PSC2002/L26 Drug Targets for T2DM Flashcards
What is the difference between type 1 and type 2 diabetes?
T1 - autoimmune destruction of insulin producing cells
T2 - defects in insulin action & glucose-induced insulin secretion
What is monogenic diabetes?
Glucokinase mutation
ABCC8 (SU), KCNJ11
HNF4-a, HNF1-a, PDX1
Give 3 diabetic complications.
Retinopathy
Nephropathy
Peripheral neuropathy
Autonomic neuropathy
Mactovascular
Give 2 effects of diabetes on life.
Decreased life expectancy
Quality of life compromised
When and who was insulin discovered by?
1921
Fred Banting & Charles Best
Why does obesity increase diabetes risk?
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
How is diabetes risk defined?
Balance between lifestyle insult and B-cell compensation
Give 2 therapies for type 2 diabetes.
Lifestyle changes (diet and exercise)
Drugs (mono or combination therapy)
First line drug monotherapy: metformin
Give 3 drugs to increase insulin release.
Insulin
Sulfonylureas
Meglitinides
Give 2 drugs to increase insulin and decrease glucagon release.
GLP-1R agonists
DPP-4 inhibitors
Give a drug to decrease hepatic glucose production.
Metoformin
Give a drug to increase insulin sensitivity.
Thazolidedones
Give a drug to delay gastric emptying.
Praminitide
Give a drug to decrease glucose absorption.
a-glucosidase inhibitors
Give a drug that binds bile acids.
Colesevelarm
Give a drug to block glucose reabsorption.
SGLT2 inhibitors
How can carbohydrate absorption be targeted? (3)
Inhibition via a-glucosidase inhibitors
Which inhibit conversion of oligosaccharides to glucose
So they can’t be absorbed into enterocytes via SGLT1 transporter
Describe first generation a-glucosidase inhibitors.
Acarbose tetrasaccharide with nitrogen between 1st & 2nd glucose residues
Not absorbed
Describe 2nd generation a-glucosidase inhibitors.
Miglitol analogue of 1-deoxynojrimycin
Absorbed
Give 3 benefits of AGIs.
- intestinal glucose absorption
- glycaemic index of food
- post-prandial blood [glucose]
- post-prandial triacylglycerides
No risk of hypoglycaemia
Give 2 adverse effects of AGIs.
Abdominal discomfort (undigested carbohydrate passes from small intestine to colon mimicking malabsorption)
Fermentation of undigested carbohydrate in colon
Explain how renal glucose excretion is increased to treat diabetes.
Inhibition of SGLT2 in kidney
In S1 segment of proximal tubule (SGLT2 is present)
How much glucose is reabsorbed per day in a non-diabetic state and in diabetes?
Non-diabetic - 180g
Diabetes - up to 500g
Where are SGLT1&2 expressed?
SGLT1 - kidney & intestine
SGLT2 - kidney (proximal kidney tubules)
Describe phlorizin. (3)
Non-selective naturally occurring inhibitor of SGLT1&2
Inhibits intestinal and renal absorption of glucose
Lowers blood glucose
Describe sergiflozin and dapaglifozin. (4)
Selective inhibitors of SGLT2
Cause 40-60% inhibition of renal glucose reabsorption
Lower blood glucose
Weight loss
Give 2 adverse effects or risks of SGLT1&2 inhibitors.
Increased urine volume
Risk of UTIs
Risk of genital fungal infections
Describe the action of sulphonylureas.
Bind and close SUR1 (Katp) channel (antagonists)
Membrane depolarisation
Increased insulin seretion
Describe incretins.
Intestinal peptides produced in response to food that stimulate insulin secretion
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)
Where are GLP-1 and GIP receptors expressed?
Pancreas
Gut
Kidney
Brain
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
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
What happens when GLP-1 binds to GLP1-R?
+cAMP
+PKA
+cAMP guanine nucleotide exchange factor (GEF/EPAC)
+Ca2+
-K(ATP) channel
+insulin secretion
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
Describe the chronic effects of GLP-1 on islet B-cells.
PI2K->AKT(PKB)
+ gene transcription
- apoptosis
- stimulating cell growth
What 2 forms of DPP4 exist?
Membrane-anchored extracellular enzyme
Soluble form which retains catalytic activity
What is the role of DPP4?
Inactivates GLP-1
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
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
Describe adipose tissue expansion in obesity. (2)
Fat cell hypertrophy
Fat cell hyperplasia (cell number)
Describe the effect of PPAR-gamma drugs. (2)
Favour adipocyte proliferation and further lipid storage
Prevent damage by lipids in other organs
What occurs when adipocytes attain maximum capacity of lipid storage?
Lipid levels raised in blood and other tissues
Describe the effects of thiazolidinediones (TZDDs) - PPARy ligands.
- blood glucose
- blood insulin
- blood TGs
+ insulin sensitivity
How do TZDs work?
Target transcription factor that promotes adipocyte affiliation and differentiation - PPARy
Describe PPARy activation by natural or synthetic PPARy ligands. (7)
- Ligand binding to PPARy
- Heterodimer with retinoic acid receptor (RXR)
- Recruitment to PPARy on DNA promoter
- Recruitment of co-activator
- P300 = histone acetylase
- Acetylation of histones exposes chromatin
- Increased transcription of PPARy target genes
Describe the mechanism of thiazolidinediones (TZDs). (3)
Adipocyte proliferation and differentiation
Conversion of glucose to lipid and TG synthesis
Glucose uptake and metabolism
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
Give 3 biological effects of metformin.
- hepatic glucose production
+ fatty acid oxidation
+ insulin sensitivity: liver & periphery
+ glucose utilisation
How does metformin work? (3)
- Enters cell via OCT1
- Accumulates in energized mitochondria (+ve to -ve inside of MTC)
- Inhibits complex (- ATP/ADP-> + AMP -> AMPK activation
Describe the metformin mechanism: complex I inhibition. (6)
- OCT1 transport
- Mitochondrial uptake
- Complex I inhibition
- ATP/ADP decreased energy for gluconeogenesis
- +AMP inhibits FBPase activity, inactivates AC, prevents glucagon signalling (- gluconeogenesis)
- +AMP-kinase (-acetyl-CoA carboxylase, +fatty acid oxidation, = fatty acid synthesis)
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
