PBL 4: Genes and Jeans

Question 1

What are the 2 main genes involved in type 2 diabetes?

Answer 1

PPARG - peroxisome proliferator activated receptor gamma

GKRP - glucokinase regulatory protein

Question 2

What is the role of GKRP?

Answer 2

When glucose levels are high -> phosphorylates G-6-P so that there is glucose uptake into cells
Inactivates glucokinase when glucose levels are low and there is low insulin inhibiting glycolysis

Question 3

What happens if there is a mutation in GKRP?

Answer 3

Glucokinase and glucose-6-phosphate not inhibited when low insulin and low glucose so can result in type 2 diabetes

Question 4

What is the role of PPARG?

Answer 4

Transcriptional regulator of adipocyte differentiation and so can change adipokine regulation as well
Increases free fatty acid levels

Question 5

What causes type 2 diabetes?

Answer 5

Insufficient production of insulin and insulin resistance

Question 6

How is obesity linked to type 2 diabetes?

Answer 6

• resistance to insulin through endocytosis and degradation of insulin receptors/lowering the number of receptors (in the liver, skeletal muscle and adipose tissue)
• hyperlipidemia as increased free fatty acid levels
• pancreas becomes exhausted from secreting so much insulin so begins to become damaged/fail
• INTRINSIC factors: mitochondrial dysfunction due to free radical damage/oxidative stress/ER stress

Question 7

How is obesity determined in diabetics?

Answer 7

BMI - not ideal for those with increased muscle mass as BMI will be high but not obese
Waist circumference is a better method as measures your visceral fat which builds up around the waistline and is more pathological

Question 8

What are the BMI ranges?

Answer 8

<18 is underweight
20-25 is normal
>25 is overweight
> 30 is obese 
> 40 is morbidly obese

Question 9

What are the main drugs for type 2 diabetes?

Answer 9

Metformin
Pioglitazone
Sulfonylurea

Others:
Sitagliptin

Question 10

What does metformin do?

Answer 10

1st line

• inhibits gluconeogenesis by inhibiting complex 1 in mitochondria and activating AMPK
• Increases glucose uptake in muscle via GLUT4

Question 11

Why is metformin a preferred drug?

Answer 11

Low risk of becoming hypoglycaemic

Question 12

What does pioglitazone do?

Answer 12

Thiazolidinedione (TZD)
Increases glucose uptake by acting on PPARG (TF)
Works on adipose tissue to reduce FA responsible for increasing glucose

Question 13

What is the disadvantage to pioglitazone?

Answer 13

Weight gain as less fatty acids in adipose tissue used to make glucose and get increase of FFA deposited there

Question 14

What does sulfonylureas do?

Answer 14

Stimulates the closure of potassium channels in the pancreas beta cells -> depolarisation so you get an increase in insulin release

Question 15

What drugs have a similar action to sulfonylureas?

Answer 15

Meglitdines

Gliclazide

Question 16

What does sitagliptin do?

Answer 16

DPP4 inhibitor so increases GLP-1 levels which increases insulin secretion and reduces glucose levels

Question 17

What treatment is there for obesity?

Answer 17

Drugs - orlistat

Surgery - restrictive gastric banding/malabsorptive Gastirc bypass or duodenal switch

Question 18

What is gastric banding?

Answer 18

Inflatable adjustable band placed around the top of the stomach to reduce and slow down food consumption so only a small amount of food is allowed in at one time, induces satiety

Question 19

What is gastric bypass?

Answer 19

Stomach is made smaller by joining together the upper part and lower part with the small intestine
Means less food can be taken in and induces satiety as greater gastric stretch after little food intake
Causes the patient to be full and vomit as no space for high food intake

Question 20

When would surgical procedures for obesity be used?

Answer 20

In very severe chronic morbidly obese individuals where their obesity is having severe impacts on other parts of their health

• diet control and exercise is not working over a long period of time and effort
• drugs orlistat and others are showing no effect