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Australian College of Veterinary Scientists – Science Week 2007 – Small Animal Medicine Chapter meeting Advances in human diabetes care including insulin delivery and
continuous glucose monitoring that may be applicable to animals.
University of Melbourne, Department of Medicine,
Introduction: Rates of both Type 1 and Type 2 diabetes mellitus and of gestational
diabetes are increasing in humans1 related to higher prevalence of people being
overweight or obese and physically inactive, and there being a larger pool of genetically
pre-disposed people. Insulin is essential for life in Type 1 diabetes and is often required
within 10 years of Type 2 diabetes diagnosis. Tight glycaemic control, with a mean
HbA1c under 8%, is associated with significantly lower rates of retinal, renal, neural
and cardiovascular complications2,3. In addition, good glycaemic control is also
associated with less infection, better wound healing, improved mood and concentration.
Disadvantages of tight glycaemic control are greater weight gain and a higher frequency
of hypoglycaemia2. Recent developments in human diabetes clinical practice and on-
going research that may have relevance to animal care and research are: New insulins
and modes of delivery, and means of monitoring glucose control are discussed.
New insulins and modes of insulin delivery:
New insulins recently available in Australia are Lantus (Sanofi-Aventis) and Levemir
(Novo Nordisk). These recombinant human insulins, which are injected
subcutaneously without admixture with other insulins, have relatively flat action
profiles and last approximately 20-24 hours and 12-17 hours respectively. Insulin
absorption is less variable, glycaemic control smoother and there is a lower risk of
hypoglycaemia. In Type 2 diabetes these insulins can be a useful adjunct to oral agents,
but if used alone, or in Type 1 diabetes require a pre-meal (separate site) subcutaneous
injection of a rapid acting insulin (Novorapid or Humalog)4,5.

Insulin pumps are an alternate modes of insulin delivery, used primarily in Type 1
diabetes, that reduces the number of injections from 2-4 daily to one insertion every
third day5,6. Continuous subcutaneous insulin infusion (CSII) delivers rapid acting
insulin (Novorapid or Humalog) subcutaneously via a programmable pager sized device
with a 1.2 – 3 ml insulin reservoir. Basal insulin delivery rates can be varied according
to the time of day, and during periods of exercise. A patient (or parent)-initiated bolus
of insulin can be delivered in a variety of profiles aimed to match the nature of the
ingested meal or to correct hyperglycaemia. Remote control devices are available
Relative to multiple daily injections (MDI), CSII allows for more accurate delivery,
reduced variability in insulin absorption, and greater flexibility with both basal and
bolus insulin delivery allowing greater lifestyle flexibility5,6.
Alternate routes of insulin delivery recently trialled in Australia, and available for
clinical use overseas, are inhaled insulin (though this would not be practical for
animals). Research is ongoing with an insulin patch and insulin tablet.
Subcutaneous insulin pellets of bovine or of human insulin are efficacious, but so far
are only approved for research use only. Insulin pellets or part thereof (Linshin Canada,
Australian College of Veterinary Scientists – Science Week 2007 – Small Animal Medicine Chapter meeting
Scarborough, Ontario, Canada) are inserted subcutaneously by needle and can provide
basal insulin therapy for up to 60 days7.
An insulin alternative for Type 2 diabetes that can be used in conjunction with
sulphonylureas, metformin and thiozilidinediones is the incretin mimetic, exanetide
(Byetta), expected to be available in Australia in 20078. Exanetide, a glucagon-like
peptide-1 (GLP-1) receptor agonist, has glucose-dependent insulinotropism, suppresses
inappropriately high glucagon levels, delays gastric emptying and reduces food intake.
Given by subcutaneous injection twice a day it is not associated with hypoglycaemia
risk. Weekly and monthly injections are in development. Another GLP-1 based
therapy is sitagliptin, a competitive fully reversible inhibitor of dipeptidyl peptidase 4,
the enzyme responsible for the rapid degradation of the GLP-1. Given once daily as a
tablet it is approved for monotherapy or combination therapy of Type 2 diabetes9, but is
not yet available in Australia.

Means to assess blood glucose control:
HbA1c, fructoseamine, home blood glucose monitoring, urinanalysis, continuous
glucose monitoring, and 1,5-AG are means to monitor glucose levels.
HbA1c and fructoseamine reflect average blood glucose over 2 – 3 months and 2 – 3
weeks respectively), but not reflect its variability. A recently available tool to measure
blood glucose control and variability is continuous glucose monitoring via measures
of interstitial fluid glucose. The continuous glucose monitoring system measures
interstitial glucose via glucose oxidase methodology every 10 seconds and providing an
average glucose value every 5 minutes for 72 hours10,11. At least two and preferably
four blood glucose readings done at times of stable glucose control need to be provided
per day to calibrate interstitial and blood glucose readings. The output, which is not
available to the wearer in ‘real time’, is downloaded from the pager sized device and
analyzed by the health care team. CGMS readout is an excellent assessment tool to
assess glycaemic fluctuations in stabilizing patients with insulin treatment on an insulin
pump or on basal bolus multiple daily injection insulin regimens10. In addition, it is also
a useful tool in the management of diabetes in pregnancy to discern if the pregnant
woman has optimal glycaemic control, or is experiencing frequent hypoglycaemic
episodes or frequent episodes of high glucose such that insulin treatment is required
during gestational diabetes11. A CGMS service requires hardware including the
reusable recorder and transmitter and disposable sensors and the docking device and
computer software to download and interpret the glucose profile. Each 3-day glucose
sensor costs $75. In August 2006 Medtronic (Australia) launched a real-time CGM
device, that must be used with an insulin pump, that provides data visible at the time,
and incorporates alarms to alert high or low glucose levels. Medtronic and other
companies have stand alone devices, not yet available in Australia10. While most real-
time CGM devices use a subcutaneous sensor inserted for the short term (usually about
three days and up to seven days) long term implantable devices are currently in
development.
A serum based assay that may reflect glycaemic excursions, at least those into the high
range, is 1,5-anhydroglucitol (1,5-AG), or the GlycoMark assay12-15. 1,5-AG is a
dietary derived monosaccharide similar in structure to glucose. Plasma or serum levels
are in steady state, with constant levels in non-diabetic subjects. 1.5-AG is filtered by
Australian College of Veterinary Scientists – Science Week 2007 – Small Animal Medicine Chapter meeting
the kidneys and reabsorbed, but glucose competes for the reabsorption, hence in the
presence of hyperglycaemia less 1,5-AG is reabsorbed and blood levels fall. Hence
with worse (higher) blood glucose levels the 1,5-AG levels fall. In non-diabetic patients
or in diabetic patients with HbA1c <6.5% and no major post-prandial glucose
excursions levels are 17-22 ug/ml. In poorly controlled diabetes levels are < 2 ug/ml
correlates with shorter term (2-14 days) glycaemic variability12-15. The Glycomark
assay has been shown to correlate with glycaemic variability, in particular post-prandial
glucose control as assessed by CGMS13. There is potential for serum 1,5-AG levels to
be a useful adjunct in the assessment of glycaemic control in diabetes. This
spectroscopic assay has been approved for use overseas since 1991, but is not yet
available in Australia for clinical use.
Dogs played a key role in the development of insulin therapy for Type 1 diabetes, and
animal species may now benefit from recent advances in the treatment of human
diabetes.
References:
1. AUSDIAB 2004/5 data: www.diabetes.com.au 2. Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B; DCCT/EDIC Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):2643-53. 3. UKPDS Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837-53. 4. Peterson GE. Intermediate and long-acting insulins: a review of NPH insulin, insulin glargine and insulin detemir. Curr Med Res Opin. 2006;22(12):2613-9. 5. Cohen ND, Shaw JE. Diabetes: advances in treatment. Intern Med J. 2007;37(6):383-8. 6. Weissberg-Benchell J, Antisdel-Lomaglio J, Seshadri R. Insulin pump therapy: a meta-analysis. 8. Cvetkovic RS, Plosker GL. Exenatide: a review of its use in patients with type 2 diabetes mellitus (as an adjunct to metformin and/or a sulfonylurea). Drugs. 2007;67(6):935-54. 9. Pratley RE, Salsali A. Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes. Curr Med Res Opin. 2007;23(4):919-31. 10. D O’Neal and Jenkins AJ. Continuous glucose monitoring. Diabetes Management. 2006. 11. McLachlan K, Jenkins A, O’Neal D. The Role of Continuous Glucose Monitoring in Clinical Decision Making in Diabetes. ANZ J Ob and Gynae. In press 2007 12. Nowatzke W, Sarno MJ, Birch NC, Stickle DF, Eden T, Cole TG. Evaluation of an assay for serum 1,5-anhydroglucitol (GlycoMark) and determination of reference intervals on the Hitachi 917 analyzer. Clin Chim Acta. 2004;350(1-2):201-9. 13. Buse JB, Freeman JL, Edelman SV, Jovanovic L, McGill JB. Serum 1,5-anhydroglucitol (GlycoMark ): a short-term glycemic marker. Diabetes Technol Ther. 2003;5(3):355-63. 14. McGill JB, Cole TG, Nowatzke W, Houghton S, Ammirati EB, Gautille T, Sarno MJ; U.S. trial of the GlycoMark assay. Circulating 1,5-anhydroglucitol levels in adult patients with diabetes reflect longitudinal changes of glycemia: a U.S. trial of the GlycoMark assay. Diabetes Care. 2004;27(8):1859-65. 15. Dungan KM, Buse JB, Largay J, Kelly MM, Button EA, Kato S, Wittlin S. 1,5-anhydroglucitol and postprandial hyperglycemia as measured by continuous glucose monitoring system in moderately controlled patients with diabetes. Diabetes Care. 2006;29(6):1214-9.

Source: http://samedicine.anzcvs.org.au/samedicine_assets/documents/2007%20sam%20proceedings/jenkins.pdf