Obesity, Diabetes and Nutrition Flashcards
1
Q
What are the main trends regarding obesity in the developed and developing world?
A
- Since the 1970s it has been reported as increasing
- This increase was first seen in developed countries due to the rise of both the fast food industry and white collar jobs with low physical activity but is now seen in developing countries also
- Globally the prevalence of overweight is 35% and there are over 500 million obese adults
- Developing countries face a double burden of both under and over nutrition
2
Q
How is BMI calculated and categorised?
A
BMI= weight (kg)/ height (m) squared <18.5= underweight 18.5-24.9 = normal weight 25-29.9 = overweight >30 = obese (class increases with each 5 BMI points)q >40 = morbidly obese
- BMI is a crude measure that can be altered by high muscle density etc. however it can identify is someone might need to follow up with a medical practitioner
3
Q
Describe the prevalence of obesity in Japan and how it is managed?
A
- Japan has relatively low levels of obesity in comparison to other developed nations
- In Japan there is ‘Metabo’ Law which mandates that older citizens have to go for waistline checks and health check ups with doctors and deal with any weight issues
4
Q
What is the priority in addressing obesity in childhood?
A
- Educating parents is the priority
- Children eat what is provided to them, so it society’s responsibility to educate them
- Parents bad lifestyle is often passed onto children
- Childhood obesity is strongly linked to adult obesity
5
Q
How are socioeconimic status and obesity linked in low and middle income countries?
A
- Positive association with socioeconomic status and obesity
- People with higher socio-economic status are more likely to live in urban settings, be more likely to drive, have greater access to more food and less likely to have a job involving manual labour
6
Q
What are the health consequences of obesity?
A
- Increased weight increases the risk of many diseases including: diabetes, CVD, sleep apnoea, cancer, gallbladder disease, osteoarthritis and depression
7
Q
How can the economic costs of obesity be calculated?
A
- Obesity has almost as much of an economic impact as smoking and armed violence, war and terrorism
- These costs in Australia are covered 34.3% by the federal government and 29.4% by individuals
Direct costs:
- Medical costs to treat associated medical conditions
Indirect costs:
- Reduction in productivity and size of workforce
8
Q
How do changes in the global food system drive obesity?
A
- The increased availability of more processed food which is more affordable and better marketed is a key driver of obesity
- A key issue is that highest calorie foods tend to be the least expensive which targets the socioeconomically disadvantaged
9
Q
What action has the UN general assembly taken on tackling issues with nutrition?
A
- The UN general assembly has called on governments to set national targets for 2025 to address malnutrition (including under and over nutrition)
10
Q
How can a social network influence obesity?
A
- Studies have shown that an individual is more likely to be obese if individuals in close social contact with them are also overweight/obese
- Therefore social networks could be used as a platform for improving education about healthy lifestyle and reducing obesity
11
Q
What are the main causes of obesity?
A
- Complex and multifactorial including:
1. Genetics/epigenetics
2. Lifestyle eating/exercise patterns
3. Socioeconomic status
4. Psychological factors
5. Cultural background
6. Age
7. Hormonal, metabolic and physiological factors
8. Sleep disturbances
12
Q
Describe the monogenic mutation that causes obesity:
A
- Monogenic mutations that cause obesity are very rare
- Mutation of the obese (ob) gene results in profound obesity
- It is thought the mutation prevents the production of leptin from adipose tissue causing: uncontrolled hunger and low energy expenditure (low BMR and body temp)
- Congenital deficiency of leptin in humans causes extreme childhood obesity
13
Q
Describe the features of the ‘set-point’ of body weight:
A
- There is an innate setpoint of weight in animals and humans
- It is more evident in humans
- Determined by genetics and environment: mutations of other genes does not affect it
- Occurs in mice despite changing baseline
- Set point in human ONLY OCCURS IN ADULTS (it is not established until after puberty)
- It is very difficult to lower the set point once it has been established in adulthood
- It is important to intervene prior to puberty
14
Q
How is the set point maintained by counterregulatory mechanisms?
A
- The set point is maintained through counterregulatory mechanisms
- In response to weight loss there is a long-term homeostatic drive to increase body weight (still present after 2 years)
- In response to weight gain the counterregulatory mechnanisms are generally fairly acute (occur for a few months before body adapts to increased weight)
15
Q
What were the two gene variants that matched with different phenotypes associated with obesity?
A
- FTO: Fat mass and oesity associated gene (SNP)
- MC4-R
16
Q
Describe how FTO was discovered and its effect when mutated in mice:
A
FTO= fat mass and obesity associated gene
- It was discovered via a GWAS study that showed that when individuals had 2 variant (SNP) versions of the gene they were 1.67x more likely to be obese
- It is the most commonly associated gene with any index of increased body weight
- It is NOT a monogenic cause of obesity however
Overexpression of FTO in mice:
- Increased body weight
- Drastically increased fat mass
- Increased food intake
- Increased preference of higher calorie foods
- Reduced physical activity and energy expenditure and impaired browning of white adipose tissue
17
Q
What variants of FTO are seen in humans?
A
- There are numerous variants of FTO in humans
- 89 genetic variants within introns 1 and 2 of FTO have been associated with BMI
- These FTO genetic variants increase the copy number of the gene and increase the propensity to become obese
- GWAS studies have identified nearly 10,000 SNPs however 90% of these are in non-coding regions
18
Q
What is metabolic syndrome?
A
- Metabolic syndrome (MetS) represents a combination of cardiovascular risk determinants including:
- Obesity (especially central adiposity)
- Glucose intolerance and insuline resistance
- Dyslipidaemia (hypertriglyceridaemia, increased FFAs and decreased HDL)
- Hypertension
MetS is associated with clinical manifestations such as PCOS, atherosclerosis and NAFLD
MetS is diagnosed by:
- An accumulation of visceral fat (waist circumference)
- 2 or more of the following: increased fasting blood glucose, increased BP and altered serum lipids
19
Q
Describe the spectrum of non-alcoholic fatty liver disease:
A
- Healthy liver becomes fatty liver (NAFLD):
- Due to obesity when body has to store fat in ectopic tissue
- This causes hepatic steatosis with lipid accumulation in the liver
- Reversible - NAFLD develops into non-alcoholic steatohepatitis (NASH)
- A liver immune response causes oxidative stress, mitochondrial dysfunction, cytokine production and release, adipocytokine imbalance and stellate cell activation
- NASH is characterised by increased lipid deposition, immune infiltraiton and fibrosis/scarring - If left un-treated NASH can develop into cirrhosis (scarring) and carcinoma
- Non-reversible
- NASH progresses and fibrosis occurs and can lead to cirrhosis where hepatocytes are replaced by scar tissue
20
Q
How are NAFLD and NASH diagnosed?
A
- Measuring liver function via blood testing:
- Can measure bilirubin, ALT and ALS
- Elevated bilirubin indicates a type of steatosis - Can measure liver stiffness
- Increased stiffness is a sign of fibrosis - Biopsy of liver tissue:
- Histological analysis is the only way to distinguish between NAFLD and NASH
21
Q
Describe the general principles of glucose homeostasis and the role of insulin:
A
- When a person has fasted, their blood glucose is approximately 5mM
- After eating a typical meal, blood glucose will rise to 7mM
- After a meal peripheral tissues take up glucose from circulation and within 1-2 hours the blood glucose levels will go back down to 5mM
Role of insulin:
- When blood glucose levels rise after a meal, the pancreas responds by increasing secretion of insulin
1. Insulin shuts down hepatic glucose output
2. Insulin acts on skeletal muscle to increase glucose uptake
3. Insulin acts on adipose tissue to increase glucose uptake
22
Q
What is Diabetes?
A
- A chronic condition in which the body cannot properly use glucose due to either:
- The pancreas not producing enough insulin (type 1)
- The body being unable to effectively use and respond to the insulin produced (type 2)
- Diabetes is characterised by the abnormal buildup of glucose in the blood and can have serious complications
- Many individuals have high blood glucose levels and high insulin resistance, but not high enough to be diagnosed with type 2 diabetes
23
Q
Describe the pathological progression of type 2 diabetes:
A
- Healthy people with normal glucose tolerance (GT) tend to have low levels of insulin secretion, high insulin sensitivity and low levels of plasma glucose
- When an individual becomes obese and has impaired glucose tolerance, the peripheral insulin sensitivity will decrease
- A secondary response following a decrease in peripheral insulin sensitivity is a rapid rise in insulin secretion from the pancreas (which will initially keep plasma glucose stable)
- As peripheral tissues become further impaired and cannot take up more glucose, the pancreas will reach a tipping point and then there will be a rapid reduction in insulin secretion
- The reduction in insulin secretion causes a rapid increase in plasma glucose levels
24
Q
How is diabetes diagnosed?
A
- It is estimated that 1/3 of people with diabetes do not know they have it
- It is diagnosed using:
- Fasting blood glucose
- Normal <5.5
- If over 7 on more than one occasion shows diabetes - Oral glucose tolerance test:
- 75g glucose drink consumed
- 2 hours later blood sample
- Blood glucose >11.1 = diabetes
25
Q
Describe the epidemiology of diabetes in Australia:
A
- 90% of people with diabetes have T2D
- 10% of people with diabetes have T1D
- Between 2007/8 and now proportion of people with diabetes has increased from 4.4% to 7%
- 92% of diabetics are 45 years and older
- The proportion of diabetics across Australia is quite similar expect NT (high level of diabetes due to Indigenous population)
26
Q
Describe the heritability of type 2 diabetes:
A
- A person with T2D most likely has an inherited predisposition for developing the disease
- Estimates of the additive genetic heritability of T2D range from 25-40%
- GWAS studies have shown that there are 40-60 independent SNPs associated with an increased risk of T2D
- 12 T2D susceptability loci have been identified
- Variants in the TCF7L2 (transcription factor associated with cancer progression) gene appear to be associated with the highest risk of developing T2D
- These risk alleles often ct through beta-cell dysfunction (rather than peripheral insulin resistance), indicating that peripheral insulin resistance is environmentally driven
- Most genetic associations are quite modest leading researchers to believe that the increased risk of diabetes in offspring of parents with diabetes is largely due to shared environmental/lifestyle factors
27
Q
How is type 2 diabetes associated with obesity?
A
- Diabetes prevalence increased with increased body weight
- There is a negative correlation between insulin sensitivity and body fat/VAT
- Obese people require a greater level of insulin for peripheral glucose uptake to occur, and this peripheral glucose uptake is diminshed
- Obese people require more plasma insulin and take longer for hepatic glucose production to decrease by a given amount (and this decrease is not as much)
28
Q
How is insulin sensitivity assessed in the lab?
A
Done using a hyperinsulinemic-euglycemic clamp:
- Subject is cannulated
- Insulin is infused at a high set rate
- Glucose is infused at a variable rate
- Blood glucose is measured- depending on insulin sensitivity, more or less glucose will need to be infused to keep blood glucose at a steady rate (someone with reduced insulin sensitivity would require less glucose infusion to become euglycaemic)
- A tracer (radioactively labelled glucose molecule) can also be infused to look at the disposal of glucose into different tissues (mainly done in mice
29
Q
Describe the common progression of T2D:
A
- Insulin resistance
- Beta cell compensation (increased insulin secretion)
- Beta cell failure (decreased insulin secretion)
30
Q
What is insulin resistance and what occurs physiologically in the body?
A
- Insulin resistance is when cells in the body become less sensitive to the effects of insulin
- Results in:
1. Impaired glucose uptake
2. Impaired suppression of hepatic glucose production
3. Reduced anti-lipolytic effect
4. Reduced insulin signal transduction
5. Blunted suppression of feeding
31
Q
What is the effect of IR/T2D on skeletal muscle glucose uptake?
A
- Skeletal muscle glucose uptake should increase dramatically after a meal
- In IR/T2D the capacity for glucose uptake after a meal dramatically decreases
32
Q
Describe insulin resistance at a molecular level:
A
- Insulin receptors are on the surface of many cells (including skeletal muscle)
- Activation of insulin receptors by insulin leads to the activation of the insulin signalling cascade -> activation of AKT -> increased glycogen synthesis, decreased gluconeogenesis and lipolysis -> GLUT4 transporters moved to the membrane
- In obesity there is increased plasma circulation of FFAs
- The intermediates produced in the storage of fats e.g. ceramide, inhibit the activity of AKT interfere with insulin signalling and therefore glucose uptake
- Cytokines from adipocytes and macrophages also interfere with the insulin signalling cascade and can lead to further expression of pro-inflammatory markers by the tissue itself
33
Q
What happens in obesity to cause insulin resistance?
A
- Lipotoxicity
- The intermediates produced in the storage of fats interfere with insulin signalling and thus glucose uptake
- E.g. ceramide inhibits the activity of AKT - Inflammation (low-grade)
- Altered endocrine signals
e. g. changes in ghrelin and leptin - Mitochondrial dysfunction
- Obese people tend to have less mitochondria as well as mitochondria that are smaller and less functional
- This causes a decreased capacity to ‘clear’ lipids and well as an increased production of reactive oxygen species
34
Q
Describe the ‘adipose-centric’ view of obesity and insulin resistance:
A
- This view is that:
1. Adipose tissue stores are important in regulating how much fatty acids are released into circulation
2. In obesity there is an increase in circulating FFA, cholesterol and lipoproteins
3. More circulating fats results in more fat deposition in adipose tissue, as well as the liver and skeletal muscle (which leads to insulin resistance
4. In obesity there is greater inflammation in adipose tissue which released cytokines that negatively affect metabolic health in peripheral tissues
