Reading: Harper's Biochemistry Chapter 21, Lehninger Principles of Biochemistry 3rd Ed. pp. 878-884.

1. Hormonal Regulation:Hormonal Regulation:
glycolysis/gluconeogenesisglycolysis/gluconeogenesis
- glucose homeostasis- glucose homeostasis
Reading:
Harper’s Biochemistry Chapter 21
Lehninger Principles of Biochemistry
3rd Ed. pp. 878-884

2. OBJECTIVESOBJECTIVES
1. To understand how blood glucose levels are
regulated by hormones, especially epinephrine,
glucagon, and insulin.
2. To examine metabolic consequences of loss of
glucose homeostasis.

3. Some Facts -Some Facts -
The most important metabolic fuels are glucose and fatty
acids.
In normal circumstances, glucose is the only fuel the brain
uses.
Glucose is also preferentially used by muscle during the
initial stages of exercise.
To ensure the continuous provision of glucose to the brain
and other tissues, metabolic fuels are stored.
Carbohydrates are stored as glycogen - the amount of
available glycogen stored is not large - about 75g in the liver
and 400g in the muscles. Liver glycogen can supply
glucose for no longer than 16h.
To provide glucose over longer periods, the body
transforms non-carbohydrate compounds into glucose
through gluconeogenesis.

4. Long-chain fatty acids are the idealLong-chain fatty acids are the ideal
storage fuelstorage fuel
The caloric value of fats (9 Kcal/g) is higher than
that of either carbohydrate or protein (4 Kcal/g),
and therefore long-chain fatty acids are ideal
storage fuel.
The body has a virtually unlimited capacity for the
accumulation of fats e.g. a 150 lb. man will have on
average 30 lbs. of fat stored as adipose tissue
triglycerides.
Fatty acids can support the body’s energy needs
over prolonged periods of time. In extreme
circumstances, humans can fast for as long as 60-
90 days and obese persons longer.

5. The concentration of blood glucose isThe concentration of blood glucose is
regulated with narrow limitsregulated with narrow limits
Physiological effects of
low blood glucose in
humans. Blood glucose
levels of 40 mg/100ml
and below constitute
severe hypoglycemia

6. Sources of blood glucoseSources of blood glucose
Diet - most digestible carbohydrates
ultimately form glucose and other
simple sugars that are transported
to the liver via the hepatic portal
vein.
Gluconeogenesis - from
gluconeogenic compounds.
- Net conversion to glucose without
significant recycling e.g. certain
amino acids and proprionate
- compounds which are the
products of the partial metabolism
of glucose in certain tissues and are
conveyed to the liver/kidney and re-
synthesized to glucose e.g. lactate
via Cori cycle
Glucose is also formed from liver
glycogen by glycogenolysis

7. Blood glucose levelBlood glucose level
The minute-by-minute adjustments that keep the blood
glucose level near 4.5 mM involve the integrated
actions of several hormones (insulin, glucagon, and
epinephrine) on metabolic processes in many tissues,
primarily liver, muscle, and adipose tissue.
- Insulin - signals that blood glucose concentration is
higher than necessary - cells respond by taking up
glucose and converting to storage forms.
- Glucagon - signals that blood glucose is too low -
cells respond by producing glucose through
gluconeogenesis and glycogen breakdown.
- Epinephrine - released into the blood to prepare the
muscles, lungs, and heart for a burst of activity

8. Hormones that affect blood glucoseHormones that affect blood glucose
Epinephrine:Epinephrine:
Secreted by the adrenal medulla in response to
stressful stimuli (fear, excitement, hemorrhage,
hypoxia, hypoglycemia, etc)
Leads to glycogen breakdown in the liver and muscle -
epinephrine→receptor →activates adenylate cyclase →cAMP
→PKA activated→phosphorylates/activates phosphorylase;
phosphorylates/inactivates glycogen synthase
Stimulates fat mobilization in adipose tissue, activating
(via PKA) triacylglycerol lipase.
Stimulates glucagon secretion and inhibits insulin
secretion, reinforcing its effect of mobilizing fuels.

10. Glucagon:Glucagon:
Even in the absence of significant physical activity or stress,
several hours after carbohydrate intake, blood glucose levels fall
below 4.5 mM because of utilization by brain and other tissues.
Lowered blood glucose triggers secretion of glucagon, a
hormone produced by the α cells of the islets of Langerhans.
Glucagon increases blood glucose in several ways:
- stimulates breakdown of liver glycogen
- inhibits glucose breakdown in liver
- stimulates liver gluconeogenesis
Together, these lead to accumulation of liver glucose, allowing
its export to blood
Glucagon stimulates fatty acid mobilization in adipose tissue,
liberating an alternate fuel for tissues (other than brain)
Hormones that affect blood glucoseHormones that affect blood glucose

12. Hormones that affect blood glucoseHormones that affect blood glucose
Insulin:Insulin:
Insulin plays a central role in regulating blood
glucose concentration
It is produced by the β cells of the islets of
Langerhans in the pancreas, as a direct response
to the degree of hyperglycemia
It is a heterodimeric polypeptide consisting of two
chains linked by disulfide bridges.
It is synthesized as pre-proinsulin, stored in
secretory granules as proinsulin, and released as
mature insulin

14. Insulin stimulates glucose uptake in muscle and
liver, and activates glycogen synthesis, so that
glucose is channeled into storage.
As a consequence of accelerated uptake of blood
glucose, the concentration falls to the normal range,
slowing insulin release from the pancreas.
There is a closely adjusted feedback mechanism
between the rate of insulin secretion and blood
glucose concentration which holds blood glucose
nearly constant despite large fluctuations in dietary
intake
Insulin also stimulates the storage of excess fuel as
fat - it promotes glycolysis and thereby acetyl-CoA
production used for fatty acid synthesis

16. Effects of insulin are mediated byEffects of insulin are mediated by
insulin receptor, a transmembraneinsulin receptor, a transmembrane
tyrosine kinasetyrosine kinase
Relationship of the
insulin receptor to
insulin action. Insulin
binds to its membrane
receptor, and this
interaction generates
one or more
transmembrane
signals. This signal
(or signals) modulates
a wide variety of
intracellular events

17. Diabetes is a defect of insulinDiabetes is a defect of insulin
production or actionproduction or action
Diabetes mellitus -
group of metabolic
diseases
characterized by
hyperglycemia due to
defective insulin
activity

18. Symptoms of DiabetesSymptoms of Diabetes
Excessive thirst; frequent urination (polyuria); large
intake of water (polydipsia). These changes are due
to excretion of large amounts of glucose in the urine
(glucosuria).
Excessive but incomplete oxidation of fatty acids in
the liver, resulting in overproduction of the ketone
bodies acetoacetate and β-hydroxybutyrate.
Acetoacetate can convert to acetone, found in the
blood of diabetics (breath odor like ethanol).
The overproduction of ketone bodies is called
ketosis, and their production is accompanied by
decreased blood pH, (acidosis) or ketoacidosis,
potentially life-threatening.

19. Treatment of diabetesTreatment of diabetes
Type 1 - insulin injections daily, or insulin
infusion from pump.
Type 2 - do not usually require insulin
treatment because insulin synthesis partially
preserved. Treatment relies on diet and oral
hypoglycemic agents

20. A sensitive diagnostic
criterion is provided by the
glucose-tolerance test.
Glucose tolerance test.
Blood glucose curves of a
normal and a diabetic
individual after oral
administration of 50 g of
glucose. Note the initial
raised concentration in the
diabetic. A criterion of
normality is the return of
the curve to the initial
value within 2 hours.
Treatment of diabetesTreatment of diabetes

21. Fasting and starvationFasting and starvation
Fuel reserves in normal human adult are:
- glycogen in liver and muscle (small amounts)
- triacylglycerols in adipose tissue
- tissue proteins, which can be degraded if needed.

22. Fuel metabolism in the liver during prolonged starvation. After
depletion of stored carbohydrates, proteins become an
important source of glucose, produced from glucogenic amino
acids by gluconeogenesis (steps through ), fatty acids
imported from adipose tissue are converted into ketone bodies
for export to the brain (steps through ). Broken arrows
represent reactions through which there is reduced flux during
starvation.

23. Alcohol excess can lead toAlcohol excess can lead to
hypoglycemiahypoglycemia
Case study
middle-aged man, emaciated, chronic alcoholic,
collapses in bar at 11 a.m.
Physical exam reveals clammy skin, rapid breathing,
rapid heart beat.
Lab test: blood glucose = 2.5 mM; blood alcohol = 0.2%;
creatine phosphokinase - normal; serum aspartate
aminotransferase (indicative of liver damage)- high;
slightly acidic blood; low pCO2; high blood lactate.
After an infusion of glucose, he regained consciousness,
had some food, and was referred to a counselor.
What happened?

24. ExplanationExplanation
Poor diet, low glycogen stores
Dependent on gluconeogenesis
Gluconeogenesis compromised by liver damage and
limited muscle mass
Alcohol metabolized primarily in the liver via NAD+
reduction
CH3CH2OH CH3CHO CH3COOH
Oxidation of ethanol reduces NAD+
and increases NADH
Redox imbalance inhibits the flux of major substrates
into gluconeogenesis
Low blood glucose leads to a stress response
Rapid breathing is a response to metabolic acidosis from
lactic acid accumulation
NAD+
NADH NAD+
NADH