Stijn J.M. Niessen, DVM, PhD, DECVIM, PGCertVetEd, FHEA, MRCVS
Senior Lecturer Internal Medicine, Royal Veterinary College, University of London, London, UK; Research Associate, Newcastle Medical School, Newcastle, UK; Consultant, Veterinary Information Network, Davis, CA, USA
This lecture will inform delegates of a structured approach to the diabetic dog suffering from insulin resistance. It will feature examples of the most common case scenarios encountered in practice and will illustrate possible solutions. The session is therefore ideally suited for practitioners with a high diabetic case load.
True and Pseudo-Insulin Resistance
The concept of insulin resistance usually features in the context of the difficult diabetic, or a diabetic which is not reliably responding to a seemingly adequate insulin dose. This could actually represent two different situations: 1. true insulin resistance or 2. pseudo-insulin resistance. However, both could present in a similar fashion. Additionally, it remains important to remember (and communicate to the owner) that diabetes mellitus is a dynamic disease and many variables in the management protocol are also variable in nature. It can therefore seem an extremely difficult affair to identify the one factor that could improve the diabetic control in any given patient presented with suboptimal diabetic control. Adopting a structured stepwise approach can help here.
A Stepwise Approach: Owner, Vet or Pet
The number one cause associated with lack of appropriate response to the insulin therapy is a cause which is somehow connected with the owner of the diabetic pet. Clinicians should, therefore, try their utmost best to exclude such owner-related management issues prior to undertaking more elaborate and expensive specialist investigations. In order to achieve this, diabetic pet owners should be encouraged to demonstrate an adequate insulin injection technique and appropriate insulin handling and storage habits. This might seem obvious, but it is the very obvious nature of the issue, that leads to its proper assessment often being forgotten or skipped. Clinicians should also not be ashamed to question the owner on these issues, although a tactful manner of asking the right questions might be needed with owners that might take offence if they feel the quality of their management is being doubted. It is not uncommon for owners to initially show fantastic management habits, for those to be subsequently forgotten or replaced by alternatives weeks to months later; continued and repeated assessment is therefore warranted. A good example of an owner related error is the use of the wrong syringe type for a given insulin type, especially relevant to the use of Caninsulin/Vetsulin (MSD Animal Health) or ProZinc (Boehringer Ingelheim) which requires U-40 type syringes. The provision of midday snacks, without the contemporary additional injection of insulin to help cope with the induced post-snack hyperglycemia, is another owner-related factor that makes obtaining good glycemic control a difficult to obtain, moving target. Another example constitutes the lack of variation of injection site, which might induce areas of inflammation and reduced insulin absorption. It is also of paramount importance that clinicians ensure that all individuals involved in the diabetic care receive and comply with the same veterinary instructions, despite perhaps only ever finding one member of the family visiting the veterinary practice. A thorough assessment of the quality of life of the diabetic pet and its owner(s) might prove advantageous, since it might lay bare those areas that make consistent good management less likely to occur, for instance if owners are struggling to integrate the diabetic care with their social or work life. Validated structured quality of life tools to investigate these practical and psycho-social factors have become available.
The number two cause associated with lack of appropriate response to the insulin therapy is in fact clinician-related. Before arriving at a diagnosis of true insulin resistance, it is strongly advised to ensure we carefully interpret the combination of clinical (i.e., persistent diabetes-related) signs and a range of diagnostic data (e.g., fructosamine, multiple at-home collected urine glucose samples, multiple hospital and/or home blood glucose curves). A single blood glucose levels does not prove the presence of insulin resistance. In some dogs, more frequently in the cat, the explanation might be the presence of stress hyperglycaemia, though it is also important to realise that blood glucose curves vary significantly from day-to-day, without having changed any management parameter. Studies comparing the blood glucose curves of two consecutive days demonstrated that different conclusions were drawn and therefore different management interventions were planned depending on which of those two consecutive curves was taken as the true curve. The latter might lead us to dismiss completely the use of the blood glucose curve, although this would at the same time mean we throw away the one single glycaemic assessment method that at least has the potential to demonstrate to us the duration of insulin action as well as the daily nadir. It is therefore probably best to not completely abandon the blood glucose curve as a tool, but instead adopt a critical attitude in interpreting the obtained glycaemic data of a curve. It can in fact prove very useful to run a series of curves (instead of one single curve) in a difficult diabetic, without necessarily changing a parameter in the management, since it is likely that the overall trend shown by these multiple curves closely resembles the true glycaemic control of the patient. Other commonly management associated issues include insulin underdosing, overdosing and subsequent hypoglycaemia induced hyperglycaemia and short duration of insulin action. Insulin underdosing is common and it is important to realize that one would only consider true insulin resistance to be present in diabetic pets receiving in excess of 1.5–2 units per kilo per injection on a twice daily injection protocol, prior to which underdosing is a possible cause for the inferior clinical control.
The number three cause associated with lack of appropriate response to insulin therapy constitutes concurrent disease of the diabetic pet.
Mechanisms through which insulin resistance arises are varied and many are still under investigation or are likely yet to be discovered. Such mechanisms include: down-regulation of the number of insulin receptors (this can occur in a state of hyperinsulinaemia) and slowing down of post-receptor communication (which can occur with hyperglycaemia, hyperlipidaemia, inflammatory processes and dysregulation of hormones other than insulin, e.g., progesterone and growth hormone excess associated with acromegaly in the female entire dog). Accumulation of ectopic lipid metabolites, activation of the so-called "unfolded protein response pathway," and pathways of the innate immune system have all been hypothesised to be involved.
Infectious disease features high on the list of specific disease processes associated with true insulin resistance, with a particular mention for urinary tract infections and dental disease, both commonly occurring in the diabetic dog. Inflammatory diseases like pancreatitis, inflammatory bowel disease and gingivostomatitis are further important considerations given their prevalence among diabetic pets and their potential to affect insulin sensitivity, as well as their negative effect on reliable appetite rendering diabetic management more challenging. Treatment of inflammatory conditions, which often requires the administration of diabetogenic drugs, can pose additional challenges to the clinician, although creative solutions can be explored in many cases and will be discussed in the lecture. Endocrinopathies like hypothyroidism, hyperadrenocorticism, as well as iatrogenic hormone administration (including topical preparations) could lead to both insulin resistance as well as variable insulin sensitivity without actual overt insulin resistance. The diagnosis of hypothyroidism and especially hyperadrenocorticism can prove challenging in the uncontrolled diabetic dog given the confusion with sick euthyroid syndrome as well as the effects of stress and concurrent disease on pituitary-adrenal axis testing. Suggestions for, usually successful, approaches to such difficult cases will be discussed using case examples.
Double-Check the Diagnosis
Finally, clinicians should also ensure that the initial diagnosis of type 1 DM in the dog was in fact correct. If not, the subsequent treatment with insulin could easily prove difficult. In the female entire dog, dioestrus induced DM might be present and neutering is therefore indicated at the earliest opportunity, since diabetic remission might even be obtained. Furthermore, treating a female entire diabetic dog with insulin invariable leads to much frustration, due to the encountered continuous variation in insulin sensitivity.