Diabetes III: Insulins

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What is insulin?

  • Peptide hormone produced by pancreatic beta cells

    • Regulates metabolism by promoting absorption of glucose from blood into liver, fat, and muscle, for these cells to convert to glycogen or fat.

    • Simultaneously, is a strong inhibitor of gluconeogenesis in the liver.

  • How did we get synthetic insulin?

    • 1869 - Paul Langerhans identifies small tissue clumps throughout the bulk of pancreas not previously described in Western literature - islets of Langerhans (where Beta cells are clustered)

    • 1889 - Joseph Von Mering removes pancreas from a healthy dog and identifies sugar in the urine, which was later isolated to the function of the islets of Langerhans.

    • 1916 - Nicolae Paulescu develops a pancreatic extract that normalizes blood sugar in diabetic dogs.

    • 1921 - Frederic Banting and Charles Best isolate extract from islets in dogs, and later move towards experiments in cows.

    • 1922 - Leonard Thompson, a 14-year old Canadian boy, receives first injection of insulin from cows

      • So impure he suffered a severe allergic reaction.

      • Received another injection 12 days later which was noted to eliminate his glucosuria.

    • 1922 - the team of researchers, recognizing the need for quality control and safe distribution, make a pact to patent insulin and transfer it to a public university.

      • They settled on the University of Toronto, which bought the patents to insulin and the purification processes of bovine insulin in 1923 for $1.

      • Banting and JRR Macleod would share the 1923 Nobel Prize for this work.

    • 1978 - first synthetic “human” insulin was engineered in E. coli with recombinant DNA technology by the Beckman Research Institute and Genentech.

      • Genentech would go on to sell the first commercially available form of this - Humilin.

  • Today, there are multiple types of insulin used for optimal control of diabetes mellitus, all of which are synthetic forms.

    • However, shared amongst them has been the absurdly high cost in the USA. 

  • New legislation has spurred reduction in cost which will start benefiting patients this year!

    • Inflation Reduction Act 2023: Capped cost of insulin at $35/mo for all Medicare beneficiaries

      • Eli Lilly subsequently announced (March 1, 2023) that they are capping out-of-pocket insulin costs at $35/mo.

        • www.insulinaffordability.com will allow all patients regardless of insurance status to procure Lilly-branded insulin at $35/mo.

        • Some of these price changes will not take effect until later in 2023.

      • Sanofi (maker of Lantus) has also capped the cost of Lantus at $35/mo as of March 16.

      • Novo Nordisk (maker of NovoLog) will follow with plans to implement cost-lowering on its insulin products on Jan 1, 2024.

Types of Insulin

  • Broadly, five main types: ultra-long acting, long-acting (basal), intermediate-acting, short-acting, and rapid acting

    • We’re going to stick with three categories for ease - basal (long-acting), intermediate, and short/rapid.

    • You may also see forms of insulin we mention in “U200” or “U500”

      • These are “ultra concentrated.” 

      • Typically, insulin in rapid-acting forms is concentrated at 100 units per mL - “U100.”

        • If you see U500, for example - that means that the concentration is now 500 units in one mL - or five times more concentrated.

        • These formulations are helpful for patients who have high insulin requirements, and are available across the spectrum of long-to-rapid acting insulins.

  • Long-Acting, Basal Insulins

    • These provide a low-peak, sustained coverage of insulin over multiple hours-days. 

      • “Background coverage” of insulin so there is always some on board - in effect, these control your fasting blood sugar values.

      • Long-acting coverage is obtained by modifying the base insulin molecule with an amino-acid substitution or linking to other molecules to slow absorption 

    • Varieties:

      • Degludec

        • Brand name: Tresiba

        • Duration of action: 42 hours

          • Minimizes plasma concentration variability with once-daily dosing.

        • No noticeable “peak of action” - so minimal nocturnal hypoglycemia.

      • Glargine

        • Brand name: Lantus, Basaglar, Semglee, Toujeo (U300)

        • Duration of action: 24 hours

          • Half life is 12 hours, though, so some individuals benefit from BID dosing.

        • No noticeable “peak of action.”

      • Detemir

        • Brand name: Levemir

        • Duration of action: Less than 24 hours

          • Often requires BID dosing, particularly in T1DM or pregnancy.

        • Does have a small peak effect at 6-8 hours post-injection.

  • Intermediate-Acting Insulins

    • These are not quite enough to provide full coverage through the day, but in practice are often employed in multiple injection therapies for basal coverage of fasting and nighttime sugar levels.

    • Varieties:

      • Neutral protein Hagedorn (NPH) 

        • Suspension of insulin, protamine, and zinc in a buffered solution that helps to delay release of insulin in the bloodstream.

        • Duration of action: 14-16 hours

          • Requires BID dosing to achieve basal coverage

        • Peak effect: 4-6 hours

          • If given at night, a bedtime snack is frequently required to avoid nocturnal hypoglycemia

          • There can also be a “dawn effect” that is pronounced with NPH - fasting concentrations remain above target, as the insulin effect peaks early relative to waking time.

        • Can be mixed with regular insulin or rapid-acting insulins to minimize the number of daily injections. 

          • Regular insulin should be drawn up before the NPH to avoid injecting buffer solution into the rapid-acting insulin vial.

      • U-500 regular insulin

        • We’ll talk more about regular insulin momentarily, but U500 is the 5x concentrated form of it. 

        • Duration of action: approximately 20 hours

        • Peak effect: 4 hours

          • In effect, similar to NPH, but has a quicker peak onset.

        • Rarely used in T2DM, but given that the GLP-1 agonists are not used in pregnancy, occasionally you may encounter this for patients needing lots of insulin.

          • Important to recognize that given the high concentration, the pharmacokinetics actually are closer to an intermediate than a short-acting in this form.

  • Short/Rapid-Acting Insulins

    • These insulins are intended to provide rapid coverage, typically in response to mealtime insulin demands.

      • These are also the insulins that you will see in insulin drips and insulin pumps, as they rapidly change blood glucose concentrations and if given IV or constantly SQ, need to be frequently titrated to maintain control.

    • Varieties:

      • Regular insulin

        • Human insulin is complexed with zinc, slightly delaying absorption.

        • Duration of action: ~8 hours

        • Peak effect: 2-3 hours

          • This can be challenging timing, as postprandial rise in blood sugar usually occurs at ~1-2 hours after eating

          • Because of this, some folks using regular insulin may have post-meal hypoglycemia if they eat meals not containing much carbs/fat.

      • Rapid acting insulins - aspart, lispro, glulisine

        • All are human insulin analogs with amino acid modifications to facilitate rapid absorption.

        • Duration of action: ~4 hours

        • Peak effect: ~1 hour

          • Preferred insulin in pumps - most of the algorithms driving pump management are built on rapid-acting insulin pharmacokinetics.

          • Recognize that when correcting with rapid acting insulin, you are only getting to peak effect at 1 hour - so careful with redosing frequently, as you may “stack” insulin effect and cause hypoglycemia with frequent boluses.

            • We’ll save intrapartum glucose management for another episode!

UPTODATE

Approach to Insulin Therapy

  • In pregnancy, insulin requirements:

    • May decrease slightly in the first trimester, particularly pronounced at about 10 weeks.

    • After 10-12 weeks, insulin needs start to increase rapidly thanks to the action of the placenta.

    • By the end of pregnancy:

      • T1DM: expect 2-3x increase in insulin requirement 

      • T2DM: expect 3-6x increase in insulin requirement

    • These insulin requirements then rapidly fall off postpartum with the loss of the placenta and the mediating hormones in insulin resistance, hPL and progesterone.

    • Historically, with pregnancy and DM control, we’ve employed a split-mix regimen.

      • We covered this in our previous episodes with Dr. Coustan on GDM, but we’ll re-link that algorithm to our website.

      • This is built off of using NPH for basal coverage, and regular or rapid-acting insulins for meal coverage, with cheap insulin and convenient 2x daily injections.

      • Potential disadvantages:

        • NPH - we discussed the challenges with peak-effect issues of NPH

        • Fasting control - may need to split into three injections, with NPH taken just before bed, to improve control if the nighttime peak is too early

        • Risk of nocturnal hypoglycemia - for the same reason

      • How to start a split-mix regimen:

        • Specifically in the context of GDM, and T2DM – for T1DM, please do not do this (though they’ll come to you on their insulin of choice already).

          • Weight in kg, x 0.7 - 1.0  (based on trimester/underlying insulin resistance) = total daily insulin dose

          • Split into ⅔ of that into AM dose, and ⅓ into PM dose.

          • AM dose: ⅔ should be NPH, and ⅓ should be rapid-acting.

          • PM dose: ½ should be NPH, and ½ should be rapid acting (though you may find some folks need less rapid acting and more basal).

    • More and more, we’re seeing folks utilize a basal-bolus regimen.

      • This combines a newer, longer-acting basal insulin with rapid-acting insulin to cover mealtimes.

      • Advantages:

        • For GDM and T2DM, basal insulin may be all that is needed for some individuals with appropriate lifestyle counseling.

        • Basal provides more stable overnight coverage.

        • Rapid-acting insulin allows for individual meal titration (whereas with split-mix, your AM NPH covered lunch – what if the nausea comes and you can’t eat lunch?)

      • Disadvantages:

        • For GDM and T2DM in particular, we may be slower to getting folks to control as we may be prone to be less aggressive with upfront insulin - completely anecdotal, don’t have to say it.

        • Requires 4-5x daily injections - most basal insulins cannot be mixed with rapid-acting insulins.

      • How to start a basal-bolus regimen:

        • Again, specifically in the context of GDM or T2DM in pregnancy:

          • Weight in kg x 0.7 - 1.0 (based on trimester/underlying insulin resistance) = total daily insulin dose – this step is the same.

          • Split into 50% basal coverage, and 50% mealtime coverage.

            • Based on your insulin of choice, your basal may be injected once or twice daily.

            • Rapid mealtime coverage split into TID, but dose may vary by time of day and number of carbs patient eats.

              • For even tighter control, rather than a set number of units with mealtime coverage, patients can calculate the dose to give with a carb ratio.

                • You can approximate carb ratios for mealtime coverage using the rule of 500

                  • 500 / TDD = number of grams of carbs covered by 1u of insulin.

                  • So if my expected TDD is 50u (based on our previous weight calculation), my carb ratio would be 1:10

        • Some folks may need only basal coverage to get controlled, and that’s OK!

          • You can start at some reasonable dose of basal insulin, then have the patient increase by 2u every other day until fastings are under 95 mg/DL.

          • Reassess mealtime control at that point and need for mealtime insulin.

    • How to titrate insulin to achieve better control:

      • Small steps are OK – adjust by small amounts (10% steps) most frequently.

      • If you’re finding globally high or low sugars, consider where your basal insulin is at - this likely needs adjustment.

      • If you’re finding situationally high sugars, recall some pregnancy physiology that can make insulin timing challenging:

        • Delayed gastric emptying: may need to “pre-bolus” rapid insulin 30-45 mins before a meal to allow for mealtime peak and insulin peak to coincide better.

        • Nausea: similarly, may need to split rapid insulin up into microboluses, as folks may not eat what they originally intended to eat!

      • Know your insulin correction factor (ICF) 

        • This is the expected blood sugar drop in mg/dL for every 1 unit of correctional insulin given.

          • I.e., an ICF of 50 means that my blood sugar will drop 50 mg/dL for every unit of correctional insulin given.

        • ICF is a function of expected total daily dose of insulin:

          • Type 1s: use the rule of 1800: 1800 / TDD insulin (units) = expected ICF

          • Type 2/GDM: use the rule of 1500: 1500 / TDD insulin (units) = expected ICF

            • So if I’m taking 50 units total of insulin per day, I would have a correction factor of 30 - meaning 1u of insulin would bring my blood sugar down about 30 mg/dL

            • This is helpful for the floor - if you need to cover someone, knowing their total daily insulin dose (or approximating using their weight) can help you provide more reliable amounts of insulin. 

    • Disclaimer regarding all of this:

      • While we love to provide this as a guide that has been pretty consistent across places we’ve trained, please do not substitute this for true medical advice!

        • Some folks may be more insulin sensitive, particularly with longstanding T1DM with comorbidities, or insulin-naive folks with GDM.

        • These are some good starting rules that are generally helpful, but your mentors can help guide you with more complex or concerning scenarios.