20, 21 - Diabetes Flashcards
What are the 3 types of diabetes?
- Type 1 – autoimmune destruction of insulin-producing beta cells
- Type 2 – metabolic disorder characterized by hyperglycemia
- Gestational diabetes – development of DM during pregnancy
What are the causes of type 1 DM?
Genetic and environmental (autoimmune, viral, exposure to toxic chemicals)
What is insulin?
- Peptide hormone produced by beta cells in pancreas
- Central for regulating carbohydrate and fat metabolism
- Causes skeletal muscles and fat tissue to absorb glucose from blood, lowering blood glucose levels
- Stops use of fat as an energy source and inhibits release of glucagon
What is glucagon?
Peptide hormone produced by alpha cells in pancreas, raising blood glucose levels
What is the insulin receptor?
- Transmembrane receptor
- Tyrosine kinase mediates activity by phosphorylation of tyrosine that starts many protein activation cascades
What happens when insulin binds to insulin receptor?
1) Protein activation
2) Translocation of glut-4 transporter to plasma membrane and glucose influx
3) Glycogen synthesis
4) Glycolysis
5) Fatty acid synthesis
What are the problems w/ insulin binding in type 1 and type 2 DM?
- Type 1 = ineffective activation of glut-4, resulting in diminished glucose uptake
- Type 2 = defective activation/signaling to glut-4, resulting in diminished glucose uptake
What are the 3 tests for diabetes?
- Fasting plasma glucose (normal = 80-100 mg/dL)
- A1C - reflects average plasma glucose over 3 months (normal = 5%)
- 2h fasting plasma glucose (normal = below 200 mg/dL)
Diabetes is the most common cause of _____
Blindness
What is the target organ of each diabetes drug class?
- Pancreas = sulfonylureas, DPP-4 inhibitors and meglitinides
- Muscle and fat = thiazolidinediones, biguanides, and insulin
- Gut = alpha-glucosidase inhibitors
- Liver = biguanides, thiazolidinediones, DPP-4 inhibitors, GLP-1 inhibitors, and insulin
How is insulin produced (as what)?
- Produced and stored as hexamer
- Inactive, giving long-term stability
- Contains 2 polypeptide chains, A and B linked together by disulfide bonds
What is important about insulin monomer?
Fast-reacting, higher diffusion rate
What happens with lantus (insulin glargine)?
- Precipitation on injection
- Slow release (18-26 h)
What substitutions occur in lantus (insulin glargine)? Why are these beneficial? What is the benefit to the parent compound?
- Substitute glycine for asparagine w/ two arginines added to carboxy terminal B chain
- Arginine shifts isoelectric point from 5.4 to 6.7, making it more soluble at acidic pH
- Glycine substitution avoids deamidization at pH 4
What substitution occurs in NovoRapid (insulin aspart)? What effect does this have on release rate?
- Aspartic acid substituted for proline, which increases charge repulsion and prevents formation of hexamers
- Modification allows quick absorption into bloodstream, onset in 15 min
What modification occurs in Humalog (insulin lispro)? What effect does this have? What is the onset?
- Penultimate lysine and proline residues on C-terminal end of B-chain are reversed
- Blocks formation of insulin dimers and hexamers; doesn’t alter receptor binding
- Faster onset than regular insulin
What is the modification in Levemir (insulin detemir)? What effect does this have?
- Fatty acid (myristic acid) bound to lysine aa at position B29
- Quickly absorbed and binds to albumin in blood
What is the modification in Apidra (insulin glulisine)? What effect does this have? Is this a short or long acting form?
- Asparagine at B3 replaced w/ lysine and lysine at B29 replaced w/ glutamic acid
- Decreases zinc-free self-association (decreased dimers)
- Since it decreases dimers, it is a short acting form (taken before meals)
Which drugs are first gen sulphonylureas?
- Acetohexamide
- Chlopropamide
- Tolbutamide
- Tolazamide
Which drugs are second gen sulphonylureas?
- Glipizide
- Gliclazide
- Glibenclamide
- Gliquidone
- Glyclopyramide
Which drug is a third gen sulphonylurea?
Glimepiride
What is the MOA of sulphonylureas?
- Binds to ATP-dependent K+ channels on cell membranes of pancreatic beta-cells, preventing K+ efflux
- Potential over cell becomes positive and opens voltage gated Ca2+ channels
- Increased Ca2+ causes increased fusion of insulin granulae w/ cell membrane, increasing secretion of insulin
Which 2 sulphonylureas are used most often?
Glibenclamide (glyburide) and glimepiride
What is a severe side effect of sulphonylureas?
Hypoglycemia
What is the MOA of meglitinides?
- Bind to ATP-dependent K+ channel on cell membrane of pancreatic beta cells; have weaker affinity and faster dissociation from SUR1 binding site than sulphonylureas
- Increased intracellular K+ causes positive potential to develop across membrane, depolarizing voltage-gated Ca2+ channels, increasing fusion of insulin
What is the main meglitinide?
Repaglinide
Which drug is a biguanide?
Metformin
What is a difference between metformin and sulphonylureas?
Metformin doesn’t affect ouput of insulin; sulphonylureas do
What is the MOA of metformin?
- Suppresses hepatic gluconeogenesis (generation of glucose from non-carbohydrates)
- Increases insulin sensitivity and fatty acid oxidation
- Decreases absorption of glucose in GI tract
How does metformin increase insulin sensitivity?
- Reduces hepatic glucose production and artificially lowers plasma glucose levels
- So less insulin is needed to keep plasma glucose levels normal, resulting in increased insulin sensitivity and decreased insulin resistance
What occurs in obese people w/ type 2 DM w/ respect to insulin?
- Failure to activate postreceptor tyrosine kinase, causing insulin resistance and hyperglycemia, meaning higher amounts of insulin needed to reduce plasma glucose
- This is insulin resistance/sensitivity (needing more insulin to keep plasma glucose low or normal)
Which anti-diabetic drug is shown to prevent CV complications of diabetes?
Metformin
What is a contraindication to metformin?
Those who may develop lactic acidosis, such as those w/ kidney disorders
What effect does metformin have on lactate?
- Metformin reduces gluconeogenesis, so less lactate is taken up by the liver, so must be excreted through kidneys
- Those w/ kidney disorders can have a build-up of lactic acid
Which other drugs can metformin be combined w/?
- Thiazolidinediones
- Sulfonylureas
- DPP-4 inhibitors
What is the effect and MOA of alpha-glucosidase inhibitors?
- Prevent digestion of carbohydrates (starch and sugars)
- Long-term effects include small decrease in hemoglogin A1C levels (post-prandial), so increased control of type 2 DM
- MOA = competitive inhibition of digestive enzyme alpha-glucosidase, reducing rate of hydrolysis of oligosaccharides to glucose
What is the MOA of acarbose? What is its short-term and long-term effects? What are some SE?
- Inhibits both alpha-glucosidase and pancreatic alpha-amylase
- Short-term lowers blood glucose levels
- Long-term lowers Hb A1C levels
- SE = flatulence and diarrhea
What is the main use of alpha-glucosidase inhibitors?
Lower blood glucose after a meal
What is the MOA of miglitol and voglibose? When are they taken? What are the main differences?
- Inhibits glycoside hydrolysis of alpha-glucosidase, lowering degree of post-prandial hyperglycemia
- Taken at start of meal
- Voglibose has better SE profile, but reduced efficacy on fasting plasma glucose than acarbose
Which drugs are sodium-glucose cotransporter 2 inhibitors?
- Canagliflozin
- Dapagliflozin
- Empagliflozin
- Can be used in combination w/ metformin
What is the effect of SGLT2 inhibitors?
Lower blood sugar by causing the kidneys to remove sugar from the body (urination)
Are SGLT2 inhibitors safe for type 1 DM?
Unknown
What is the MOA of SGLT2 inhibitors?
- SGLT2 = protein that facilitates glucose reabsorption in kidneys; located in proximal tubule
- SGLT2 inhibitors block reabsorption of glucose in kidneys, increasing glucose excretion
What is phlorizin?
- Potent and non-selective inhibitor of SGLT1 and SGLT2
- Beta-glucoside
What is the MOA of thiazolidinediones?
- Activate peroxisome proliferator-activated receptor gamma (PPAR-gamma), a nuclear receptor which regulates fatty acid and glucose metabolism
- PPAR-gamma receptor agonists
- When activated, receptor binds to DNA in complex w/ retinoid X receptor (RXR), increasing and decreasing transcription of specific genes
- Process is called PPAR-gamma transactivation and PPAR-gamma transrepression
What is another name for thiazolidinediones?
Glitazones
What occurs in PPAR-gamma transactivation?
On DNA strand, PPAR/RXR heterodimer binds to peroxisome proliferator hormone response elements upstream of target genes, in complex w/ cofactors, causing upregulation of genes via transcription
What occurs in PPAR-gamma transrepression?
1) Binding of PPAR-gamma to coactivators reduces levels of coactivators available for binding to pro-inflammatory transcription factors, causing a decrease in transcription of specific genes
- PPAR/RXR/ligand complexes block signaling cascades
2) Can also physically bind directly w/ transcription factors to decrease transcription
3) PPAR/RXR complex can inhibit activation of MAPK to block transcription factors and decrease transcription
What is the benefit to thiazolidinediones causing PPAR-gamma transactivation?
- Decreases insulin resistance
- Decrease leptin levels, increasing appetite
What else do thiazolidinediones do?
Increase synthesis of specific proteins involved in fat and glucose metabolism
What is insulin resistance?
- Reduced responsiveness to normal circulating insulin levels => hyperinsulinemia
- Pancreas unable to keep up w/ increased insulin requirements, so hyperglycemia occurs
What tissues do thiazolidinediones act on and what do they do?
- Liver and skeletal muscle
- Sensitize them to insulin action, increasing glucose uptake and decreasing glucose hepatic output
Are thiazolidinediones used alone or in combination?
Can be used alone or in combination w/ metformin or a sulfonylurea
What is a thiazolidinedione?
5-membered thiazole-diketone
Which drugs are thiazolidinediones?
- Troglitazone (not used anymore b/c drug-induced hepatitis)
- Pioglitazone (not used anymore b/c associated w/ bladder cancer)
- Rosiglitazone
What are incretins?
- Hormones produced by GI tract in response to incoming nutrients
- Contribute to glucose homeostasis
- 2 hormones = gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)
What secretes GLP-1 and what are the effects of GLP-1?
- Intestinal L-cells; produced by cleavage of proglucagon
- Increases insulin secretion in glucose-dependent manner, decreases glucagon secretion, promotes insulin sensitivity, and increases satiety in brain
What are the therapeutic options targeting GLP-1 since GLP-1 itself can’t be used therapeutically (very short half life b/c of metabolism by DPP-4)?
- Incretin mimics acting as GLP-1 agonists
- Dipeptidyl peptidase-4 (DPP-4) antagonists that inhibit breakdown of GLP-1?
What is exenatide?
- GLP-1 receptor agonist
- Resistant to DPP-4 inactivation
- Measurably present in plasma for 10 h (BID dosing)
What is the difference between exenatide and liraglutide?
- Both are GLP-1 agonists, but liraglutide has much longer half life so only requires once daily dosing while exenatide requires twice daily
- Liraglutide has longer half life b/c attached fatty acid molecule enables albumin binding, decreasing elimination
What is the effect of liraglutide for diabetes?
- Improves control of blood glucose
- Reduces meal-related hyperglycemia by increasing insulin secretion, delaying gastric emptying and suppressing glucagon secretion
- Works in glucose-dependent manner, so only stimulates insulin secretion when blood glucose is high
What is budyreon?
Microspheres of exenatide which require once weekly dosing
What is pramlinitide? When is it used? What does it do?
- Amylin analogue (proline substitution on pramlinitide allows for better protein properties)
- Used as an adjunct therapy
- Aids in absorption of glucose by slowing gastric emptying and promoting satiety
What is amylin?
Small peptide hormone released into bloodstream by beta cells along w/ insulin
What is dipeptidyl peptidase-4?
- Glycoprotein expressed on surface of most cells
- Cleaves dipeptide proline units from N-terminus (forms an imidate intermediate)
- Degrades incretins
What do DPP-4 inhibitors do and what effect do they have on diabetes?
- Increase incretin levels of GLP-1 and GIP by preventing inactivating cleavage
- Inhibit glucagon release, increase glucose-dependent insulin secretion, decrease gastric emptying, and decrease plasma glucose levels
Which drugs are DPP-4 inhibitors?
- Sitagliptin
- Saxagliptin
- Linagliptin
- Alogliptin
What kind of inhibitors are DPP-4 inhibitors?
- “Substrate-like inhibitors”, so bind either covalently or non-covalently
- “Analog inhibitors” so mimic transition state of protease/peptidase
How do DPP-4 inhibitors bind in the pockets of a protease?
- P1 (proline mimetic) occupies S1 pocket
- P2 occupies S2 pocket
- P1 and P2 connected via amino-carbonyl linker
What is an imidate group?
- Carbon attached to proline is double bonded to N which is attached to remainder of peptide and carbon is single bonded to O which is attached to serine of DPP-4
- Imidate = Serine-O-C=N-peptide (carbon is also attached to proline)
What is important about the proline mimetic group of a DPP-4 inhibitor?
Act as covalent inhibitors
What is the MOA of DPP-4 inhibitors (model 1)?
Electrophilic group (-CN or C=N) interacts w/ hydroxyl group of catalytic serine in active binding site
What is the difference between the 2 models of DPP-4 inhibitors?
- Model 1 (proline mimetics) are covalent inhibitors
- Model 2 are non-covalent and non-substrate-like inhibitors
