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Diabetes in Pets

Duration

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The length of time an insulin continues to lower blood glucose.

The four duration categories[1] are:

  • Rapid-acting or Fast-acting insulin begins to work shortly after injection, peaks in about 1 hour, and continue to work for 2 to 4 hours.
  • Regular or Short-acting insulin reaches the bloodstream 30 minutes to an hour after injection, peaks anywhere from 2 to 3 hours after injection, and is effective for approximately 6-8 hours.
  • Intermediate-acting insulin generally reaches the bloodstream about 1-2 hours after injection, and is effective for about 8 to 12 hours.
  • Long-acting insulin generally reaches the bloodstream about 2 to 4 hours after injection, peaks 4 to 8 hours later and is effective for about 12 to 18 hours.

Note that an insulin that is long-acting in dogs may be intermediate-acting in cats. The duration classes used in this wiki are for humans and usually match those in dogs -- for their classifications in cats (which are less well-researched) see cats' faster metabolism.

Intro to durationEdit

Since activity decays on a half-life curve, there is no actual hard time when duration has ended -- it's a matter of degree. The usual time used for reference is either whatever the manufacturer claims, or the time when blood glucose levels have reached the same point they were at shot time. Any residual effect of the insulin beyond that time is carryover.

Duration varies from species to species -- cats usually experience shorter durations than dogs on most insulins. Duration is also quite individual--can vary from patient to patient and even with the same patient[2][3]. Though it is classed as a long-acting insulin, some humans, like their feline counterparts, do not get this type of duration from r-DNA ultralente insulin. For them, ultralente only has intermediate acting duration[4].

The insulin time activity profiles[5][6][7] you see are basically averages of blood glucose levels in a test group or groups of patients for a given time period. Some tested patients experienced longer than average duration, while for others it was less than average. Many of the duration test results done by manufacturers of human approved insulins are based on two patient groups--those with diabetes and non-diabetics who agreed to assist in the study. This combined and averaged data is used to generate the time activity profile. It means that there are VERY few with diabetes whose personal insulin activity profile is a perfect replica of those displayed.

It follows then, that onset and peak times found on insulin time activity profiles are just as subject to variability as is duration, since they are all obtained in the manner above.

Duration varies by species and strength, in addition to type[8][9]. With regard to the non-analog insulins, duration can also be influenced by the size of the insulin dose itself, with larger doses having a stronger effect and a longer duration than smaller ones[10].

Duration ProblemsEdit

Short Duration

This is a blood glucose graph of a cat who is receiving one shot of Bovine (beef) Lente insulin daily. After the 8 hour point, blood glucose values begin climbing. Interestingly enough, the insulin peak is within acceptable values. This insulin is working for this cat, but he/she is not getting enough duration from only one shot a day. Note: blood glucose values are shown in mmol/l (non-US) measurements.

From what's seen here, it would appear that this is a problem which can be easily solved by increasing from once-daily to twice daily doses of the Bovine (beef) Lente. There appears not to be any Insulin resistance but just a matter of the Intermediate-acting beef Lente not providing adequate control when given only once a day.

http://www.vin.com/ImageDBPub/TN20000/TN_IMC16197_550X0Y.jpg

In contrast, let's look at a blood glucose graph of an animal who is being given Lente insulin twice daily, but has resistance to it. (Note: species of animal and insulin not stated. Blood glucose values shown in mmol/l (non-US) measurements.)

You see the cat above with one injection of Bovine (beef) Lente respond to the insulin, but that it simply does not last long enough for him/her. Without knowledge of the species of animal, species of insulin or other information, it is not possible to even speculate as to why the twice daily Lente insulin is not working. There's negligible response to the two Lente insulin shots given in the graph of the animal shown below, and it's provided as an example of resistance/lack of duration only.

http://www.vin.com/ImageDBPub/TN20000/TN_IMC16199_550X0Y.jpg

Duration By SpeciesEdit

An initial note: Different species metabolize insulin differently, sometimes dramatically so. In general, veterinarians and caregivers have found that most insulins last about the same length of time in dogs as in humans, but about half the time in cats. The duration classes used in this wiki are for humans and usually match those in dogs -- for their classifications in cats (which are less well-researched) see cats' faster metabolism. The following notes on duration change by species have a much smaller effect.

With regard to cats and dogs, the closest or perfect amino acid matches to their own native insulin (cats=beef) (dogs=pork) means faster onset, peak and shorter duration, all other things held equal. For both, use of r-DNA/GE/GM insulins would mean a slower onset, peak and a longer duration[11], due to these differences. It's just the reverse for people[12][13], with the r-DNA/GE/GM insulins acting and peaking faster and having less duration[14] than either beef[15] or pork insulin products[16][17][18][19][20].

Canineinsulin8

Canine insulin compared with Bovine, Human, & Porcine versions. Up to 2 amino acids differ. Canine and porcine are identical[21].

Looking at the amino acid matches or differences, we can predict what they mean to duration for each. Dogs would have the shortest duration from pork insulin, slightly longer from r-DNA/GE/GM human insulin (one amino acid difference at insulin B chain, position #30)[22], but longer from beef[23][24], with amino acid differences in 2 positions--insulin A chain positions #8 & #10.

Felineinsulin8

Feline insulin compared with Bovine, Human, & Porcine versions. Up to 4 amino acids differ. The closest match is bovine with only one amino acid difference; the least close is human with four amino acid differences.

Cats would have less duration from beef insulin, as there is only the 1 amino acid difference there--the insulin A chain position #18. They would get more duration from pork insulin because there are 3 differing amino acids in the comparison. Longest lasting of all would be r-DNA/GE/GM human insulin--because none of the key amino acids match[25][26].

In humans, their longest-duration insulin would be beef[27][28][29], due to the 3 amino acid difference[30]. pork would have slightly more duration for them than r-DNA/GE/GM insulins, because of the 1 amino acid's difference[31][32][33]. One injection of Bovine Ultralente insulin can last up to 40 hours when administered to a human--longer than Lantus; it is also peakless[34][35].

Origin, species, or source is very important as it directly affects the absorption, peak and duration of an insulin[36]

When looking at extending duration in this way, one needs to realize that the amino acid differences produce antibodies; these antibodies are what prevents the insulin from being used so quickly[37]. The possible drawback to extending duration by choosing insulins which are less akin to the native insulin of the diabetic is that the antibodies created by this may cause Insulin resistance[38]. Since the antibodies indicate an immune system reaction, all the effects of an overstimulated immune system should be considered. When there is sufficient resistance, duration can decrease instead of increase; at that point, the effectiveness of the insulin is compromised[39].

Duration By StrengthEdit

Comparing similar insulins with only strength differences means that the U100 strength insulin will have a slower onset, peak and longer duration than an insulin which is U40, U50 or even U80, which is available in some countries[40], assuming the insulins are otherwise identical[41][42].

An example of comparison for strength would be the 3 versions of 100% bovine PZI insulin available. Hypurin Bovine Protamine Zinc and Insuvet Protamine Zinc are both U100 insulins. BCP also produces a U100 version of its 100% beef PZI. All three would have the same length of duration.

Switching strengths, however, changes things. Having BCP PZI in either U40 or U50 strength, as opposed to the BCP U100 PZI, Hypurin and Insuvet, means that the U40 and U50 strengths of the PZI BCP makes will have a faster onset, peak and less duration than the 3 U100 100% beef PZI insulins. The type of insulin is the same-PZI, the species is the same-beef.

Duration By DoseEdit

The larger the dose of insulin, the longer it takes to be absorbed[43] and the more duration it will have[44].

Less strength=speedEdit

Insulin hex di mon

Insulin hexamers (as produced by the body or injected) must break down into dimers and monomers to be absorbed[45].

The hexamers of insulin tend to associate with each other (stay together); they cannot be readily absorbed while they remain this way. Diluting insulin into U40 strength forces them into dissociating (staying apart from each other, and becoming dimers and monomers), which means they are absorbed[46][47] better and more rapidly. An easy way to visualize this might be to think of a whole pie, slicing it into 6 pieces, then putting each piece on a separate plate. The pie can't be eaten until it's cut and everyone has a piece on his or her plate.

A normally working pancreas secretes insulin in monomer form, so there's no formation of hexamers by self-association and nothing to break down; the monomer insulin is ready to work[48].

The less strength an insulin has, the better it is absorbed[49][50][51]. Better or faster absorption means a faster onset and peak but shorter duration. Using a less than U100 strength insulin is on the same principle as rapid-acting analog insulins. The analog insulins have their amino acid sequences altered to produce a faster onset and peak with shorter duration[52]. Diluting insulin from U100 strength does the same thing without altering the molecule.

Knowing this, particularly in the case of cats, who are the primary users of PZI insulins, means that you can switch from a U40 or U50 insulin strength to U100 if duration is a problem and conversely, away from U100 to U40 or U50 if less duration or faster onset is needed--all without leaving bovine PZI.

More strength=durationEdit

It is also possible to delay the absorption (thus increase the duration) of an insulin by increasing its strength. U500 insulin[53], which is five times more concentrated than U100, has been available through both Lilly and Novo Nordisk (Note: Their similar product is U400 strength insulin[54]) by special order for many years[55]. The insulin's main use is for people with extreme Insulin resistance, and is commercially available only in R/Neutral type.
Though it is R/Neutral-type insulin, U400 & U500 insulins have a pharmacokinetic profile more like NPH insulin than U100 R/Neutral[56].
Since there are no additives such as suspensions to alter R/Neutral insulin's action, the strength of the insulin formula hinders its breakdown into dimers and monomers, thus making it much slower-absorbed than U100 and lesser strength insulins[57][58].
In cases of severe insulin resistance, using a much higher concentration of insulin appears to "negate" the effects of immune-related Insulin resistance.
The studies at the link below shows that there was no difference regarding antibodies when these patients were transferred from Iletin II NPH at U100 strength to a form of Iletin II R at U500 strength. However, the stronger insulin reduced their insulin needs from 33-75%[59][60].

Whether the insulin is slowed by the size of its crystals, by its suspension, by the strength of its concentration, or has been designed to release slowly--all of these are different mechanisms with the same goal in mind--to keep the insulin in hexamer form (thus preventing its fast absorption) as long as possible.

If you're having a hard time visualizing the role of strength regarding duration in an insulin, perhaps thinking of the following might help. If you had two stones, one which was pebble sized and the other which was somewhat larger, think about what it would take to break them down into small pieces with a hammer. It would take many more hammer blows to break the larger stone (U100 strength) into small pieces than for the pebble (U40 or U 50 strength); the duration of your work to shatter the larger one would be longer than for the smaller of the two.

Further ReadingEdit

Wikicat3

ReferencesEdit

  1. RxEd.org-Insulin Therapy
  2. BD Diabetes-Insulin for Cats
  3. Insulin Treatment-Individual Factors
  4. Diabetes Forecast-ADA, 2006-Page 2
  5. How Insulin Time Activity Profiles Are Created
  6. Absorption Kinetics of Regular (Neutral) & Isophane (NPH) Insulin in the Normal Dog-Domestic Animal Endocrinology-1987
  7. Establishment of Time-Action Profiles for Regular (Neutral) NPH (Isophane) Insulin Using Pharmacodynamic Modeling-Diabetes Care-ADA-1994
  8. Type I Diabetes and Insulin Therapy Nursing Clinics of North America-Hirsch-Farkas-Hirsch 1993
  9. Feline Endocrinology-Injections & Insulin-Quote from Dr. Nelson
  10. Insulin-Dependent Diabetes--Dr. Ragnar Hanas (Page 6)
  11. Duration of GE Insulin in Pets
  12. Duration of GE & Animal Insulins in Humans
  13. Comparative of NPH (Isophane) Human & Porcine (Pork) Insulin in Diabetic Subjects-Diabetes Care-ADA-1982
  14. New Patient & Transfer Studies-GE Duration Shorter Than Animal Insulins in Humans--Diabetes Care-ADA-1982
  15. Comparative Study of r-DNA NPH Insulin and Bovine NPH Insulin in Humans-Diabetes Care, 1982
  16. Comparison of Pork & GE Insulin in Human Subjects
  17. Human & Porcine NPH (Isophane) Insulins Unequally Effective in Diabetic Patients-Acta Diabetologica Latina-1984
  18. Diabetes-World Mailing List Web Site-Questions About Insulin
  19. ChildrenWithDiabetes-Ask the Diabetes Team: People Have Faster Onset & Less Duration with GE Insulin than Either Beef or Pork
  20. Diabetes Health-GE Insulin of Shorter Duration Than Animal Insulin in Humans
  21. Intervet-Caninsulin-Product Information
  22. Veterinary Partner-The Hard to Regulate Diabetic Pet
  23. Evaluation of an Insulin Zinc Suspension for Control of Naturally Occurring Diabetes Mellitus in Dogs-Australian Veterinary Journal,-2000 (Page 3)
  24. Selecting an Insulin for Treatment of Diabetes Mellitus in Dogs 7 Cats-Nelson-Page 40
  25. BCP Veterinary Pharmacy--Bovine PZI Insulin
  26. Comparison of 2 Ultralente Insulins With Protamine Zinc Insulin in Normal Cats-American Journal of Veterinary Research-1994
  27. Diabetes-World Mailing List Web Site-Questions About Insulin
  28. Subcutaneous Absorption of Insulin in Insulin-dependent Diabetic Patients. Influence of Species, Physico-chemical Properties of Insulin and Physiological Factors-PubMed-Danish Medical Bulletin 1991
  29. RxEd.org-Insulin Therapy
  30. Comparative Study of NPH (Isophane) Human Insulin & NPH (Isophane) Bovine Insulin in Human Subjects-Diabetes Care-ADA-1982
  31. Human & Porcine NPH (Isophane) Insulins are Unequally Effective in Diabetic Patients-Acta Diabetelogica-1984
  32. Type 1 Diabetes Mellitus & Use of Flexible Insulin Regimens-Hirsch-American Family Physician-1999
  33. Human, Porcine and Bovine Ultralente Insulin: Subcutaneous Administration in Normal Man-Diabetic Medicine-1986
  34. Use of Beef Ultralente for Basal Insulin Delivery-Diabetes Care-American Diabetes Association-1986
  35. Comparison of the Safety and Effectiveness of Human and Bovine Long-acting Insulins-Diabetes Research-1989
  36. Diabetes Forecast-ADA, 2006-Page 3
  37. Veterinary Partner-The Hard to Regulate Diabetic Pet
  38. WSAVA 2001-Diabetes Mellitus: Treatment Options-Dr. David Bruyette
  39. Selecting an Insulin for Treatment of Diabetes Mellitus in Dogs 7 Cats-Nelson-Page 40
  40. The Absorption of Subcutaneously Injected Short-Acting Soluble Insulin: Influence of Injection Technique & Concentration-Diabetes Care-ADA-1983
  41. Absorption Comparison U40 & U100 Insulins-PubMed
  42. Insulin-Dependent Diabetes-Dr. Ragnar Hanas
  43. Bernstein-The Law of Small Numbers Part 2
  44. Diabetic Phenomena-WSAVA 2008
  45. Insulin Dependent Diabetes-Dr. Ragnar Hanas-1999 (Page 5)
  46. Comparison of U100 and U40 Insulins-PubMed
  47. Type 1 Diabetes Mellitus & Use of Flexible Insulin Regimens--Hirsch-American Family Physician-1999
  48. Chemistry and Pharmacology of Therapeutic Insulin Preparations, Abrams-Ogg, ACVIM 2007
  49. Insulin Dependent Diabetes-Dr. Ragnar Hamas-1999 (Page 6)
  50. Type 1 Diabetes Mellitus & Use of Flexible Insulin Regimens--Hirsch-American Family Physician-1999
  51. Subcutaneous Absorption of Insulin in Insulin-dependent Diabetic Patients. Influence of Species, Physico-chemical Properties of Insulin and Physiological Factors--PubMed-Danish Medical Bulletin 1991
  52. Comparison of U40 & U100 Regular (Neutral) Insulin & Rapid-Acting Insulin Lispro (Humalog)-1998-PubMed
  53. Resource Guide-2005-American Diabetes Association
  54. Use of U500 Insulin in Patients With Extreme Insulin Resistance-Diabetes Care-ADA-2005
  55. Diabetes Forecast-ADA,2006-Page 4
  56. Diabetes World Mailing List Web Site-Questions About Insulin
  57. Five Fold Increase of Insulin Concentration Delays the Absorption of Human Insulin Injections in Pigs-Diabetes Research & Clinical Practice-2000
  58. Use of U500 R Insulin by Continuous Insulin Infusion (Insulin Pump)in Patients With Type 2 Diabetes & Severe Insulin Resistance Endocrine Practice-2006
  59. U500 Insulin in the Treatment of Antibody-Mediated Insulin Resistance-Annals of Internal Medicine-1981
  60. Enhanced Efficacy of U500 Insulin in the Treatment of Insulin Resistance Caused by Target Tissue Insensitivity-American Journal of Medicine-1984

See also peak, onset, carryover and Insulin. --Steve and Jock 14:46, 10 December 2006 (UTC)

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