8/16/2016 1 Any insulin for Any Patient? Why not? Thomas Schermerhorn, VMD, DACVIM(SAIM) Kansas State University Manhattan, Kansas, USA Outline • Insulin Physiology • Insulin Pharmacology • Basal-Bolus Concept • Clinical Applications Insulin molecule. From Clinical Medicine and Research, Vol. 6, Iss. 2. Insulin Physiology A chain Man GIVEQCCTSICSLYQLENYCN 21 Dog GIVEQCCTSICSLYQLENYCN 21 Cat GIVEQCCASVCSLYQLEHYCN 21 Pig GIVEQCCTSICSLYQLENYCN 21 Cow GIVEQCCASVCSLYQLENYCN 21 B chain FVNQHLCGSHLVEALYLVCGERGFFYTPKT 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKA 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKA 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKA 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKA 30 Insulin Protein is Highly Conserved Insulin is equipotent across species. Horse GIVEQCCTGICSLYQLENYCN 21 Mouse1 GIVDQCCTSICSLYQLENYCN 21 Rat1 GIVDQCCTSICSLYQLENYCN 21 SquirMonk GVVDQCCTSICSLYQLQNYCN 21 CEmacaque GIVEQCCTSICSLYQLENYCN 21 Elephant GIVEQCCTGVCSLYQLENYCN 21 Sheep GIVEQCCAGVCSLYQLENYCN 21 Camel GIVEQCCASVCSLYQLENYCN 21 Opossum GIVEQCCNSICSLYQLETYCN 21 Rabbit GIVEQCCTSICSLYQLENYCN 21 ChiHamster GIVDQCCTSICSLYQLENYCN 21 GuineaPig GIVDQCCTGTCTRHQLQSYCN 21 *:*:*** . *: :**:.*** FVNQHLCGSHLVEALYLVCGERGFFYTPKA 30 FVKQHLCGPHLVEALYLVCGERGFFYTPKS 30 FVKQHLCGPHLVEALYLVCGERGFFYTPKS 30 FVNQHLCGPHLVEALYLVCGERGFFYAPKT 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKT 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKT 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKA 30 FANQHLCGSHLVEALYLVCGERGFFYTPKA 30 LVNQHLCGSHLVEALYLVCGERGFFYTPKA 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKS 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKS 30 FVSRHLCGSNLVETLYSVCQDDGFFYIPKD 30 :..:****.:***:** ** : **** ** Alignments modified from Wallis Lab (http://www.lifesci.sussex.ac.uk/home/Mike_Wallis/Protein_Hormones/Insulin.html)
Any insulin for Any Patient? Why not?
Mar 08, 2023
Any insulin for Any Patient? Why not?
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Any insulin for Any Patient? Why not?
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Microsoft PowerPoint - ISVMA Any insulin Any patient D1.pptxThomas Schermerhorn, VMD, DACVIM(SAIM) Kansas State University Manhattan, Kansas, USA
Outline
• Insulin Physiology • Insulin Pharmacology • Basal-Bolus Concept • Clinical Applications
Insulin molecule. From Clinical Medicine and Research, Vol. 6, Iss. 2.
Insulin Physiology
A chain
B chain
Horse GIVEQCCTGICSLYQLENYCN 21 Mouse1 GIVDQCCTSICSLYQLENYCN 21 Rat1 GIVDQCCTSICSLYQLENYCN 21 SquirMonk GVVDQCCTSICSLYQLQNYCN 21 CEmacaque GIVEQCCTSICSLYQLENYCN 21 Elephant GIVEQCCTGVCSLYQLENYCN 21 Sheep GIVEQCCAGVCSLYQLENYCN 21 Camel GIVEQCCASVCSLYQLENYCN 21 Opossum GIVEQCCNSICSLYQLETYCN 21 Rabbit GIVEQCCTSICSLYQLENYCN 21 ChiHamster GIVDQCCTSICSLYQLENYCN 21 GuineaPig GIVDQCCTGTCTRHQLQSYCN 21 *:*:*** . *: :**:.***
FVNQHLCGSHLVEALYLVCGERGFFYTPKA 30 FVKQHLCGPHLVEALYLVCGERGFFYTPKS 30 FVKQHLCGPHLVEALYLVCGERGFFYTPKS 30 FVNQHLCGPHLVEALYLVCGERGFFYAPKT 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKT 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKT 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKA 30 FANQHLCGSHLVEALYLVCGERGFFYTPKA 30 LVNQHLCGSHLVEALYLVCGERGFFYTPKA 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKS 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKS 30 FVSRHLCGSNLVETLYSVCQDDGFFYIPKD 30 :..:****.:***:** ** : **** **
8/16/2016
2
Insulin Action on Target Tissues Insulin Pharmacology
Natural insulin (animal insulin) – isolated from pancreas of cattle and pigs. Only a few products are commercially available (veterinary)
Recombinant insulin – human insulin produced by genetically altered bacteria. ALL insulins for humans contain human recombinant insulin
Synthetic insulin – insulin chemically altered to achieve a specific pharmacologic action.
Insulin suspension – complexed insulin is suspended in a vehicle. Insulin solution –insulin monomers dissolved in an aqueous vehicle.
Insulins in veterinary medicine Human products (U-100)
Regular HUMULIN R® NPH (Neutral Protamine Hagedorn) HUMULIN N®
Synthetic long acting insulin Lantus® - insulin glargine Synthetic short-acting insulin Humalog® – lispro insulin
Veterinary products (U-40) PZI ProZinc® (human insulin) Lente Vetsulin® (porcine insulin)
Insulin Pharmacokinetics ‘what the body does to the drug’
8/16/2016
3
Time-Action Profile
Basal-Bolus Concept
Bolus insulin released after meals.
From Ahmad, B, Pharmacology of Insulin. Br J Diabetes Vasc Dis 2004; 4:10-14.
Ideal insulin therapy replicates the physiologic insulin profile
Basal insulin to modulate HGP during fasting periods. Bolus insulin to modulate glucose disposal after meals.
No single insulin product replicates the physiologic insulin profile
Modified from Brink SJ. Diabetes Mellitus: A Fundamental and Clinical Text (3rd Ed). Lippincott Williams & Wilkins, 2004.
8/16/2016
4
BOLUS REPLACEMENT REGULAR INSULIN LISPRO INSULIN ASPART
Need for a true basal insulin drove development of long-acting insulin products • Delayed absorption and prolonged duration of action.
Need for a true bolus insulin drove development of short-acting insulin products • Rapid onset and short duration of action.
Normal Pre-Diabetes Diabetes
ANY Insulin ANY Patient
Regular, NPH, and Lente An investigation of the action of Neutral Protamine Hagedorn human analogue insulin in dogs with naturally occurring diabetes mellitus. Palm CA, Boston RC, Refsal KR, Hess RS. J Vet Intern Med. 2009 Jan-Feb;23(1):50-5.
Comparison of time-action profiles of insulin glargine and NPH insulin in normal and diabetic dogs. Mori A, Sako T, Lee P, Motoike T, Iwase K, Kanaya Y, Fukuta H, Mizutani H, Arai T. Vet Res Commun. 2008 Oct;32(7):563-73. Epub 2008 Jun 25.
Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs. Monroe WE, Laxton D, Fallin EA, Richter KP, Santen DR, Panciera DL, Towell TL, Williams KA, Hart JR, Hill S, Finkler MR, Shinn JS.. J Vet Intern Med. 2005 Sep- Oct;19(5):675-82.
Absorption kinetics of regular, isophane, and protamine zinc insulin in normal cats. Wallace MS Peterson ME Nichols CE Domest Anim Endocrinol 1990 Oct;7(4):509 15Wallace MS, Peterson ME, Nichols CE. Domest Anim Endocrinol. 1990 Oct;7(4):509-15.
Absorption kinetics of regular and isophane (NPH) insulin in the normal dog. Goeders LA, Esposito LA, Peterson ME. Domest Anim Endocrinol. 1987 Jan;4(1):43-50.
Glargine and Detemir Use of insulin glargine in dogs with diabetes mellitus. Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, Reusch CE.. Vet Rec. 2012 Jan;170(2):52.
Insulin glargine has a long duration of effect following administration either once daily or twice daily in divided doses in healthy cats. Marshall RD, Rand JS, Morton JM. J Feline Med Surg. 2008 Oct;10(5):488-94.
Pharmacodynamics of insulin detemir and insulin glargine assessed by an isoglycemic clamp method in healthy cats. Gilor C, Ridge TK, Attermeier KJ, Graves TK. J Vet Intern Med. 2010 Jul-Aug;24(4):870-4.
Time-action profiles of insulin detemir in normal and diabetic dogs. Sako T, Mori A, Lee P, Oda H, Saeki K, Miki Y, Kurishima M, Mimura K, Nozawa S, Mizutani H, Makino Y, Ishioka K, Arai T. Res Vet Sci. 2011 Jun;90(3):396-403.
PZI Efficacy of protamine zinc recombinant human insulin for controlling hyperglycemia in dogs with diabetes mellitus. Maggiore AD, Nelson RW, Dennis J, Johnson E, Kass PH. J Vet Intern Med. 2012 Jan-Feb;26(1):109-15.
Field safety and efficacy of protamine zinc recombinant human insulin for treatment of diabetes mellitus in cats. Nelson RW, Henley K, Cole C; PZIR Clinical Study Group. J Vet Intern Med. 2009 Jul-Aug;23(4):787-93.
Then why are there ANY unregulated diabetics?
• Limitations of insulin monotherapy
• Recommendations broadly based on 24-hr glucose profile. • Dog – intermediate-acting insulin administered B.I.D. • Cat – long-acting insulin administered daily or B.I.D
• Effective for most patients • Improves clinical signs of diabetes • Elimination of insulin requirement
• Ineffective for some patients
Species differences and effective insulin monotherapy
DOGS • Insulin dependence at diagnosis. • Mixed diet composition, inconsistent diet • Periodic feeding causes postprandial GLU surges. • Overnight fast
Normal < 150 mg/dl
Pre-Diabetes 150-220 mg/dl
Diabetes >220 mg/dl
CATS • Insulin reserve may remain at diagnosis. • Diet typically CHO restricted • Continuous feeding pattern. • Nocturnal feeding behavior
Normal < 150 mg/dl
Pre-Diabetes 150-220 mg/dl
Diabetes >220 mg/dl
Why isn’t Combination Insulin Therapy Used for Canine and Feline Diabetes?
Species differences in ‘normal’’.
Recognizing veterinary patients in the pre-diabetic state is difficult. • Insulin dependent at the time of diagnosis • Poorly defined metabolic markers for pre-diabetes. • Available tests are impractical, poorly standardized or both. • No justification for early identification/intervention of at-risk patients.
Patient/Owner compliance may be a major factor. • Basal-Bolus requires monitoring and multiple daily injections. • Scant evidence for use of multiple insulins in diabetic dogs or cats.
Variability – Differences in the metabolic actions of
Variability “What is the reason for the fact that repeated application of an identical insulin dose does not induce an identical metabolic response?”
Lutz Heinemann*
Variability – Differences in the metabolic actions of insulin due to environmental and biologic factors that affect insulin absorption or action.
Clinically relevant variability in the insulin effect
* Heinemann, L, Diab Tech Therap, 2002
8/16/2016
6
Biologic Variability
• Insulin sensitivity is not static • Variability in insulin action after IV administration
to healthy human subjects • Day-to-day within an individual - 15-25%Day to day within an individual 15 25% • Between individuals - 25-35%
Potential Sources of Variability Insulin type and formulation Ambient temperature Activity level Inadvertent IM injection Metabolic state (hypoglycemia ketoacidosis)Metabolic state (hypoglycemia, ketoacidosis) Local factors at injection site
•Daily insulin effects are not reproducible.
•Optimal metabolic control is not achieved.
Impact of Variability
•Frustration for owner and veterinarian.
•Added expense.
Current methods are retrospective or temporal • Clinical history and signs • Fructosamine Level • Spot glucose • Glucose curve
Poor predictors of future glycemic control or insulin needs.
8/16/2016
7
Variability in Blood Glucose Curves
CE Reusch et al., JFMS, 2006
Pharmacodynamic Variability
Gilor C, et al., J Vet Intern Med 2010;24:870–874
Summary • Insulin is highly conserved and has similar functions across species.
• Bioactive insulin, regardless of its source or formulation, will exert a glucose-lowering effect in dogs and cats.
• Ideal insulin replacement replicates the basal-bolus pattern of endogenous insulin secretion No single insulin product is idealendogenous insulin secretion. No single insulin product is ideal replacement therapy.
• Insulin monotherapy as used in veterinary medicine has efficacy in the majority of patients
• Variability from numerous sources may influence insulin absorption and action and produce in an apparent lack of efficacy.
Outline
• Insulin Physiology • Insulin Pharmacology • Basal-Bolus Concept • Clinical Applications
Insulin molecule. From Clinical Medicine and Research, Vol. 6, Iss. 2.
Insulin Physiology
A chain
B chain
Horse GIVEQCCTGICSLYQLENYCN 21 Mouse1 GIVDQCCTSICSLYQLENYCN 21 Rat1 GIVDQCCTSICSLYQLENYCN 21 SquirMonk GVVDQCCTSICSLYQLQNYCN 21 CEmacaque GIVEQCCTSICSLYQLENYCN 21 Elephant GIVEQCCTGVCSLYQLENYCN 21 Sheep GIVEQCCAGVCSLYQLENYCN 21 Camel GIVEQCCASVCSLYQLENYCN 21 Opossum GIVEQCCNSICSLYQLETYCN 21 Rabbit GIVEQCCTSICSLYQLENYCN 21 ChiHamster GIVDQCCTSICSLYQLENYCN 21 GuineaPig GIVDQCCTGTCTRHQLQSYCN 21 *:*:*** . *: :**:.***
FVNQHLCGSHLVEALYLVCGERGFFYTPKA 30 FVKQHLCGPHLVEALYLVCGERGFFYTPKS 30 FVKQHLCGPHLVEALYLVCGERGFFYTPKS 30 FVNQHLCGPHLVEALYLVCGERGFFYAPKT 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKT 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKT 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKA 30 FANQHLCGSHLVEALYLVCGERGFFYTPKA 30 LVNQHLCGSHLVEALYLVCGERGFFYTPKA 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKS 30 FVNQHLCGSHLVEALYLVCGERGFFYTPKS 30 FVSRHLCGSNLVETLYSVCQDDGFFYIPKD 30 :..:****.:***:** ** : **** **
8/16/2016
2
Insulin Action on Target Tissues Insulin Pharmacology
Natural insulin (animal insulin) – isolated from pancreas of cattle and pigs. Only a few products are commercially available (veterinary)
Recombinant insulin – human insulin produced by genetically altered bacteria. ALL insulins for humans contain human recombinant insulin
Synthetic insulin – insulin chemically altered to achieve a specific pharmacologic action.
Insulin suspension – complexed insulin is suspended in a vehicle. Insulin solution –insulin monomers dissolved in an aqueous vehicle.
Insulins in veterinary medicine Human products (U-100)
Regular HUMULIN R® NPH (Neutral Protamine Hagedorn) HUMULIN N®
Synthetic long acting insulin Lantus® - insulin glargine Synthetic short-acting insulin Humalog® – lispro insulin
Veterinary products (U-40) PZI ProZinc® (human insulin) Lente Vetsulin® (porcine insulin)
Insulin Pharmacokinetics ‘what the body does to the drug’
8/16/2016
3
Time-Action Profile
Basal-Bolus Concept
Bolus insulin released after meals.
From Ahmad, B, Pharmacology of Insulin. Br J Diabetes Vasc Dis 2004; 4:10-14.
Ideal insulin therapy replicates the physiologic insulin profile
Basal insulin to modulate HGP during fasting periods. Bolus insulin to modulate glucose disposal after meals.
No single insulin product replicates the physiologic insulin profile
Modified from Brink SJ. Diabetes Mellitus: A Fundamental and Clinical Text (3rd Ed). Lippincott Williams & Wilkins, 2004.
8/16/2016
4
BOLUS REPLACEMENT REGULAR INSULIN LISPRO INSULIN ASPART
Need for a true basal insulin drove development of long-acting insulin products • Delayed absorption and prolonged duration of action.
Need for a true bolus insulin drove development of short-acting insulin products • Rapid onset and short duration of action.
Normal Pre-Diabetes Diabetes
ANY Insulin ANY Patient
Regular, NPH, and Lente An investigation of the action of Neutral Protamine Hagedorn human analogue insulin in dogs with naturally occurring diabetes mellitus. Palm CA, Boston RC, Refsal KR, Hess RS. J Vet Intern Med. 2009 Jan-Feb;23(1):50-5.
Comparison of time-action profiles of insulin glargine and NPH insulin in normal and diabetic dogs. Mori A, Sako T, Lee P, Motoike T, Iwase K, Kanaya Y, Fukuta H, Mizutani H, Arai T. Vet Res Commun. 2008 Oct;32(7):563-73. Epub 2008 Jun 25.
Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs. Monroe WE, Laxton D, Fallin EA, Richter KP, Santen DR, Panciera DL, Towell TL, Williams KA, Hart JR, Hill S, Finkler MR, Shinn JS.. J Vet Intern Med. 2005 Sep- Oct;19(5):675-82.
Absorption kinetics of regular, isophane, and protamine zinc insulin in normal cats. Wallace MS Peterson ME Nichols CE Domest Anim Endocrinol 1990 Oct;7(4):509 15Wallace MS, Peterson ME, Nichols CE. Domest Anim Endocrinol. 1990 Oct;7(4):509-15.
Absorption kinetics of regular and isophane (NPH) insulin in the normal dog. Goeders LA, Esposito LA, Peterson ME. Domest Anim Endocrinol. 1987 Jan;4(1):43-50.
Glargine and Detemir Use of insulin glargine in dogs with diabetes mellitus. Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, Reusch CE.. Vet Rec. 2012 Jan;170(2):52.
Insulin glargine has a long duration of effect following administration either once daily or twice daily in divided doses in healthy cats. Marshall RD, Rand JS, Morton JM. J Feline Med Surg. 2008 Oct;10(5):488-94.
Pharmacodynamics of insulin detemir and insulin glargine assessed by an isoglycemic clamp method in healthy cats. Gilor C, Ridge TK, Attermeier KJ, Graves TK. J Vet Intern Med. 2010 Jul-Aug;24(4):870-4.
Time-action profiles of insulin detemir in normal and diabetic dogs. Sako T, Mori A, Lee P, Oda H, Saeki K, Miki Y, Kurishima M, Mimura K, Nozawa S, Mizutani H, Makino Y, Ishioka K, Arai T. Res Vet Sci. 2011 Jun;90(3):396-403.
PZI Efficacy of protamine zinc recombinant human insulin for controlling hyperglycemia in dogs with diabetes mellitus. Maggiore AD, Nelson RW, Dennis J, Johnson E, Kass PH. J Vet Intern Med. 2012 Jan-Feb;26(1):109-15.
Field safety and efficacy of protamine zinc recombinant human insulin for treatment of diabetes mellitus in cats. Nelson RW, Henley K, Cole C; PZIR Clinical Study Group. J Vet Intern Med. 2009 Jul-Aug;23(4):787-93.
Then why are there ANY unregulated diabetics?
• Limitations of insulin monotherapy
• Recommendations broadly based on 24-hr glucose profile. • Dog – intermediate-acting insulin administered B.I.D. • Cat – long-acting insulin administered daily or B.I.D
• Effective for most patients • Improves clinical signs of diabetes • Elimination of insulin requirement
• Ineffective for some patients
Species differences and effective insulin monotherapy
DOGS • Insulin dependence at diagnosis. • Mixed diet composition, inconsistent diet • Periodic feeding causes postprandial GLU surges. • Overnight fast
Normal < 150 mg/dl
Pre-Diabetes 150-220 mg/dl
Diabetes >220 mg/dl
CATS • Insulin reserve may remain at diagnosis. • Diet typically CHO restricted • Continuous feeding pattern. • Nocturnal feeding behavior
Normal < 150 mg/dl
Pre-Diabetes 150-220 mg/dl
Diabetes >220 mg/dl
Why isn’t Combination Insulin Therapy Used for Canine and Feline Diabetes?
Species differences in ‘normal’’.
Recognizing veterinary patients in the pre-diabetic state is difficult. • Insulin dependent at the time of diagnosis • Poorly defined metabolic markers for pre-diabetes. • Available tests are impractical, poorly standardized or both. • No justification for early identification/intervention of at-risk patients.
Patient/Owner compliance may be a major factor. • Basal-Bolus requires monitoring and multiple daily injections. • Scant evidence for use of multiple insulins in diabetic dogs or cats.
Variability – Differences in the metabolic actions of
Variability “What is the reason for the fact that repeated application of an identical insulin dose does not induce an identical metabolic response?”
Lutz Heinemann*
Variability – Differences in the metabolic actions of insulin due to environmental and biologic factors that affect insulin absorption or action.
Clinically relevant variability in the insulin effect
* Heinemann, L, Diab Tech Therap, 2002
8/16/2016
6
Biologic Variability
• Insulin sensitivity is not static • Variability in insulin action after IV administration
to healthy human subjects • Day-to-day within an individual - 15-25%Day to day within an individual 15 25% • Between individuals - 25-35%
Potential Sources of Variability Insulin type and formulation Ambient temperature Activity level Inadvertent IM injection Metabolic state (hypoglycemia ketoacidosis)Metabolic state (hypoglycemia, ketoacidosis) Local factors at injection site
•Daily insulin effects are not reproducible.
•Optimal metabolic control is not achieved.
Impact of Variability
•Frustration for owner and veterinarian.
•Added expense.
Current methods are retrospective or temporal • Clinical history and signs • Fructosamine Level • Spot glucose • Glucose curve
Poor predictors of future glycemic control or insulin needs.
8/16/2016
7
Variability in Blood Glucose Curves
CE Reusch et al., JFMS, 2006
Pharmacodynamic Variability
Gilor C, et al., J Vet Intern Med 2010;24:870–874
Summary • Insulin is highly conserved and has similar functions across species.
• Bioactive insulin, regardless of its source or formulation, will exert a glucose-lowering effect in dogs and cats.
• Ideal insulin replacement replicates the basal-bolus pattern of endogenous insulin secretion No single insulin product is idealendogenous insulin secretion. No single insulin product is ideal replacement therapy.
• Insulin monotherapy as used in veterinary medicine has efficacy in the majority of patients
• Variability from numerous sources may influence insulin absorption and action and produce in an apparent lack of efficacy.
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