Transcript Document

COMPARISON OF THE EFFECT OF MATERNAL
HYPOTHYROIDISM ON CARBOHYDRATE
METABOLISM IN YOUNG AND AGED MALE
OFFSPRING IN RATS.
Narges Karbalaee*,Saleh Zahediasl, Asghar Ghasemi,
Farzaneh Faraji Shahrivar
Endocrine Research Center, Research Institute for Endocrine
Sciences, Shaheed Beheshti University of Medical Sciences,
Tehran, Iran
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Introduction
Critical periods of development (Composite data are from rodents and humans)
Introduction (cont.)
Causes and consequences of intrauterine programming
Introduction (cont.)
adulthood
Hypertension
Hyperlipidemia
Reproductive disorders
Intrauterine
growth
retardation
Renal failure
Ischaemic heart disease
Obstructive pulmonary disease
Insulin resistance
Glucose intolerance
Type 2 diabetes
Introduction (cont.)
There are evidences that maternal hormonal status markedly influence
intra-uterine growth and developmen
Cardiovascula
r
Hemodynamic
CNS
Metabolic
Activities in
Most Tissue
Growth
and
Development
Reproductive
system
Liver
function
Immune
System
Introduction (cont.)
Thyroid hormones act as metabolic and maturational signals, any
changes in the levels of these hormones in uterus alters fetal
development and has long term consequences for cardiovascular,
reproductive,and metabolic function.
There is a relationship between serum thyroid hormone levels and
diabetes risk and also various abnormalities in carbohydrate
metabolism
occur in patients with thyroid disease. So
abnormalities in carbohydrate metabolism may take place in fetal
hypothyroidism.
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Aim
This study aims to assess the glucose
tolerance and insulin secretion capacity
of islets in young and aged male
offspring of mothers who were
hypothyroid during pregnancy.
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Materials & Methods
Animals and study design
Male and female Wistar rats were
crossed for 24 h
Pregnant femaleWistar
rats
Control
Fetal Hypothyroid
Pregnant rats consumed tap
water during gestation
Pregnant rats received
water containing 0.02 % of
PTU during gestation
Delivery
Male offspring (3 and 12 month)
Mother and
Offspring
(Blood)
Assessed for
Thyroid hormones (T3, T4)
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Material and Methods
Intravenous Glucose Tolerance Test (IVGTT)
 In young and old male offsprings, after over night fasting (12 h), IVGTT
was carried out by intravenous infusion of 50% glucose (0.5 g/kg body
weight)
 The plasma glucose and insulin levels of rats were assayed at 0, 5,10,15,
20, 30, and 60 minutes after an intravenous glucose load.
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Material and Methods
Glucose-stimulated insulin secretion (GSIS) ASSAY
 Islet isolation
 Incubation with different glucose concentrations (5.6, 8.3, 16.7 mM) ( 60
min, 37°C ,95 % O 2 / 5 % CO 2 )
 Collection of supernatant for insulin determination
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Materials & Methods (cont.)
Measurements
 Weight
 Plasma T3 & T4(ELISA kits )
 Plasma Glucose concentration(glucose oxidase method )
 Plasma Insulin concentration(ELISA method )
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Results
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Table I. Plasma T3 and T4 concentration in the fetal hypothyroid of control
groups at birth and adulthood (3 and 12 months ), and their mothers at the time
of delivery.
Offspring
At the time of birth
Hormones
Triiodothyronin
e
(T 3 , ng /dl)
Thyroxine
(T 4 , µg /dl)
Mothers
Adulthood
3 months
12 months
Control
Fetal
Control
Fetal
(n=15)
(n=7)
hypothyroid
hypothyroid
(n=15)
(n=8)
Control
(n=10)
Fetal
hypothyroid
(n=9)
69.1 ± 3.3
40.1 ± 5.5**
98.8 ± 4.03
85.86 ± 5.6
85.4 ± 3.3
0.98 ± .07
0.44 ± .06*
3.5 ± 0.1
3.3 ± 0.1
2.5±0.08
At the time of delivery
Control
(n=12)
Hypothyroid
(n=12)
98.5 ± 7.0
98.03 ± 5.7
49.5 ± 4.9***
2.9 ± 0.2
2.3 ± 0.3
0.34 ± 0.03***
Values are means ± SEM. * p< 0.05, *** p<0.0001 and *** p<0.0001 Significant
difference compared to controls
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Table II. Effect of hypothyroid during pregnancy on reproductive performance.
Parameter (units)
Control group
FH group
Gestation length (day)
21.7 ± 0.2
22.8 ± 0.3 
Percent maternal weight gain
(%) a
49.2± 1.8
44.7 ± 2.0
Litter size
10.2±0.8
9.6±0.4
Offspring mortality rate (%)
10.8
43.7***
Birth weight (gr) b
6.0±0.0
4.6±0.1***
a Percent
weight gain relative to the weight on day 1 of pregnancy. Day 1 weight in all groups ranged
from 180-220 g.
bAll pups in a litter were weighed and the average pup weight of a litter computed and reported as a
single point. This was done for all litters in a group and the mean of these points is reported as the
group mean in the table.
Values are means ± SEM. * p< 0.05 and *** p<0.001 Significantly from control
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Body weight in control and Fetal hypothyroid (FH) male offspring rats. Values
are mean ± SE ; n=14.
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Plasma glucose and insulin cocentrations and their AUC during intravenous glucose tolerance test in
the young ( a , c n = 11) and old ( b , d n = 12) rats of fetal hypothyroid and control groups. Values
are mean ± SE.
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Comparison of the islets insulin secretion in the fetal hypothyroid and control groups in
old ( a) and young (b) rats. Values are means ± SE
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Conclusions
The results of this study have shown that maternal hypothyroid during
pregnancy leads to:
Intrauterine growth restriction in rat fetuses
Glucose intolerance and lower insulin secretion capacity in their
adult off spring particularly in aged animals.
From the results of this study we can conclude that
carbohydrate metabolism in the offspring of fetal
hypothyroid subjects is a matter of concern particularly
in the old ages.
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Ghasemi
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 Definition of term `programming‘
A stimulus or insult during a critical or sensitive period of
development can have long-term or lifetime effects on an
organism’, as well as with the ‘predictive adaptive response’ .
(Holness ,2000; Hales and Barker (2001 Lucas A, 2000; Gluckman PD,,2006)
 Disturbance in the metabolic intrauterine environment alters
the development of the endocrine pancreas and the insulin
sensitive tissues.
 lPerturbed nutritional and hormona environment are
responsible for the altered β-cell mass.
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Diagram illustrating the relationships between nutritional state, hormone
concentrations, metabolism and tissue accretion and differentiation in the
fetus.
(A L Fowden and A J Forhead(2004)