1. DESIGNER INSULINS IN GESTATIONAL DIABETES
DR.T.RAMANI DEVI MD DGO FICS FICOG
RAMAKRISHNA NURSING HOME
TRICHY

2. Maternal Diabetes Two lives.. Twice as special
An oppurtunity for primary prevention
-Maternal health
-Child health

3. 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

4. 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

7. GDM prevalence linked to background IGT rates2%
Agarwal S, Gupta AN. Gestational Diabetes. J Assoc Physicians India 1982;30:203
Ramachandran A, et .al., High prevalence of diabetes in an urban population in south India. BMJ 1988;3; 297(6648):587-90
1980s
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:
1990s
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:
2000s 7

8. 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.

9. FREINKEL HYPOTHESIS Uterine At Birth After Birth placenta Macrosomia
Obesity
Hypoglycemia
Maternal DM
Metabolic syndrome
A Insulin
IGT/DM
A.A
Fat
CHO
Fetus
CVD

10. 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

11. IUGR & Macrosomia Pederson’s hypothesis Macrosomia
Predicts development of HTN, Type 2 DM & IGT
Barker’s Hypothesis Low birth weight
Pederson’s hypothesis Macrosomia
Solution Optimal nutrition+ Optimal glycemic control=Optimal birth weight – 3500 g.

13. SCREENING FOR DIABETES

14. WHO Criteria FPG (mg/dl) 2h PG (mg/dl) IGT <126 140-200 Diabetes
>126
>200

15. ADA recommendation
Screening Procedure
Criteria
Perform a 75-g OGTT , with plasma glucose measurement fasting and at 1 and 2 h, at 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)

16. THRESHOLDS FOR DIAGNOSIS OF GDM

17. GLYCEMIC THRESHOLDS FOR PREVENTION OF DIABETIC COMPLICATION

18. Comparison of the Foetal Outcome in a NGT & GDM
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 5
11 / 148 10 90
P value
< --
0.07
0.01
0.23
0.002
0.157

19. 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

20. 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

21. How to treat? MNT Exercise Insulin Glyburide Metformin Acarbose?
Insulin pump

22. 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.

23. 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

24. 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

25. ORAL AGENTS IN PREGNANCY
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

27. Animal insulin  Insulin Analogues
1920- Introduction of insulin revolutionized Diabetes Management
Introduced insulin had impurities and batch to batch variation
1980- higher quality insulin from bovine and porcine sources . Then came recombinant Insulin

28. 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.

29. 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.

30. 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

31. 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)

32. Pharmacokinetics of HI and IA

33. RECEPTOR BINDING, METABOLIC AND MITOGENIC POTENCY OF IA

34. 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

36. GLYCEMIC STATUS IN GDM
FASTING HYPOGLYCEMIA POSTPRANDIAL HYPERGLYCEMIA Normalisation of this is possible by Insulin Analogues.

37. Insulin aspart qualifies for use in GDM
Insulin analogues does not cross the placenta but placental concentration is higher than in maternal blood.

38. 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

39. 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

45. Mean cord blood insulin level is lower in IA group

50. INSULIN TACTICS Twice-daily Split-mixed Regimens
Regular
NPH
Insulin Effect
Slide 6-23
INSULIN TACTICS
Twice-daily Split-mixed Regimens
Twice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years. In some cases, premixed 70/30 insulin is used for this purpose. Patient profiles of insulin levels resulting from this method, as shown in this figure, do not come close to matching the normal endogenous secretory pattern, shown in the shaded background. Patients with type 1 diabetes using this “split-mixed” regimen rarely achieve reasonably good glycemic control by present standards, since they lack endogenous insulin to supplement the partially adequate profile of injected insulin. Type 2 diabetes patients who have substantial endogenous insulin may fare much better with this regimen, but may experience late morning or nocturnal hypoglycemia because of excessive levels of insulin at these times.
Berger M, Jorgens V, Mühlhauser I. Rationale for the use of insulin therapy alone as the pharmacological treatment of type 2 diabetes. Diabetes Care. 1999;22(suppl 3):C71-C75; Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: applications, benefits, and risks. Diabetes Reviews. 1995;3: B L S HS B
6-23

51. C

53. FUTURE CONCEPTS IN INSULIN THERAPY

54. 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.

55. 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.

56. e-health system
Patient has her data in USB device which can be analyzed and seek guidance from internet.

57. CSII & CGMS
Paradigm device connects CGMS and delivery device through bluetooth. This early trial is about to be started in USA.

59. THANK YOU