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DESIGNER INSULINS IN GESTATIONAL DIABETES
DR.T.RAMANI DEVI MD DGO FICS FICOGRAMAKRISHNA NURSING HOME
TRICHY
Maternal DiabetesTwo lives.. Twice as specialAn 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
GDMGDM IGTIGT
2% 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
1980s1980s
7.6%Narendra J, Munichoodappa C, et al, Prevalence of glucose intolerance during pregnancy. Int J Diab Dev Countries 1991;11:2-4
8.2%Ramachandran A, Snehalatha c, Dharmaraj D, Viswanathan M. Prevalence of glucose intolerance in Asian Indians. Diabetes Care 1992; 15:1348-55
1990s1990s
16.6%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.
2000s2000s
GDM prevalence linked to background IGT rates
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 HYPOTHESISUterine
After Birth
Matern
al D
M
pla
centa
A.AFatCHO
At Birth
Macrosomia
Hypoglycemia
Fetus
A Insulin
Obesity
Metabolic syndrome
CVD
IGT/DM
Diabetes and Pregnancy – Why it is relevant?
IUGR & Macrosomia
SolutionOptimal 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 recommendationScreening Procedure Criteria
Perform a 75-g OGTT , with plasma glucose measurement fasting and at 1 and 2 h, at 24-28 weeks of gestation in women not previously diagnosed with overt diabetes
The OGTT should be performed in the morning after an overnight fast of at least 8 hrs.
The diagnosis of GDM is made when any of the following plasma glucose values are exceeded
-Fasting >= 92mg/dL(5.1mmol/L)-1 hr >=180mg/dL(10.0 mmol/L)-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
Normal
Abortions
Still birth
Died after birth
Congenital anomalies
Premature deliveries
Sick babies
Big baby ( 3.5 kg)
NGT (n = 851)
804
6
3
1
8
9 / 831
22
78
GDM (n =211)
122
0
5
5
5
11 / 148
10
90
P value
< 0.0001
--
0.07
0.01
0.23
0.002
0.157
< 0.0001
GDM increases the risk of offspring DM
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: Glyburide study: ›Randomized trial glyburide vs insulin›404 GDMs FPG >95 but <140 mg/dl or 2- hr 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 labelMultinational study - Decreased hypoglycemic spells- Increased fetal outcome
Insulin Aspart in pregnancy status compared with Human Insulin
Primary objective – Hypoglycemic attacksSecondary 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
RegularNPH
B SL HS
Insu
lin E
ffect
B
6-23
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