Metablic And Endocrine Control During Special Circumstances

Question 1

What are teh fuel sources normally available in blood

Answer 1

Glucose
• Glucose is the preferred fuel source
• Little (~12g) free glucose available
• More glucose (~300g) stored as glycogen

Fatty acids
• Can be used as fuel by most cells
except red blood cells, brain and
CNS 
• Stored as triacylglycerol (fat) in adipose 
• 10-15 kg fat in 70kg man (~2
months fuel supply)

Question 2

What are the fuel sources available under special conditions?

Answer 2

Available under special conditions
Amino acids
• Some muscle protein (~6kg) can be broken down to provide amino acids for fuel 
• Converted to glucose or ketone bodies 
• ~2 weeks supply of energy

Ketone bodies
• Mainly from fatty acids
• Used when glucose is critically short
• Brain can metabolise instead of glucose

Lactate
• Product of anaerobic metabolism in muscle • Liver can convert back to glucose (Cori cycle)
or can be utilised as fuel source for TCA cycle
in other tissues (e.g. heart)

Question 3

Name some energy stores

Answer 3

Glycogen ~ 400g
Readily available source of glucose Made & stored in liver and muscle Made when glucose is in excess in blood

Fat ~10 -15kg Made from glucose and dietary fats when in excess Stored as triacylglycerol in adipose tissue Source of:
• Fatty acids • Glycerol

Muscle protein ~ 6kg available
Used in emergency Amino acids can be:
Glucogenic (e.g. Ala & Val)
Ketogenic (Lys & Leu)
or both (e.g. Tyr & Phe) Store ‘filled’ by normal growth and repair processes

Question 4

What are the key features of metabolic control

Answer 4

See slide

Question 5

Name anabolic and catabolic hormoens

Answer 5

Anabolic hormones
• Promote fuel storage
• Insulin
• (Growth Hormone)
increases protein synthesis
Lack of insulin -> Catabolic state

Catabolic hormones
• Promote release from
stores & utilisation
• Glucagon • Adrenaline • Cortisol • Growth hormone
(increases lipolysis & gluconeogenesis)
• Thyroid hormones

Question 6

What is the action of insulin

Answer 6

Reduces • Gluconeogenesis • Glycogenolysis • Lipolysis • Ketogenesis • Proteolysis

Increases
• Glucose uptake in
muscle and adipose
(GLUT 4). • Glycolysis • Glycogen synthesis • Protein synthesis

Question 7

What are the effects of feeding

Answer 7

Effects of feeding insulin.
• Increase in blood glucose stimulates pancreas to release insulin 
• Increases glucose uptake and
utilisation by muscle and
adipose (GLUT 4) 
• Promotes storage of glucose
as glycogen in liver and muscle. 
• Promotes amino acid uptake
and protein synthesis in liver
and muscle. 
• Promotes lipogenesis and storage of fatty acids as triacylglycerols in adipose tissue.

Question 8

What are the effects of fasting

Answer 8

Effects of fasting
• Blood glucose falls & insulin secretion depressed.
• Reduces uptake of glucose by adipose and muscle.
• Low blood glucose stimulates glucagon which stimulates:
• Glycogenolysis in the liver to
maintain blood glucose for
brain and other glucose
dependent tissues.
• Lipolysis in adipose tissue to
provide fatty acids for use by
tissues.
• Gluconeogenesis to maintain
supplies of glucose for the
brain.

Question 9

What is energy starvation

Answer 9

• Reduction of blood glucose stimulates release of cortisol from adrenal
cortex & glucagon from pancreas.
• Stimulate gluconeogenesis & breakdown of protein & fat.
• Reduction in insulin & anti-insulin effects of cortisol prevent most
cells from using glucose & fatty acids are preferentially metabolised. • Glycerol from fat provides important substrate for gluconeogenesis,
reducing the need for breakdown of proteins.
• Liver starts to produce ketone bodies & brain starts to utilise these
sparing glucose requirement from protein
• Kidneys begin to contribute to gluconeogenesis
• Once fat stores depleted system must revert to use of protein as fuel
• Death related to loss of muscle mass (respiratory muscle: infection).

Question 10

Describe the metabolic and endocrine adaptations to pregnancy

Answer 10

• Number of alterations to
maternal metabolism
and endocrine system 
• Accommodate increased
demands of developing fetus
and placenta 
• Growth of fetus requires lots of energy & raw materials!
• 2/3rds of fetal growth occurs
over the last 1/3 of pregnancy • From 28 weeks onwards fetus
grows from  ~1000g to ~3500g

Question 11

What are the 2 main phases of metabolic adaptation during pregnancy?

Answer 11

Anabolic phase 
• In early pregnancy, mother is in an
anabolic state
• Increase in maternal fat stores • Small increase in level of insulin
sensitivity.
• Nutrients are stored to meet future
demands of rapid fetal growth in late
gestation and lactation after birth.

Catabolic phase
• Late pregnancy characterised as
catabolic state
• Decreased insulin sensitivity
(increased insulin resistance).
• Increase in insulin resistance results in an increase in maternal glucose and free fatty acid concentration
• Allows for greater substrate availability for fetal growth.

Question 12

What is placental transfer ?

Answer 12

• Most substances transfer by simple diffusion down concentration gradients (some active transport e.g. amino acid transporters)
• Glucose is principal fuel for fetus and transfer facilitated by transporters (mainly GLUT 1).

Question 13

How does the foetus affect maternal metabolism?

Answer 13

• Fetus controls maternal metabolism to ensure its own survival
• The placenta, fetal adrenal glands and fetal liver, constitute a new endocrine entity, known as the
fetoplacental unit
• Placenta secretes a wide range of proteins that can control the maternal Hypothalamic pituitary axis
EE slide for table
Important placental steroid hormones include:
Oestriol & progesterone

Question 14

Describe the maternal metabolic Chang’s during the first half of pregnancy

Answer 14

• Changes to maternal metabolism during first 20 weeks of pregnancy related to a preparatory increase in maternal nutrient stores (mainly adipose tissue).
• In preparation for:
• Rapid growth rate of fetus
• Birth
• Subsequent lactation
• Increasing levels of insulin ( ↑ insulin/anti-insulin ratio) promote an anabolic state in mother that results in
increased nutrient storage.

Question 15

What are the maternal metabolic changes in the second half of pregnancy?

Answer 15

• Maternal metabolism adapts to meet increasing demands
• Concentration of nutrients in the maternal circulation kept relatively high by:
Maternal metabolic changes during second half of pregnancy
• Reducing maternal utilisation of glucose by switching tissues to use of fatty acids.
• Delaying maternal disposal of nutrients after meals.
• Releasing fatty acids from stores built up during 1st half of pregnancy.
• Maternal insulin levels continue to increase but the production
of anti-insulin hormones by the fetal placental unit increases at an even faster rate and the insulin/anti-insulin ratio therefore falls

Question 16

What are the anti insulin hordes secresd by the placenta?

Answer 16

• Placenta secretes several hormones that exert an anti-insulin
effect on maternal metabolism
• Corticotropin releasing hormone
• Human placental lactogen
• Progesterone } Also implicated but
mechanism less clear
• Tend to result in transient hyperglycaemia after meals
because of increased insulin resistance • Overall late pregnancy has blood glucose ~10% lower since
insulin levels are ~1.65 x higher in fasting state and ~ 3 x higher in postprandial state.
• Hypoglycaemia can occur between meals and at night because
of the continuous fetal draw of glucose

Question 17

What is the role of cortotropin releasing hormone in pregnancy?

Answer 17

Increases CRH in maternal blood by >1000 fold. Maternal Anterior Pituitary becomes desensitised resulting in a more modest increase in ACTH & cortisol

Question 18

Describe insulin secretion in pregnancy

Answer 18

• Increased appetite in pregnancy means more glucose is ingested
• Oestrogens and progesterone increase sensitivity of maternal pancreatic β-cells to blood glucose
• β-cell Hyperplasia (more cells)
• β-cell Hypertrophy (bigger cells)
• Leads to increased insulin synthesis & secretion
• If β-cells do not respond normally, blood glucose may become seriously elevated & Gestatio nal diabetes may
develop

Question 19

What is gestational diabetes?

Answer 19

Disease in which pancreatic β-cells do not produce sufficient insulin to meet increased requirement in late pregnancy
3 known underlying causes:
1) Autoantibodies similar to those characteristic - <10%
of Type I DM
2) Genetic susceptibility similar to maturity onset diabetes - 1-5% rare
3) β-cell dysfunction in setting of obesity and chronic insulin resistance (i.e. “evolving” type II DM) - vast majority

Question 20

What are the clinical implications of gestational diabetes

Answer 20

Clinical implications
• Affects 3–10% of pregnancies
• Increased incidence of miscarriage
• Incidence of congenital malformation 4x higher
• Fetal macrosomia (large body - big baby)
• Disproportionate amount of adipose
around shoulders and chest could lead to shoulder dystocia - shoulders get “stuck” during birth
• Associated with hypertensive disorders of pregnancy such as Gestational hypertension and Preeclampsia - high bl protein in urine
• Risk of complications greatly reduced if gestational diabetes is diagnosed and managed.

Question 21

Describe the insulin existence/age graph

Answer 21

See slide

Question 22

What are risk factors for gestational diabetes?

Answer 22

Risk factorsq
• Maternal age >25 years • Body mass index >25 kg/m2
• Race/Ethnicity
• More common in Asian, Black and Hispanic ethnic groups
• Personal or family history of Diabetes • Family history of macrosomia

Question 23

Describe teh management of gestational diabetes

Answer 23

Management
• Initial dietary modification including calorific reduction in obese patients
• Insulin injection if persistent hyperglycaemia is present: (7.5-8 mmol/l postprandial or >5.5-6 mmol/L fasting)
• Regular ultrasound scans to assess fetal growth & well being

Question 24

Describe the metabolic response to exercise

Answer 24

The switch from rest to exercise involves rapid adaptations in a range of systems:
• Musculo-skeletal system • Cardiovascular system • Respiratory system • Temperature regulation
The metabolic response needs to ensure:
• Increased energy demands of skeletal and cardiac muscle
are met by mobilisation of energy stores.
• Minimal disturbances to metabolic homeostasis by keeping
rate of mobilisation equal to rate of utilisation.
• Glucose supply to brain is maintained.
• End products of metabolism are removed as quickly as
possible.

Question 25

What does the magnitude/a true of the metabolic response to exercise depend on?

Answer 25

Magnitude and nature of response depends on:
• Type of exercise (muscles used)
• Intensity and duration of exercise
• Physical condition and nutritional state of individual

Question 26

What are the energy requirements of exercise?

Answer 26

• ATP “stores” in muscle are limited (~5 mmol/kg)
• In theory enough to last ~2 seconds during a sprint - ATP concentration would nto fall by >205 due to rapid regeneration
• ATP must therefore be rapidly resynthesised at a rate that meets the
metabolic demands placed upon cell
• Depending on rate of ATP hydrolysis, cell will employ different metabolic strategies to match re-synthesis rate with hydrolysis rate

Question 27

Descrie the muscle atp turnover during excerise

Answer 27

Myosin ATPase accounts for ~70% of the ATP usage. Remainder comes from other cellular processes such as maintaining ionic gradients across cell membrane (Na+, K+, Ca2+)
50 fold increase 100m sprint than rest

Question 28

Whee does the energy for muscle contraction come from

Answer 28

• Muscle creatine phosphate stores (~17mmol/kg muscle) can rapidly replenish ATP to provide immediate energy
• Still only enough for ~5 seconds worth of energy during a 100m sprint
• Beyond initial burst of energy, further ATP must be supplied by:
• Glycolysis - inefficient
• Oxidative phosphorylation - required o2
• Must therefore draw on energy stores to provide substrate for these pathways

Question 29

How can additional intensive exercise be sustained?

Answer 29

• Additional intensive exercise (anaerobic) for up to ~2 minutes can be
sustained by breakdown of muscle glycogen
• If exercise is low intensity enough O2 can be supplied for complete oxidation of glucose and glycogen stores (from muscle + liver) could theoretically last for ~60 minutes (e.g. jogging)
See slide

Question 30

Describe bld glucose regualtion and th cori cycle

Answer 30

• Liver is principal organ for regulating blood
glucose
• Exercise results in an increase in hepatic blood glucose production through glycogenolysis
and gluconeogenesis
• Liver recycles lactate produced by anaerobic metabolism (Cori cycle).
• Muscle takes up blood glucose via GLUT4 transporter (insulin promotes translocation to plasma membrane) and GLUT1 (constitutively active)
• Exercising muscle also has insulin independent process of glucose
uptake ( rise in AMP stimulates AMPK resulting in signalling cascade which
increases GLUT4 translocation)
• Rate of glucose production from liver however is insufficient to meet full
demands of exercising muscle
• Essential that blood glucose levels maintained for use by brain

Question 31

Describe fatty acids as a fuel

Answer 31

• Major store of triacylglycerol in
adipose (~15kg) but also some in muscle itself 
• Theoretically could provide
enough energy for ~48 hours of
low intensity exercise 
• Can only be used in aerobic conditions
• Slow release from adipose tissue 
• Limited carrying capacity in blood 
• Capacity limited by uptake across mitochondrial membrane (carnitine shuttle)

Question 32

Devirbe wjat happens in 100m sprint

Answer 32

• Short, high intensity exercise • Cannot deliver sufficient oxygen to muscles
in time • Once high energy phosphate stores used
(~5 sec) must create ATP anaerobically
• Inefficient • Incomplete metabolism of glucose
• Produces lactate (lactic acid) with subsequent build up in H+
produces fatigue • Cannot deliver extra glucose to muscle cells fast enough • Need muscle store of glycogen • Helps to spare blood glucose for brain

Question 33

Describe what happens in a 1500 run

Answer 33

• Medium intensity • Can deliver some extra oxygen to muscles • However, still ~40% anaerobic metabolism • Aerobic metabolism can use fatty acids as
well as glucose • Three phases to race:
• Initial start uses creatine phosphate and anaerobic glycogen
metabolism. • Long middle phase in which ATP is produced aerobically from muscle glycogen (relies on adequate supply of O2 to muscles). • Final finishing sprint relies again on the anaerobic metabolism of
glycogen and produces lactate.

Question 34

What happens in a marathon

Answer 34

• Low intensity, long duration • 95% aerobic • Use of
• Muscle glycogen • Liver glycogen • Fatty acids
• Muscle glycogen depleted in a few minutes. Glucose from liver
glycogen peaks at ~1 hour then declines steadily • Utilisation of fatty acids rises steadily from 20-30 minutes
See side

Question 35

Give an overview of energy sources during exercise

Answer 35

See slide

Question 36

Describe the hormone control of the metabolic response to prolonged exercise

Answer 36

Over the course of running a marathon:
• Insulin levels fall slowly (inhibition of secretion by adrenaline)
• Glucagon levels rise:
• Stimulates glycogenolysis (activates glycogen phosphorylase)
• Stimulates gluconeogenesis (PEPCK & fructose 1,6 bisphosphatase)
• Stimulate lipolysis (Hormone sensitive lipase)
• Adrenaline and growth hormone rise rapidly
• Adrenaline stimulates glycogenolysis & lipolysis
• Growth hormone stimulates lipolysis & gluconeogenesis
• Cortisol rises slowly
• Stimulates lipolysis & gluconeogenesis

Question 37

What are the benefits of exercise?

Answer 37

• Body composition changes
(adipose ↓, muscle ↑). *
• Glucose tolerance improves
(muscle glycogenesis ↑). *
• Insulin sensitivity of tissues
increases * 
• Blood triglycerides decrease
(VLDL & LDL ↓, HDL ↑) *
• Blood pressure falls. * 
• Psychological effects Feeling of “well-being”
* Especially important for diabetics
• Reverses progression of
metabolic disease 
• More successful that pharmacological intervention
for treatment of T2DM