Lipid metabolism, obesity and diabetes

Question 1

What is the role of HDL?

Answer 1

Picks up excess cholesterol from the periphery and transports it to liver

Question 2

Describe the uptake of cholesterol by the intestinal epithelium.

Answer 2

Cholesterol entering the intestines will come from the diet and bile

Cholesterol will be solubilised in mixed micelles

It is then transported across the intestinal epithelium by NPC1L1 (this is the main determinant of cholesterol transport)

Question 3

What is the main component of mixed micelles?

Answer 3

Bile acids

Question 4

Where are bile acids reabsorbed?

Answer 4

Terminal ileum

Question 5

What controls the amount of cholesterol reabsorbed into the intestine?

Answer 5

Balance of 2 enzymes: NPC1L1 (transports cholesterol OUT of the intestinal lumen) and ABC G5/G8 (transports cholesterol back INTO the intestinal lumen)

Question 6

What are the two fates of cholesterol that is either produced by or transported to the liver?

Answer 6

Hydroxylation by 7 alpha-hydroxylase to produce bile acids

Esterification by ACAT to produce cholesteryl ester which is incorporated into VLDLs along with triglycerides and ApoB

Question 7

What is the role of CETP in cholesterol metabolism?

Answer 7

Cholesterol Ester Transfer Protein:

Mediates the movement of cholesterol from HDL to VLDL

Mediates the movement of triglycerides from VLDL to HDL

Question 8

Describe the transport and metabolism of triglycerides.

Answer 8

Triglycerides from fatty foods are hydrolysed to fatty acids, absorbed, and resynthesized into triglycerides which are transported by chylomicrons into the plasma

Chylomicrons are hydrolysed by lipoprotein lipase into free fatty acids

Some free fatty acids are taken up by the liver, and some by adipose tissue

The liver resynthesizes fatty acids into triglycerides and packages them into VLDLs

VLDLs are acted upon by lipoprotein lipase to liberate free fatty acids

Question 9

MOA of statin

Answer 9

HMG CoA inhibitor

Question 10

Recall 3 clinical signs of hypercholesterolaemia

Answer 10

Xanthalasma
Arcus
Tendon xanthoma

Question 11

What is an atheroma made of

Answer 11

Necrotic core (dead macrophages) of cholesterol crystals surrounded by foam cells (macrophages), all topped with a fibrous cap

Question 12

Types of primary Hypercholesterolaemia

Answer 12

 Familial hypercholesterolaemia (FH) – AD (or rarely, AR) mutation LDL-R, apoB or PCSK9-FH from AD-inherited gain-mutation in PCSK- increased LDL-R degradation
 Polygenic hypercholesterolaemia – NPC1L1, HMG-CoA Reductase, CYP7A1 polymorphisms
 Familial hyper--lipoproteinaemia – CETP deficiency
 Phytosterolaemia

Question 13

Types of bariatric surgery

Answer 13

Gastric banding, bypass, biliopancreatic bypass

Question 14

Types of bariatric surgery

Answer 14

Gastric banding, bypass, biliopancreatic bypass

Question 15

Options for statin-intolerant patients

Answer 15

o	Ezetemibe (reduced absorption – block NPC1L1)
o	Plasma exchange (where available)
o	Evolocumab (PCSK9 monoclonal antibody)

Question 16

What is the legacy effect

Answer 16

Continuous beneficial effect of the intensive control on disease outcomes or complications even after a long duration of cessation of the intervention
i.e. having good blood glucose control, even for a short while, can improve later mortality

Question 17

How many years to see significant glucose control effects in Dm

Answer 17

It takes 15 years of good glucose control in newly diagnosed T2DM before you see real benefits to health

Question 18

What did accord find out about sudden aggressive control of glucose in DM

Answer 18

Aggressively controlling the blood glucose of people who have had poor control for decades leads to reduced complications but increased mortality

CAREFUL management of previously badly controlled GLUCOSE
i.e. no rapid correction in those that had poor control as increases mortality

Question 19

Should you aggressively treat BP and lipids ?

Answer 19

Aggressive management of blood pressure and lipids improves survival

Question 20

Action of SGLT2 inhibitors

Answer 20

SGLT2 inhibitors- reduced glucose re-uptake in kidneys

Question 21

Action of GLP1 analogues

Answer 21

GLP-1 -secreted from gut L-cells and signals pancreas to make insulin

Question 22

Action of DPP4 inhibitor (Gliptin)

Answer 22

Increase incretin(GLP) levels - by inibitoing enzyme that degrades them

Question 23

Action of Sulphonylureas

Answer 23

Increase insulin secretion- can cause hypo

Question 24

Guidelines for treatment of T2DM

Answer 24

DIABETES can be treated with METFORMIN and either SGLT-2 or GLP-1 analogues

o (1) Metformin

o (2) Dual therapy:
 1st: Metformin + Sulphonylureas (glibenclamide)
 1st: Metformin + Thiazolidinedione (pioglitazone)
 1st: Metformin + Gliptins (DPP4 inhibitor; i.e. sitagliptin)
 2nd: Metformin + SGLT-2i (empagliflozin)

o (3) Triple therapy:
 1st: Metformin + Sulphonylureas + Gliptin
 1st: Metformin + Sulphonylurea + Thiazolidinedione
 1st: Metformin + Sulphonylurea/Thiazolidinedione + SGLT-2 inhibitors
 2nd: Insulin

o (4) Metformin + sulphonylurea + GLP-1 analogue (liraglutide)