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12/09/2013
1
Andy E Durham
“a collection of risk factors which indicate
an increased risk of coronary artery
disease”
12/09/2013
2
“a collection of risk factors which indicate
an increased risk of laminitis”
Laminitis = the equine heart attack!
Q: What do you get if you always do what you’ve
always done?
A: What you always got!
Henry Ford
EEEENDOGENOUSNDOGENOUSNDOGENOUSNDOGENOUSEEEEXOGENOUSXOGENOUSXOGENOUSXOGENOUS
SIGNALMENT CLINICAL CLINICOPATHOLOGICAL
1. age 1. obesity 1. IR/
hyperinsulinaemia
1. little exercise
2. breed 2. PPID 2. dyslipidaemia 2. dietary excess
3. gender 3. previous
laminitis
3. abnormal
adipokines
3. season
12/09/2013
3
• 40 laminitis cases (Donaldson et al 2004)
• 70% had PPID
• 23% had EMS
• 7% not tested
• 36 laminitis cases (Karikoski et al 2011)
• 31% had PPID
• 58% had EMS
• 11% no hormonal abnormality
LiphookEquine Hospital
93%93%93%93%
7%
89%89%89%89%
11%
ABOUT 90% OF LAMINITIS CASES HAVE AN UNDERLYING HORMONAL DISORDER
93%93%93%93%
89%89%89%89%
1. Laminitis occurring regardless of type (e.g. a young, fit TB)
◦ carbohydrate overload (grain engorgement)
◦ other endotoxaemic (retained placenta)
◦ weight bearing (post-fracture fixation)
2. Laminitis tending to occur in certain susceptible individuals
◦ endocrinopathic (PPID, EMS)
◦ pasture-induced laminitis
Type
1
Type
2
Insulin Resistance
HyperinsulinaemiaHyperglycaemia
(glucose intolerance)
compensatory
pancreatic secretion,
decreased insulin clearance
impaired glucose
uptake
stimulates
pancreatic secretion
receptor
downregulation?
12/09/2013
4
Insulin Resistance
HyperinsulinaemiaHyperglycaemia
(glucose intolerance)
impaired glucose
uptake
stimulates
pancreatic secretion
receptor
downregulation?
compensatory
pancreatic secretion,
decreased insulin clearance
5 TREATED PONIES 4 CONTROL PONIES
• iv insulin infusion 0.36 mU/kg/h• iv saline infusion
• iv glucose infusion 0.34 g/kg/h
• mean serum insulin 1036 mU/L • mean serum insulin 15 mU/L
• mean plasma glucose 5.2 mmol/L • mean plasma glucose 5.2 mmol/L
• 5/5 clinical laminitis in 48 h • 0/4 laminitis
treatment:
response:
blood:
feet:
Insulin Resistance
HyperinsulinaemiaHyperglycaemia
(glucose intolerance)
impaired glucose
uptake
stimulates
pancreatic secretion
receptor
downregulation?
compensatory
pancreatic secretion,
decreased insulin clearance
12/09/2013
5
EPIDEMIOLOGIC STUDIES
� Age
� Breed
� Gender
� Season
� Exercise
� Obesity (regional)
� Pasture
� PPID
Predispose to
hyperinsulinaemia
� Compared insulin responses to feeding:
◦ 12 normal horses vs 8 IR ponies
� H hay + ricebran
� H+G hay + ricebran + 0.75 g/kg glucose
IR ponies showed an
excessive insulinaemic response
to glucose
0
50
100
150
200
250
300
350
400
450
horses ponies
seru
m in
suli
n m
U/L
H H+G
Tinworth et al 2011
Borer et al 2012
0
100
200
300
400
500
600
700
800
900
1000
normal laminitic
seru
m in
suli
n m
U/L
resting insulin
peak insulin
Compared diet effects in 7 normal vs 5 laminitic ponies:
• Resting insulin
• Peak insulin after chaff + glucose
• laminitic ponies showed an
excessive insulinaemic response
to glucose
12/09/2013
6
� certain individuals may be prone to grass-induced laminitis
because of an excessive insulinaemic response to carbohydrate
ingestion
� Oral sugar challenge tests may directly mimic this effect
� Frank 2012
◦ Karo light corn syrup 15 mL/100 kg)
◦ measure serum insulin 60-90 mins later
◦ normal response < 60 mU/L
LiphookEquine Hospital
� fast overnight
� fasting insulin (optional)
� feed chopped chaff mixed with 1 g/kg BWT glucose/dextrose
� insulin measured 2 hours later
++++ ����
LiphookEquine Hospital
� 24 normal horses and ponies
� Compared with 367 submissions from horses and ponies with
history of laminitis (97 with fasting results also)
InsFmU/L
Ins120mU/L
Median normals <2.0 24.3
Median laminitics 9.9
P (Mann Whitney) <0.0001
InsFastmU/L
Ins120mU/L
Median normals <2.0 24.3
12/09/2013
7
LiphookEquine Hospital
� 24 normal horses and ponies
� Compared with 367 submissions from horses and ponies with
history of laminitis (97 with fasting results also)
InsFastmU/L
Ins120mU/L
Median normals <2.0 24.3
Median laminitics 11.5 199.0
P (Mann Whitney) <0.0001 <0.0001
LiphookEquine Hospital
Comparison of glucose challenge with fasting results:
� 97 submissions from horses and ponies with history of laminitis
with both fasting and 2 hr Insulin
n %
Fasting Insulin > 20 mU/L 23/97 24%
2 hour PG Insulin > 81 mU/L 75/97 77%
• requires a bolus of
5.0-10.0 g/kg
• effect occurs at
<1.0 g/kg
A. Dysfermentation of sugars disturbs the colon mucosal barrier leading to systemic absorption of “trigger factors” (carbohydrate overload model)
B. Absorbed sugars stimulate hyperinsulinaemia which then triggers laminitis (hyperinsulinaemic model)
12/09/2013
8
� Intake of 5% BWT (as dry matter) daily is high
� Non-structural carbohydrate (NSC) content of 20% is high
◦ 5% x 20% = NSC intake of 1% BWT daily = 10 g/kg
◦ = 10 g/kg NSC ingested over 16 h grazing
◦ = average 0.6 g/kg/h
????
?
The Liphook Equine Hospital
?
12/09/2013
9
• “good doing type”
• “eats nothing”
• “lives on fresh air”
• “puts on weight when he looks
at the grass”
• “I couldn’t feed him any less”
You have 2 choices:
1. Accept there is a problem
and deal with it
2. Wait for your horse or
pony to die prematurely
from laminitis
LAMINITIS RISK FACTORS
� Age
� Breed
� Gender
� Season
� Exercise
� Obesity (regional)
� Pasture
� (PPID)
CONTROL SOLUTIONS
� x
� x
� x
� extra care in spring/summer
� increase exercise
� control diet / increase exercise
� limit pasture access
� (see later!)
12/09/2013
10
1. Durham et al 2008
◦ 15 mg/kg q 12h
� significant decrease in insulin and glucose
2. Hustace et al 2009
◦ only 4 to 7% absorbed
3. Firschman et al 2009
◦ 15 mg/kg q 12 h normal horses
� no effect on insulin sensitivity (HEC)
4. Tinworth et al 2011
◦ 15 mg/kg q 12h IR ponies
� no effect on insulin sensitivity (FSIGT)
3.0
3.5
4.0
4.5
5.0
5.5
6.0
0 30 60 90 120 150 180 210 240
plasma
plasma
plasma
plasma glucose
glucose
glucose
glucose (( ((mmol/L
mmol/L
mmol/L
mmol/L)) ))
time posttime posttime posttime post----glucose (mins)glucose (mins)glucose (mins)glucose (mins)
No metformin
Metformin 30 mg/kg
Peak P=0.016
% increase P=0.047
AUC P=0.016
� 8 Ponies dosed with 0.5 g/kg
glucose,
� with and without 30 mg/kg
metformin 30 mins prior to
glucose
Rendle et al 2013
No metformin
Metformin 30 mg/kg
0
5
10
15
20
25
30
35
40
0 90 120 150
serum insulin (mIU/L)
serum insulin (mIU/L)
serum insulin (mIU/L)
serum insulin (mIU/L)
time posttime posttime posttime post----glucose (mins)glucose (mins)glucose (mins)glucose (mins)
Ins 90 P=0.094
Ins 120 P=0.031
Ins 150 P=0.125
� 8 Ponies dosed with 0.5 g/kg
glucose,
� with and without 30 mg/kg
metformin 30 mins prior to
glucose
Rendle et al 2013
12/09/2013
11
� Metformin impairs glucose absorption in horses
� Metformin reduces insulin response to glucose ingestion
� Metformin might:
◦ aid weight loss by reducing sugar absorption
◦ protect against diet-induced insulin responses
• Comprises insulin resistance and obesity (at least)
• Represents a risk for laminitis (at least)
• May be suspected and diagnosed with relative ease
• Dietary management is crucial for improvement/reversal
• Exercise probably also helpful
• L-thyroxine (£££) and metformin (£) may also help
………the pony has a
greater hyperinsulinaemic
response.
12/09/2013
12
HyperinsulinHyperinsulinHyperinsulinHyperinsulin
----aemiaaemiaaemiaaemia
Native Native Native Native
BreedBreedBreedBreed
Regional Regional Regional Regional
ObesityObesityObesityObesity
Lack of Lack of Lack of Lack of
exerciseexerciseexerciseexercise
LAMINITISLAMINITISLAMINITISLAMINITIS
PPIDPPIDPPIDPPID
PasturePasturePasturePasture
Equine Metabolic Equine Metabolic Equine Metabolic Equine Metabolic SyndromeSyndromeSyndromeSyndrome