Insulin Preparations for Diabetes Mellitus Therapy Flashcards
What do alpha cells secrete?
Glucagon
What is the function of Glucagon?
Increase blood glucose
What do beta cells secrete?
Insulin and amylin
What is the function of Insulin?
Decrease blood glucose
What is the function of amylin?
Suppress glucagon release; delay gastric emptying and decrease food intake
What do delta cells secrete?
Somatostatin
What is the function of somatostatin?
Inhibit insulin & glucagon secretion
What do F cells secrete?
Pancreatic polypeptide
What is the function of pancreatic polypetide?
Unknown
What is C-peptide used as?
used as marker for insulin secretion (can help distinguish between different types of diabetes)
What is the main factor that controls the synthesis and secretion of insulin?
Blood glucose concentration
What are the nutrient stimulants of insulin synthesis and secretion?
Glucose, amino acids, and fatty acids
What are the nutrient inhibitors of insulin synthesis and secretion?
Chronic elevations in glucose and fatty acids
what are hormone stimulants of insulin synthesis and secretion?
Glucagon-like polypeptide (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP)
What are the hormone inhibitors of insulin synthesis and secretion?
Somatostatin
What are the neural stimulants of insulin synthesis and secretion?
Parasympathetic (Vagal) activation
What are the neural inhibitors of insulin synthesis and secretion?
Sympathetic (alpha-2 receptor) activation
What are then drugs stimulants of insulin synthesis and secretion?
Sulfonylureas, meglitinide, nateglinide
What are the drug inhibitors of insulin synthesis and secretion?
Diaxozide
What is the insulin release like from beta cells (in low concentration of glucose) ?
- Low glucose
- Low ATP
- The ATP-sensitive K+ channels open when low concentrations of ATP
- The K+ leaves the cell, and it reaches the resting membrane potential
- The Ca2+ channels stay closed, and no calcium enters the cell
- No exocytosis is triggered and the insulin remains in the vesicles
Where is GLUT 5 found?
Gut and kidney
What is the function of GLUT5?
Absorption of fructose
What is insulin?
Anabolic hormone –> required for normal growth and protein synthesis
When is insulin secreted?
In response to increased blood glucose levels
How does insulin lower blood glucose levels?
- Increase in GLUT 4 mediated glucose uptake & utilization in skeletal muscle and adipose tissue
- Inhibition of liver gluconeogenesis and glycogenolysis and prevention of glucose release from the liver into the blood
- Stimulation of glycogen production, protein synthesis and triglyceride formation in target organs
What are the effects of insulin on the liver? (7)
Increase glycolysis
Increase glycogenesis
Decrease gluconeogenesis
Decrease glycogenolysis
Increase lipogenesis
Decrease lipolysis
Decrease protein breakdown
What are the effects of insulin on the adipose tissues? (5)
Increase glucose uptake
Increase glycerol synthesis
Increase triglyceride synthesis
Increase fatty acid synthesis
Decrease lipolysis
What are the effects of insulin on the skeletal muscle? (5)
Increase glucose uptake
Increase glycolysis
Increase glycogenesis
Increase amino acid uptake
Increase protein synthesis
Where is insulin secreted from?
Beta cells of Langerhans
What is insulin synthesized from?
Two precursors (preproinsulin and proinsulin)
What is insulin stored as?
Hexamers in secretory vesicles
How does insulin circulate?
As a free monomer with a half-life of about 5 minutes
Where does the degredation of insulin occur?
In the liver (60%) by Thiol metalloproteinase
In the kidney (40%) in the renal tubulses
Why is exogenous insulin usually administered parenterally?
Usually given as an SC injection because insulin is a protein that is rapidly degraded ORALLY
How can we measure insulin levels in blood when its half-life is only 5 minutes?
C-peptide has relatively longer half-life and it is used as a marker for insulin secretion
What is the half-life of C-peptide?
About 30 minutes
What insulin formulations were previously used clinically in humans?
Porcine and bovine but now “human” insulin made by recombinant technology is used instead
How is recombinant technology used for insulin formulations?
Amino acid sequence of insulin is being altered to produce analogues of insulin, which differ in their rate of absorption from the site of inection
How can the duration of action of short-acting, unmodified insulin be extended?
It can be extended by the addition of protamine and zinc at neutral pH or excess zinc ions
What is the appearance of the modified “depot” insulins?
It goes from a clear solution to cloudy preparations
What are the classifications of insulin preparations? (5)
- Rapid-acting (very fast onset & short duration)
- Short-acting (rapid onset of action)
- Intermediate-acting (intermediate onset & duration)
- Long-acting (slow onset and long duration)
- Pre-0mixed Insulins (Intermediate and rapid/short-acting insulin)
What are examples of rapid-acting insulins?
Insulin lispro
Insulin aspart
Insulin glulisine
What are examples of short-acting insulins?
Regular soluble insulin
What are examples of intermediate-acting insulins?
Neutral Protamine Hagedorn or Isophane (NPH) insulin
What are examples of long-acting insulins?
Insulin glargine
Insulin detemir
Degludec (Ultra-long acting)
What are examples of the Pre-mixed insulins?
70 NPH/30 Regular
70 NPA/30 Aspart
75 NPL/25 Lispro
What are the properties of rapid-acting insulins?
Amino acids are modified to favor dissociation and aid absorption from the injected site
What are the properties of short-acting insulins?
Contains small amounts of zinc to improve stability and shelf-life
What are the properties of intermediate-acting insulins?
Complexed with protamine to delay absorption from injected site
What are the properties of long-acting insulins?
Amino acids are modified to delay absorption from injected site
What is the administration of rapid-acting insulins like?
Insulin is administered as a monomer, and it can go into the bloodstream straight away and thus act rapidly
Mimics beta cell release of insulin in response to a meal
At what pH is Insulin Glargine formulated?
pH 4
What is the administration of Insulin Glargine like?
It forms micro-precipitates at the physiological pH of SC tissue, which delays its absorption from the injection site
To provide a constant low-level of insulin
Which type of insulins can be administered before meal?
Prandial:
1. Regular (30 minutes before)
2. Lispro (Just before meal)
3. Aspart (Just before meal)
4. Glulisine (ust before meal)
When are Basal Insulins given?
Once or twice daily
Which is the insulin choice in pregnancy?
NPH
Which basal insulins have low risk of nocturnal hypoglycemia compared to NPH?
Glargine
Detemir
When is Degludec given?
Once daily or thrice weekly
What are the clinical uses of insulin?
For the treatment of both Types 1 and 2
Short-acting (regular) insulin –> for the management of diabetic ketoacidosis
What are the adverse effects of insulin ?
Hypoglycemia
Weight gain
Lipodystrophy (atrophy of subcutaneous fat at the site of inaction)
Hypersensitivity (with local urticaria; rarely, anaphylaxis might occur)
What are the signs and symptoms of hypoglycemia?
Tachycardia
Palpitations
Sweating
Nausea
Hunger
May progress to convulsion and coma
What are the insulin regimens like?
–> The majority of patients will require more than one daily injection, however, a once a day intermediate injection may be effective
–> Twice-daily mixtures of short and intermediate-acting insulin are commonly used
What regimen is often given in the morning and what is it followed by?
Short and intermediate-acting insulin in the morning
Followed by further doses of short-acting given before lunch and dinner and an evening dose of intermediate-acting insulin given at bedtime
What is the action of long-acting basal-analogues of insulin like?
Onset: 2 hours
Peak: none
Duration: 18 to 24 hrs
What is the action of rapid-acting insulin-analogues like?
Onset: 0 to 15 minutes
Peak: 1 to 2 hours
Duration: 3 to 5 hours
What is the action of intermediate human isophane insulin like?
Onset: -
Peak: 4 to 8 hours
Duration: 14 to 16 hours
When are rapid-acting insulins taken?
Just before a meal or to lower blood glucose levels
When are short-acting insulins taken?
30 minutes before a meal or to lower blood glucose levels
When are intermediate-acting insulins taken?
Bedtime, or twice a day (morning and night)
When are extended long-acting analogues taken?
Usually once or twice daily
When are premixed analogues taken?
Depends on the combination
What is the self-care of diabetes like?
Patients should be educated to practice self-care:
1. Blood-glucose monitoring
2. Body weight monitoring
3. Foot-care
4. Personal hygiene
5. Healthy lifestyle
6. Identify targets for conrol
7. Smoking cessation
What is inhalable insulin?
Afrezza
Human insulin product that is rapidly absorbed upon inhalation
Who is inhalable insulin for?
For patients searching for non-parenteral insulin to take just before meals
What is the Pk of inhalable insulin like?
More closely resembles ultra-short-acting insulin
What may inhalable insulin cause?
Bronchospasms or cough (contraindicated in asthma and COPD)
How is inhalable insulin used in patients with Type 1 diabetes?
Must be used in combination with long-acting insulin
How is inhalable insulin used in patients with Type 2 diabetes?
COmbination with other anti-diabetes drugs
What are the different stages of Type 1 diabetes?
Stage 1
Stage 2
Stage 3
What is stage 1 of type 1 diabetes like?
An asymptomatic period defined by seroconversion with the presence of at least two diabetes-related autoantibodies but preserved normoglycemia
What is stage 2 of type 1 diabetes like?
Characterized by asymptomatic progression to dysglycemia
What is stage 3 of type 1 diabetes like?
Onset of clinical disease and is defined by glycemic criteria
What is Teplizumab therapy like?
Humanized, anti-CD3 monoclonal antibody, which is the only therapy with regulatory approval in the US for delaying the onset of clinical type 1 diabetes in individuals with the PRECLINICAL disease
What is Teplizumab therapy approved for?
For individuals aged 8 years or older who have stage 2 diabetes and in administered as a single 14-day course of daily IV infusions
What is the MOA of Teplizumab?
A monoclonal antibody that improves beta cell function via binding to the CD molecules on the surface of CD4+ and CD8+ T cells, both of which are involved in the destruction of pancreatic beta cells
What are the adverse effects of Teplizumab?
Transient lymphopenia,
Rash,
Anemia,
Fever
