Anti-Diabetic Drugs Flashcards
Cell Types in Islets of Langerhans in the Pancreas
- A (α2) cells secrete glucagon
- B (β) cells secrete insulin (& amylin); these comprise 70% of islet cells
- D (α1;D) cells secrete somatostatin
- F (PP) cells secrete pancreatic polypeptide
Insulin
processing
- intended for fuel storage (energy conservation)
- decreases blood sugar
- increases glucose uptake
- increases glycogen storage
- decreases gluconeogenesis
- decreases glycogen breakdown
Processing of insulin:
- Preproinsulin
- Proinsulin
- Insulin & C-Peptide
Insulin Structure: 51 AAs, 2 chains (A,B) linked by disulfide bonds
C-Peptide: Can be a measure of endogenous insulin (vs. exogenous)
Glucagon
- intended for fuel mobilization (energy use)
- increases blood sugar
- stimulates gluconeogenesis & glycogenolysis
- stimulates lipolysis
Mechanism of Insulin Release from Pancreatic Beta Cells
** Glucose uptake via Glut2 transporter in beta cell
→ glycolysis
→ production of ATP
→ block of K+ channel (puts cell in depolarized state)
→ depolarization
→ Ca2+ influx
→ insulin release
Stimulators of Insulin release (& biosynthesis)
Nutrients:
- glucose (direct & permissive)
- fatty acids, ketone bodies
- amino acids (Arg, Leu, Gly)
GI Hormones
- Secretin; Enteroglucagon
- Incretins: GLP‐1 & GIP
Parasympathetic stimulation (& muscarinic agonists)
Beta‐2 receptor agonists
Food intake > IV Glucose: due to stimulation of vagus and release of GI hormones
Inhibitors of Insulin release
- Sympathetic stimulation (via NorEpi α2 receptors) (note: Beta-2 receptors stimulate)
- Somatostatin
- Insulin (negative feedback)
- Beta receptor blockers
- Amylin (released from β cells)
Insulin Receptor Activation
2 subunits - α: extracellular; binding pocket - β: transmembrane; enzymatic activity
Ligand binding causes dimerization (2
αβs combine) and autophosphorylation
(receptor activation)
Activated receptor acts as TYROSINE KINASE
- Multiple intracellular substrates
- A major substrate is IRS‐1
Glucose Transporters
- Mainly GLUT 2 and GLUT 4
GLUT2: transporter in Beta cells that regulate insulin release
- least sensitive (high Km): only want activation at high blood glucose levels
- also found on liver cells: site of glycogenesis
GLUT4: Insulin-mediated glucose uptake in muscle & fat cells
- lowers blood glucose
- promotes energy storage
Primary Treatment for Type 1 Diabetes
Insulin Replacement Therapy
- today recombinant products dominate
- Normally injected s.c.; in emergency i.v. or i.m. can be used
- Different kinetics than physiological insulin
Strategy: Use mixture of forms throughout day:
- Bolus: short‐acting at meals
- Basal: longer-acting for continuous effects
- Monitor response via blood glucose or glycated hemoglobin
“Dawn effect”
- during sleep there is a metabolic pattern that leads to a surge in blood glucose levels prior to awakening
- use long-acting insulin preparation to ensure sufficient insulin levels overnight to compensate for Dawn Effect
Adverse Effects of Insulin
Major: hypoglycemia (<70 mg/dl; too high &/or mistimed dose)
- can be reversed by glucose or glucagon
- exacerbated by alcohol, beta blockers, salicylates
- many symptoms; can be serious, even fatal; associated w/ dementia in later life
Other: Hypersensitivity reactions; lipoatrophy; lipohypertrophy
Insulin responses to glucose challenge
Normal:
- biphasic response: Initial large peak of insulin; followed by second peak in insulin
Type 1: No rise in insulin
Type 2: No peak in 1st phase
First Line Therapy for Type 2 Diabetes
- exercise & weight control
- Dietary restriction
- If not sufficient, add drugs (Metformin)
- Insulin typically not used initially, but can be added as disease progresses to include beta cell fatigue, degeneration
Metformin (Biguanide)
- an INSULIN SENSITIZER (enhances effect of insulin)
- Considered first‐line drug for Type 2 diabetes; often used in combination with oral antidiabetics with different mechanisms
Mechanism: activates AMP‐dependent protein kinase (AMPK) in LIVER; result: - ↑ fatty acid oxidation - ↑ glucose uptake: lowers blood sugar - ↓ lipogenesis - ↓ gluconeogenesis
Benefits:
- Not hypoglycemic
- No weight gain (may be small weight loss)
- Demonstrated to inhibit microvascular complications
Negatives:
- GI effects common
- Abdominal pain, diarrhea, metallic taste
- Typically abate over time
- Avoid ethanol, conditions that may yield lactic acidosis (rare but serious)
CONTRAINDICATED in:
- acute heart failure
- renal insufficiency
Glypizide (Sulfonylureas)
Mechanism: Bind to and inhibit ATP‐sensitive K+
channel
-Channel made of two separate proteins; one named “SUR1” binds sulfonylureas
- Blockade of K+ efflux causes depolarization and Ca2+ influx
- Result: enhanced release of insulin from β cells
Therapeutic effect:
- Acute: enhanced glucose‐stimulated insulin release
- w/ chronic Tx: insulin levels return to pretreatment, but reduced plasma glucose is maintained
- gradual loss of response after 5 yrs of tx (possibly due to Beta cell degeneration)
Side Effects:
- HYPOGLYCEMIA is major problem, esp. in elderly; Hypoglycemia risk increased with many drugs, including NSAIDS, salicylates; ethanol; beta blockers (can mask symptoms)
- Weight gain
- Avoid in pregnancy: fetal hypoglycemia; teratogenicity
Repaglinide (Meglitinides)
Mech (same as sulfonylureas): block ATP‐K+ channel, stimulate insulin release
- Used alone or with metformin or TZDs
- Compared to sulfonylureas: shorter acting; T ½ 1 hr
- Can give quicker response w/ meals, but, must take 3x/day
Adverse effects like sulfonylureas:
- Hypoglycemia
- Weight gain
- Possible drug interactions w/ inhibitors or inducers of CYP3A4 (clarithomycin; rifampin)
Pioglitazone (Thiazolidinediones)
Mech: Binds to & activates PPARγ (nuclear receptor proteins) in ADIPOCYTES, causing altered gene expression
- Increase in glucose transporters
- Increase in adiponectin
- Increase in FFA transporters
- Increase in lipid metabolic enzymes
- Decrease in resistin (normally released from adipocytes; contributes to insulin resistance)
Therapeutic:
- Not hypoglycemic
- Act at target tissues to decrease insulin
resistance and improve glucose metabolism
Net effects: enhanced insulin sensitivity
- ↑ uptake & utilization of glucose and FFAs
- ↓gluconeogenesis
- ↓ lower insulinemia
- improved fasting & postprandial hyperglycemia
ALSO:
- demonstrated anti‐inflammatory effects
- For pioglitazone: improved lipid profile; anti‐atherosclerotic effects by lowering triglycerides and increasing HDL
- Onset of actions slow; may be 1‐3 months for maximal effect
Common side effects:
- Fluid retention, edema
- mild anemia
- Increased appetite; weight gain
- Decreased bone density; risk of fractures
- Increased risk of congestive heart failure (contraindicated in CHF)
- TZDs other than Pioglitazone may increase risk for MI
mechanisms linking obesity to type 2 diabetes
Adipocytes release various signaling molecules:
increase insulin sensitivity:
- leptin
- adiponectin
increase insulin resistance:
- TNF‐α
- FFAs
- resistin
Diabetics show lower levels of leptin & adiponectin,
and higher levels of TNF‐α, FFAs and resistin
Incretins
- GI hormones released from gut upon feeding
GLP‐1 (=glucagon‐like peptide) & GIP (gastric inhibitory peptide) enhance glucose‐mediated insulin release - decrease glucagon release - increase beta cell number & function - lower appetite - slow gastric emptying
Drugs that mimic these hormones provide a novel strategy for treatment of Type 2 diabetes
- can act directly
- Or act to inhibit breakdown of GLP-1 by DPP‐4
Exenatide
- Direct acting GLP-1 Analog
- subcutaneous injectable dosage forms
- must be kept cool; expensive
- Exenatide 2x daily injections; Bydureon® : once‐weekly injection of exenatide
- Primary adverse effects: GI distress, urticaria
- Drug interactions (due to slower gastric emptying)
Sitagliptin
- DPP‐4 inhibitor (indirect; enhance endogenous GLP‐1)
Main adverse effects:
- Respiratory: runny nose, sore throat, upper respiratory infection
- Headache
- GI: nausea, constipation
- hypoglycemia
- Reports of serious allergic / hypersensitivity (incl. Stevens‐ Johnson syndrome)
Acarbose
- α-glucosidase inhibitors: Inhibit brush‐border enzyme in gut
- This interferes w/ starch hydrolysis &
carbohydrate absorption - Blunts post‐prandial rise in blood glucose
- Used alone or w/ sulfonylureas
- GI effects common (bloating, diarrhea)
- Decreased iron absorption and bioavailability of metformin
