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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
Describe phlorizin. (3)
Non-selective naturally occurring inhibitor of SGLT1&2 Inhibits intestinal and renal absorption of glucose Lowers blood glucose
26
Describe sergiflozin and dapaglifozin. (4)
Selective inhibitors of SGLT2 Cause 40-60% inhibition of renal glucose reabsorption Lower blood glucose Weight loss
27
Give 2 adverse effects or risks of SGLT1&2 inhibitors.
Increased urine volume Risk of UTIs Risk of genital fungal infections
28
Describe the action of sulphonylureas.
Bind and close SUR1 (Katp) channel (antagonists) Membrane depolarisation Increased insulin seretion
29
Describe incretins.
Intestinal peptides produced in response to food that stimulate insulin secretion
30
Give 2 incretins and the cells that they are released from.
GIP (glucose-dependent insulinotropic peptide) from K cells (proximal gut) GLP-1 (glucagon-like peptide-1) from small intestine (distal)
31
Where are GLP-1 and GIP receptors expressed?
Pancreas Gut Kidney Brain
32
Give 3 effects of GLP-1.
- caloric intake + heart rate + insulin secretion - gastric emptying - Na excretion + meal-associated bone remodelling + glucose uptake, glycogen - hepatic glucose production - intrahepatic fat
33
Give 3 effects of GIP.
- caloric intake +heart rate ++insulin/+glucagon secretion + glucose & TG uptake +TG storage + meal-associated bone remodelling +glucose uptake, glycogen - hepatic glucose production
34
What happens when GLP-1 binds to GLP1-R?
+cAMP +PKA +cAMP guanine nucleotide exchange factor (GEF/EPAC) +Ca2+ -K(ATP) channel +insulin secretion
35
Describe the series of events following GLP-1 binding to the GLP1-R. (4)
Activates via G alpha subunit (AC) Accumulation of cAMP Acts on PKA and EPAC pathway ER releases intracellular Ca2+ stores
36
Describe the chronic effects of GLP-1 on islet B-cells.
PI2K->AKT(PKB) + gene transcription - apoptosis - stimulating cell growth
37
What 2 forms of DPP4 exist?
Membrane-anchored extracellular enzyme Soluble form which retains catalytic activity
38
What is the role of DPP4?
Inactivates GLP-1
39
Give 2 benefits and 2 adverse effects of sulphonylureas.
B: - blood glucose + insulin secretion independently of blood glucose A: + risk of hypoglycaemia + weight gain + cardiovascular events
40
Give 2 benefits and 2 adverse effects of GLp-1R agonists and DPP-4 inhibitors.
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
Describe adipose tissue expansion in obesity. (2)
Fat cell hypertrophy Fat cell hyperplasia (cell number)
42
Describe the effect of PPAR-gamma drugs. (2)
Favour adipocyte proliferation and further lipid storage Prevent damage by lipids in other organs
43
What occurs when adipocytes attain maximum capacity of lipid storage?
Lipid levels raised in blood and other tissues
44
Describe the effects of thiazolidinediones (TZDDs) - PPARy ligands.
- blood glucose - blood insulin - blood TGs + insulin sensitivity
45
How do TZDs work?
Target transcription factor that promotes adipocyte affiliation and differentiation - PPARy
46
Describe PPARy activation by natural or synthetic PPARy ligands. (7)
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
Describe the mechanism of thiazolidinediones (TZDs). (3)
Adipocyte proliferation and differentiation Conversion of glucose to lipid and TG synthesis Glucose uptake and metabolism
48
Give 2 benefits and 2 adverse effects to TZDs.
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
Give 3 biological effects of metformin.
- hepatic glucose production + fatty acid oxidation + insulin sensitivity: liver & periphery + glucose utilisation
50
How does metformin work? (3)
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
Describe the metformin mechanism: complex I inhibition. (6)
1. OCT1 transport 2. Mitochondrial uptake 3. Complex I inhibition 4. - 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
Describe the effects of increased AMPK levels induced by metformin.
+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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