Insulin

See Also

Definitions

Insulin
1. Insulin is a polypeptide produced by pancreatic beta cells, with release stimulated by Blood Glucose concentration
2. Insulin promotes energy utilization via Glycolysis, and energy storage as glycogen, Protein and Triglycerides
3. First used in Diabetes Mellitus in 1922, by Drs Banting and Best
Bolus Insulin (short-acting)
1. Similar to physiologic Insulin, with immediate onset (15-30 min) and short duration (2 to 4 hours)
2. Primarily covers short-term Blood Glucose spikes with meals
Basal insulin (long-acting)
1. Long-acting coverage to maintain Blood Glucose control throughout the day, between meals
2. Mimics the low level continuous Insulin release by a normal human Pancreas
3. Insulin Glargine (Lantus) and similar agents that last approximately 24 hours have largely replaced NPH Insulin (12 hour duration)
Insulin Analog
1. Historically, short-acting Regular Insulin has been sourced from animal Pancreas (pigs, cows)
2. As of the 1980s, human Insulins were synthesized in Bacteria
3. Synthetic Insulins have since been modfied for rapid onset bolus (e.g. Lispro) and longer-acting basal (e.g. Glargine)

Physiology

Images
Blood Glucose
1. Released from hepatic stores between meals
2. Derived from ingested Carbohydrates
  1. Postprandial Glucose >20 fold over hepatic release
Insulin
1. General
  1. Insulin is a polypeptide produced by pancreatic beta cells
  2. Insulin release stimulated by increased Blood Glucose concentration
  3. Insulin release is also stimulated by glucogenic Amino Acids (all Amino Acids except Leucine and Lysine)
  4. Insulin response to Glucose is linear
    1. Insulin response is based on Glucose sensitivity
    2. Glucose sensitivity depends on Ambient Glucose
      1. Normal: Rapid Insulin release with a meal
      2. Fasting: Steeper rate of Insulin release
      3. Prolonged Hyperglycemia: Flattened response
  5. Overall Insulin effects
    1. Promotes Glucose uptake by liver and Muscle and for storage as glycogen
      1. Does not effect brain Glucose uptake (Glucose freely crosses blood brain barrier)
    2. Promotes cellular uptake of Amino Acids and Protein synthesis
    3. Promotes hepatic synthesis of Fatty Acids, VLDL transport to adipose for Triglyceride storage
    4. Promotes Glycolysis for energy utilization
    5. Suppresses Gluconeogenesis
  6. Muscle Effects
    1. Increased synthesis of Glycogen, Protein and Triglycerides
    2. Increased Glucose transport into Muscle Cells
  7. Hepatic Effects
    1. Increased synthesis of Glycogen and Protein
    2. Increased Glucose transport into Muscle Cells
    3. Increased Glucose utilization for energy (Glycolysis, TCA Cycle)
  8. Fatty tissue Effects (Adipose)
    1. Increased synthesis of Glycogen and Triglycerides
    2. Increased Glucose transport into Muscle Cells
2. Phase 1 Insulin Release
  1. Duration: 10 minutes
  2. Suppresses hepatic Glucose release
3. Phase 2 Insulin Release
  1. Duration: 2 hours
  2. Controls mealtime Carbohydrates
4. Basal insulin Release
  1. Low continuous Insulin level
  2. Covers metabolic needs between meals

Pathophysiology

Insulin excess
1. See Hypoglcemia
2. See Insulin Shock (Insulin Overdose, Insulin Reaction)
Insulin at low levels or deficiency
1. Causes
  1. Low Insulin due to Diabetes Mellitus
    1. In Type I Diabetes, Insulin deficiency is key
    2. In Type II Diabetes, Insulin Resistance is key initially, but later Insulin deficiency results
  2. Low Insulin as a normal physiologic response to Hypoglycemia
2. Low Insulin effects
  1. Gluconeogenesis and Glycogenolysis results in Hyperglycemia
  2. Lipolysis (Triglyceride breakdown to Fatty Acids)
    1. Further lysed into acetyl coA to be utilized in the Kreb Cycle (TCA Cycle, Citric Acid Cycle)
    2. Other Fatty Acids are diverted to Ketogenesis (Ketone formation)
      1. Occurs in Diabetic Ketoacidosis, Starvation Ketosis, Alcoholic Ketoacidosis
    3. Fatty Acids also form excess Cholesterol, Triglycerides within VLDL with increasing atherosclerosis

Technique
Injection

Injection sites: Abdomen, outer thigh, back of arm, flank and buttocks
Insert needle at 90 degree angle into skin
Insulin injection is subcutaneous (not intramuscular)
1. Intramuscular Injection results in rapid absorption and risk of Hypoglycemia
2. Prevent too deep of injection (esp. longer needles) by pinching an inch of skin at the injection site
Hold needle in place for 5-10 seconds after injection to prevent leakage of Insulin
Rotate injection sites to prevent lipohypertrophy (see adverse effects below)

Medications
Insulin Selection

Insulin anologs are preferred
1. More consistent absorption than traditional Insulin
2. Bolus analogues have more rapid onset
3. Basal agents release at more constant rate
Insulin anologs are however 10 fold more expensive than Regular Insulin and NPH
1. Very high cost results in patients stopping Insulin, resulting in hospitalization and even death
2. Vials of NPH Insulin and Regular Insulin are each $26 per vial OTC at Walmart as of 2017
  1. Contrast with $250 per vial for analogues (e.g. Insulin Lispro, Insulin Glargine)
3. Outcomes are similar with newer analogues versus older NPH Insulin and Regular Insulin
4. (2015) Presc Lett 22(11):61-2
5. (2019) Presc Lett 26(8): 43-4
Combination agents are discouraged unless noncompliant
1. Insulin 70/30 is also $26 OTC at Walmart as of 2017 (Reli-On)
2. Reduces flexibility in meal and activity timing

Medications
Syringes and needles

Needle length
1. Longer needles risk deeper, intramuscular penetration, with more rapid absorption and Hypoglycemia risk
2. Insulin Pen needles 4 mm are sufficiently long
3. Insulin syringe needles should be at least 6 mm long to clear the syringe stopper
Needle gauge
1. Smaller needles (higher gauge) 30 or 31 are preferred for the least discomfort on insertion
Syringe volume
1. Select smallest Insulin syringe that will hold each of the Insulin doses, allowing for added coverage
2. Prescribe syringes in number of boxes (100 syringes per box)
3. Syringes are sized at 100 units Insulin/ml
  1. Insulin 30 units per 0.3 ml syringe
  2. Insulin 50 units per 0.5 ml syringe
  3. Insulin100 units per 1 ml syringe
References
1. (2014) Presc Lett 22(1): 4

Medications
Insulin Pens

Supplied
1. Insulin Pens are supplied in boxes of 5 pens each containing 3 ml at 100 units Insulin per ml
Precautions
1. Insulin Pens appear similar to one another despite containing different Insulins (basal or bolus)
2. Read each syringe carefully (and note its color) prior to each injection to prevent Overdose errors
3. Prepare cloudy Insulins (e.g. NPH) by gently rolling and inverting the pen 10 times prior to injection
4. Confirm proper use by asking the patient to demonstrate preparation and injection at clinic visits
5. Multidose prefilled pens are intended for use by one individual patient only (do not share pens)
  1. Sharing pens among patients risks blood borne infection transmission
Technique
1. Attach a new needle to Insulin Pen before each use
2. Prime the new needle with 2 units prior to use (removes air bubbles)
3. Dial the dose
4. Apply to pen to injection site, press the button, and hold in place for 5-10 seconds
5. Discard the used needle

Medications
Intravenous Regular Insulin

Note that all other Insulins listed on this page are subcutaneous
See Insulin Drip
Onset: Immediate
Half-Life: 5-10 minutes

Precautions
Insulin-Related Errors

Insulin errors result in >100,000 emergency visits (typically Hypoglycemia related) annually in United States
Wrong Insulin (Bolus Insulin mistakenly taken)
1. Prescribers should carefully check prescriptions and home instructions for errors
  1. Example: Lispro prescribed instead of Lantus
2. Patients should check Insulin label everytime they inject
  1. Bolus Insulin in vials and pen devices may be easily mistaken for Basal insulin devices
Wrong time
1. Patients must eat following Bolus Insulin (e.g. Lispro) or do not take Bolus Insulin if plan to skip the meal
Wrong dose
1. Decrease Insulin for anticipated decreased oral intake
2. Assist patients with poor Vision or dexterity who have difficulty drawing the correct dose
  1. Consider syring magnifier, pen device which click per unit, count-a-dose syringe
Wrong technique
1. Mix Insulin suspensions before use (e.g. NPH Insulin, Premixed Insulin such as Insulin 70/30)
  1. Roll vials or pens 10 times to mix
2. Clinic staff should periodically observe patient's technique
  1. Obtaining fingerstick Glucose
  2. Calculating their Insulin dose with expected oral intake
  3. Drawing up Insulin dose
  4. Injecting Insulin
References
1. (2014) Presc Lett 21(7): 40

Drug Interactions
Diabetes Agents

Agents safe to use with Insulin
Agents safe to use with Basal insulin (Lantus, Levemir); avoid or use caution if used with Bolus Insulin (Lispro, Aspart)
1. Sulfonylureas
2. Glitinides

Medications
Bolus Insulins (Meal-time Insulin)

See Bolus Insulin
Traditional Bolus Insulins
1. Regular Insulin (Novolin R, Humulin R)
  1. Onset: 15 to 30 minutes
  2. Peak: 2.5 to 5 hours
  3. Duration: 6 to 8 hours
  4. Avoid in Stage IV or Stage V significant Chronic Kidney Disease
  5. Avoid if history of severe Hypoglycemia
  6. Available concentrations
    1. Humulin R U-100 (100 units/ml, orange)
    2. Humulin R U-500 (500 units/ml, green)
      1. High concentration AND basal and Bolus Insulin activity (similar to 70/30)
      2. See Basal insulins below for description
Analogue Bolus Insulins (Rapid, consistent absorption)
1. Glulisine (Apidra)
  1. Onset: 5 to 15 minutes
  2. Peak: 1 to 2 hours
  3. Duration: 3 to 5 hours
  4. Similar to other bolus analogues
  5. FDA approved to take after meal
    1. Other analogues expected with same effect
2. Lispro (Humalog, Admelog)
  1. Onset: 5 to 15 minutes
  2. Peak: 1 to 2 hours
  3. Duration: 3 to 5 hours
  4. Concentrations
    1. Humalog U-100 (100 units/ml) vial or KwikPen
    2. Humalog U-200 (200 units/ml) KwikPen - for patients using >20 units/day
3. Lispro-aabc (Lyumjev)
  1. Same manufacturer as Humalog
  2. Four letter designation refers to new FDA labeling of Insulins as biologics
  3. Marketed as 10 minutes faster onset that typical Lispro Insulin
  4. Unlikely to offer any real benefit over other Lispro Insulin
  5. Concentrations
    1. Lyumjev U-100 (100 units/ml) vial or KwikPen
    2. Lyumjev U-200 (200 units/ml) KwikPen - for patients using >20 units/day
4. Aspart (Novolog, Fiasp)
  1. Onset: 5 to 15 minutes
  2. Peak: 1 to 2 hours
  3. Duration: 3 to 5 hours

Medications
Basal insulins

Traditional Insulins
1. NPH Insulin, Novolin N, Humulin N, Humulin L (Lente)
  1. Onset: 1 to 2 hours
  2. Peak: 6 to 8 hours
    1. Peak time is higher risk of hypoglcemia
    2. Consider snack at 6 hours after dose
  3. Duration: 10 to 16 hours (Lente slightly longer)
  4. Humulin L (Lente) discontinued in U.S. in 2006
  5. Increased risk of Hypoglycemia (esp nocturnal) compared with newer analogues
  6. NPH is much less expensive than analogues (still $25/vial as of 2016 at Walmart)
2. Humulin R U-500 (500 units/ml, green)
  1. Indicated for those with very high Insulin requirements (>200 units per day)
  2. High risk for dosing errors (very concentrated Insulin)
    1. Specific U-500 green capped syringes are available as of 2016 to reduce dosing errors
    2. Pens are preferred for less dosing errors over vials and syringes
      1. Use pen dosing window (not the number of clicks to determine dose)
      2. Each click of a U-500 pen adds 5 units of Insulin (contrast with 1 unit/click with U-100)
  3. Activity is similar to Insulin 70/30
    1. Onset in 30 minutes
    2. Longer duration (>12 hours) than other Bolus Insulins
  4. Divide dosing twice (60 and 40%) to three times (e.g. 40, 30 and 30%) daily
  5. Do not combine with other Insulins (i.e. stop basal and mealtime Bolus Insulins)
  6. References
    1. (2022) Presc Lett 29(3): 14
3. Ultralente Insulin (extended Insulin zinc suspension)
  1. Discontinued in U.S. in 2006
  2. Significant inconsistent effect even in same person
  3. Onset: 6-10 hours
  4. Peak: No peak
  5. Duration: 18 to 24 hours
Analog Basal Insulin
1. See Analog Basal Insulin
2. Insulin Glargine U-100 (Lantus, Basaglar, Semglee)
  1. Onset: 1-2 hours
  2. Duration: 21 to 24 hours
  3. Peak: No peak (flat action curve mimics continuous Insulin Infusion)
3. Detemir U-100 (Levemir)
  1. Onset: 2-4 hours
  2. Peak: 6-8 hours
  3. Duration: 12 to 20 hours (varies by dosage)
  4. Manufacturer discontinuing drug in U.S. in 2024 (for business reasons)
4. Insulin Degludec (Tresiba)
  1. Onset: 90 minutes
  2. No peak activity
  3. Duration: Up to 42 hours (ultra-long)
  4. Available as U-100 or U-200
5. Insulin Glargine U-300 (Toujeo, Toujeo Max Solostar)
  1. Onset: 6 hours
  2. No peak activity
  3. Duration: 24 to 36 hours

Medications
Combination Agents (Type II Diabetes if poor compliance)

NPH 70/Regular 30 (Humulin 70/30 or Novolin 70/30)
1. Onset: 30 to 60 min
2. Peak: 2 to 10 hours (biphasic)
3. Duration: 10 to 16 hours
Aspart Protamine 70/Aspart 30 (Novolog Mix 70/30)
1. Onset: 15 min
2. Peak: 1 to 4 hours (biphasic)
3. Duration: 10 to 16 hours
Lispro Protamine 75/Lispro 25 (Humalog Mix 75/25)
1. Onset: 15 min
2. Peak: 1 to 3 hours (biphasic)
3. Duration: 10 to 16 hours
Degludec 70/Aspart 30 (Ryzodeg 70/30)
1. Onset: 15 min
2. Peak: 2 to 3 hours
3. Duration: 24 hours

Adverse Effects

Hypoglycemia
1. Increased risk when Hemoglobin A1C <7.4%
2. Decreased risk with analogue Insulins
3. Higher risk with severe Renal Insufficiency
  1. Insulin is excreted by the Kidney (30% of total)
  2. Gluconeogenesis occurs in the Kidney (30% of total)
Weight gain (Excess of 4 kg over 10 years)
1. Countered with Metformin in type 2 diabetics
2. Countered with diet and Exercise
3. Benefits of Glucose control outweigh weight risks
Lipohypertrophy
1. Localized fat hypertrophy and scar tissue from repeated injections in the same area
2. Results in variable Insulin absorption as below
3. Prevent by rotating injection sites (see below)
4. Medical providers should examine injection sites
Variable Insulin absorption
1. Insulin absorption varies by body site
  1. Abdomen (best absorption)
  2. Arms
  3. Thigh
  4. Buttocks (least absorption)
2. Variable absorption at lipohypertrophy sites
  1. Poor absorption causes early postprandial Hyperglycemia
  2. Depot formation causes delayed Hypoglycemia
3. Site rotation (prevents lipohypertrophy - see above)
  1. Rotate injections within same body region
    1. Avoids Insulin absorption variability
  2. Rotate to widely different sites within region
    1. Example: Abdomen rotate to LUQ, RUQ, LLQ, RLQ

Reources

FDA Insulin storage and emergency switching
1. https://www.fda.gov/Drugs/EmergencyPreparedness/ucm085213.htm

References

(2014) Presc Lett 21(12): 69
Lepore (2000) Diabetes 49:2142-8 [PubMed]
Mayfield (2004) Am Fam Physician 70(3):489-512 [PubMed]