ERS42 Insulin And Oral Anti-diabetics Agents Flashcards
Blood glucose homeostasis
Controlled within narrow range
Input:
- Food intake (Postprandial)
- Glycogen breakdown (Short term fasting)
- Gluconeogenesis (Long term fasting)
Output:
- Energy supply
- Glycogen storage (Short term output)
- Lipid synthesis (Long term output)
Both Hyperglycaemia / Hypoglycaemia are harmful
Hyperglycaemia:
- Macrovascular / Microvascular complications
1. Stroke
2. Gangrene
3. Heart attack
4. Nephropathy
5. Neuropathy
6. Retinopathy
Hypoglycaemia:
- Fatigue
- Nausea
- Dizziness
- Coma
- Confusion
Normal glucose level
2 hours oral glucose level <11.1
Fasting blood glucose 4-7
Classification of DM
Type 1:
- Autoimmune destruction of β cells
- Insulin dependent (IDDM)
- Lack of insulin production
- Onset usually before 20 yo
- Absolute requirement for exogenous insulin
Type 1B:
- Idiopathic
Type 2:
- Major form (>90% of Asian)
- NIDDM
- Combined defect of insulin secretion and insulin resistance
- Obesity-associated
Gestational (GDM):
- Pregnancy-associated
Latent autoimmune diabetes (LADA) (1.5 type):
- > 10%
- caused by Type 1 + Type 2
Maturity Onset Diabetes of Young (MODY):
- caused by genetic mutation
Strategies for management of Diabetes
Type 1:
- Diet
- Exercise
- Insulin
Type 2:
- Diet
- Exercise
- Anti-diabetic drugs
- Insulin
GDM:
- Diet
- Anti-diabetic drugs
- Insulin
Insulin
Indication:
- ALL Type 1 (except those with β cell transplantation)
- 1/3 Type 2
- GDM
Endogenous insulin:
- **Short t1/2 in circulation (~5 mins)
- Quick action
- Rapidly released from β cell granules upon stimulation of nutrients (Glucose, Fatty acids etc.)
—> pattern of insulin secretion almost identical to glucose profile (齊上齊落)
—> Goal of insulin treatment: **Mimic natural endogenous insulin secretion
—> ***Basal-bolus insulin
Criteria for Basal + Bolus insulin preparations
Basal insulin:
- Mimic normal pancreatic basal insulin secretion
- Long lasting effect: >= 24 hours
- Smooth, peakless profile
- Reproducible, predictable effects
Bolus insulin:
- Rapid onset of action: to be given just before meals
- Short duration of action: to avoid Hypoglycaemia
- Reproducible, predictable effects
***4 principal types of Insulin preparations
- Short acting:
- Regular human insulin - Rapid onset, Ultrashort-acting (peak within <15 mins):
- Lispro
- Aspart - Intermediate acting:
- Protamine (NPH)
- Lente - Long acting:
- Glargine
- Detemir
ALL produced by recombinant DNA technology using special strains of E. Coli / Yeast as expression system
- Short acting: Regular human insulin
***Humulin, Novolin
Features:
- Standard insulin without any mutation
- Crystalline ***zinc insulin in soluble form
- **Self-aggregate in antiparallel fashion —> form **Dimers —> stabilise around Zinc ions —> ***Hexamers
- Hexameric nature (inactive) causes delayed onset (only Monomer / Dimer can bind to Insulin receptor) —> prolong time to peak actions
Effect:
- Onset: <30 mins
- Peak: 1-2 hrs
- Duration: 5-8 hrs
Use:
- Management of ***Diabetic ketoacidosis
- When insulin requirement is changing rapidly (post-surgery / acute infection)
Administration:
- SC/IM
- IV (so can constantly adjust amount)
Limitations for bolus injection:
- Slow onset (∵ self aggregation)
—> ***inconvenient administration (20-40 mins before meal)
—> risk of hypoglycaemia if meal further delayed
—> mismatch with postprandial hyperglycaemia peak
- Long duration
—> up to 12 hrs
—> ***potential for late postprandial hypoglycaemia
- Rapid onset, Ultrashort-acting: Lispro
***Lispro: Humalog (by Eli Lily)
Features:
- Produced by reversing 2 a.a. near carboxyl terminal of B chain (**Proline 28, Lysine 29)
—> prevents hexameric formation of insulin, but does not affect receptor binding activity
—> able to achieve **rapid onset
—> closely **mimic endogenous postprandial insulin secretion
—> improved **postprandial glucose control without risk of hypoglycaemia between meals
Effect:
- Onset: 10-15 mins
- Peak: 30-60 mins
Use:
- Taken just before meals
- Rapid onset, Ultrashort-acting: Aspart
***NovoLog (Novo Nordisk)
Features:
- Produced by substitution of B chain Proline 28 with -ve charged ***Aspartic acid
- Rapidly ***breaks into monomer after SC injection
Effect:
- Onset: 10-20 mins
- Peak: 1 hr
- Duration: 2-4 hrs
- Intermediate acting: Protamine (NPH) + Lente
Neutral Protamine Hagedorn (NPH):
- mixture of Insulin + ***Protamine
Lente insulin:
- 30% Semilente + 70% Ultralente (poorly soluble crystal of ***Zinc insulin with delayed onset and prolonged duration)
Features: Insulin ***bound to Zinc / Protamine —> slowly dissolve in body fluids —> prolong t1/2 —> facilitate control of glycaemia over extended period (peak 4-10 hr)
Effect:
- Peak: 4-10 hrs
- Duration: 10-18 hrs
- Long acting: Glargine
***Lantus (Sanofi-Aventis)
Features:
- Attachment of **2 Arginines to B chain carboxyl terminus + Substitution by Glycine 21 for **Asparagine 21 at A chain
—> **shift Isoelectric point to pH 7.0 (~physiological pH)
—> Low solubility at pH 7.0
—> **precipitates in SC milieu after injection
—> stabilising insulin hexamers
—> ***delaying hexamer dissociation
—> slow, consistent absorption into systemic circulation
—> ultra-long-acting
Effect:
- Peak: NO peak (clear solution - no zinc in formula)
- Duration: >=24 hrs
Use:
- OD at bedtime
- Long acting: Detemir
Levemir (Novo Nordisk)
Features:
- Add **Myristic acid (a fatty-acid moiety) to **Lysine a.a. at position B29
- Threonine in B30 omitted
—> when enter circulation
—> fatty acid causes Detemir to ***bind to Albumin
—> slow release, extended circulating life
Effect:
- t1/2: 23 hours
Mode of Insulin administration
Current:
- SC / IM
- Insulin pump (precise control of insulin delivery)
Trial
- Transdermal
- Inhalation
- Oral
- Pancreatic transplantation / Stem cell therapy
(Insulin pump)
(Continuous SC insulin infusion device (CSII)
Major components:
- Pump
- Disposable reservoir for insulin (inside pump)
- Disposable infusion set (Cannula for SC insertion, Tubing system to interface insulin reservoir to cannula))
Key points for using insulin preparation to treat diabetes
- Keep blood glucose relatively normal but avoid Hypoglycaemia / Ketoacidosis
- Balance Dose / Timing of insulin injections with Content of meals / Amount of physical activity
- Requiring that patient be educated about their disease + monitor blood glucose at home
Complications of insulin therapy
- **1. Hypoglycaemia
- confusion, weakness, coma
- Treatment: Glucose administration
- **2. Lipodystrophy at injection sites
- corrected by Multi-site injection
- Insulin allergy / Immune resistance
- rare now due to genetic engineering —> improvement in insulin presentation - Abuse
- long term risks: Development of Type 2 DM
- potential lifetime dependency on exogenous insulin
Glucose tolerance test
Normal:
- go up then back to normal within 2 hours
Type 2 DM: - basal glucose level already higher - glucose challenge: marked ↑ in glucose - glucose level not returned to baseline after 4-5 hours —> Glucose intolerance
Insulin secretion in Type 2 DM
Normal:
- 1st phase: sharp ↑ (for ↓ postprandial glucose)
- 2nd phase: small ↑
Type 2 DM:
- No 1st phase
- 2nd phase: normal
***Major Anti-diabetic drugs
- **↑ Insulin secretion by residual β cells:
1. Insulin secretagogues - Sulfonylureas (Glipizide, Glimepiride)
- Meglitinide analogs (Repaglinide, Nateglinide)
- Incretin mimetics
- Glucagon-like peptide (GLP) analogs (Exenatide, Liraglutide) - DPP-4 (Dipeptidyl peptidase-4) inhibitors (Sitagliptin, Vidagliptin)
- **↑ Insulin sensitivity:
4. Biguanides (Metformin)
5. Thiazolidinedione (Rosiglitazone, Pioglitazone) - **↓ Glucose absorption:
6. α-Glucosidase inhibitors (Acarbose, Miglitol) - **↑ Glucose excretion:
7. SGLT2 inhibitors (Dapagliflozin, Canagliflozin)
Sulfonylureas
1st generation: Chlorpropamide, Tolbutamide (no longer used ∵ long duration + SE)
2nd generation: **Gliclazide, **Glipizide, ***Glibenclamide (more commonly used ∵ fewer SE, DDI)
MOA:
Bind to 140kDa high affinity receptor associated with β cell inward-rectifier ATP-sensitive K channel
—> ↑ insulin secretion from β cells
Effect:
- ***Long duration: 12-48 hours
Use:
- Type 2 patients with ***residual β cell function
- Adjunctive to nutritional + exercise therapy
- Primary failure: 20-25% of newly diagnosed diabetics will fail to respond to initial sulfonylurea therapy
- Secondary failure: 3-5% ***lose responsiveness every year
SE:
- ***Stimulate appetite (∵ insulin secretion?) —> Weight gain (∵ sulfonylurea ↓ glucose excreted in urine —> glucose reabsorbed —> fat)
- ***Hypoglycaemia (∵ Long acting, esp. Hepatic / Renal insufficiency)
- GI upset (give with food)
- rashes
- traverse placenta, deplete insulin from fetal pancreas
Non-Sulfonylurea secretagogue: Meglitinide analogs (Repaglinide, Nateglinide)
***Repaglinide, Nateglinide
MOA (~ Sulfonylurea):
Bind to ***distinct site on Sulfonylurea receptor of ATP-sensitive K channel
—> stimulate very rapid + transient insulin release
—> action also depend on functioning β cells
Vs Sulfonylurea:
- Onset: ***Rapid
- Duration: ***Short (~2 hrs)
Advantage over Sulfonylurea:
- Good for controlling ***postprandial glucose
- Incidence of Hypoglycaemia much lower
Disadvantage:
- Minimal effect on overnight / fasting glucose levels
Incretins
- ***Gut-derived hormones
- **GLP-1, **GIP (secreted by ***L cells of Enteroendocrine cells)
- Very short t1/2 (1-2 mins) due to ***rapid degradation by DPP4
Action:
- ***↑ Glucose-dependent Insulin synthesis/secretion (act on β)
- ***↓ Glucagon release (act on α cells)
- Incretin mimetics
- Glucagon-like peptide (GLP) analogs (Exenatide, Liraglutide)
- **Exenatide:
- ***GLP-1 agonist
- for Type 2 DM
- synthetic version of exendin-4 (hormone in Gila monster saliva)
- 53% homology with GLP —> ***↑ resistance to degradation by DPP4 —> longer t1/2
- Slow down gastric emptying + Appetite suppression —> ***Weight loss
- also ↓ Fatty liver
- **Liraglutide:
- GLP-1 analog (by Novo Nordisk)
- ***Long acting
- adding Palmitic acid chain with a Glutamic acid spacer on Lysine residue at position 26 to improve pharmacokinetic effects
- ***Weight loss: ↓ Body weight by up to 10 kg
- DPP-4 (Dipeptidyl peptidase-4) inhibitors (Sitagliptin, Vidagliptin)
Sitagliptin (Januvia), Vidagliptin
DPP-4: cut 2 a.a. residues at N terminal of GLP-1
MOA:
Inhibit DPP-4
—> ↑ active GLP-1
Use:
- Monotherapy / Combination therapy with other drugs
- Long term blood glucose control
SE:
- ***URT infection
- sore throat
- diarrhoea
- Biguanides (Metformin)
***1st line of Anti-diabetic drug
MOA (Not clearly known):
Liver
—> Activation of **AMP-activated protein kinase (AMPK)
1. ↓ Gluconeogenic genes (PEPCK, G6Pc) —> ↓ Hepatic glucose production —> ↓ **Hyperglycaemia
2. ↓ Fatty acid synthesis, ↑ Fatty acid oxidation —> ↓ ***Hyperlipidaemia
3. Modulate gut microbiota
Use:
- ***Obese patients / patients with insulin resistance
- ↓ risk of CVS complications —> prolong lifespan
- ↓ incidence of Diabetes-related cancers
SE:
- GI upsets
- **Lactic acidosis (rare but potentially fatal)
—> perhaps ∵ **inhibition of Pyruvate dehydrogenase activity and Mitochondrial transport of reducing agents
—> ↑ Anaerobic metabolism
—> ↑ Pyruvate to Lactate conversion
CI:
- Renal disease
- Hepatic disease
- Alcoholism
- Severe infection
Long term use: ***Vit B12 deficiency (overcome by simultaneous B12 supplement)
- Thiazolidinedione (Rosiglitazone, Pioglitazone)
***Most potent insulin-sensitising drugs
Major action site: ***Adipose tissue
MOA:
Major molecular target:
**PPARγ (Peroxisome proliferator-activated receptor γ) (nuclear hormone receptor)
—> Bind to PPARγ
1. **↓ Insulin resistance of adipocytes
2. **↑ Fatty acid uptake by adipocytes —> Improve lipid profile
3. Preferential differentiation of pre-adipocytes to SC rather than visceral (i.e. abdominal) adipocytes
4. **Anti-inflammatory properties
SE:
- ***Weight gain (∵ ↑ adipogenesis)
- Fluid retention
- ***↑ risk of heart attack (Rosiglitazone)
- ***possible bladder cancer (Pioglitazone)
CI:
- ***Heart disease
Use:
- Potential use in prevention of Type 2 DM
- α-Glucosidase inhibitors (Acarbose, Miglitol)
***Acarbose, Miglitol
MOA:
**Inhibit α-Glucosidase through competition with substrate
—> **block postprandial digestion + absorption of starch / disaccharide from small intestine
—> ↓ glucose + insulin levels after meals
Advantages:
- ***NOT cause Hypoglycaemia (only act in GI tract)
- NO effect on body weight
- NOT absorbed into blood
Disadvantage:
- weak effect —> need to use in combination with other drugs
- not particularly effective in Caucasian’s diet
SE:
- ***Flatulence, diarrhoea, abdominal pain
- SGLT2 inhibitors (Dapagliflozin, Canagliflozin)
Dapagliflozin, Canagliflozin, Empagliflozin
MOA:
↓ Glucose reabsorption via inhibiting **SGLT2 in **Proximal tubule
—> ↑ Glucose excretion
Advantages:
- potential ↓ CVS disease
SE:
- ***UTI
***Summary of Antidiabetic drugs
- Sulfonylureas (Glipizide, Glimepiride)
- Pancreatic β cells
- ↑ insulin secretion
- Weight gain, Hypoglycaemia - Meglitinide analogs (Repaglinide, Nateglinide)
- Pancreatic β cells
- ↑ insulin secretion
- Weight gain, Hypoglycaemia (rare compared to SU) - Incretin mimetics (GLP analogs / agonists) (Exenatide, Liraglutide)
- Pancreatic α + β cells
- ↑ Insulin secretion + ↓ Glucagon secretion
- Weight loss
- GI disorder, dizziness, headache - DPP-4 (Dipeptidyl peptidase-4) inhibitors (Sitagliptin, Vidagliptin)
- Gut
- ↑ GLP-1 levels by inhibiting DPP4
- URT infections, sore throat, diarrhoea - Biguanides (Metformin)
- Liver
- ↓ Hepatic Glucose production —> ↓ Hyperglycaemia
- ↓ Fatty acid synthesis, ↑ Fatty acid oxidation —> ↓ Hyperlipidaemia
- ***Lactic acidosis, GI disturbance, B12 deficiency - Thiazolidinedione (Rosiglitazone, Pioglitazone)
- Adipose tissue, muscle, liver
- Bind to PPARγ to ↓ Insulin resistance + ↑ Fatty acid uptake + Anti-inflammatory
- Weight gain, fluid retention, ***CVS risk - α-Glucosidase inhibitors (Acarbose, Miglitol)
- Gut
- ↓ Glucose absorption
- Flatulence, diarrhoea, abdominal cramping - SGLT2 inhibitors (Dapagliflozin, Canagliflozin)
- Kidney
- ↑ Glucose excretion by inhibit glucose reabsorption
- UTI
Stepwise management of Type 2 DM
Diet + Exercise
—> Monotherapy
—> Combination
—> Insulin +/- Anti-diabetic drugs
