Programming of the Metabolic Syndrome

Question 1

LO

Answer 1

• 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.

Question 2

Todays lecture

Answer 2

• 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?

Question 3

What is the metabolic syndrome?

Give examples of conditions in which it effects

Answer 3

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

Question 4

One of the definitions of metabolic syndrome…

Answer 4

Question 5

What is the aetiology of the metabolic syndrome?

Answer 5

‘Epidemic’ of obesity and type 2 diabetes

complex interplay between genetic predisposition and environmental factors

• inactivity
• poor diet

Question 6

What are some features of the metabolic syndrome?

Answer 6

• hypertension
• impaired glucose tolerance
• insulin resistance
• dyslipidaemia
• obesity

Question 7

What do we mean by glucose tolerance?

Answer 7

Question 8

Does the early life environment affect the risk of the metabolic syndrome (or its components)?

Epidemiology

The role of maternal nutrition

Answer 8

Question 9

The Dutch famine: risk of obesity

Answer 9

Question 10

The Dutch famine: risk of heart disease

Answer 10

Question 11

The Dutch famine: risk of metabolic disorders

Answer 11

Question 12

The Dutch famine: risk of ‘metabolic syndrome’

Answer 12

Question 13

The post natal environment (early)

Answer 13

persistent thinness (low BMI) during infancy is also associated with metabolic abnormalities in adult life

Question 14

What are the postnatal growth trajectories (later in childhood)?

Answer 14

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

Question 15

Foetal vs postnatal growth

Answer 15

Question 16

Postnatal (only) origins of adult disease

Answer 16

Question 17

What are the 4 key tissues of metabolism of glucose-insulin?

How does the release of insulin from the pancreas affect this?

Answer 17

Question 18

What tissue is the most sensitive to insulin?

Answer 18

muscle

Question 19

The role of insulin with plasma glucose

Answer 19

Question 20

Steps to insulin signalling

Answer 20

Question 21

What is the main site of glucose disposal and explain this in rat model

Answer 21

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

Question 22

muscle and glucose…

Answer 22

Question 23

What tissue has reduced insulin sensitivity?

Answer 23

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

Question 24

What is the liver the site of in regard to glucose production?

Tell me about this

Answer 24

The liver is the site of endogenous glucose production

rats exposed to a low protein diet in utero:

• decreased ability of insulin to suppress glucose output (Holemans et al. (1996))

–> glucose output continues even in face of high circulating glucose

• decrease in PPAR alpha (Burdge et al. (2007))

regulates partitioning of fatty acids between circulation and metabolism in liver

–> dyslipidaemia

Question 25

What occurs with the pancreas of rats who are exposed to a low protein diet in utero?

Answer 25

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

Question 26

What effects occur on the glucose-insulin metabolism tissues where there is a poor early environment?

Answer 26

Question 27

A 'life course' approach When can metabolic abnormalities first be detected?

Answer 27

Question 28

With maternal nutrient restriction, what is seen at 1 year?

Answer 28

**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

Question 29

Low birth weight in pigs is followed by what?

Answer 29

Catch-up growth in early postnatal life

Question 30

Insulin sensitivity in pigs

Answer 30

* 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

Question 31

Glucose tolerance in pigs

Answer 31

increased insulin sensitivity in low BW juveniles allows body weight to catch-up relative to high BW pigs

Question 32

Poor early environment

Answer 32