muscle/RBC/brain glycolysis; the Cori and
Alanine cycles

17. Gluconeogenesis
• Occurs in all animals, plants, fungi and
microbes
• Occurs largely in the liver; some in renal
cortex
• Of 10 enzymatic steps, 7 are reversals of
glycolytic reactions

18. Carbohydrate
synthesis
from simple
precursors

19. Metabolites feed into
gluconeogenesis at various points
main
path

20. All AA can
feed into
gluconeogenesis
except
leucine
and
lysine

21. TCA
intermediates
are
gluconeogenic;
funnel
through
oxaloacetate

22. Bypass of irreversible
steps in glycolysis

23. Irreversible glycolytic steps
bypassed
1. Hexokinase (hexK)
2. Phosphofructokinase-1
(PFK-1)
3. Pyruvate kinase (PyrK)
by Glucose-6-phosphatase
by Fructose 1,6-
bisphosphatase (FBP-1)
by Pyruvate Carboxylase
& Phosphoenolpyruvate
carboxykinase (PEPCK)
These 3 key enzymes
glycolysis gluconeogenesis

24. Pyruvate can go
“up” or “down”
depending upon
energy needs

25. First bypass step
is generation of
PEP from pyruvate
via oxaloacetate
*Note:
In order to cross the
mito membrane,
oxaloacetate must:
1. Be reduced to malate
2. Go through the
malate shuttle
3. Be reoxidized to
oxaloacetate

26. Addition of CO2 to pyruvate to
form oxaloacetate
• Hydrolysis of ATP

27. Decarboxylation
and
phosphorylation
to PEP

28. 2nd
& 3rd
bypass
steps are near
the end of
gluconeogenesis
(“top” of
glycolysis)
Regulation of FBP-1
by AMP and F2,6P

29. Dephosphorylation of G6P,
3rd
bypass reaction

30. Glucose 6-phosphatase removes the
phosphate to liberate free glucose
• This is primarily a function of the liver to buffer
blood glucose levels
• G6Pase is NOT present in brain and muscle!
(Gluconeogenesis does not occur in these tissues)
glucose-6-P + H2O  glucose + Pi
G6Pase

31. Gluconeogenesis is energetically
expensive to cells (hepatocytes)
cost

32. Liver is the major source of
blood glucose from GN
Is the primary
gluconeogenic organ
Produces glucose for
export to brain, muscle,
RBC’s
Uses many small
metabolites and fatty
acids to feed GN
Liver function is highly
sensitive to insulin &
glucagon

33. The Cori Cycle
2 ATP
6 ATP
2
Lactate and glucose shuttle
between active
muscle/RBC and liver
(glucagon/insulin reg.)
Liver gluconeogenesis
buffers the blood
glucose for use by
muscle, RBC’s and brain
(120 g/day)
*Note: the brain fully
oxidizes glucose, so it
does not funnel back
lactate
GN
GL
RBCs

34. The Alanine Cycle
The liver can also use the
amino acid Alanine similarly
to Lactate
Following transamination to
pyruvate, gluconeogenesis
allows the liver to convert it
to glucose for secretion into
the blood

35. Significance
Remove lactate in muscle
Increase blood sugar level using amino
acids(alanine) in special situation

36. You should know:
1. Chemical steps of GN; associate enzymes
2. Requirement for mito shuttle system
3. Precursors that can enter GN;
4. Relationship of GL to GN; shared enzymes, irreversible
steps
5. Liver as the primary GN organ; Cori Cycle, Alanine Cycle