Diabetes mellitus (DM)

Diabetes mellitus (DM) is a heterogeneous group of diseases with multiple etiologies characterized by hyperglycaemia resulting from inadequate insulin secretion, inadequate insulin action or both.

ALIVE criteria for diagnosing DM in dogs
1. DM in dogs is diagnosed:
In a patient with a random (fasted or unfasted) BG>= 200 mg/dl (11.1 mmol/l) with classic clinical signs of hyperglycaemia (with no other plausible cause) or hyperglycaemic crisis
• In some cases clinical signs may not have been reported by the owner
• In cases with uncertainty over presence/absence of clinical signs diagnosis should be confirmed by repeat BG measurement and/or documentation of alternative glycaemic parameters such as increased glycated proteins and/or glucosuria.
2. In some patients with fasting BG > 7 mmol/L <= 11mmol/l with or without clinical signs of hyperglcaemia or hyperglycaemic crisis . DM is differentiated from stress hyperglycaemia by documentation of persistent fasting hyperglycaemia for more than 24 hours or increased glycated proteins.

Comments:
Fasting is defined by a period of a minimum of 8 hours withholding food, not water (fasting should only be considered when it is safe for the patient). The definition implies use of a species-validated method to measure glucose as well as glycated protein, and conditions other than DM that specifically affect the concentration of glycated protein are excluded. Glycated blood proteins should be measured by a methodology with relevant, internally established reference interval, and regular quality assurance. Variations in protein concentration and metabolism can affect glycated protein concentrations. The diagnosis of DM is more likely than stress hyperglycaemia in dogs when contributing factors are present (e.g. HAC, diabetogenic treatment, dioestrus, pancreatitis).

ALIVE criteria for diagnosing DM in cats
The potential for stress hyperglycaemia warrants caution in interpretation of hyperglycaemia of any magnitude in cats.

DM in cats is diagnosed:
1. In a patient with a random (fasted or unfasted) BG>= 270 mg/dl (15 mmol/l) with classic clinical signs of hyperglcaemia (with no other plausible cause) or hyperglycaemic crisis AND at least one of the following criteria:
• increased glycated proteins
• glucosuria on more than one occasion on a naturally voided sample acquired in a home environment at least 2 days after any stressfull events.
2. In some cases clinical signs may not have been reported by the owner
In a patient with random (fasted or unfasted) BG > 7 mmol/L <= 15 mmol/l and at least two of the following:
• classic clinical signs of hyperglycaemia (with no other plausible cause) or hyperglycaemic crisis
• increased glycated proteins
• glucosuria on more than one occasion on a naturally voided sample acquired in a home environment at least 2 days after any stressfull events.

Applying the above ALIVE criteria permits the possible existence of a subpopulation of cats where DM or stress hyperglycaemia cannot be confidently confirmed or excluded; if concerns over presence of DM persist, periodic re-evaluation is warranted.

Comments:
The definition implies use of a species-validated method to measure glucose as well as glycated protein, and conditions other than DM that specifically affect the concentration of glycated protein are excluded. Glycated blood proteins should be measured by a methodology with relevant, internally established reference interval, and regular quality assurance. Variations in protein concentration and metabolism can affect glycated protein concentrations. DM is more likely when DM-contributing factors are present (e.g. diabetogenic treatment, hypersomatotropism).

Clinical diabetes mellitus in dogs and cats
Clinical diabetes mellitus in dogs and cats that meet the ALIVE definition and criteria for diagnosing diabetes mellitus, WITH classic clinical signs compatible with DM, (e.g., polyuria, polydipsia, polyphagia, weight loss) with no other plausible cause.

Subclinical diabetes mellitus in dogs and cats
Diabetes mellitus in a dog or cat is defined as subclinical if they meet the ALIVE definition of DM, without the presence of classic clinical signs compatible with DM. Differentiation of subclinical DM and stress-induced hyperglycemia is challenging, particularly in cats.

Prediabetes in human medicine is defined as hyperglycemia below cut-off for diabetes mellitus and/or impaired glucose tolerance. This definition may also be applicable for dogs and cats with hyperglycemia below cut-off for DM. However, there is a lack of information/evidence on the topic e.g., validated glucose tolerance tests, to make this condition clinically relevant for dogs and cats.

Disease complex in dogs and cats as defined by the ALIVE project

1. Insulin deficient DM (beta-cell-related disorders)

1. Reduced insulin secretion
   • Beta-cell dysfunction
   • Beta-cell destruction
     1. Immune-mediated
     2. Beta-cell loss associated with exocrine pancreatic disease
        • Pancreatitis
        • Neoplasia
        • Idiopathic
     3. Toxicity (diazoxide)
     4. Infection
     5. Idiopathic
   • Beta-cell death (apoptosis)
     1. Glucotoxicity
     2. Lipotoxicity
     3. Idiopathic
   • Beta-cell aplasia/abiotrophy/hypoplasia
2. Production of defect insulin

2. Insulin resistant DM (target-organ disorders)

• Endocrine influence
  • Growth hormone
    1. Endogenous hypersecretion
       • Pituitary origin
       • Mammary origin
    2. Exogenous GH
  • Steroids
    1. Glucocorticoids
       • Endogenous hypersecretion
       • Exogenous glucocorticoids
    2. Progesterone/progestines
       • Luteal phase
         • Pregnancy
         • Diestrus (dog)
       • Exogenous progestins
    3. Other
  • Catecholamines
  • Thyroid hormone
    1. Hyperthyroidism
• Obesity
• Drugs
  • Thiazide diuretics
  • Beta adrenergic agonists
• Inflammatory mediators
• Disorders of receptor and intracellular signaling

Comments
An individual can concurrently have more than one underlying cause.

The ALIVE diabetes mellitus characterisation checklists are designed to assist in classification and to alert clinicians and researchers to patient-related factors that might impact on the management of the patient. ALIVE recommends completing the checklist at time of diagnosis. Several factors are also relevant for ongoing management, though this list does not represent a comprehensive checklist for evaluation of complicated patients.

Canine DM checklist

Date of diagnosis:
Date of evaluation:

Y: yes (likely), N: no (unlikely), X: not ascertained

Feline DM checklist

Date of diagnosis:
Date of evaluation:

Y: yes (likely), N: no (unlikely), X: not ascertained

The extent to which the above steps are being evaluated will vary according to circumstances (clinical versus research scenario). The steps do not imply whether or how tests need to be carried out.

The ALIVE guidelines recognise existing challenges surrounding definitive diagnosis of several conditions listed, as well as the limited availability of C-peptide and autoantibody assays.

The ALIVE consensus recommends the following goals to be considered:
• Good quality of life of pet and owner
• Resolution of the classic clinical signs of diabetes mellitus
• Avoidance of hypoglycaemia and DKA
• Normalisation of body conditions score

The physiological mechanisms through which these aims are achieved include:
• Decreasing hepatic glucose output
• Improving insulin sensitivity
• Ensuring appropriate insulin availability
• Reducing post-prandial hyperglycaemia
• Attending underlying causes or co-morbidities

The success of the therapy can be assessed through:
• Systematic and standardised assessment of classic clinical signs of DM ideally incorporating a scoring system.
• Assessment of glycaemic parameters in blood, interstitium and/or urine.
• There is no prospective high level evidence that setting a specific glycaemic goal is correlated with a specific treatment outcome, including remission.
• Glycaemic parameters within the reference interval of non-diabetic animals commonly indicates diabetic remission or insulin overdosing and therefore implies possibility of episodes of hypoglycaemia in a treated diabetic patient.

The ALIVE consensus emphasises the need for appreciation that:
• Serial glucose assessment shows substantial day to day variation.
• Fructosamine evaluation suffers from reliability problems and the use of the same validated assay in the same patient is recommended if this parameter is chosen to be used.
• Negative urine glucose can indicate periods of hypoglycaemia in a treated diabetic patient.
• Co-morbidities are common and should especially be considered when there are clinical signs which are not classic clinical signs of DM.
• Specific blood glucose targets are not a goal.

Hypoglycaemia is defined as a blood glucose measurement of less than 3.3 mmol/l (60 mg/dl). This may or may not be associated with clinical signs. Clinical signs of hypoglycaemia are diverse and can include lethargy, weakness, tremor, ataxia, collapse and seizures, among others, usually related to neuroglycopenia and/or autonomic activation.

The ALIVE recommendation is to use the term ‘insulin resistance’ to describe the presence of varying degrees of interference of insulin action on target cells. The term is not defined by the exogenous insulin dose required or by the change of blood glucose following insulin injection. However, when there is concern over the need for a high insulin dose, the presence of insulin resistance should be considered among other potential causes.

Proposed score 1
• Range total score: 0-12
• Treatment aim: lowest score possible without unacceptably high risk of hypoglycaemia