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Diabetes in Pets

Absorption

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After you inject insulin, it goes into the bloodstream to work[1]. If the insulin is R/neutral or one of the non-mixed analogs, it will be absorbed quickly. Fast-acting insulins are designed to be absorbed even faster, while insulin suspensions are made to "hinder" the rapid absorption of the insulin, to make them work for a longer time period.

The importance of how insulin is absorbed after it is injected under the skin is illustrated in this 2002 ADA Diabetes Care study, where Short-acting R/Neutral and Long-acting Lantus were compared when given intravenously, as opposed to subcutaneous use. Researchers found nothing slow-acting about Lantus when it was given intravenously, and they concluded that it is the absorption process from beneath the skin which produces the quite different effects these two have[2].

Absorption varies from patient to patient; this is why some patients get more or less duration from an insulin than another patient using the same thing[3]. It also can vary for the individual patient from day to day[4]. Absorption is one of the factors in insulin variability[5][6].

NeutralEdit

Neutral or R insulin is basically zinc insulin crystals dissolved in clear fluid with nothing added to alter its action or speed[7]. This is true regardless of the insulin's species of origin; it has a normal absorption profile. Insulin molecules clump together naturally into "hexamers" (groups of six), which then drift apart when sufficiently diluted. The clumped form of hexamers, cannot be used directly, so there's a bit of time delay using R insulin while they are broken down into dimers and monomers.

Insulin hex di mon
Insulin hexamers (as produced by the body or injected) must break down into dimers and monomers to be absorbed[8].
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It might be easier to visualize this by thinking of a whole pie, slicing it into 6 pieces and putting one slice each on separate plates. The pie can't be eaten until it has been cut and served on plates.

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[9].

Faster-actingEdit

It is possible to "speed" the absorption of insulin; one way is to alter the amino acid sequence(s) of them, producing analog insulins like Humalog, Novolog, NovoRapid and Apidra. Some of these (Humalog, Novolog) work by substituting or exchanging one or two amino acids at or near positions B-#28 & B-#29 so that insulin molecules will tend to remain separate instead of allowing them to clump together naturally into hexamers[10]. Apidra's substitutions are a bit different-at B-#3 and B-#29[11]. Using these types of alterations to force the insulin molecules to dissociate (remain apart, in the form of dimers and monomers, rather than their natural tendency to stay together), means they will be absorbed by the body faster.

Another way of forcing the insulin hexamers to stay apart and speed their absorption is with a less than U100 strength of insulin. Diluting insulin into U40 strength forces them into dissociating (staying apart from each other, and becoming dimers and monomers), which means they are absorbed[12][13] better and more rapidly[14].

The fact[15] that U40 insulin has a similar pharmacokinetic profile to analog insulin, has not been lost on the German Institute for Health Care Quality (government department). They proposed a cost-cutting move which would stop prescription coverage of the rapid-acting analogs for all newly-diagnosed Type 2 diabetics in Germany. This measure passed July 17, 2006[16], with rapid-acting analogs being covered only if they are similarly priced to non-analog insulin or if genuine intolerance can be medically demonstrated by the patient.

The "Strength" section of the insulin page has more information and references regarding comparisons of the speed of U40 & U100 insulins.

Slower-actingEdit

Other insulins, whether suspended or not, contain minute crystals of varying sizes which are deposited under the skin with the injection. Those with larger crystals, such as Ultralente, are absorbed slower than those with microfine ones, such as Semilente. Lente-type insulins are a "blend" of 30% faster-acting semilente crystals and 70% slower-acting Ultralente ones; this produces an intermediate-acting insulin. Mixed insulins are combined with a protamine suspension to keep them from being absorbed rapidly.

Though it is not a suspended insulin, Lantus delays its absorption by not forming crystals until AFTER it has been injected and also via alterations made to the basic human insulin molecule[17]. Lantus's suspension is a special acidic preparation (pH 4.0) that reacts with the injection site forming micro-precipitates around the insulin crystals, which keeps them trapped for a while. Once the crystals make it to the bloodstream, they're absorbed as fast as any other insulin. Don't rub the injection site after injection or you can speed up absorption of Lantus and all other insulins[18].

Levemir uses an ordinary protamine suspension but has a genetically-engineered sticky "acyl side chain" that clings for a while to albumin (protein) molecules found in the bloodstream (and under the skin) that makes the Levemir molecule too big to enter/exit the bloodstream and therefore slows down its absorption, not only at the site but also in the bloodstream and at the target tissues.

It is also possible to delay the absorption of an insulin by increasing its strength. U500 insulin, 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[19]) by special order for many years[20]. 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[21].

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[22][23].

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%[24][25].

Whether the insulin is slowed by the size of its crystals, by its suspension, by the strength of its concentration, or by amino acid alterations designed to delay its absorption--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.

Effect of originEdit

Felineinsulin8
Feline insulin compared with Bovine, Human, & Porcine versions. Up to 4 amino acids differ. The closest match to feline is bovine with only one amino acid difference; the least close is human with four amino acid differences.

People absorb r-DNA/GE/GM insulin at a faster rate than an otherwise identical pork or beef insulin[26][27][28][29], because it is an exact amino acid match to their own[30][31]. They absorb pork insulin a bit slower, because it is one amino acid away from theirs[32][33]. Slowest of all is beef insulin, as it is three amino acids away from a person's natural insulin[34][35][36].

Canineinsulin8
Canine insulin compared with Bovine, Human, & Porcine versions. Up to 2 amino acids differ with porcine and canine being identical[37].

It would be exactly opposite for dogs because their natural insulin is a perfect match to pork insulin, and one amino acid away from r-DNA/GE/GM insulin. Dogs would absorb pork insulin faster than an otherwise identical r-DNA/GE/GM human insulin. They would absorb beef insulin slower than either pork or r-DNA/GE/GM human insulin, as it is two amino acids away from a perfect match to their own.

Origin, species, or source is very important as it directly affects the absorption, peak and duration of an insulin[38]

Beef insulin, which is quite slow for human beings[39], owing to the three amino acid difference between beef insulin and a human's own, would act more rapidly in cats, since it is the closest match we have to native feline insulin until r-DNA/GE/GM feline insulin comes along. Cats would absorb pork insulin slower than an otherwise identical beef insulin because of the 3 amino acid differences between them; they would absorb r-DNA/GE/GM human insulin slowest of all, because there are 4 amino acid differences in feline and human insulin[40][41].

Effect of injection siteEdit

Taking absorption outside the lab, many other factors come into play. A study done at the University of Minnesota showed that there is an 29-39% variation on the amount of insulin going into the bloodstream from one day to another[42].

Absorption is faster when insulin is injected into limbs which are in motion[43][44] than in injection sites which are not--such as the back. Insulin also is absorbed faster via warmth--including the heat of summer[45][46]. When blood flow is increased to the site of the insulin injection, absorption also increases[47]. Both warmth and movement of the injection site increase increase blood flow[48][49].

Some diabetic cat caregivers report differing absorption rates with the same insulin depending on the injection site, the shot technique, and the needle length on the syringe.

Absorption problems can occur possibly causing hypoglycemia[50] or hyperglycemia if the insulin injection sites are not varied.

The area needn't be very far from where the last shot was given--the distance of the width of 2 fingers will do fine as a measure[51].

When shots are given again & again into an area of skin, the tissue becomes thicker at that point; a fairly good analogy would be the calluses people get on hands and feet. The callus skin is thicker and harder; injection areas become similar to this too from repeated shots. This thicker, harder skin doesn't let the body absorb the injected insulin as well as thinner, non-hardened areas[52].

Most of us dealing with pet diabetes vary the side we give the injections in--right side mornings and left side evenings, for example. This is another help in avoiding giving shots in the same areas[53].

Many people give insulin shots in the scruff of the pet's neck, which is now considered to be a less than optimum choice. The neck area provides poor insulin absorption, due to it not having many capillaries, veins. etc. (vascularization).

Other sites suggested by Dr. Greco include the flank and armpit[54].

Intervet recommends giving injections from just back of the shoulder blades to just in front of the hipbone on either side, from 1 to 2 inches from the middle of the back[55].

Levemir is too new to show any feline or canine data, but the manufacturer claims[56] that in their testing on humans they found much lower day-to-day variability[57], even when shooting at different sites. They claim that this is because the Levemir "clinging" action[58] takes place throughout the body and in the blood, and so is not dependent on injection site conditions.

Depth of injectionEdit

Subcutaneous (under the skin) injections are absorbed the slowest. Intramuscularly (into the muscle) given ones are absorbed much faster, but should not be given other than on the advice of a medical professional[59].

Insulin doseEdit

The larger the dose of insulin, the longer it takes to be absorbed[60] and the more duration it will have[61].

Effect of body conditionEdit

Cats and dogs who are dehydrated may have reduced insulin absorption rates; vomiting and diarrhea can cause both dehydration and hypoglycemia from them[62].

Dehydration can change the way subcutaneous insulin is absorbed[63], causing either hyperglycemia or hypoglycemia[64].

Those with diabetes are at risk for dehydration as it is triggered by hyperglycemia[65].

Other factors modulating insulin absorption[66] include regional blood flow which is affected by exercise, rubbing or massage, and temperature.

Effect of needle lengthEdit

Some caregivers report difference in insulin absorption with different length needles. BD Diabetes[67] explains that you should consult with your health care professional before using a short needle, and carefully monitor blood glucose when changing to a shorter needle.

People have found their blood glucose not well-controlled when switching to the shorter needles; this also has been the case with some dogs. Switching back to a longer needle solved the problem. You should consider experimenting with the different length needles as insulin absorption may vary[68].

Further ReadingEdit

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ReferencesEdit

  1. Merck Veterinary Manual-Disposition & Fate of Drugs
  2. Intravenous Glargine (Lantus) & Regular (Neutral) Insulin Similar Effects on Endogenous Glucose Output & Peripheral Activation/Deactivation Kinetic Profiles-ADA-Diabetes Care-2002
  3. Diabetes Forecast-ADA, 2006-Page 2
  4. Merck Veterinary Manual-Disposition & Fate of Drugs
  5. Diabetes-World Mailing List Web Site-Questions About Insulin
  6. Insulin Treatment-Individual Factors
  7. US FDA-Humulin R
  8. Insulin Dependent Diabetes-Dr. Ragnar Hanas-1999 (Page 5)
  9. Chemistry and Pharmacology of Therapeutic Insulin Preparations, Abrams-Ogg, ACVIM 2007
  10. Clinchem.org-Details Human Insulin Alterations for Humalog (Lispro), Novolog/NovoRapid (Aspart) & Lantus (Glargine)
  11. Prescribing Information-Apidra-Sanofi-Aventis
  12. Comparison of U100 and U40 Insulins-PubMed
  13. Type 1 Diabetes Mellitus & Use of Flexible Insulin Regimens-Hirsch-American Family Physician-1999
  14. 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
  15. German Institute for Health Care Quality Study--English Translation
  16. Google Auto-Translated Page German Health Care Quality & Ecomony Institute Ruling
  17. Clinchem.org-Alterations of Human Insulin Producing Insulins Apart, Glargine & Lispro
  18. Insulin-Dependent Diabetes-Dr. Ragnar Hanas (Pages 12 & 13)
  19. Use of U500 Insulin in Patients With Extreme Insulin Resistance-Diabetes Care-ADA-2005
  20. Diabetes Forecast-ADA,2006-Page 4
  21. Diabetes-World Mailing List Web Site-Questions About Insulin
  22. Five Fold Increase of Insulin Concentration Delays the Absorption of Human Insulin Injections in Pigs-Diabetes Research & Clinical Practice-2000
  23. Use of U500 R Insulin by Continuous Insulin Infusion (Insulin Pump)in Patients With Type 2 Diabetes & Severe Insulin Resistance Endocrine Practice-2006
  24. U500 Insulin in the Treatment of Antibody-Mediated Insulin Resistance-Annals of Internal Medicine-1981
  25. Enhanced Efficacy of U500 Insulin in the Treatment of Insulin Resistance Caused by Target Tissue Insensitivity-American Journal of Medicine-1984
  26. Diabetes-World Mailing List Web Site-Questions About Insulin
  27. Subcutaneous Absorption of Insulin in Insulin-dependent Diabetic Patients. Influence of Species, Physico-chemical Properties of Insulin and Physiological Factor--PubMed/Danish Medical Bulletin 1991
  28. Comparison of the Safety and Effectiveness of Human and Bovine Long-acting Insulins-Diabetes Research-1989
  29. Diabetes Health-Faster Onset & Shorter Duration of GE Insulin in Humans
  30. Comparing Activity Profiles of GE R(Neutral)/NPH(Isophane) With Different Fractions to Fixed-Fraction (70/30--30/70) Pork Mixed Insulin (Pork Mixtard 30)-Diabetes Care-ADA-1982
  31. Human, Porcine and Bovine Ultralente Insulin: Subcutaneous Administration in Normal Man-iabetic Medicine-1986
  32. Human & Porcine NPH (Isophane Insulins Unequally Effective in Diabetic Patients-Acta Diabetologica Latina-1984
  33. Comparison of Effects of Protamine-Bound NPH (Isophane) Porcine Insulin & NPH (Isophane) Human Insulin in T1 & T2 Diabetes-Deutsche Medizinische Wochenschrift (Translated into English)-1986
  34. Comparison of NPH (Isophane) Human Insulin & NPH (Isophane) Bovine Insulin in Humans-Diabetes Care-ADA-1982
  35. Type I Diabetes and Insulin Therapy Nursing Clinics of North America-Hirsch-Farkas-Hirsch 1993
  36. Comparative Study of r-DNA NPH Insulin and Bovine NPH Insulin in Humans-Diabetes Care, 1982
  37. Intervet-Caninsulin Product Information
  38. Diabetes Forecast-ADA, 2006-Page 3
  39. Insulin Therapy-Overview
  40. BCP Veterinary Pharmacy-Bovine PZI Insulin
  41. Comparison of 2 Ultralente Insulin Preparations With Protamine Zinc Insulin in Normal Cats-Americal Journal of Veterinary Research-1994
  42. Day To Day Variability Of Insulin
  43. Diabetes-World Mailing List Web Site-Questions About Insulin
  44. Diabetic Phenomena--WSAVA 2008
  45. Diabetes Mellitus Treatment-PetHealth101
  46. Diabetic Phenomena--WSAVA 2008
  47. Diabetes-World Mailing List Web Site-Questions About Insulin
  48. Type 1 Diabetes Mellitus & Use of Flexible Insulin Regimens-Hirsch-American Family Physician-1999
  49. Diabetes-World Mailing List Web Site-Questions About Insulin
  50. Insulin-Section 6.1-Kinetics
  51. Joslyn Diabetes Center-Tips for Injecting Insulin
  52. BD Diabetes-Injection Site Selection
  53. BD Diabetes-FAQ's About Diabetic Dogs-Dr. Greco
  54. Better Medicine E-Newsletter-June 2006
  55. Vetsulin-Preparing Insulin & Giving Injection-Page 2
  56. Novo Nordisk Presentation--Less Variability
  57. Lower Day-to-Day Variability
  58. Levemir "Clinging" Action Movie
  59. Diabetic Phenomena-WSAVA 2008
  60. Bernstein-The Law of Small Numbers Part 2
  61. Diabetic Phenomena-WSAVA 2008
  62. DiabetesNow-UK-Page 4
  63. American College of Emergency Physicians-Pediatric Endorcrine Emergency Answer Sheet
  64. DiabetesNow-UK-Page 4
  65. Healthology.com-Diabetes/Dehydration
  66. Insulin in the Hospital Setting, Ira B. Hirsch, U of Washington Medical Center
  67. BDdiabetes.com-Using Short Needles
  68. Diabetes Care-ADA Position Statement 2004
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