Drugs in T2D Flashcards
What are the issues in T2D?
-Insulin resistance, caused by high levels of Insulin -> no response to it
-Malfunction of insulin receptor
What does the structure of the insulin receptor look like?
Ligand-binding domain (extra-cellular): Cysteine-rich-alpha domain (insulin is a negatively charged acidic protein), and ß-domain
Tyrosine-kinase domain (intra-cellular): INS-R
What type of interaction is present between the insulin receptor and insulin?
Insulin is negatively charged and cysteine is a polar amino acid
-> Ion-Dipol interaction at alpha region of the receptor
What happens if insulin binds to the receptor?
Tyrosine kinase domain (ß-domain): 3 tyrosine residues on the domain are getting autophosphorylated causing downstream signals
-> cellular proteins bind to phosphorylated tyrosine activating a cascade
What are the effects of the second messenger cascade?
-Insulin sensitivity
-Leptin sensitivity (hunger and satiety signal)
-ß-cell development
What are some drugs related to T2D?
-Metformin
-Sulfonyl Ureas (SU)
-Thiazolinedions (TZD)
-DPP-4 inhibitors (DPP4i)
-SGLT-2 inhibitors (SGLT2i)
How is diabetes treated as the disease progresses?
- Diet and exercise
- Monotherapy: Metformin (or other agents)
- Dual therapy: Metformin + GLP-1 (or other OADs)
- Triple therapy: Metformin + GLP-1 + OADs (or basal insulin)
- Combo injectables: Metformin + basal insulin + insulin + GLP-1
What are the characteristics of Metformin?
-2 attached Guanidies: Biguanide
-originally used to treat viral infections (flu, malaria)
-low blood glucose noted as side effect
How do Biguanides work?
Not fully understood:
Binds on Adenomonophosphate-Kinase (AMPK)
-AMPK shuts down anabolic processes: Gluconeogenesis
-AMPKS turns ON catabolic processes to use GLUCOSE: Glycolysis, oxidative phosphorylation, ß-oxidation
What are examples of Sulfonylurea Drugs and how do they work?
Glyburide and Glipizide
-Binding site for SUF on the K+ channel, on the external surface of the cell
-They close K+ channels in the pancreas to depolarize the membrane to open the Ca-channel -> Ca stimulates insulin release
(normally the cell would use Glucose to produce ATP -> ATP would close the K+ channel)
Why are Sulfonylurea Drugs biochemically practical?
Because it stimulates the cell to produce insulin without using ATP
Why do Sulfonyl urea drugs don’t always work in T2D patients?
Because T2D patients usually have enough insulin already, but it doesn’t work -> still used to treat T2D and see if it improves the patient’s condition
Why do Sulfonyl urea drugs don’t work in T1D patients?
Because T1D patients don’t have enough functional ß-cells
-> destroyed by an autoimmune response
How do Thiazolidinediones work?
-TZD act on the same receptors as glucocorticoids to utilize GLUCOSE
What is the role of glucocorticoids like Cortisol?
-> Glucocorticoids upregulate glucose when the cell is under stress and needs GLUCOSE
(anti-inflammatory, monitor blood pressure, Na-K electrolyte levels)
What is the mechanism of Thiazolidinediones?
-act on Adipocytes and the liver for energy utilization
-activates Peroxisome proliferator-activated receptor (PPAR) responsible for Glucose uptake (GLUT-4) and lipid utilization and release into the bloodstream
Why does it take so long (weeks) to see a response?
-act on gene transcription in adipocytes
Where is PPAR present?
-In the liver and adipocytes -> Fat synthesis
-Muscle cells -> upregulation of Glucose uptake -> increase of insulin sensitivity
What is the Glucagon‐like peptide 1 (GLP‐1)?
-a peptide hormone produced in the intestinal epithelial cells
-induces an increase of ß-cell mass -> more glucose-stimulated insulin
-inhibits glucagon secretion (glucagon works when glucose is low, produces glucose to get it back to normal)
Why can’t we just give human GLP-1 as a therapeutic drug?
Because it is metabolized very quickly, it is produced as needed and degraded afterward
To use it as a drug it needs to be altered to last longer
How is human GLP-1 altered for therapeutical use?
-DPP-4 (another diabetic drug) breaks down GLP-1 by cleaving on Alanin -> Replacement of Alanin -> GLP-1 last longer - EXENATIDE
-Addition of fatty acid to increase the half-life: LIRAGLUTIDE, SEMAGLUTIDE
-Conjugate to anti-body: too big to get excreted in urine: DULAGLUTIDE
-Conjugate to Albumin: circulates longer in the system - ALBIGLUTIDE
Why must GLP-1 altered drugs be injected and are not taken orally?
Because GLP-1 are peptides, and they would be digested in the small intestine
