TYPE 2 DIABETES PATHOGENESIS

Question 1

In diabetes, what is the lipid profile like overall?

Answer 1

In T2DM, there are high triglyceride concentrations, particularly post-prandially
➢ Low HDL concentrations
➢ Normal total and LDL cholesterol concentrations, but small dense LDL particles

Question 2

What are the five different types of lipoprotein?

Answer 2

1. VLDL (very low density lipoprotein)
2. Intermediate LDL
3. LDL
4. HDL
5. Chylomicrons

Question 3

What is the structure of the lipoprotein like?

Answer 3

➢ The apolipoprotein in the phospholipid layer plays a role in transporting the lipid around the body
➢ The centre of the lipoprotein will consist of cholesterol esters and trigylcerides
➢ The higher of cholesterol ester/triglyceride ratio, the higher density the lipoprotein
➢ Chylomicrons have the apolipoprotein ApoB48

Question 4

What does insulin do to triglycerides?

Answer 4

Insulin will increase fatty acid and glycerol uptake into cell into trigylcerides (via lipoprotein lipase- HSL), inhibiting the lipolysis of triglycerides into fatty acids and glycerol back into the circulation

Question 5

What happens to fatty acid metabolism in insulin resistance?

Answer 5

If there is resistance to insulin- there is more fatty acid degradation (because IRS promotes lipoprotein lipase activation and inhibition of hormone sensitive lipase- HSL)

Question 6

For example with VLDL what happens?

Answer 6

When VLDL passes LPL in circulation (lipoprotein lipase, found in vascular endothelium), this lipase will take out some TG from the lipoprotein → becomes Intermediate LDL (IDL)
➢ This is then further broken down to become LDL (contains even less TG)

80% of this LDL will be transported back into the liver
20% will stay in the circulation can cause deposition
➢ Increased lipid levels in circulation will increase the risk of deposition and atherosclerotic fat

Question 7

What happens in lipoprotein uptake?

Answer 7

• Will bind to the LDL receptor, and goes into cell by endocytosis
• LDL becomes degraded and used by the liver for cholesterol storage.
  If there is an overload of fatty acids in the liver during fasting state, it will leak out more FA (VLDL) into the circulation.

Question 8

What happens in reverse cholesterol transport?

Answer 8

a multi-step process resulting in the net movement of cholesterol from peripheral tissues back to the liver via the plasma.
- Another Apoprotein on VLDL, Apo-A1, can be given up and will bind onto nascent HDL (can also be secreted in gut and liver)
Nascent HDL can take up unesterified cholesterol in tissue and combine it with phospholipid within the HDL
➢ Becomes a mature HDL particle
Lecithin= cholesterol acetyltransferase

This leads to the production of GOOD CHOLESTEROL

Question 9

What does cholesterol ester do?

Answer 9

➢ Acts on various lipoproteins
➢ Can transfer TG and cholesterol from one molecule to the other allows interplay between different lipoproteins

Question 10

What is the role of the liver?

Answer 10

Hepatic lipase takes up TG back into the liver, if CETP removes TG that has been taken up by HDL. This mops up bad cholesterol back into the liver.
➢ HDL becomes smaller, and can go into muscles for oxidation to be used for energy.

When too much TG has been taken up by the liver via hepatic lipase, it releases small dense LDL
➢ This greatly increases the risk of atherosclerosis
➢ High proportion of this lipoprotein found in T2DM

Question 11

What happens in insulin resistance versus insufficient insulin?

Answer 11

In insulin resistance:
- CETP , hepatic lipase are stimulated
➢ Hypertriglyceridaemia, as CETP promotes movement of TG from one to another tends to go the WRONG way (make lipoproteins lower in density).
Reduced insulin action:
- Inhibits HSL (hormone sensitive lipase)
- Inhibits hepatic VLDL production
- Stimulates lipoprotein lipase
• However, insulin resistance causes hormone sensitive lipase to be activated. Thus, high levels of free fatty acids are released by the adipose cells.

Question 12

What is fatty liver disease? Causes and characteristics.

Answer 12

Fat deposition in the liver when no other causes can be found. It is a chronic liver disease is related to the increase in the incidence of obesity and T2DM in population
- Less common causes are medicines, antiretroviral drugs, and rapid weight loss
• Steatosis
• Mixed inflammatory cellular infiltration
• Degeneration and hepatocyte necrosis
• Nuclear glycogen, Mallory bodies (damaged intermediate filaments within the hepatocytes) and fibrosis

Question 13

How does NAFLD fit into insulin resistance and diabetes?

Answer 13

T2DM patients, the incidence of steatosis is up to 50%. It goes up to 76-90% in obese population.
➢ Insulin resistance is an important predicting factor for NAFLD.
➢ NAFLD develops in the majority of patients who exhibit morbid obesity and diabetes

Question 14

What is the role of ceramides?

Answer 14

Ceramides and T2DM:
- Ceramides are a family of sphingoloid molecules with important structural and functional roles in cell signaling, cell differention, proliferation and apoptosis.
- Ceramides accumulate within tissues and inhibit insulin action and subsequent glucose uptake
- Meditators of lipotoxicity
- Induce inflammation through activation of TNF-alpha
- Facilitate inflammatory signaling pathways which further contribute to the state of insulin resistance
- Although, not much is known about their mechanisms
Ceramides are elevated in patients with T2DM. However, this is just an observation, and relationship may not be directly causal, or just an association. They are also a major component of ectopic fat in obese individuals.

Study:

• 13 patients (10 female) who had a BMI >47kg/m2 underwent gastric bypass
• Showed that plasma ceramide subspecies was reduced, and improvement in insulin sensitivity.

Question 15

How is hormone sensitive lipase activated?

Answer 15

• Hormone-sensitive lipase is activated by glucagon (fasting) or epinephrine (exercise). Therefore, fat in adipose tissue is hydrolyzed to give glycerol and fatty acids during both fasting and exercise.
• The fatty acids can be used directly as an energy source by most tissues with mitochondria, excluding the brain
However these hormones inhibit lipoprotein lipase

Question 16

What happens in starvation?

Answer 16

• During prolonged srarvation, the fatty acids can also be converted to ketone bodies in the liver

Question 17

Overall what happens in insulin resistance?

Answer 17

increased free fatty-acid release from insulin-resistant fat cells. The increased flux of free fatty acids into the liver in the presence of adequate glycogen stores promotes triglyceride production, which in turn stimulates the secretion of apolipoprotein B (ApoB) and VLDL cholesterol.

Question 18

Decrease the level of HDL cholesterol and increase the concentration of small dense LDL-cholesterol particles how?

Answer 18

The increased number of VLDL cholesterol particles and increased plasma triglyceride levels via several processes: -VLDL-transported triglyceride is exchanged for HDL-transported cholesteryl ester through the action of the chol- esteryl ester transfer protein (CETP), which results in increased amounts of both athero- genic cholesterol-rich VLDL remnant particles and triglyceride-rich, cholesterol-depleted HDL particles.

• The triglyceride-enriched HDL is subsequently hydrolyzed by hepatic lipase or lipoprotein lipase; ApoA-I dissociates from the reduced-size HDL,
• The increased concentration of small dense LDL-cholesterol particles is explained by a similar lipid exchange. Increased levels of VLDL-transported triglyceride enable CETP to promote the transfer of triglyceride into LDL in exchange for LDL-transported cholesteryl ester. The triglyceride-rich LDL undergoes hydrolysis by hepatic lipase or lipo- protein lipase, which results in lipid-depleted small dense LDL particles (Figure 1)

Question 19

What does adiponectin do?

Answer 19

positive correlation between the levels of HDL chol- esterol and adiponectin

Question 20

What is the thrifty gene phenotype?

Answer 20

T2DM trait to environment that has changed when it was advantageous to put on weight quickly in times of abundance, especially for child bearing women, to then survive famines
Now in modern times, genetic predisposition to excess calories and diabetes.
James Neels who came up with it when it was clear that obesity had a genetic component

Question 21

What are problems with the thrift gene hypothesis?

Answer 21

• today’s populations have no history of famine
• evidence that hunter gatherers did get fat in between famines
• no evidence that fat people survived famines any better than thin people. In fact those that didn’t survive famine were the young/old

Question 22

What is the Barker hypothesis?

Answer 22

BARKER HYPOTHESIS: poor in utero environment indicates a harsh post natal one and so foetus undergoes METABOLLIC changes to prepare itself. If foetus then grows up in plentiful environment then these changes are detrimental leading to obesity and diabetes. The foetus in adult life would be thrifty

Question 23

What does the Barker hypothesis depend on?

Answer 23

Foetuses plastic and susceptible to environmental changes. The crucial window continues into the immediate post natal period.

Question 24

What is the el Nino hypothesis?

Answer 24

Susceptibility to central adiposity has evolved to protect against a variable energy supply.
A chronic energy deficiency favours central fat.
May also be beneficial for energy saving in terms of thermogenesis.S. Asians have higher visceral fat because in the absence of weight gain (previous starvation) chronic energy deficiency lead to increased allocation to this fat depot. – S Asians exposed to high levels of heat stress, famine and agiculture is dependent on monsoon cycles.

Question 25

What is the variable energy hypothesis?

Answer 25

In contrast, deep-lying fat depots are more appropriate for funding the immediate demands of the immune response and local tissue-specific variability therein

Question 26

What is the mitochondrial efficiency hypothesis?

Answer 26

Energy efficient mitochondria favoured heat and starvation, this favours energy storage not wastage which is disadvantageous now. Mitochondria are our main source of energy – generate ATP

Question 27

What are key studies in the foetus hypothesis?

Answer 27

Glucose tolerance – offspring of Dutch famine (Ravellli 1998) looked at offspring born before the famine, if they had a late, mid or early gestation when famine started or if they were born after the famine. Looked at their glucose levels after born. This showed that people born before famine had lowest glucose, - exposed to famine late in preg had greated inc in glucose – but all babies born in famine had higher blood glucose.

Leningrad siege study: Intrauterine malnutrition was not associated with glucose intolerance, dyslipidaemia, hypertension, CVD in adulthood. Subjects exposed to malnutrion showed eveidence of endothelial dysfunction and had a stronger influence of obesity on blood pressure.

2) Chinese famine study. These babies had a three times increased risk of METABOLLIC syndrome especially if they had then grown up in a western diet .

Question 28

What mechanisms might be taking place?

Answer 28

Epigenetic ones, The programming that occurs in different times for different cells may be due to IMPRINTING . Some of the transmissible changes can be seen across generations

Question 29

Another key study that in the Barker Hypothesis?

Answer 29

Hertfordshire men. Looked at men with IGT or diabetes and their birth weight corrected for BMI. Showed that light birthweight = higher risk of diabetes/igt

Question 30

What supports the hypothesis?

Answer 30

Glucocorticoids in utero lead to low birth weights

Question 31

What is the shape of birth distibution in terms of metabolic risk?

Answer 31

U SHAPED CURVE WITH BIRTH WEIGHT. Small baby through IU environment and a large baby through genes. Breast fed at the bottom of the curve as difficult to over feed baby and baby learns to regulate its own appetite more. The LONGER the baby was breast fed, the lower the incidence of METABOLLIC syndrome. BAVARIAN STUDY

Question 32

What evidence is there from gestational DM mothers?

Answer 32

There is also a high prevalence of T2DM in children of women who have gestational diabetes. The birthweight of babies born to diabetic mothers is shifter 300-500 grams right on the curve.
Growth in uterine correlates with foetal insulin (when calorie restricted, foetal splanchnic development is compromised to save energy for brain development).
have reduced post prandial thermogenesis, subtle abnormalities in intermediate metabolism, increased prevalence of T2DM, PCOS and more go on to develop HT.

Question 33

What is thought to be one of the mechanisms causing thriftiness?

Answer 33

11bHSD2 saturated and more steroids crossing the placenta

Question 34

What are the three mechanisms of foetal programming?

Answer 34

Fetal protein use
Fetal insulin hypothesis
Glucocorticoid programming

Question 35

What evidence that insulin is involved in foetal programming?

Answer 35

Small for gestational age babies have less insulin. But a french study showed these SGA babies were insulin deficient aged 22 but other studies found insulin resistance

Question 36

What else was found in SGA babies concerning adipose tissue

Answer 36

SGA babies deficient in fat and muscle tissue. Catch up associated with excess adipose tissue

Question 37

What is another factor when considering in utero environment vs genetics

Answer 37

Much higher concordance rate for both identical and non-identical twins for T2DM than T1DM

Question 38

Key study for Barker hypothesis and DM

Answer 38

Relative risk of type 2
diabetes
US Nurses’ Study (n=69,526)

Question 39

How may gestational dm be beneficial for thriftiness?

Answer 39

Lean body mass is positively proportional to resting energy expenditure, GDM have reduced post prandial thermogenesis. Women before and after GDM have reduced insulin sensitive and PPT
22% of the extra energy required for pregnancy
This may form the benefit of the predisposition to NIDDM as it helps conserve energy
The higher [Tg] in the diabetic mother is associated with fetal weight gain sufficient to increase the chances of survival