PBL 4 - Diabetes T2

Question 1

What chemical process is measured by Hba1c level? (ii) What does
Hba1c reflect? [

Answer 1

Glycation of proteins (in this case: haemoglobin) [1/2]
(ii) Elevated glucose levels over an extended period of time OR poor control of
blood glucose [

Question 2

Briefly state what are the mode of action of the drugs Metformin and
Sitagliptin? How are they used in the management of type 2 diabetes?

Answer 2

Metformin: inhibits hepatic gluconeogenesis – reducing blood glucose levels
Sitagliptin: inhibits the breakdown of GLP1 – this in turn increases insulin and
decreases glucagon secretion from the pancreas

Question 3

) What tissue is the source of (i) Leptin (ii) GLP-1? What changes cause an
increase of each of these hormones?

Answer 3

(i) Leptin:
Source: Adipocytes (OR fat cells OR white adipose tissue, NOT fat) [1/2]
Level increased by an increase in adipose tissue (OR body fat mass) [1/2]
(ii) GLP-1:
Source: Intestinal L cells in mucosa of distal ileum & in colon [1/2]
Level increased by a glucose or fat rich meal

Question 4

Why might using insulin as a therapy not work in this case?

Answer 4

Potential of insulin resistant tissues causing the type 2 diabetes – especially due to
the high weight.

Question 5

What is a BMI of 28 classified as? What is the BMI range for someone
considered mildly obese? In the scenario, why does the GP take time to measure
Mr Creosote’s waistline?

Answer 5

28 = high end of overweight [1/2] mildly obese = BMI from 30 to 34.9 [1/2]
Waistline measurement is actually better correlated with T2D than BMI. [1]

Question 6

Name four hormones triggering a feeling of satiety? [2]

Answer 6

CCK, insulin, leptin, PYY, GLP-1 – [1/2 for any of]

Question 7

Risk factors for T2D

Answer 7

Obesity
Family history
Age
Ethnicity

Question 8

Why does obesity increase risk of diabetes

Answer 8

 Accumulation of lipids + their metabolites e.g. FFA cause chronic inflammation + altered adipokine levels –> CD 36 increasing its uptake into cells –> Excess in cells affects signalling pathways–> Insulin resistance

 Hyperinsulinemia occurs to try and overcome the insulin resistance –> increases lipid synthesis –> exacerbates problem

Question 9

Why do some people have insulin resistance but not develop diabetes

Answer 9

islet compensation e.g. increase in size/number

Question 10

How to diagnose T2D

Answer 10

Glucose tolerance test

Question 11

Values for fasting, random and HbA1c to diagnose T2D

Answer 11

Fasting - >7mmol/l
Random - >11mmol/l
HbA1c - >48mmol/l

Question 12

Symptoms of T2D

Answer 12

Polyuria
Polyphagia
Thirst
Peripheral neuropathy

Question 13

Complications of T2D

Answer 13

Neuropathies, nephropathies

iscaemic heart disease/stroke –> atherosclerosis, dyslipidaemia

Question 14

Cause of T2D

Answer 14

Insufficient insulin production + insulin resistance
At the insulin receptor –> IRS is not longer phosphorylated by tyrosine –> Threonine/serine is phosphorylated instead –> No P13K/Akt activation
Impaired islet compensation

Question 15

Effect of giving insulin to T2D patients

Answer 15

hyperglycemia –> glutotoxicity –> damages Beta cells –> even less insulin secreted hence insulin may be useful

• Insulin may not be effective if receptors faulty and saturated already.
• Can cause lipogenesis

Question 16

Treatment of T2D

Answer 16

Metformin
Sitaglipin 
Pioglitazone
Sulfonylureas
Obesity treatments

Question 17

Metformin

Answer 17

Biguanide
Activation of AMPK
1) Suppresses hepatic gluconeogenesis
2) Increased peripheral uptake of glucose via GLUT
3) Increased GLP1 –> Stimulates insulin and inhibits glucagon + promotes satiety
Increases insulin sensitivity

Question 18

Sitaglipin

Answer 18

Incretin
Inhibits DDP-4 –> normally breaks down GLP-1 –> Increase insulin secretion + suppresses glucagon release
Increase POMC and decrease AGRP/NPY

Question 19

Pioglitazone

Answer 19

TZD
Stimulates PPARG
= Increases sensitivity for insulin uptake in muscles/adipocytes
2) reduce insulin resistance 3) decrease hepatic gluconeogenesis
4) Reduce level of glucose in blood

Question 20

Sulfonylureas

Answer 20

Act to stimulate insulin release by inhibiting K+ channels.

Question 21

Orlistat

Answer 21

Lipase inhibitor

Question 22

Obesity medication

Answer 22

Phentermine

Orlistat

Question 23

When surgery for overweight pts

Answer 23

Morbidly obese >40
or obese >30 with problem
Gastric banding - restrictive
Biliopancreatic diversion - absorptive

Question 24

Centre for appetite regulation

Answer 24

Arcuate nucleus in hypothalamus

Question 25

Orexigenic

Answer 25

NPY
AgRP
MHC
Ghrelin

Question 26

Anorexigenic

Answer 26

POMC
CART
a-MSH (secreted by POMC)
Insulin, leptin and CCK activate POMC neurones (without insulin it is not inhibited) 
GLP-1 and PYY

Question 27

Genes affecting diabetes

Answer 27

GKRP

PPARG

Question 28

GKRP

Answer 28

Glucokinase regulatory protein

• Protein produced that binds and moves glucokinase controlling activity and intracellular location based on insulin.
• In high levels of glucose, GKRP allows GK to enter cytoplasm and uptake glucose into hepatocytes to lower glucose.

Question 29

PPARG

Answer 29

peroxisome proliferative-activated receptor gamma
• Receptor that regulates fatty acid storage and glucose metabolism
• Genes activated by PPARG stimulate lipid uptake and adipogenesis by fat cells
• PPARG is regulator of adipocyte differentiation

Question 30

Ancanthosis Nigricans

Answer 30

Marker for hyperinsulinaemia
Dark patches of skin
Insulin binds and stimulates receptors (IGFL) on keratinocytes and dermal fibroblasts promoting its proliferation

Question 31

Hb1Ac

Answer 31

• Measures glycosylation of haemoglobin, proportion of glycosylation can indicate level of glucose in the last 3 months since RBCs have life span of 120 days