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