L42 -Insulin and anti-diabetic agents Flashcards
List some complications of hyperglycemia and hypoglycemia?
Hyper = nephropathy, neuropathy, retinopathy, stroke, gangrene, heart attack
Hypo = fatigue, nausea, dizziness, coma, confusion
Define the spectrum of type I DM?
- Type 1 IDDM
- Type 1.5 latent autoimmune diabetes of adulthood (LADA)
- Type 1B – idiopathic diabetes
- Maturity onset diabetes of young: single gene mutation (MODY)
Briefly define the cause of IDDM and NIDDM?
IDDM = Autoimmune disease that causes pancreatic islet cell destruction = lack of insulin production
NIDDM = combined defect of insulin secretion and insulin resistance
Treatment strageties for Type 1, 2 DM and GDM?
Type 1 = Diet, exercise, Insulin-dependent
Type 2 = Diet, exercise, Anti-diabetic drug, Insulin (1/3)
GDM = Diet, Insulin, Anti-diabetic drugs
Which insulin precursors are used to evaluate insulin function?
Preproinsulin = signal sequence + C peptide = determine ability to secrete insulin
Proinsulin and C peptide = determine dynamic range of B cell function
Describe the 24-h physiological insulin secretion trend?
almost identical to 24-hour glucose profile
|»_space; admin of exogenous insulin should mimic the pattern of endogenous insulin secretion
Compare basal and bolus insulin admin.?
1) Basal insulin: Mimics normal pancreatic basal insulin secretion
- Long lasting
- Smooth, peakless to avoid hypoglycaemia
2) Bolus insulin: Give before meals
- Short duration
- Avoid
hypoglycaemia
Both predictable and reproducible
List 4 principal types of insulin prearation based on acting time?
– Short acting : Regular human insulin (Humulin®, Novolin®)
– Rapid onset and ultrashort-acting: Insulin Lispro and Insulin Aspart
– Intermediate acting: protamine (NPH) and lente
– Long acting : Insulin Glargine, Insulin Detemir
Explain how regular human insulin/ Humulin®/ Novolin® extends it’s onset and duration of action?
1) self-aggregate in antiparallel fashion to form active dimers
2) stabilize around Zn2+ = inactive hexamers = cannot bind to insulin
Indications for regular human insulin injection? Define the onset and acting time?
Short onset: 30min, peak 1-2h
Short acting: 5-8h
Bolus injection for diabetic ketoacidosis, Changing insulin requirements (e.g. infection, post-op)
Give 4 limitations of regular human insulin?
- Inconvenient admin. before meal
- Risk of hypoglycaemia if delayed meal
- Mismatch with postprandial hyperglycaemia peak
- Late postprandial hypoglycaemia
Describe the structure of insulin Lispro?
Anti-aggregation: Reverse the 2 amino acids (Proline 28, Lysine 29) at C-terminal of B-chhain
> > prevents hexameric formation
Define the onset and acting time of Insulin Lispro. Give one advantage?
- Rapid onset = 10-15 min (taken just before meal)
- Ultrashort acting = 2-4h
- Peak effect 30-60 min
Mimics endogenous insulin secretion = improves postprandial glucose control without risk of hypoglycemia between meals
Describe the structure of Insulin Aspart?
Substitute the B-chain proline 28 with aspartic acid
|»_space; rapidly breaks into biologically active monomer after subcutaneous injectio
Define the onset and acting time of Insulin Aspart?
Rapid onset (10-20 min)
Ultrashort acting: 2-4 hours
Peak effect: 1 hour
Name 2 intermediate acting insulin.
Protamine (NPH) insulin
Lente insulin
Describe the structure of Protamine (NPH) insulin and Lente insulin
Neutral protamine Hagedorn (NPH) insulin = mixture of insulin + protamine
Lente insulin = mixture of 30% semilente + 70% ultralente insulin (very insoluble, delayed onset and prolonged duration of action)
Define the onset and acting time of NPH insulin?
Insulin bound to protamine slowly dissolves
Intermediate onset: peak 4-10h
Intermediate acting: 10-18h
Define the onset and acting time of Lente insulin?
Zinc-bound insulin slowly dissolves:
Intermediate onset: peak 4-10h
Intermediate acting: 10-18h
Name 2 long-acting insulin?
Insulin Glargine (Lantus)
Detemir Insulin (Levemir)
Describe the structure and MoA of Insulin Glargine?
- Attach 2 arginines to the B chain c-terminal
- Substitute asparagine with glycine at A21 (A chain)
Isoelectric point shifted to pH 7.0 (close to body pH)
> > precipitates in the subcutaneous milieu»_space; stabilizes insulin hexamers
slow, consistent absorption into systemic circulation
Describe the structure and MoA of Detemir Insulin?
- Add myristic acid (FA) to lysine at position B29
- Omit threonine in position B30
fatty acid causes it to bind to albumin
» slow release, extended circulating life
Define the acting time of Insulin Glargine and Detemir insulin?
Insulin Glargine = Ultra-long-acting (maximum activity maintained for >=24 hours)
Detemir insulin = Long acting, 23 hours
List some complications of insulin therapy?
- Hypoglycemia: confusion, weakness, coma…
- Insulin allergy, immune resistance
- Lipodystrophy at injection sites (use multi-site injection)
- Abuse: Development of type 2 diabetes + lifetime dependency
List 2 classes and examples of insulin secretogogues?
Sulfonylureas:
- 1st gen = chlorpropamide, tolbutamide
- 2nd gen***** = glipizide, glimepiride, glibenclamide
Non-sulfonylureas:
- meglitinide analogs: repaglinide, nateglinide
MoA of sulfonylureas?
1) Bind extracellularly to a high-affinity receptor
2) close the associated inward rectifier ATP-sensitive K+ channel in pancreatic β-cell
3) membrane depolarization»_space; opens voltage-gated Ca2+ channel
4) Ca2+ entry»_space; exocytosis of insulin secretion
Indication and resistance of Sulfonylureas?
- Type 2 patients with residual β-cell function
- adjunctive to nutritional, exercise therapy
Primary failure = 1/4 fail to respond
Secondary failure = lose response over time
Define the acting time and ADR of Sulfonylurea?
Long duration of action (12-48 hours)
- Weight gain: increase appetite, decrease glucose excretion
- Hypoglycaemia
- GI disturbances, Rashes
- Cross placenta and deplete fetal insulin
MoA and indication of Non-sulfonylureas/ Meglitinide analogs?
At functioning pancreatic β cells:
- Bind to a distinct site on sulfonylurea receptor of ATP-sensitive K+ channels» very rapid, transient insulin secretion
- Control post-prandial glucose
Indication and onset and acting time of Meglitinide analogs?
controlling postprandial glucose
Rapid onset
Short duration of actions (~2 hours)
ADR of Meglitinide analogs?
Hypoglycemia (incidence much lower than sulfonylureas)
Weight gain
Name one class of Incretin mimetics and give 2 examples
Glucagonlike peptide (GLP) analogues/agonist:
exenatide (GLP-1 agonsit), liraglutide (GLP-1 analog)
MoA of Incretin mimetics?
Analogues of endogenous incretins: GI hormones secreted after food ingestion:
Include glucagon-like peptide-1 (GLP-1), gastric inhibitory peptide (GIP)
> > stimulate glucose-dependent insulin secretion from B-cell
+
glucagon release from alpha cell
Describe the endogenous degradation of Incretins?
rapidly degraded by dipeptidyl peptidase-4 (DPP-4)
Describe the structure of incretin mimetics to resist DDP-4 degradation?
Exenatides = only 53% homology with GLP = decrease degradation by DPP-4
Liraglutide = fatty acid chain added, complex binds to albumin = decrease degradation by DPP-4
Indication of incretin mimetics? ADR?
Exenatide = Type 2 DM, decrease appetite and gastic emptying, WEIGHT LOSS*****
Liraglutide = WEIGHT LOSS*****
ADR: GI disturbances, Dizziness, Headache
Name 2 DDP-4 inhibitor and MoA?
Dipeptidyl peptidase-4 (DPP-4) inhibitors / incretin enhancers
Sitagliptin, vidagliptin
inhibit DPP-4-mediated degradation of active GLP-1»_space; increase insulin secretion
Indication and ADR of DDP-4 Inhibitor?
monotherapy / combination therapy for long term glucose control
ADR: URTI, Sore throat, Diarrhea
Name 2 insulin sensitizers?
Biguanides (metformin)
Thiazolidinediones: rosiglitazone , pioglitazone
MoA of Metformin?
1) Activating AMP-activated protein kinase (AMPK) in liver:
a) ↓ gluconeogenic genes (PEPCK, G6Pc) to decrease glucose production
b) ↓ fatty acid synthesis, ↑ fatty acid oxidation
2) Modulates gut microbiota
Indication of Metformin? C/O?
- Obese with insulin resistance
- Lower CVD complications
- Decrease DM-related cancers
C/O:
- Renal, hepatic diseases, Alcoholism, Severe Infection
ADR of Metformin?
GI disturbances
metformin- associated lactic acidosis (MALA)
Long-term use = vitamin B12 deficiency
MoA of Thiazolidinediones (rosiglitazone,pioglitazone) ?
insulin-sensitizing drugs:
bind to peroxisome proliferator-activated receptor γ (PPARγ, nuclear hormone receptor) in adipose tissue (fat), muscle, liver
1) decrease insulin resistance
2) anti-inflammatory effects
3) Improve lipid profiles
Indication, risks and ADR of Thiozolidinediones?
prevention of type 2 diabetes
Risks:
- Rosiglitazone > heart attack
- Bladder cancer (Pioglitazone)
ADR:
weight gain, fluid retention
Name 2α-Glucosidase inhibitors ?
Acarbose
Miglito
MoA of α-Glucosidase inhibitors ?
Competitive inhibitor of α-glucosidase
> > block postprandial digestion, absorption of starch, disaccharides from small intestine
> > inhibits glucose absorption
Indication of α-Glucosidase inhibitors ?
Combo therapy to control glucose
Weak anti-diabetic effect, no hypoglycaemia
No effect on body weight
ADR of α-Glucosidase inhibitors ?
Not absorbed into the bloodstream
Local GI ADR:
Flatulence
Diarrhoea
Abdominal pain/cramp
Name 2 Sodium glucose transporter protein-2 (SGLT2)
inhibitors?
Dapagliflozin
Canagliflozin
MoA of SGLT-2 inhibitors?
Act on kidney (proximal tubule):
Decrease active glucose reabsorption
> > increase urinary
glucose excretion
Indication of SGLT-2 inhibitors? ADR?
Decrease CVD mortality and morbidity
Control Type 2 DM
Genital infection Polysuria
Which anti-diabetic drug can cause MALA? Explain the mechanism.
Metformin: Metformin-asso.-lactic-acidosis: rare, fatal
Inhibition of Pyruvate dehydrogenase, mitochondria transport of reducing agents
» Enhance anaerobic metabolism»_space; turn pyruvate into lactate
