insulin and other hypoglycaemic agents

Question 1

Why is it necessary to have rigid blood glucose control?

Answer 1

• obligatory energy source for the brain

- tightly regulated to keep blood glucose levels within normal range

Question 2

What are the main glucose regulating hormones?

Answer 2

Insulin - β / B cells
Glucagon - α / A cells
Somatostatin - D cells

Question 3

What are some supplementary hormones that regulate glucose?

Answer 3

adrenalin - adrenal medulla
glucocorticoids - adrenal cortex
growth hormone - pituitary

Question 4

How is insulin formed?

Answer 4

Proteolytically cleaved –> mature insulin and C-peptide

Question 5

What stimulates insulin release?

Answer 5

increase glucose - hyperglycaemia
amino acid and fatty acids
peptide gut hormones - incretins - GLP1

Question 6

What are the main areas that insulin targets?

Answer 6

liver, muscle and adipose tissue

Question 7

What are the metabolic targets of insulin?

Answer 7

1. CHO
2. Fat
3. Protein

Question 8

What is the insulin receptor (Ins-R)?

Answer 8

receptor tyrosine kinase (RTK)

Question 9

What happens when insulin binds to Ins-R?

Answer 9

dimerisation and auto-phosphorylation

Question 10

What substrate does Ins-R phosphorylates?

Answer 10

IRS-1

Question 11

what does phosphorylated IRS-1 activate?

Answer 11

PI3K and Ras-MAPK pathway

Question 12

What does the PI3K and AKT pathway activate?

Answer 12

1. GLUT4 transporter –> glucose into cells
2. glycogen synthase
3. cell growth

Question 13

What is Diabetes Mellitus?

Answer 13

metabolic disorders characterised by HYPERGLYCAEMIA

Question 14

What is chronic metabolic disorders caused by?

Answer 14

relative or absolute insulin deficiency

Question 15

What is type 1 diabetes?

Answer 15

ABSOLUTE insulin deficiency

auto-immune destruction of β cells

Question 16

What is type 2 diabetes?

Answer 16

RELATIVE insulin deficiency
peripheral resistance to ‘normal’ insulin levels
subsequent progressive decrease in β cell function/mass

Question 17

What are some complications of diabetes?

Answer 17

acute

chronic

Question 18

What are some acute complications of diabetes?

Answer 18

diabetic ketoacidosis (DKA)
insufficient/absent insulin in IDDM

Question 19

What does insufficient/absent insulin in IDDM cause?

Answer 19

fats used for energy = ketones (strong acids)
decrease pH
dehydration

Question 20

What are the chronic complications of diabetes?

Answer 20

macrovascular –> cardiovascular risk

microvascular –> huge burden/costs

Question 21

What are ways of treating type 1 diabetes?

Answer 21

recapitulate normal pattern of pancreatic insulin secretion - insulin, lifestyle and monitoring

Question 22

How is insulin administered?

Answer 22

subcutaneously

injection sites must be rotated

Question 23

What is the pharmacokinetics of insulin?

Answer 23

absorption affected by formulation, blood flow, scars
short-lived effects
enzymatically inactivated in cells after uptake

Question 24

What are ways to mimic normal insulin levels?

Answer 24

ideal
basal-bolus regimen
insulin pump

Question 25

What is ideal mimicking technique?

Answer 25

constant basal insulin production | + post-prandial insulin surges

Question 26

What is the basal-bolus regimen?

Answer 26

long acting insulin at bedtime = basal prandial rapid-acting insulin = bolus 4 or more injections/day

Question 27

What is the insulin pump technique?

Answer 27

basal infusion + patient-activated boluses | improved glycaemic control

Question 28

What are some side-effects of insulin therapy for diabetes type 1?

Answer 28

hypoglycaemia weight gain injection site

Question 29

What is the main goal of treatment of type 2 diabetes?

Answer 29

lower blood glucose levels --> prevents microvascular complications individualised treatments

Question 30

What are the treatments for type 2 diabetes?

Answer 30

lifestyle oral hypoglycaemic agents insulin

Question 31

What are some hypoglycaemic drugs?

Answer 31

``` metformin sulfonylureas incretin-based therapies dapagliflozin (SGLT2 inhibitor) acarbose (intestinal α-glucosidase inhibitor) pioglitazone (thiazolidinediones) ```

Question 32

What is the mechanism of metformin?

Answer 32

mainly decrease hepatic gluconeogenesis | may cause GLP1 release

Question 33

What are the effects/benefits of metformin?

Answer 33

no hypoglycaemia improved lipid profile probable anti-cancer properties

Question 34

What is the pharmacokinetics of metformin?

Answer 34

40-60% orally bioavailable excreted unchanged in urine | decrease drug clearance with other renally excreted drugs

Question 35

What are some side-effects/caution of metformin?

Answer 35

GI - transient anorexia + diarrhoea vitamin B12 deficiency lactic acidosis C/I in severe renal failure + severe hepatic impairment

Question 36

What is the mechanism of sulfonylureas?

Answer 36

insulin secretagogues

Question 37

What is the mechanism of insulin secretagogues?

Answer 37

block SU receptor (SUR1) / K+ channel on β cells --> Ca2+ influx activates insulin secretion

Question 38

What is the pharmacokinetics of sulfonylureas?

Answer 38

albumin binding, hepatic metabolism, renal excretion | drug interactions --> increase hypoglycaemic effect

Question 39

What is the benefits of sulfonylureas?

Answer 39

robust glucose decrease in early stages of type 2 diabetes | cheap and effective

Question 40

What are some side-effects/cautions of sulfonylureas?

Answer 40

hypoglycaemia weight gain C/I in liver failure - hepatic metabolism

Question 41

What is the incretin effect?

Answer 41

oral glucose induces a much greater insulin response than an equivalent IV glucose dose

Question 42

What are incretins?

Answer 42

gut peptides that increase insulin release after food

Question 43

What are some incretin-based therapies?

Answer 43

GLP1 receptor agonists DDP-4 inhibitors GIP receptor agonist

Question 44

Why is DDP-4 inhibitors used?

Answer 44

blocks DDP-4 enzyme which inactivates GLP-1

Question 45

What is GLP1 used for?

Answer 45

stimulates insulin release | inhibits glucagon release

Question 46

What does SGLT2 inhibitors use?

Answer 46

inhibit sodium glucose co-transporter 2 block glucose reabsorption in proximal tubule --> lost in urine S/E = urinary tract infections

Question 47

What is the use of intestinal α-Glucosidase inhibitors?

Answer 47

competitive inhibition of maltose --> glucose | S/E = bloating, flatuelence, diarrhoea

Question 48

What is the use of Thiazolidinediones?

Answer 48

PPARγ agonist - activate gene transcription | increase insulin sensitivity