Diabetes mellitus

1
Diabetes mellitus what does it mean?
Clinical signs that you can comfortably attribute
to impaired insulin activity
Clinically significant glucose intolerance
2
Diabetes mellitus how does it present to us ?

• weight loss with ?? appetite
• polydipsia
• polyuria
• ? activity sometimes described as depressed
• appetite will be normal or increased
• vomiting inappetance
• usually also dehydration

3
Diabetes mellitus common questions

• What is diabetes mellitus ?
• What are the predisposing factors
• Are they important to us as clinicians?
• Diabetes in cats dogs differences ?
• How do these differences affect treatment ?
• should we use oral hypoglycaemics
• types of insulin and frequency of dosing
• feeding protocols
• assessing adequacy of treatment

4
Classification of human diabetes mellitus
I. Type 1 diabetes Beta cell destruction, usually leading to absolute insulin deficiency Immune mediated Idiopathic II. Type 2 diabetes May range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance. III. Other specific types Genetic defects of beta cell function Genetic defects in insulin action Diseases of the exocrine pancreas Endocrinopathies Drug- or chemical-induced Infections Uncommon forms of immune-mediated diabetes IV. Gestational diabetes
based on the Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. (1997) Diabetes Care 201183-1197.
5
Canine diabetes mellitus pathophysiology
Normal insulin sensitivity
diabetes mellitus
Normal islet activity
6
Canine diabetes mellitus
Absolute insulin deficiency
most (gt90) diabetic dogs
7
Feline diabetes mellitus pathophysiology
Insulin resistance
diabetes mellitus
Islet hyperactivity
Islet underactivity
8
Feline diabetes mellitus
Variably reversible insulin deficiency
most (75) diabetic cats
9
Insulin resistance what does it mean?
decreased insulin activity leading to
increased insulin secretion
10
Insulin resistance what causes it ?

• Obesity, oestrus, pregnancy
• Anxiety
• Altered metabolites
• hyperglycaemia
• elevated plasma fatty acid levels
• Hypercortisolaemia due to
• any significant illness
• stress
• Endocrinopathies

11
(No Transcript)
12
(No Transcript)
13
Effect of hyperglycaemia on insulin sensitivity
Plasma glucose mmol/l
Minutes
14
(No Transcript)
15
(No Transcript)
16
(No Transcript)
17
(No Transcript)
18
fGH ??????? ug/ml IGF1 1,200 nmol/L (30-650)
19
insulin
normal cats 35 120 ng/ml newly diagnosed
diabetic cats lt 10 - gt 1000 ng/ml well-controll
ed diabetic cats 45 500 ng/ml or gt ?
20
Hypersomatotrophism in cats in the United
Kingdom

• 148 samples submitted - gt 80 from England
• Serum IGF 1 levels in all cats
• 54 cats with basal IGF1 level gt 1000 ng/ml
• Most were markedly hyperglycaemic with elevated
  fructosamines
• 24 cats were evaluated further
• 23/24 confirmed acromegalic
• lt 10 had so-called typical phenotype

Neissen et al, ECVIM 2006
21
(No Transcript)
22
(No Transcript)
23
Clinicians dilemma with cats..
Clinically abnormal cat.....
that is also hyperglycaemic
is the glucose intolerance the main reason for
the clinical signs, or is it simply one more
manifestation of an as yet undiagnosed disease ?
is this cat suffering from diabetes mellitus ???
24
Insulin resistance what causes it ?

• Obesity, oestrus, pregnancy
• Anxiety
• Altered metabolites
• hyperglycaemia
• elevated plasma fatty acid levels
• Hypercortisolaemia due to
• any significant illness
• stress
• Endocrinopathies

25
Diabetes mellitus - definition
Clinically significant deficiency of insulin
secreting capacity
Absolute irreversible in dogs
Absolute or relative and ... often reversible in
cats
26
Diabetes mellitus pathophysiology?

• Dogs
• absolute insulin deficiency
• absent or virtually absent islet tissue
• Cats
• relative insulin deficiency
• islet numbers are reduced or unchanged
• islet amyloid deposition ???

27
Canine diabetes mellitus in the United Kingdom

• prevalence of 0.75 of accessions
• age peaks around 7-12 years
• intact females may develop transient diabetes
  mellitus during dioestrus
• females at greater risk than males
• obesity NOT a risk factor
• seasonal incidence?
• specific breed predispositions

28
UK canine diabetics age distribution
Prevalence 150 in 46,596 insured dogs (0.32)
29
UK canine diabetics seasonal distribution
Percentage newly diagnosed canine diabetics
30
Breed distribution
Breed distribution
Tibetan terrier (OR 7.2)
Labrador (OR 0.9)
XBreed
Others
Cairn terrier (OR 6.5)
Samoyed (OR 21.7)
31
Some breeds seem to be LESS susceptible to
developing DM
Some breeds are less susceptible
Boxer (OR 0.02)
GermanSD (OR 0.13)
Golden retriever (OR 0.23)
32
Feline diabetes mellitus in the United Kingdom

• diabetic cats are generally overweight
• 5.431.33 kg (2.7-9.0 kg)
• males are more prevalent (66)
• clinical signs are more variable than in dogs
• based on blood samples only so the possibility of
  non-specific disease/stress hyperglycemia is
  confounding
• gender differences in body wt
• 5.64 1.23 (males) verses 4.81 1.41 (females)
  

33
Burmese are over-represented 2.3
(0.7) diabetic Burmese are older 13.6y (10.9)
Lederer et al 2007 The Veterinary Journal
34
Diabetes mellitus history

• Dogs
• polydipsia and polyuria
• weight loss with ?? appetite
• vomiting inappetance
• Cats
• polydipsia ??
• polyuria ??
• weight loss with ?? appetite ??
• vomiting inappetance

35
Diabetes mellitus physical examination

• Dogs
• reduced body mass, muscle wasting
• hepatomegaly
• bilateral cataracts
• homgeneous lenticular opacities
• Cats
• Variable body mass lean and obese animals
• hepatomegaly ?
• no cataracts

36
obesity does not appear to be a risk factor for
canine diabetes mellitus
37
(No Transcript)
38
(No Transcript)
39
(No Transcript)
40
(No Transcript)
41
(No Transcript)
42
(No Transcript)
43
(No Transcript)
44
Clinicians dilemma with cats..
Clinically abnormal cat.....
that is also hyperglycaemic
is the glucose intolerance the main reason for
the clinical signs, or is it simply one more
manifestation of an as yet undiagnosed disease ?
is this cat suffering from diabetes mellitus ???
45
Diabetes mellitus contrasting clinical
picture..

• Happy
• polydipsia and polyuria
• weight loss with ?? appetite
• hepatomegaly
• Sad
• polydipsia and polyuria
• vomiting inappetance
• hepatomegaly
• marked ketonaemia and acidosis

46
Diabetes mellitus clinical pathology

• fasting hyperglycaemia
• fasting hyperlipaemia and ketonaemia
• significant glucosuria and ketonuria
• elevated fructosamine and glycosylated
  haemoglobin
• elevated ALP and to a lesser extent ALT
• altered total body potassium and phosphate
• metabolic acidosis

47
non-diabetic illnessgt90
48
Diabetes mellitus monitoring with fructosamine

• fructosamine - the compound created when glucose
  binds irreversibly to albumin
• binding occurs non-enzymatically
• binding occurs at a rate dependent on the overall
  concentration of glucose and albumin
• when albumin is stable it reflects the average
  blood glucose
• over 3 weeks in dogs
• over 10 - 14 days in cats

49
Fructosamine
CICICICICIC
N-
50
(No Transcript)
51
(No Transcript)
52
(No Transcript)
53
(No Transcript)
54
Diabetes mellitus stress hyperglycaemia

• perhaps better thought of as anxiety-induced
  hyperglycemia
• usually associated with accelerated muscle
  catabolism
• lasts for a short period and hence is not
  reflected by the fructosamine
• consequently fructosamine can help differentiate
  short-term elevations in blood glucose from a
  more protracted elevation

55
(No Transcript)
56
Insulin resistance what causes it ?

• Obesity, oestrus, pregnancy
• Anxiety
• Altered metabolites
• hyperglycaemia
• elevated plasma fatty acid levels
• Hypercortisolaemia due to
• any significant illness
• stress
• Endocrinopathies

57
Obesity Trends Among US AdultsBRFSS, 1985
Mokdad et al 1999, 2001
58
Obesity Trends Among US AdultsBRFSS, 1990
Mokdad et al 1999, 2001
59
Obesity Trends Among US AdultsBRFSS, 1992
Mokdad et al 1999, 2001
60
Obesity Trends Among US AdultsBRFSS, 1994
Mokdad et al 1999, 2001
61
Obesity Trends Among US AdultsBRFSS, 1996
Mokdad et al 1999, 2001
62
Obesity Trends Among US AdultsBRFSS, 1998
Mokdad et al 1999, 2001
63
Obesity Trends Among US AdultsBRFSS, 2000
Mokdad et al 1999, 2001
64
Obesity Trends Among US AdultsBRFSS, 2001
Mokdad et al 1999, 2001
65
Diabetes mellitus questions?

• diabetes mellitus is the clinical syndrome(s)
  that result from inadequate islet activity
• predisposing factors
• can cause hyperglycaemia
• can cause full-blown diabetes mellitus
• are they important in development
• yes in cats, less so in dogs?
• how do these differences affect treatment and
  management ?

66
Diabetes mellitus management ?

• where possible or practical we need to correct
  underlying causes and/or factors that interfere
  with insulins actions
• consider oral hypoglycaemic agents
• consider which insulin preparation to use
• consider daily dose dose frequency
• consider the amount and type of food
• consider the importance of the timing of the
  insulin and the meal times

67
Diabetes mellitus management ?
When should I consider using oral an
hypoglycaemic agent and which one is likely to be
best ?
Are hypoglycaemic agents safe in dogs and cats ?
68
Diabetes mellitus oral hypoglycaemic agents

• sulphonylureas
• glipizide
• glibenclamide
• biguanides (euglycaemics)
• metformin
• thiozolidendiones
• pioglitazone
• acarbose
• chromium, vanadium, etc

69
(No Transcript)
70
(No Transcript)
71
Oral hypoglycaemic agents
When should I consider using oral an
hypoglycaemic agent and which one is likely to be
best ?

• when you suspect there is a significant
  resistance component to the disease
• almost only ever in cats
• right type of owner and right type of cat
• when you know you can have reliable follow-up
• remembering it might make things worse ?

72
Diabetes mellitus management ?

• where possible or practical we need to correct
  underlying causes and/or factors that interfere
  with insulins actions
• consider oral hypoglycaemic agents
• consider which insulin preparation to use
• consider daily dose dose frequency
• consider the amount and type of food
• consider the importance of the timing of the
  insulin and the meal times

73
(No Transcript)
74
What is the duration of action of the insulins
available ?

• human and bovine lente
• lasts for between 8h - 12h
• Caninsulin
• lasts for between 8h - 14h
• human and/or bovine PZI
• lasts for between 10h - 14h
• insulin glargine
• lasts for longer between 12h - 20h
• relatively peakless effect

75
What is the duration of action of the insulins
available ?

• all of the delayed insulins last for betwen 8 and
  20 hours in dogs and cats
• most situations though only last for 8 14 hours
• insulins last for a shorter period of time in
  cats than in dogs and dogs for a shorter period
  than in people
• preference for longer lasting insulins in cats
  and on occasions a peakless effect

76
Diabetic control with 12 hourly verses 24 hourly
insulin
Fructosamine µmol/l
Months
77
Diabetes mellitus principles of insulin therapy
A recent survey of British veterinarians
indicated upto 35 of diabetic cats were
receiving once daily insulin
twice daily
78
Which insulin is best for dogs and which is best
for cats ?

• lente insulin twice daily for dogs
• lente insulin twice daily for cats
• protamine zinc insulin twice daily for cats
• insulin glargine twice daily for certain diabetic
  cats
• due to its peakless effect glargine is an
  attractive option for grazing cats
• twice daily please !!!!
• meals co-ordinated

79
Diabetes mellitus principles of insulin therapy
I usually feed my diabetics before, or at the
time of, insulin injection. Is this optimal
management ?
80
Diabetes mellitus principles of insulin therapy

• insulin will lower the blood glucose
• each meal will raise the blood glucose
• more dramatic effect if meals are given at 12
  hour intervals
• ideally we want to match the opposing effects of
  the insulin and the meal
• to minimise malutilisation and achieve relatively
  stable blood glucose levels over the twelve hour
  period

81
Effect of insulin on blood glucose
Plasma glucose
Time
82
Effect of a meal on blood glucose
Plasma glucose
Time
83
Matching insulin and a meal effects to maximise
control
Plasma glucose
Time
84
Continuous blood glucose monitoring
85
Continuous blood glucose monitoring
86
Diabetes mellitus principles of insulin therapy
I usually feed my diabetics before, or at the
time of, insulin injection. Is this optimal
management ?
Nope
87
(No Transcript)
88
(No Transcript)
89
(No Transcript)
90
Diabetes mellitus management
What should I do about managing the feeding and
exercise of my diabetic patient? Is it really
important?
91
Diabetes mellitus feeding

• caloric content needs to be standardised
• intake regulated to body weight
• 60 - 80 kcal/kg body weight
• composition should be standardised
• carbohydrate content
• fibre content ?
• fat content ?
• significant difference between species..

92
The cat is a carnivore..
the dog is an omnivore
93
Cats as carnivores
94
Cats as carnivores evolutionary development

• cats have evolved with a specific diet
  composition
• 54 dry matter protein
• 8 dry matter carbohydrate
• also have specific feeding behaviours
• tend to eat regularly throughout a 24 hour cycle
• unique nutrient metabolism
• lacking hepatic glucokinase activity
• continuous hepatic gluconeogenesis

95
Cats as carnivores evolutionary development

• Cats are relatively insensitive to insulin
• adapted for an obligate carnivore (low
  carbohydrate) diet ?
• However cats can certainly adapt to variable
  levels of dietary carbohydrate but.....
• Diabetic cats appear to have trouble adapting to
  diets which are NOT low in carbohydrate
• when controlled for different insulin regimes,
  see improved diabetic control in cats fed low
  carbohydrate diets

96
Diabetes mellitus feeding

• caloric content needs to be standardised
• intake regulated to body weight
• 60 - 80 kcal/kg body weight
• composition needs to be standardised
• low carbohydrate diet in diabetic cats

• in dogs, increasing dietary fibre has little, if
  any, value in improving diabetic control in
  clinical diabetics
• feed as set meals or allow grazing

97
(No Transcript)
98
(No Transcript)
99
Diabetes mellitus monitoring

• clinical signs
• reduced polydipsia and polyuria
• normalised body condition score
• glucose curves average daily blood glucose
• home glucose monitoring
• fructosamine, glycosylated haemoglobin

100
Diabetes mellitus home glucose monitoring

• Suitable process for majority of animals owners
• 75 of cases appear suitable
• marked differences in gt 50 of cases between
  in-hospital v out-patient derived results
• various home-glucose monitoring devices available
  using lt25?l of blood

Casella et al, JFMS 2005 Alt et al, JAVMA 2007
101
Diabetes mellitus management
How often do we see diabetes resolve, either
temporarily or permanently ?
102
Feline diabetes mellitus pathophysiology
? insulin demand
??
? insulin secretion
return of insulin secretion
? glucose intolerance
exogenous insulin administration
? insulin resistance
absent insulin secretion
103
Diabetes mellitus remission rates in cats

• Remission reported in 15 - 68 of cats
• mixed insulins studies
• 68 remission
• lente insulin 12 hourly
• 43 - 65 remission
• glargine insulin 12 hourly
• 40 remission
• 66 - 84 remission
• confounding factors disease, phenotype

Bennet et al 2006 Weaver et al 2006 Boari et al
2008 Roomp Rand 2008
104
Diabetes mellitus remission rates in cats

• Remission rates markedly higher if diabetes
  present for lt 6 months
• highest if on low carbohydrate diets
• 20-25 v 60 corrected for insulins
• highest with intense management
• 12-24h monitoring dose changes.
• home monitoring almost essential
• glargine/determir less variable than lente ?

Bennet et al 2006 Weaver et al 2006 Boari et al
2008 Roomp Rand 2008
105
Diabetes mellitus remission rates in cats

• dont be in a hurry
• reduce by 0.5 - 1 IU every week
• then reduce to once daily dosing
• 1 IU/cat/24h
• checking glucose gt 12hr post insulin
• only stop insulin if euglycemic at gt 12hr
• maintain cat on a low carbohydrate diet
  continue regular checks

Bennet et al 2006 Weaver et al 2006 Boari et al
2008 Roomp Rand 2008
106
Effect of hyperglycaemia on insulin sensitivity
Plasma glucose mmol/l
Minutes
107
Diabetes mellitus management summary

• twice daily insulin whenever possible
• two meals roughly 12 hours apart
• meals after insulin injection (1 -1.5 hr)
• dietary manipulation
• consistent caloric content
• low carbohydrate diet in cats
• monitoring home hospital
• remember in cats this is a dynamic problem

insulin infusion
108
Vets and nurses (5 minutes)www.rvc.ac.uk/diabete
svet

• Owners of insulin treated cats and dogs
• www.rvc.ac.uk/diabetes

109
(No Transcript)
110
(No Transcript)