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PSC2002 Membrane Transport & Cell Signalling > PSC2002/L26 Drug Targets for T2DM > Flashcards

PSC2002/L26 Drug Targets for T2DM Flashcards

1
Q

What is the difference between type 1 and type 2 diabetes?

A

T1 - autoimmune destruction of insulin producing cells
T2 - defects in insulin action & glucose-induced insulin secretion

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2
Q

What is monogenic diabetes?

A

Glucokinase mutation
ABCC8 (SU), KCNJ11
HNF4-a, HNF1-a, PDX1

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3
Q

Give 3 diabetic complications.

A

Retinopathy
Nephropathy
Peripheral neuropathy
Autonomic neuropathy
Mactovascular

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4
Q

Give 2 effects of diabetes on life.

A

Decreased life expectancy
Quality of life compromised

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5
Q

When and who was insulin discovered by?

A

1921
Fred Banting & Charles Best

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6
Q

Why does obesity increase diabetes risk?

A

Obesity associated with insulin resistance and enlargement of islet cells
Genetic background determines extent to which B-cells can compensate
T2DM develops when B-cells can no longer compensate for insulin resistance

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7
Q

How is diabetes risk defined?

A

Balance between lifestyle insult and B-cell compensation

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8
Q

Give 2 therapies for type 2 diabetes.

A

Lifestyle changes (diet and exercise)
Drugs (mono or combination therapy)
First line drug monotherapy: metformin

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9
Q

Give 3 drugs to increase insulin release.

A

Insulin
Sulfonylureas
Meglitinides

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10
Q

Give 2 drugs to increase insulin and decrease glucagon release.

A

GLP-1R agonists
DPP-4 inhibitors

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11
Q

Give a drug to decrease hepatic glucose production.

A

Metoformin

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12
Q

Give a drug to increase insulin sensitivity.

A

Thazolidedones

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13
Q

Give a drug to delay gastric emptying.

A

Praminitide

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14
Q

Give a drug to decrease glucose absorption.

A

a-glucosidase inhibitors

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15
Q

Give a drug that binds bile acids.

A

Colesevelarm

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16
Q

Give a drug to block glucose reabsorption.

A

SGLT2 inhibitors

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17
Q

How can carbohydrate absorption be targeted? (3)

A

Inhibition via a-glucosidase inhibitors
Which inhibit conversion of oligosaccharides to glucose
So they can’t be absorbed into enterocytes via SGLT1 transporter

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18
Q

Describe first generation a-glucosidase inhibitors.

A

Acarbose tetrasaccharide with nitrogen between 1st & 2nd glucose residues
Not absorbed

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19
Q

Describe 2nd generation a-glucosidase inhibitors.

A

Miglitol analogue of 1-deoxynojrimycin
Absorbed

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20
Q

Give 3 benefits of AGIs.

A
  • intestinal glucose absorption
  • glycaemic index of food
  • post-prandial blood [glucose]
  • post-prandial triacylglycerides
    No risk of hypoglycaemia
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21
Q

Give 2 adverse effects of AGIs.

A

Abdominal discomfort (undigested carbohydrate passes from small intestine to colon mimicking malabsorption)
Fermentation of undigested carbohydrate in colon

22
Q

Explain how renal glucose excretion is increased to treat diabetes.

A

Inhibition of SGLT2 in kidney
In S1 segment of proximal tubule (SGLT2 is present)

23
Q

How much glucose is reabsorbed per day in a non-diabetic state and in diabetes?

A

Non-diabetic - 180g
Diabetes - up to 500g

24
Q

Where are SGLT1&2 expressed?

A

SGLT1 - kidney & intestine
SGLT2 - kidney (proximal kidney tubules)

25
Q

Describe phlorizin. (3)

A

Non-selective naturally occurring inhibitor of SGLT1&2
Inhibits intestinal and renal absorption of glucose
Lowers blood glucose

26
Q

Describe sergiflozin and dapaglifozin. (4)

A

Selective inhibitors of SGLT2
Cause 40-60% inhibition of renal glucose reabsorption
Lower blood glucose
Weight loss

27
Q

Give 2 adverse effects or risks of SGLT1&2 inhibitors.

A

Increased urine volume
Risk of UTIs
Risk of genital fungal infections

28
Q

Describe the action of sulphonylureas.

A

Bind and close SUR1 (Katp) channel (antagonists)
Membrane depolarisation
Increased insulin seretion

29
Q

Describe incretins.

A

Intestinal peptides produced in response to food that stimulate insulin secretion

30
Q

Give 2 incretins and the cells that they are released from.

A

GIP (glucose-dependent insulinotropic peptide) from K cells (proximal gut)
GLP-1 (glucagon-like peptide-1) from small intestine (distal)

31
Q

Where are GLP-1 and GIP receptors expressed?

A

Pancreas
Gut
Kidney
Brain

32
Q

Give 3 effects of GLP-1.

A
  • caloric intake
    + heart rate
    + insulin secretion
  • gastric emptying
  • Na excretion
    + meal-associated bone remodelling
    + glucose uptake, glycogen
  • hepatic glucose production
  • intrahepatic fat
33
Q

Give 3 effects of GIP.

A
  • caloric intake
    +heart rate
    ++insulin/+glucagon secretion
    + glucose & TG uptake
    +TG storage
    + meal-associated bone remodelling
    +glucose uptake, glycogen
  • hepatic glucose production
34
Q

What happens when GLP-1 binds to GLP1-R?

A

+cAMP
+PKA
+cAMP guanine nucleotide exchange factor (GEF/EPAC)
+Ca2+
-K(ATP) channel
+insulin secretion

35
Q

Describe the series of events following GLP-1 binding to the GLP1-R. (4)

A

Activates via G alpha subunit (AC)
Accumulation of cAMP
Acts on PKA and EPAC pathway
ER releases intracellular Ca2+ stores

36
Q

Describe the chronic effects of GLP-1 on islet B-cells.

A

PI2K->AKT(PKB)
+ gene transcription
- apoptosis
- stimulating cell growth

37
Q

What 2 forms of DPP4 exist?

A

Membrane-anchored extracellular enzyme
Soluble form which retains catalytic activity

38
Q

What is the role of DPP4?

A

Inactivates GLP-1

39
Q

Give 2 benefits and 2 adverse effects of sulphonylureas.

A

B:
- blood glucose
+ insulin secretion independently of blood glucose
A:
+ risk of hypoglycaemia
+ weight gain
+ cardiovascular events

40
Q

Give 2 benefits and 2 adverse effects of GLp-1R agonists and DPP-4 inhibitors.

A

b:
Moderate - blood glucose
+ insulin secretion dependently of blood glucose
- glucagon secretion
No risk of hypoglycaemia
- food intake
- bodyweight
A:
Potential risks for pancreatitis or pancreatic cancer (since disproved)
Gastric discomfort

41
Q

Describe adipose tissue expansion in obesity. (2)

A

Fat cell hypertrophy
Fat cell hyperplasia (cell number)

42
Q

Describe the effect of PPAR-gamma drugs. (2)

A

Favour adipocyte proliferation and further lipid storage
Prevent damage by lipids in other organs

43
Q

What occurs when adipocytes attain maximum capacity of lipid storage?

A

Lipid levels raised in blood and other tissues

44
Q

Describe the effects of thiazolidinediones (TZDDs) - PPARy ligands.

A
  • blood glucose
  • blood insulin
  • blood TGs
    + insulin sensitivity
45
Q

How do TZDs work?

A

Target transcription factor that promotes adipocyte affiliation and differentiation - PPARy

46
Q

Describe PPARy activation by natural or synthetic PPARy ligands. (7)

A
  1. Ligand binding to PPARy
  2. Heterodimer with retinoic acid receptor (RXR)
  3. Recruitment to PPARy on DNA promoter
  4. Recruitment of co-activator
  5. P300 = histone acetylase
  6. Acetylation of histones exposes chromatin
  7. Increased transcription of PPARy target genes
47
Q

Describe the mechanism of thiazolidinediones (TZDs). (3)

A

Adipocyte proliferation and differentiation
Conversion of glucose to lipid and TG synthesis
Glucose uptake and metabolism

48
Q

Give 2 benefits and 2 adverse effects to TZDs.

A

B:
- blood glucose and insulin
+ insulin sensitivity in obesity
(+ bodyweight and adiposity)
A:
Troglitazone withdrawn because of liver damage
Rosiglitazone prescribing restrictions - risk of MI
Only pioglitazone in current clinical use

49
Q

Give 3 biological effects of metformin.

A
  • hepatic glucose production
    + fatty acid oxidation
    + insulin sensitivity: liver & periphery
    + glucose utilisation
50
Q

How does metformin work? (3)

A
  1. Enters cell via OCT1
  2. Accumulates in energized mitochondria (+ve to -ve inside of MTC)
  3. Inhibits complex (- ATP/ADP-> + AMP -> AMPK activation
51
Q

Describe the metformin mechanism: complex I inhibition. (6)

A
  1. OCT1 transport
  2. Mitochondrial uptake
  3. Complex I inhibition
    • ATP/ADP decreased energy for gluconeogenesis
  5. +AMP inhibits FBPase activity, inactivates AC, prevents glucagon signalling (- gluconeogenesis)
  6. +AMP-kinase (-acetyl-CoA carboxylase, +fatty acid oxidation, = fatty acid synthesis)
52
Q

Describe the effects of increased AMPK levels induced by metformin.

A

+AMP-kinase
- acetyl-CoA carboxylase activity
- fatty acid synthesis
- malonyl-CoA concentration
Relieves inhibition of CPT1
+ fatty acyl-CoA uptake
+ fatty acid oxidation

PSC2002 Membrane Transport & Cell Signalling (25 decks)

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