Lecture 6.2: Adaptations of Metabolism Flashcards
Placental Transfer
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)
Anabolic Phase of Pregnancy
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
Catabolic Phase of Pregnancy
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
The Foetal-Placental Unit
• Its own hormones produced by the endocrineglands (steroid hormones)
• Maternal hormones (e.g. insulin, glucagon, cortisol)
• Placental hormones
The Foetal-Placental Unit: Placental Hormones
Chorionic Gonadotropin (HCG)
Corticotropin Releasing Hormone (CRH)
Placental Lactogen (PL)
Chorionic Thyrotropin (CT)
Oestrogen
Progesterone
Anti-Insulin Hormones
Placenta secretes hormones that exert an anti-insulin effect (impaired glucose uptake in adipose and muscle) on maternal metabolism
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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
Insulin Secretion in Pregnancy
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
Gestational Diabetes: Glucose Levels
• Fasting plasma glucose >5.6mmol/l or
• 2-hr OGTT plasma glucose level > 7.8mmol/l
Gestational Diabetes: Underlying Causes (Least to Most likely )
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)
Gestational Diabetes: Clinical Implications
• 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
Gestational Diabetes: Risk Factors
• 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
Gestational Diabetes: 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 foetal growth and well-being
Benefits of Exercise
• 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
Resting Metabolic Rate
~4 kJ per minute
Energy Requirements of Exercise
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
Where Does the Energy Come From?
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
Muscle Glycogen
Blood Glucose as Fuel
What organ regulates blood glucose?
Liver
What effect does exercise have on blood glucose? How?
Exercise results in an increase in hepatic blood glucose production through glycogenolysis and gluconeogenesis
Glycogenolysis
Glycogenolysis is the biochemical pathway in which glycogen breaks down into glucose-1-phosphate and glucose
Gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates
How does liver recycle lactate produced during exercise?
Cori Cycle
Via what does muscle take up blood glucose?
GLUT4 transporter (insulin promotes translocation to plasma membrane) GLUT1 (constitutively active)
How is exercising muscle special in term of glucose uptake?
Exercising muscle also has insulin independent process of glucose uptake (increased AMP increases GLUT4 translocation)
Fatty Acids as Fuel
• 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
Metabolic Response to Starvation
Tissues switch from glucose to fatty acids/ ketones to conserve glucose for the brain
