Lecture 6.2: Adaptations of Metabolism

Question 1

Placental Transfer

Answer 1

Most substances transfer by simple and facilitated diffusion down
concentration gradients (some active transport e.g. amino acid transporters)

Glucose is the principal fuel for the fetus and transfer is facilitated by active transporters (mainly GLUT 1)

Question 2

Anabolic Phase of Pregnancy

Answer 2

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 foetal growth in late gestation and lactation after birth

Question 3

Catabolic Phase of Pregnancy

Answer 3

Late pregnancy is a catabolic state, maternal metabolism adapts to meet an increasing demand by foetal-placental unit

Increase in maternal nutrients in blood

Decreased insulin sensitivity (increased insulin resistance)

Increase in insulin resistance results in an increase in maternal glucose, free fatty acid and ketones concentrations

Allows for greater glucose availability for foetal growth

Question 4

The Foetal-Placental Unit

Answer 4

• Its own hormones produced by the endocrineglands (steroid hormones)
• Maternal hormones (e.g. insulin, glucagon, cortisol)
• Placental hormones

Question 5

The Foetal-Placental Unit: Placental Hormones

Answer 5

Chorionic Gonadotropin (HCG)
Corticotropin Releasing Hormone (CRH)
Placental Lactogen (PL)
Chorionic Thyrotropin (CT)
Oestrogen
Progesterone

Question 6

Anti-Insulin Hormones

Answer 6

Placenta secretes hormones that exert an anti-insulin effect (impaired glucose uptake in adipose and muscle) on maternal metabolism
≥≥≥≥≥≥≥.≥≥≥≥≥≥≥≥≥≥≥≥≥≥≥≥≥≥≥≥≥≥≥≥≥≥.≤≤≤≤≤≤
Tend to result in transient hyperglycaemia after meals because of increased insulin resistance

Hypoglycaemia can occur between meals and at night because of the continuous foetal usage and draw of glucose

Question 7

Insulin Secretion in Pregnancy

Answer 7

Increased appetite in pregnancy increases glucose 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 and secretion

If β cells do not respond normally, blood glucose may become seriously elevated and gestational diabetes may develop

Question 8

Gestational Diabetes: Glucose Levels

Answer 8

• Fasting plasma glucose >5.6mmol/l or
• 2-hr OGTT plasma glucose level > 7.8mmol/l

Question 9

Gestational Diabetes: Underlying Causes (Least to Most likely )

Answer 9

1) Genetic susceptibility similar to maturity onset diabetes

2) Autoantibodies similar to those characteristic of Type 1 Diabetes (DM)

3) β cell dysfunction associated with obesity and chronic insulin resistance (“evolving” type 2DM)

Question 10

Gestational Diabetes: Clinical Implications

Answer 10

• Affects 3–10% of pregnancies
• Increased incidence of miscarriage
• Incidence of congenital malformation 4x higher
• Fetal macrosomia
• Disproportionate amount of adipose around shoulders and chest could lead to shoulderdystocia
• Associated with hypertensive disorders of pregnancy such as gestational
hypertension and preeclampsia
• Risk of complications greatly reduced if GD is diagnosed and managed

Question 11

Gestational Diabetes: Risk Factors

Answer 11

• 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 12

Gestational Diabetes: Management

Answer 12

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 foetal growth and well-being

Question 13

Benefits of Exercise

Answer 13

• Body composition changes (less adipose, more muscle)
• Glucose tolerance improves (muscle glycogenesis increases)
• Insulin sensitivity of tissues increases
• Blood triglycerides decrease
• Blood pressure falls
• Psychological effects
• Reverses progression of metabolic disease
• More successful than pharmacological intervention for treatment of T2DM

Question 14

Resting Metabolic Rate

Answer 14

~4 kJ per minute

Question 15

Energy Requirements of Exercise

Answer 15

ATP —> ADP + Pi +energy

ATP “stores” in muscle are limited (~5 mmol/kg) which lasts for ~2 seconds during a sprint

ATP must therefore be rapidly resynthesised at a rate that meets the metabolic demands placed upon the cell

Depending on the rate of ATP hydrolysis, cells will employ different metabolic
strategies to match re-synthesis rate with hydrolysis rate

Question 16

Where Does the Energy Come From?

Answer 16

Muscle creatine phosphate stores (~17 mmol/kg muscle) can rapidly
replenish ATP to provide immediate energy

Beyond initial burst of energy, further ATP must be supplied by:
• Glycolysis
• Oxidative phosphorylation

Must therefore draw on energy stores to provide substrate for these
pathways

Question 17

Muscle Glycogen

Question 18

Blood Glucose as Fuel

Question 19

What organ regulates blood glucose?

Answer 19

Liver

Question 20

What effect does exercise have on blood glucose? How?

Answer 20

Exercise results in an increase in hepatic blood glucose production through glycogenolysis and gluconeogenesis

Question 21

Glycogenolysis

Answer 21

Glycogenolysis is the biochemical pathway in which glycogen breaks down into glucose-1-phosphate and glucose

Question 22

Gluconeogenesis

Answer 22

Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates

Question 23

How does liver recycle lactate produced during exercise?

Answer 23

Cori Cycle

Question 24

Via what does muscle take up blood glucose?

Answer 24

GLUT4 transporter (insulin promotes translocation to plasma membrane) GLUT1 (constitutively active)

Question 25

How is exercising muscle special in term of glucose uptake?

Answer 25

Exercising muscle also has insulin independent process of glucose uptake (increased AMP increases GLUT4 translocation)

Question 26

Fatty Acids as Fuel

Answer 26

• 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)
• Low rate of ATP production but high capacity for sustained production

Question 27

Metabolic Response to Starvation

Answer 27

Tissues switch from glucose to fatty acids/ ketones to conserve glucose for the brain