Drugs and Their Targets in T2DM

Question 1

Mechanisms of actions of T2DM therapies?

Answer 1

1. Increase secretion of insulin (insulin DEPENDENT action):
   • Sulphonylureas
   • Incretin mimetics (AKA megaglitinides)
   • DDP-4 inhibitors
2. Decreasing insulin resistance and reducing hepatic glucose output (insulin DEPENDENT action):
   • Biguanides
   • Thiazolidinediones (AKA glitazones)
3. Slowing glucose absorption from GI tract (insulin INDEPENDENT action):
   • α-glucosidase inhibitors
4. Enhancing glucose excretion by the kidney (insulin INDEPENDENT action):
   • SGLT2 (sodium glucose type-2) inhibitors

Question 2

What is cellular energy status linked to?

Answer 2

Linked to insulin secretion in the pancreatic β-cell

Question 3

Mechanism of insulin secretion?

Answer 3

1. Elevation of BG conc.
2. Increased diffusion of glutamate into the β-cell by facilitated transport (GLUT2)
3. Phosphorylation of glucose by glucokinase
4. Glycolysis of glucose-6-phosphate in mitochondria yielding ATP
5. Increased ATP/ATP ratio within cell closes ATP-sensitive K+ channels (KATP) channels causing membrane depolarisation
6. Opening of voltage-activated Ca2+ channels increases intracellular Ca2+ (triggers insulin secretion)

Question 4

Structure of the KATP channel?

Answer 4

Octomeric complex of:
• 4 potassium inward rectifier 6.2 subunits (Kir6.2)
• 4 sulphonylurea receptor 1 subunits (SUR1)

Tetramer of Kir6.2 subunits form a potassium selective ion channel

Question 5

Regular of the KATP channel?

Answer 5

SUR1 subunits regulate potassium channel activity

ATP binding to each of the Kir6.2 subunits CLOSES the channel causing depolarisation of the β-cell and insulin release (when extracellular glucose is high)

ADP-Mg2+ binding to the SUR1 subunits OPENS the channel maintain the resting potential of the β-cell and inhibits insulin secretion (when extracellular glucose is low)

Question 6

Mechanism of action of sulphonylureas (SUs)?

Answer 6

Used in T2DM

1. Seem to act by displacing binding of ADP-Mg2+ from the SUR1 subunit
2. Bind to SUR1 and CLOSE the channel; this causes depolarisation and insulin release INDEPENDENT of plasma glucose conc.

This means that insulin release is essentially uncoupled from glucose conc. which explains why these drugs can cause hypoglycaemia

Question 7

Examples of sulfonylureas?

Answer 7

First generation:
• Tolbutamide

Second generation:
• Glibenclamide (AKA glyburide)
• Glipizide

Question 8

Which of the SUs are longer-acting?

Answer 8

Glibenclamide and Glipazide are more potent and longer-acting; this is likely to have no significant clinical advantage and may in fact cause hypoglycaemia more easily

Question 9

At risk patients with SUs?

Answer 9

Risk of hypoglycaemia due to excessive insulin secretion; there is a greater risk with:
• Longer-acting agents
• In the elderly
• In patients with reduced hepatic/renal function

Question 10

Which drugs can SUs be combined with?

Answer 10

Metformin

Thiazolidinediones

Question 11

Adverse effects of SUs?

Answer 11

Undesirable weight gain

Question 12

Mechanism of action of Glinides?

Answer 12

Similar to SUs as they bind to SUR1 (at a separate site) to close the KATP channel

Triggers insulin release

Question 13

Examples of Glinides?

Answer 13

Repaglinide

Nateglinide

Question 14

Advantage of Glinides over SUs?

Answer 14

Rapid onset/offset kinetics and so are less likely to cause hypoglycaemic

Question 15

Administration of Glinides?

Answer 15

Active orally and are taken before meals to reduce post-prandial rise in BG

They can be used in conjunction:
• Metformin
• Thiazolidinediones

Question 16

Describe the incretin effect

Answer 16

Ingestion of food stimulates release of the following from enteroendocrine cells in the SI:
• Glucagon-like 1 (GLP-1) from L-cells in the ileum and colon
• Glucose dependent insulinotropic peptide (GIP) from K-cells in the jejunum/duodenum

These enter the portal blood and cause decreased BG by:
• GLP-1 and GIP enhance (INCREMENT) insulin release from pancreatic β-cells and decrease gastric emptying; there is enhanced glucose uptake and utilisation
• GLP-1 decreases glucagon release from pancreatic α-cells; there is decreased glucose production

Question 17

Mechanism of action of incretin analogues?

Answer 17

Mimic action of GLP-1 but are longer lasting

Binds to GPCR GLP-1 receptors, which increase intracellular cAMP conc.

Increase insulin secretion, suppresses glucagon secretion, slows gastric emptying and reduces appetite

Question 18

Examples of incretin analogues?

Answer 18

Exenatide

Liraglutide (longer-acting agent)

Question 19

Benefits of incretin analogues?

Answer 19

Modest weight loss

Reduce hepatic fat accumulation

Question 20

Adverse effects of incretin analogues?

Answer 20

Nausea

Hypoglycaemic

Pancreatits (very rarely)

Question 21

Administration of Liraglutide?

Answer 21

Once daily subcutaneous injection

Question 22

Function of DPP-4 enzyme?

Answer 22

AKA dipeptidyl peptidase-4 (DPP-4)

Rapidly terminates actions of GLP-1 and GIP

Question 23

Mechanism of action of DPP-4 inhibitors (AKA Gliptins)

Answer 23

Competitively inhibit DPP-4 and thus prolong the actions of GLP-1 and GIP

Question 24

Examples of Gliptins?

Answer 24

Sitagliptin

Saxigliptin

Vildagliptin

Question 25

Administration of Gliptins?

Answer 25

Usually combined with thiazolidinediones or metformin; can be used as a monotherapy Sitagliptin is orally administered once daily and is mostly well tolerated

Question 26

Benefits of Gliptins?

Answer 26

No hypoglycaemic (when used as a MONOTHERAPY) Weight-neutral

Question 27

What is α-Glucosidase inhibitor?

Answer 27

Dietary carbohydrates require digestion to monosaccharides to be absorbed in the SI It is a brush-border enzyme that breaks down starch and disaccharides to absorbable glucose

Question 28

Mechanism of action of α-Glucosidase inhibitors?

Answer 28

Delay absorption of glucose and so reduce post-prandial increase in BG

Question 29

Uses of α-Glucosidase inhibitors?

Answer 29

Used in T2DM patients who are inadequately controlled by lifestyle measures or other drugs

Question 30

Example of α-Glucosidase inhibitors?

Answer 30

Acarbose (only clinically relevant one)

Question 31

Adverse effects of α-Glucosidase inhibitors?

Answer 31

``` Occur in the GI tract as the undigested carbohydrates are welcomed by the colonic bacteria: • Flatulence • Loose stools and diarrhoea • Abdominal pain • Bloating ```

Question 32

Benefit of α-Glucosidase inhibitors?

Answer 32

NO RISK OF HYPOGLYCAEMIA

Question 33

Examples of Biguanides?

Answer 33

METFORMIN - 1st line agent for T2DM (with normal hepatic and renal function)

Question 34

Mechanism of action of Metformin?

Answer 34

Reduce hepatic gluconeogenesis (by stimulating AMP-activated protein kinase (AMPK)) Increases glucose uptake and utilisation by skeletal muscle (increases insulin signalling) Reduces carbohydrate absorption Increases fatty acid oxidation

Question 35

Benefits of Metformin?

Answer 35

Suitable for oral administration Prevent hyperglycaemic but does NOT cause hypoglycaemic Cause WEIGHT LOSS (unlike insulin and agents that promote insulin release) Can be combined with, e.g: insulin, TZDs, SUs

Question 36

Adverse effects of Metformin?

Answer 36

GI upsets (diarrhoea, nausea and anorexia) Rarely, LACTIC ACIDOSIS (avoid routine use in patients with hepatic/renal disease)

Question 37

Main effect of TZDs?

Answer 37

Enhance the action of insulin at target tissues but do not directly affect insulin secretion They reduce amount of insulin required to maintain a given BG

Question 38

Mechanism of action of TZDs (AKA Glitazones)

Answer 38

Exogenous agonists of PPARγ, which is mostly in adipose tissue, that assoc. with retinoid-receptor X (RXR) Activated PPARγ-RXR complex acts as a transcription factor and binds to DNA to promote gene expression of proteins inv. with insulin signalling: • Lipoprotein lipase • Fatty acid transport protein • GLUT4 (this is regulated by insulin)

Question 39

Benefits of TZDs?

Answer 39

Promote fatty acid uptake and storage in adipocytes, rather than in skeletal muscle and liver Reduced hepatic glucose output

Question 40

Adverse effects of TZDs?

Answer 40

Weight gain Fluid retention Some of the drugs in this class can cause serious hepatotoxicity (they are not used anymore) • Ciglitazone • Troglitazone Increased incidence of bone fractures

Question 41

Only TZDs still in use?

Answer 41

Pioglitazone

Question 42

Combination therapy with TZDs?

Answer 42

May be combined with either metformin or an SU, to achieve control of BG

Question 43

Mechanism of action of SGLT2 (Sodium-Glucose co-transporter 2) inhibitors?

Answer 43

Selectively block reabsorption of glucose by SGLT2 in the proximal tubule of the kidney nephron to cause GLYCOURIA; this decreases BG

Question 44

Benefits of SGLT2 inhibitors?

Answer 44

Little risk of hypoglycaemia Calorific loss, i.e: glucose voided, and water accompanying glucose, i.e: osmotic diuresis, contributes to weight loss

Question 45

Example of SGLT2 inhibitors?

Answer 45

Dapagliflozin

Question 46

Adverse effects of SGLT2 inhibitors?

Answer 46

Glycosuria increases risk of thrush and other urinary infections, etc