Programming of the Metabolic Syndrome Flashcards
LO
- To examine the evidence that the early life environment affects the risk of developing features of the metabolic syndrome.
- To investigate how the postnatal environment (eg. ‘lifestyle’) can interact with a predisposition for the metabolic syndrome.
- To discuss possible adaptations made in response to the early environment that can have long-term influences on later health ie. the mechanisms involved in the programming of the metabolic syndrome.
Todays lecture
- what is the metabolic syndrome?
- does the early life environment affect the risk of the metabolic syndrome i.e. cardiovascular and metabolic abnormalities?
human epidemiological studies
experimental animal studies
- how does the early life environment affect the risk of metabolic syndrome in older age?
potential mechanisms
how early can metabolic abnormalities be detected?
do these effects change with age?
What is the metabolic syndrome?
Give examples of conditions in which it effects
a cluster of inter-related risk factors that predispose for cardiovascular and metabolic disease
- hypertension
- impaired glucose tolerance (precedes type 2 diabetes)
- insulin resistance (feature of type 2 diabetes)
- dyslipidaemia (altered circulating fats)
- central obesity
One of the definitions of metabolic syndrome…
What is the aetiology of the metabolic syndrome?
‘Epidemic’ of obesity and type 2 diabetes
complex interplay between genetic predisposition and environmental factors
- inactivity
- poor diet
What are some features of the metabolic syndrome?
- hypertension
- impaired glucose tolerance
- insulin resistance
- dyslipidaemia
- obesity
What do we mean by glucose tolerance?
Does the early life environment affect the risk of the metabolic syndrome (or its components)?
Epidemiology
The role of maternal nutrition
The Dutch famine: risk of obesity
The Dutch famine: risk of heart disease
The Dutch famine: risk of metabolic disorders
The Dutch famine: risk of ‘metabolic syndrome’
The post natal environment (early)
persistent thinness (low BMI) during infancy is also associated with metabolic abnormalities in adult life
What are the postnatal growth trajectories (later in childhood)?
the risk for type 2 diabetes associated with small size at birth is amplified by accelerated growth rates during childhood
A Z-score of 0 corresponds to the mean value in the whole cohort
Z-score is the mean of the population
Foetal vs postnatal growth
Postnatal (only) origins of adult disease
What are the 4 key tissues of metabolism of glucose-insulin?
How does the release of insulin from the pancreas affect this?
The role of insulin with plasma glucose
Steps to insulin signalling
What is the main site of glucose disposal and explain this in rat model
Adult rats exposed to a low protein diet in utero:
components of insulin signalling pathways impaired in old age (NB compare with effect at younger age)
–> reduced insulin sensitivity
muscle and glucose…
What tissue has reduced insulin sensitivity?
rats exposed to a low protein diet in utero:decrease in PPAR gamma (Burdge et al. (2004))
- facilitates clearance of fats from circulation under influence of insulin
- consistent with reduced insulin sensitivity and dyslipidaemia
PPARs are susceptible to epigenetic regulation
What occurs with the pancreas of rats who are exposed to a low protein diet in utero?
rats exposed to a low protein diet in utero:reduced pancreatic mass and β cell area
- reduced insulin output in response to glucose
reduced insulin sensitivity (insulin resistance) AND reduced insulin output
What effects occur on the glucose-insulin metabolism tissues where there is a poor early environment?
A ‘life course’ approach
When can metabolic abnormalities first be detected?
With maternal nutrient restriction, what is seen at 1 year?
Maternal nutrient restriction: sheep at 1 year
late but not early nutrient restriction (NR) impaired glucose tolerance, in absence of any change in birth weight
early NR: 50% of nutritional requirement from 0 – 30 days gestation
late NR: 50% of nutritional requirement from 110 – term
nutrient restriction in late gestation was associated with increased body fat and reduced expression of the insulin-sensitive glucose transport GLUT-4 in adipose tissue
impaired glucose tolerance may be related to a defect in glucose uptake into adipose tissue
may change with age
Low birth weight in pigs is followed by what?
Catch-up growth in early postnatal life
Insulin sensitivity in pigs
- Catch-up growth during suckling (first month of life) is associated with improved insulin sensitivity in juvenile life
- but catch-up growth is associated with reduced insulin sensitivity in adulthood
Glucose tolerance in pigs
increased insulin sensitivity in low BW juveniles allows body weight to catch-up relative to high BW pigs
Poor early environment
