Endocrine Pancreas and Antidiabetic Drugs Flashcards
Describe the endocrine pancreas
- The pancreas lies in close contact with the stomach and small intestine; most of the gland is made up of cells that secrete digestive juices for the intestinal tract
- The hormone-secreting cells are arranged in small islets, called the Islets of Langerhans, scattered throughout the pancreas
- Pharmacology of insulin, glucagon and other major hormones that control glucose homeostasis
- Diabetes
- Hypoglycemia (factor of diabetes)
- Hyperinsulinemia
Describe insulin release
- Insulin release is not controlled by the pituitary
- Produced by β cells of Islets of Langerhans (pancreas)
- Released primarily in response to glucose
- Also vagal and β2- adrenergic stimulation,
- Leucine, arginine, and various GI hormones - Inhibited by somatostatin and ⍺-adrenergic stimulation
- Insulin circulates as free-monomer; short half-life of 3-5 minutes; metabolized mainly by liver
Describe Photo:
→ When no glucose, open ATP channel and low release of insulin from β cells
→ When glucose enters the cell via glucose transporter, hexokinase phosphorylates ATP to ADP which closes the channel, this induces depolarization of the membrane, which induces the opening of the calcium channel, calcium binds to granules that contain insulin and release the insulin outside the cell
Describe the insulin receptor
Tyrosine kinase on β subunit will phosphorylate β subunit which will induce phosphorylation of IRS which will induce the proper action/function of insulin
Describe insulin actions and effects in liver, skeletal muscle and adipose tissue
- Insulin is the primary hormone responsible for:
1. Uptake
2. Utilization
3. Storage of cellular nutrients - Insulin binds to membrane receptors possessing tyrosine kinase activity to produce cellular effects
Liver: - Promotes glucose uptake and storage as glycogen
- Increases fatty acid synthesis from glucose to be transported to adipocytes for storage
Skeletal muscle: - Promotes protein synthesis from amino acid uptake
- Increases glucose uptake and storage as glycogen
Adipose tissue: - Increases triglyceride synthesis and storage from fatty acids and glycerol
Clinical Applications - what is Type 1 and Type 2 Diabetes Mellitus?
Type 1:
- Marked by β-cell destruction with severe to absolute insulin deficiency
- Childhood/puberty onset
- Immune-mediated or idiopathic (unknown cause)
- Clinical signs: persistent hyperglycemia, polyuria polydipsia and weighty loss
- Possible ketoacidosis with severe diabetes
- Insulin therapy is required
Type 2 (most common form):
- Marked by tissue resistance to the action of insulin combined with a relative disease in insulin secretion (receptor not functioning properly)
- Usually older onset and obesity present
- Similar signs to Type 1, but less severe
- May not require insulin, bit may benefit from it
- Individuals may go on to become Type 1 diabetics
- Lifestyle changes and oral hypoglycemic agents are crucial for treatment
In preparation of insulin describe the duration of action: theoretical basis
- Regular insulin aggregates as a hexamer coordinated by zinc
- Lispro – penultimate lysine and proline residues order inverted
- Aspart – one proline changed to aspartate
- NO effect on receptor binding, but release into blood as monomer increased, therefore faster acting
- Lente insulin and ultralente insulin are suspensions of zinc aggregates in acetate buffer – insulin monomer is slowly released
- NPH insulin is insulin complexed with a basic protein (protamine) which modulates its release
- Glargine insulin has one asparagine in the A chain replaced by glycine and two arginine’s are added to the C-terminus of the B-chain; very slow release into the blood, slow metabolism, once a day injections are often sufficient
In preparation of insulin describe the duration of action: Short-acting
- Short-acting (rapid acting)
- Regular insulin, “lispro” (Lilly), “aspart” (Novo-Nordisk)
- Lispro and aspart have very fast onset and short duration of action
- Formulated as solutions, zinc, no added protein, +/- buffer (pH 7.2-7.4)
- Used to cover prandial (mealtime) hyperglycemia and emergencies
- Lispro and aspart dissociate to monomers very quickly
In preparation of insulin describe the duration of action: Intermediate-acting
- NPH (neutral protamine Hagedorn) and Lente
- Formulated as cloudy suspensions with buffers and zinc
- Used to cover basal and prandial hyperglycemia
In preparation of insulin describe the duration of action: Long-acting
- Long-acting (slow-acting)
- Ultralente insulin and insulin glargine are long-acting formulations; coverage up to 24h
- Ultralente is cloudy and buffered while glargine is clear with no buffer
- Both have higher [Zn] concentrations – aggregates
- Glargine is very slow acting, and peakless
- Used to provide basal insulin coverage over the day
What are the goals of insulin therapy
- Near-normalize blood glucose and metabolism
- Fasting blood glucose (90-120 mg/dL)
- Post-prandial blood glucose (<150 mg/dL) - Maintain diet, exercise, insulin therapy and monitoring
- Blood glucose and hemoglobin A1c level monitoring - Prevent long-term problems – blindness, kidney disease, peripheral nerve damage, and cardiovascular disease
- Hyperglycemia is a major risk factor for problems
What are the regimens used in insulin therapy?
- “Basal-bolus” regimen; most popular
- Basal administration of intermediate (or long-acting) before breakfast or bedtime
- Prandial injections of short-acting insulin
- Lispro or Aspart - “Split-mixed” regimen
- Pre-breakfast and pre-supper mix of short-acting and intermediate-acting insulins
- Premixes available; NPH + lispro and NPH + aspart
What are the complications of insulin therapy?
- Hypoglycemia (most common complication) – low glucose
Causes:
- Inadequate food (CHO – carbohydrate) intake; mismatch
- Increased exertion
- Too large insulin dose
- Other diseases
- Glucagon and epinephrine release by body counter decre4ased blood glucose levels and reverse effects
Symptoms:
- Increased autonomic activity prevails
- Sympathetics: tachycardia, sweats, tremors
- Parasympathetics: hunger, nausea
Treatment:
- Mild (glucose PO) vs severe (glucose IV)
- Can progress to coma and death if untreated - Immunopathology
- Partial insulin resistance can develop from IgG anti-insulin antibodies in most diabetics
- Rarely a clinical problem with human insulin forms
What are the four classes of Oral Hypoglycemic Agents?
- Insulin Secretagogues → Sulfonylureas & Meglitinides
- Insulin Sensitizers → Biguanides & Thiazolidinediones
- Alpha glucosidase inhibitors (Acarbose)
- Incretins
What are the oral hypoglycemics insulin secretagogues?
Oral Hypoglycemic Agents: Type 2 diabetes – where some β-cell activity is still present
1. Insulin Secretagogues → Sulfonylureas & Meglitinides
- Bind and inhibit β-cell ATP-sensitive-K+ channels – leads to cell depolarization and insulin release
- Type 2 patients where diet change alone is insufficient
- General caution with hypoglycemia; particularly elderly and patients with liver or kidney disease/failure
Sulfonylureas (Glyburide, Glipizide):
- 2nd generation compounds prevail over earlier agents
- More potent than 1st generation agents
- Longer-acting agents; once daily dosing possible
- Less adverse effects
Meglitinides (Repaglinide):
- Rapidly absorbed and have a short half-life
- Allows for multiple pre-prandial use
- Used in combination with longer-acting agents
- Less hypoglycemia seen than with sulfonylureas
What are the oral hypoglycemics insulin sensitizers?
- Insulin Sensitizers → Biguanides & Thiazolidinediones
- Require insulin, but do not promote its release
Biguanides (Metformin):
- Reduces hepatic gluconeogenesis (in liver) and increases insulin utilization by peripheral target cells (muscle, fat)
- Used alone or in combination with the secretagogues
- Also used with insulin therapy
Thiazolidinediones (Pioglitazone):
- Act to decrease peripheral insulin resistance
- Are ligands at the peroxisome proliferator-activated receptor-gamma (PPAR-γ); regulate genes for lipid and glucose metabolism including glucose transporters
- Because actions involve gene transcription – slow onset
- Are used alone or as additions to other agents and insulin
What are the oral hypoglycemics incretins?
- Natural hormones that enhance the insulin response to rising plasma glucose
- Increase the sensitivity of the pancreas to rising glucose, increasing insulin release, as well as increasing sensitivity to insulin while decreasing appetite
- Since high free fatty acid levels decrease insulin sensitivity, all these actions oppose the pathology underlying type 2 diabetes
- Two ways to increase incretin levels:
1. Inhibit the enzyme that breaks them down (DPP-4 inhibitors, small molecules, orally active)
2. Inject long acting analogs (Liraglutide, or exendin – main disadvantage, they can’t be taken orally)
