Type 2 Diabetes

Question 1

Which diabetes is more common

Answer 1

T2d - 90% of cases

Question 2

What parameters looked at for diagnosis

Answer 2

Fasting plasma glucose

And hbac1 (avg bgc over 2-3 months)

Question 3

Why is it called a complex disease

Answer 3

Many genetic factors and environmental factors

Question 4

How many validated snp variants which increase risk slightly

Answer 4

3 but around 400 found altogether

Question 5

Give an example of a validated variant

Answer 5

PPARG / y - allowing insulin sensitivity usually and reg of adipogenesis

Question 6

Did the study find there were gene x diet interactions in t2d

Answer 6

No they were independent risk factors which had no additive effect together

Question 7

Which gene pathway polygenic risk score was highest

Answer 7

B cell dysfunction

Question 8

Which had bigger impact on risk

Answer 8

Genes around 50% vs 38% for diet

Question 9

Did poor diet increase risk

Answer 9

Yes by 30%

Question 10

Which twin defect is in t2d pathogenesis

Answer 10

Insulin resistance and b cell dysfunction

Question 11

What imbalance is there

Answer 11

More resistance than sensitivity. So more insulin can’t compensate for the resistance = BGC high

Question 12

What does insulin usually do

Answer 12

Glycogenesis in liver and muscle

Decrease gluconeogenesis

Reduce fat breakdown/lipolysis from adipose tissue (which increases fat flow into liver)

Question 13

What does insulin sensitivity of liver cause it to form

Answer 13

De novo lipogenesis (insulin activates tf - see nafld)

Question 14

What sort of issues seen in insulin resistance eg in muscle

Answer 14

Glut4 imapired so glucose can’t form glycogen

Also impaired glycogen synthase

Question 15

What has evidence found about exercise and glut4

Answer 15

It improves translocation of glut4 = less glucose more glycogen

Question 16

Which 2 toxicities impair b cells

Answer 16

Lip toxicity and Glucotoxicity

Question 17

What do they both induce when high in blood

Answer 17

Induce b cell apoptosis

As well as decrease insulin expression in response to glucose

Question 18

How does glucotoxicity affect the tf and repressors for insulin expression

Answer 18

Oxidative stress / ros generation

Question 19

Why is lipotoxicity dependant on glucose

Answer 19

Because need glucose and insulin both to induce de novo lipogenesis

Question 20

Why can’t the fa be oxidised after lipogenesis and so what forms instead

Answer 20

Malonyl coa blocks cpt1

More vldl-TG release = issues on pancreas

Question 21

Explain the twin cycle pathogenesis

Answer 21

Calorie excess and decreased insulin sensitivity eg from genetics

Need more insulin release from pancreas because more glucose

Insulin and the high BGC will cause liver de novo lipogenesis

Lipid fat accumulates

Lipid becomes insulin resistant from the fat

Glucose can’t be controlled = no glycogenesis

Plus more vldl-tg release

Pancreatic fat builds and glucose = gluco and lipotoxicity

Reduced insulin response to glucose

Question 22

What fa found in vldl which causes pancreatic b dysfunction by de differentiation

Answer 22

Palmitate / palmitic acid

Question 23

What by products of de novo lipogenesis blocks IRS-1 signalling I.e causing liver insulin resistance

Answer 23

Diacglycerol

Question 24

What could be some reasons for IR in skeletal muscle which is the smoking gun along with calorie excess

Answer 24

History or t2d, obesity, hypertension and ageing

Question 25

Why would obesity and mitochondrial genetic defects cause muscle IR

Answer 25

Build up of fats in myocytes (no oxidation by mt)

Fat in myocytes blocks glycogen synthase activity

Question 26

What improves muscle sensitivity meaning less insulin needs released to have detrimental effects in liver

Answer 26

Exercise = glut4 translocation

Question 27

What other treatments can return normal insulin

Answer 27

Calorie deficits
Gastric banding / Bari attic surgery
Insulin sensitivity drugs

Question 28

What have intervention studies found about calorie deficits/ strict reduction in diet

Answer 28

Improves sensitivity in b cell, reduces glucose and triacylglycerol

Mainly for those who have had diabetes less than 4 years

Question 29

What is the evidence at a certain point b cell dysfunction becomes irreversible

Answer 29

Only 50% of people with diabetes over 8 years actually had lowered glucose after intervention

Question 30

What level of kg weight loss has best remission levels at 24 months

Answer 30

15kg or more

Question 31

Why does weight loss need maintained

Answer 31

Can relapse because it isn’t a cure

Question 32

What was seen in relapsers who gained weight

Answer 32

Had increased vldl palmitic acid and b cell function response to insulin declined again
Also more intrapancreatic fat

Question 33

What is the personal fat threshold hypothesis

Answer 33

People with no excess fat still develop t2d as a whole popn we have more fat than our ancestors

It depends on how well personally someone can store fat safely before it travels to visceral organs eg the pancreas