DESIGNER INSULINS IN
GESTATIONAL DIABETES
DR.T.RAMANI DEVI MD DGO FICS FICOG
RAMAKRISHNA NURSING HOME
TRICHY
Maternal Diabetes
Two lives.. Twice as special
An oppurtunity for primary prevention
-Maternal health
-Child health
Definition
GDM is defined as carbohydrate in tolerance of variable severity
with onset or first recognition during pregnancy.
The definition is applicable regardless of whether insulin is used
to treat the disease or if the condition persists after pregnancy.
It does not exclude the possibility that unrecognized glucose
intolerance may have antedated the pregnancy
Introduction
• Incidence of GDM is variable from 17% to 29%
of all pregnancies
• Associated with maternal and perinatal
complications.
• 90% of all Diabetics are GDM and 10% are due
to pregestational diabetes.
• 4 million pregnancies in India are complicated
by GDM
• This may contribute a part of MMR in India
GDM prevalence linked to background IGT rates
GDM
2%
1980s
1990s
Agarwal S, Gupta AN. Gestational
Diabetes. J Assoc Physicians India
1982;30:203
2%
Ramachandran A, et .al., High prevalence of
diabetes in an urban population in south India.
BMJ 1988;3; 297(6648):587-90
7.6%
8.2%
Narendra J, Munichoodappa C, et al, Prevalence of
glucose intolerance during pregnancy. Int J Diab Dev
Countries 1991;11:2-4
Ramachandran A, Snehalatha c, Dharmaraj D,
Viswanathan M. Prevalence of glucose intolerance in
Asian Indians. Diabetes Care 1992; 15:1348-55
16.6%
2000s
IGT
V Seshiah, V Balaji, Madhuri S Balaji, CB Sanjeevi, A.
Green. Gestational Diabetes Mellitus in India. J Assoc
Physicians India 2004;52:707
14.5%
Ramachandran A, Snehalatha C, Kapur A, Vijay V,
Mohan V,Das AK, Rao PV, Yajnik CS, Prasanna Kumar
KM, Nair JD.For the Diabetes Epidemiology Study Group
in India (DESI).Diabetologia 2001;44:1094-1101.
Significance of Diabetes and Pregnancy
• Malformation rate in 94/1000 Vs 9.7/1000 in general population
•
Still birth is 15 times higher 25/1000 Vs 5/1000
• PNM is 3 times higher 19.9/1000 Vs 6.8/1000
• Recent concept of adult diseases having their origin inutero insults
has been established.
• 1989 WHO/IDF discussed the problem of hyperglycemia in pregnant
women. They wanted to achieve pregnancy outcome in diabetic
women same as in non diabetic women.
FREINKEL HYPOTHESIS
Uterine
At Birth
Macrosomia
After Birth
Obesity
Hypoglycemia
placenta
Maternal DM
A.A
Fat
CHO
Metabolic syndrome
IGT/DM
A Insulin
Fetus
CVD
Diabetes and Pregnancy – Why it is relevant?
Hyperglycaemia
during pregnancy
is associated with
high risk of
maternal and
perinatal morbidity
and mortality and
poor pregnancy
outcome
Diagnosis of GDM
identifies women
at high risk of
future diabetes,
offers opportunity
of primary
prevention
Maternal
hyperglycaemia
is associated with
development of
metabolic
problems
including type 2
diabetes in the
offspring
IUGR & Macrosomia
Barker’s Hypothesis
Pederson’s hypothesis
Low birth weight
Macrosomia
Predicts
development
of HTN, Type
2 DM & IGT
Solution
Optimal nutrition+ Optimal glycemic
control=Optimal birth weight
3000 – 3500 g.
SCREENING FOR DIABETES
WHO Criteria
FPG (mg/dl)
2h PG (mg/dl)
IGT
<126
140-200
Diabetes
>126
>200
ADA recommendation
Screening Procedure
Criteria
Perform a 75-g OGTT , with
plasma glucose measurement
fasting and at 1 and 2 h, at 2428 weeks of gestation in
women not previously
diagnosed with overt diabetes
The diagnosis of GDM is made
when any of the following
plasma glucose values are
exceeded
-Fasting >=
92mg/dL(5.1mmol/L)
The OGTT should be performed -1 hr >=180mg/dL(10.0
in the morning after an
mmol/L)
overnight fast of at least 8 hrs. -2 hr>=153 mg/dL (8.5mmol/L)
THRESHOLDS FOR DIAGNOSIS OF GDM
GLYCEMIC THRESHOLDS FOR PREVENTION
OF DIABETIC COMPLICATION
Comparison of the Foetal Outcome in a NGT & GDM
Foetal outcome
NGT (n = 851)
GDM (n =211)
P value
804
122
< 0.0001
Abortions
6
0
--
Still birth
3
5
0.07
Died after birth
1
5
0.01
Congenital anomalies
8
5
0.23
Premature deliveries
9 / 831
11 / 148
0.002
Sick babies
22
10
0.157
Big baby ( 3.5 kg)
78
90
< 0.0001
Normal
GDM increases the risk of offspring DM
25
20
O-BP
15
O-Type1
O-NoGDM
10
O-GDM
5
0
Type 1 diabetes
Type 2/ Prediabetes
Offspring's of women with GDM, have a 4 to 8 fold increased risk of diabetes.
Clausen TD et al., Diabetes Care 2008
How to reduce this
•
•
•
•
Early screening for GDM
Monitoring frequently
Proper uses of diet plan , exercise and insulin.
Future concepts of CSII, CGMS, telemedicine,
e-health, will revolutionize the management of
GDM
How to treat?
•
•
•
•
•
•
•
MNT
Exercise
Insulin
Glyburide
Metformin
Acarbose?
Insulin pump
Calorie allotment
• 30 kcal per kg current weight per day in pregnant
women who are BMI 22 to 25.
• 24 kcal per kg current weight per day in overweight
pregnant women (BMI 26 to 29).
• 12 to 15 kcal per kg current weight per day for severely
obese pregnant women (BMI >30).
• 40 kcal per kg current weight per day in pregnant
women who are less than BMI 22.
• Jovanovic-Peterson L, Peterson, CM. Nutritional
management of the obese gestational diabetic
woman. J Am Coll Nutr 1992; 11:246.
How long MNT?
• Consensus and hard data are lacking regarding how long diet
therapy should be maintained before initiating pharmacologic
treatment.
• 70% of the subjects with initial fasting plasma glucose less
than 95 mg/dL achieved targeted levels of glycemia within 2
weeks of dietary management, but no significant
improvement occurred thereafter
• McFarland et al obstet gynecol 1999
Exercise Prescription
 Can continue prepregnancy




activity
Keeping physically active is
essential for good glycemic
control
Upperbody ergometric
exercise useful
Do not start new vigorous
exercise for glucose
control
Uterine contractions,fetal
tachy, maternal heart rate
to be monitored
ORAL AGENTS IN
PREGNANCY
Glyburide study:
›Randomized trial glyburide vs insulin
›404 GDMs FPG >95 but <140 mg/dl or 2hr pp >120 on diet
›Similar success of glucose control in both
groups
Langer et al: NEJM 200:343:1134
Animal insulin  Insulin Analogues
• 1920- Introduction of insulin revolutionized
Diabetes Management
• 1920- Introduced insulin had impurities and
batch to batch variation
• 1980- higher quality insulin from bovine and
porcine sources . Then came recombinant
Insulin
IDEAL AGENT SHOULD FULFILL
• Mimic physiological control
• No adverse effect upon maternal and fetal
outcome.
• Should not interfere with antenatal , perinatal
and post natal care
• Insulin Analogues fulfills all the criteria when
given in right doses in right manner.
ADVANTAGES
•
•
•
•
Batch to Batch consistency
No allergy, antibody formation
No immune mediated lipoatrophy
Glucose control is similar in endogenous
insulin production
• Preprandial hypoglycemia and postprandial
hyperglycemia are well controlled.
• Mealtime flexibility is possible with analogues.
Safety issues with Insulin Analogues
•
-
Ideal insulin
Mimic physiological insulin secretion
Does not cross placenta
No mitogenic potential
Since IgG bound insulin can cross placenta,
therapeutic agent should not induce antibody
generation
STRUCTURAL MODIFICATION OF INSULIN ANALOGUE
Insulin Lispro
28-29 Proline and Lysine are interchanged
Insulin Aspart
Proline at 28 replaced by aspartic acid. (decreases hexamer
formation )
Insulin glulisine
Position 3 of Lysine with Asparagine ; Lysine at 29 replaced by
glutamine
Insulin glargine
Asparagine at A2 1 is replaced by glycine. 2 arginine added to C
terminal of Beta chain
Insulin detemir
Binds with albumin. Threonine omitted at position 30th of Beta
chain and replaced by myristic acid at C 14 FA chain. (delays’
absorption by albumin binding)
Pharmacokinetics of HI and IA
RECEPTOR BINDING, METABOLIC AND
MITOGENIC POTENCY OF IA
HAPO: Hyperglycemia And Adverse Pregnancy
Outcome
• 9 countries, 25 centers, 23,325 patients
• 7 year study
• Women were screened between 24-32weeks with
fasting glucose, 1 hour and 2 hour post 75 gm
glucose .
• Medical caregivers were blinded to results except
that exceeded pre defined cut offs[ 5.8 fasting, 11.1
post 75 gm glucose] and were then removed from
the study.
• Birth weight, maternal complications, operative
delivery, insulin levels in newborn were studied.
Int J,Gynecology & Obstetrics. 2002,78, (1);69-77
GLYCEMIC STATUS IN GDM
FASTING HYPOGLYCEMIA
POSTPRANDIAL HYPERGLYCEMIA
Normalisation of this is possible by Insulin
Analogues.
Insulin aspart qualifies for use in GDM
• Insulin analogues does not cross the placenta
but placental concentration is higher than in
maternal blood.
Insulin Aspart in pregnancy status
compared with Human Insulin
Moshe Hod et al.,
Studied insulin aspart in Type I diabetic patient
Randomized parallel group open label
Multinational study
- Decreased hypoglycemic spells
- Increased fetal outcome
Insulin Aspart in pregnancy status
compared with Human Insulin
Primary objective – Hypoglycemic attacks
Secondary objective – Analyze maternal/fetal
outcome
- HbA1c
- 8 point glucose profile
- Number of mild hypoglycemia
- cord blood insulin AB
• Mean cord blood insulin level is lower in IA group
INSULIN TACTICS
Twice-daily Split-mixed Regimens
Insulin Effect
Regular
NPH
B
L
S
HS
B
6-
C
FUTURE CONCEPTS IN INSULIN
THERAPY
Continuous Subcutaneous Insulin
Infusion (CSII)
• Blood glucose levels monitored continuously
• Pre specified insulin dose is subcutaneously
delivered by pump
• This minimized timing and dosing errors.
Continuous Glucose Monitoring
System (CGMS)
• Blood glucose is assessed periodically
• Insulin dose is calculated
• CGMS integrated monitoring system with a
delivery device
• Hence round the clock blood glucose is
controlled.
e-health system
• Patient has her data in USB device which can
be analyzed and seek guidance from internet.
CSII & CGMS
• Paradigm device connects CGMS and delivery
device through bluetooth. This early trial is
about to be started in USA.
THANK YOU