The ZDSD Rat as a Translational Model
for the Development of Drugs for
Obesity, Metabolic Syndrome and
Diabetes that Demonstrates Many of the
Serious Complications of Diabetes.
PreClinOmics, Inc.
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ZDSD as a Preclinical Model of
Metabolic Syndrome
Metabolic Syndrome affects a large proportion of the population and is
becoming increasingly important in adolescents. The syndrome has many
components including central obesity, insulin resistance, dyslipidemia and
hypertension. In addition, the syndrome features a chronic low grade
inflammatory state, vascular endothelial dysfunction, and a prothrombotic
environment. Long standing metabolic syndrome can thus pre-dispose to
atherosclerosis, microvasculature disease (retina), stroke, renal injury and
diabetes. Due to the complicated mechanisms involved in the syndrome and
its sequelae, current standard of care reflects poly-pharmacy and is aimed at
controlling atherogenic dyslipidemia, hyperglycemia and hypertension as well
as intervening in secondary diseases such as renal dysfunction, stroke, and
micro-vascular disease related to retinopathy. Development of new chemical
entities with the potential to control more than one risk factor is hampered by
currently available animal models. To that end, the ZDSD rat was designed
to spontaneously develop a phenotype that mimics many aspects of the
human metabolic syndrome, including hypertension and the progression to
frank diabetes with long-standing disease.
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Development Scheme:
Zucker Diabetic-Sprague Dawley Rat (ZDSD)
• Produced by crossing diet induced obese (DIO) rats
derived from the Crl:CD (SD) strain (exhibiting
polygenetic obesity and insulin resistance) with
homozygous lean ZDF/Crl rats (which expresses
beta cell failure with the Leprfa/Leprfa genotype).
• Selectively bred for obesity and diabetes.
• Selected for genetically matched breeders to
develop phenotypic homogeneity.
• Studied male rats at different ages.
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Characteristics of Metabolic Syndrome
seen in the ZDSD Rat
•
•
•
•
•
•
Increased body weight with increased abdominal fat
Increased fed and fasting glucose and HbA1c levels
Insulin resistance / Glucose intolerance
Hyperlipidemia
Increased blood pressure --> Hypertension
Increased Serum Biomarkers of Coagulation,
Inflammation and Vascular Disease
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Comparative Growth Curves
in SD and ZDSD Rat Fed 5008 chow
ZDSD rats were significantly
(15%) heavier than their SD
counterparts at 8 weeks of
age. In addition, the rate of
body weight gain was
increased in ZDSD rats as
evidenced by an 82% vs
62% weight gain when
compared to SD rats over
24 weeks of observation.
All time points statistically different
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Study # 09-550-170
Spontaneous Development of Obesity in
ZDSD Rats Fed 5008 Chow
Body composition was
assessed using QNMR .
The percentage of body
weight identified as fat was
50 % higher in ZDSD rats
compared to SD controls as
early as 8 weeks of age.
Body fat percentage
continued to increase
throughout the study and
remained significantly
higher than control rats at
each time-point.
All time points statistically different
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Study # 09-550-170
Spontaneous Development of Hyperglycemia
in ZDSD Rats Fed 5008 Chow
All time points statistically different
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Study # 09-550-170
Spontaneous Development of Glucose Intolerance
Shown by OGTT in ZDSD Rats Fed 5008 Chow
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Progressive Development of Insulin
Resistance (HOMA-IR) in ZDSD Rats
ZDSD rats become
increasingly more insulin
resistant with age as
evidenced by the calculated
HOMA-IR. The insulin
resistance is evident
compared to SD rats as
early as 8 weeks of age
(fed Purina 5008 chow).
All time points statistically different
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Representative Islets from 28 wk old
ZDSD Rats
Pre-diabetic
Diabetic
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Blood Pressure in ZDSD vs CD Rats
8-16 weeks of age
Systolic BP (mmHg)
160
ZDSD
CD
140
120
100
80
60
70
80
90
100
Age in Days
Blood pressure data produced in collaboration with
Dr. Subah Packer’s Laboratory, IU School of Medicine
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Urinary albumin (mg/day)
Urinary albumin
150
beta-2 microglobulin
2000
SD
ZDSD
125
Urinary -2 microglobulin ( g/day)
b
m
Time Course of Urinary Biomarkers
SD
ZDSD
1500
100
75
1000
50
25
0
10
20
22
24
26
30
Age (weeks)
500
0
10
20
24
26
30
KIM-1
Urinary KIM-1 (ng/day)
Urinary cystatin C ( g/day)
m
Cystatin C
30
22
Age (weeks)
SD
ZDSD
20
10
0
15.0
SD
ZDSD
12.5
10.0
7.5
5.0
2.5
0.0
10
20
22
24
Age (weeks)
26
30
10
20
22
24
26
30
Age (weeks)
12
Glomerular Basement Membrane Thickness
Thickness (mm)
500
400
300
200
100
0
CD Control
12 Weeks
16.5 Weeks
Time of Diabetes in the ZDSD Rat
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Kidney Histopathology of the ZDSD Rat
4.0
Histopathology Score (0-5)
3.5
3.0
* compared to Non-diabetic animals
Non-diabetic
Diabetic
(t-test p<0.05)
*
*
*
*
2.5
2.0
1.5
1.0
0.5
0.0
Glomerulopathy Tubular dilation Protein casts
/degeneration
Inflammation
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Wound Healing in the ZDSD Rat
0
SD
Diabetic ZDSD
*
-20
*
*
*
-40
Non-Diabetic ZDSD
*
*
-60
*
-80
*compared to SD (Dunnett's)
-100
4
7
9
11
14
Time(days) post-wounding
Combined ZDSD Data
% Change From Iniital Wound
% Change From Iniital Wound
Separated Diabetic and Non-Diabetic ZDSD
0
*
SD
*
-20
ZDSD
*
-40
*
*
-60
-80
*compared to SD (t-test)
-100
4
7
9
11
14
Time(days) post-wounding
This figure demonstrates the wound healing in the three groups of
animals. There were no differences between diabetic and nondiabetic ZDSD animals. There were several statistically significant
differences between the SD group and the ZDSD groups (* p<0.05).
Since the data were not different in the ZDSD groups there were also
analyzed as a combined group.
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Structural Properties L4 vertebrae
P-values for differences in diabetic rats vs. respective controls
Biomechanical Test – axial compression
ZDF
ZDSD
p<0.050
p<0.001
Stiffness (N/mm)
p<0.001
p<0.005
Ultimate Load (N)
p<0.001
p<0.001
Energy to Ultimate Load (mJ)
p<0.050
p<0.001
90
90
80
70
60
50
40
30
20
10
*
Energy to Ultimate Load (mJ)
Energy to Ultimate Load (mJ)
Yield Force (N)
Mean ±SEM
n=12-17/group
80
70
60
50
40
*
30
20
10
0
0
ZDF (fa/fa) ZDF (+/fa)
ZDSD
Controls
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The ZDSD Rat: One Rat – Many Models
ZDSD
Obesity
Metabolic Syndrome
Diabetes
Obesity Model
before
diabetes develops,
5-16 weeks of age
Insulin
Resistance
Hyperlipidemia
Metabolic
Syndrome
Obesity
Diabetes Models
Spontaneous
Development
Diet
Synchronized
(LabDiet 5008; Slower &
more random)
(RD D12468 or TestDiet
5SCA)
Hypertension
Delayed
Wound
Healing
Diabetic
Nephropathy
Diabetic
Nephropathy
Osteoporosis
Osteoporosis
Cardiovascular/
Inflammatory
Biomarkers
Cardiovascular/
Inflammatory
Biomarkers
Delayed Wound
Healing
Delayed Wound
Healing
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ZDSD Summary- One Rat, Many Models
• Polygenic phenotype that can be modulated by diet
• Functional Leptin Pathway
• Early onset of hyperglycemia with slower
progression to frank diabetes when compared to
the ZDF rat
• Mirrors human development of type II diabetes
• Manifests diabetic complications:
• Diabetic nephropathy
• Hypertension
• Inflammation
• Osteoporosis
• Delayed wound healing
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