1. GESTATIONAL DIABETES MELLITUS - CURRENT CONCEPTS
Dr.Vivek Sundaram.MD.DNB.MRCP(UK)
Consultant – Internal Medicine,Diabetes & Critical Care
Sundaram Hospital,Trichy.

2. Watching TV for 2 hours/day increases
Risk of diabetes by 20%....JAMA,June 2011

3. ARETAEUS(200 A.D.)
“….wonderful affliction with melting down of flesh and limbs into urine…..patient never stops making water ..……illness is chronic but the patient shortlived”

4. Definition
Gestational Diabetes Mellitus (GDM) is defined as - “carbohydrate intolerance with recognition or onset during pregnancy, irrespective of the treatment with diet or insulin.”
The importance of GDM is that two generations are at risk of developing diabetes in the future.

5. The maternal metabolic adaptation is to maintain the mean FBG of 74
The maternal metabolic adaptation is to maintain the mean FBG of 74.5 ± 11 mg/dl and the PPG peak of ± 16.9mg/dl.1
Compensatory hyperinsulinaemia due to insulin resistance.
Failure of beta cells secretion to overcome the insulin resistance leads to GDM.

6. Diabetes and Pregnancy – Why it is relevant?
Hyperglycaemia during pregnancy is associated with high risk of maternal and perinatal morbidity and mortality
Maternal hyperglycaemia is associated with development of type 2 diabetes in the offspring
Diagnosis of GDM identifies women at high risk of future diabetes, offers opportunity of primary prevention

7. GDM……… Pregnancy – diabetogenic condition (metabolic stress test)
Unmasks a compensated metabolic abnormality
A direct consequence of the altered maternal metabolism
stemming from the changing hormonal milieu.

8. 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 8

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

10. Pathophysiology Human Placental Lactogen (HPL)
Produced by syncytiotrophoblasts of placenta.
Acts to promote lipolysis  increased Free fatty acids contributing to tissue insulin resistance.
Estrogen and Progesterone
Interfere with insulin-glucose relationship.
Insulinase
Placental product that may play a minor role.

11. Pathophysiology Normal pregnancy :
- Mild fasting hypoglycemia – increased lipolysis and FFAs become the main fuel substrate for the mother ( Mediated by human placental growth harmone)-”accelerated starvation”
- Postprandial hyperglycemia – insulin resistance aids glucose transfer to the fetus –”facilitated anabolism”

12. GDM –POSTPRANDIAL HYPERGLYCEMIA IS MORE RELEVANT
Fetal renal thershold for glucose < 110 mg/dl
Maternal hyperglycemia (>110 mg/dl) – increased iv glucose load to the fetus producing fetal glycosuria
Fetal polyuria - polyhyramnios
20 wks GA – fetus ingests glucose rich amniotic fluid
Gut stimulus to insulin secretion is more potent than transient iv hyperglycemia
IV + Oral route (glucose) – overfed,fat fetus

13. INDIAN - ETHNICITY Risk Factors Age  35 years
Obesity (BMI  30 kg/m2)
Family history
Previous delivery of a macrosomic infant
Member of a high-risk population
Polycystic ovarian syndrome
Previous abnormal glucose tolerance
INDIAN - ETHNICITY

14. GDM dilemmas Early or late sreening? To treat or not ?
WHO or ADA criteria
One step or twostep?
75 or 100 gm?
1 hour or 2 hour?
To treat or not ?
Insulin or pills?
Early or late delivery?
C section or normal?
Breast feed or not?

15. Who & When to screen? UNIVERSAL
First booking – Differentiates pre GDM from GDM
24-28 weeks [ Repeat - GTT]
weeks [ Repeat -GTT]

16. How to screen? One Step Approach – Validated in the indian population
2 hrs value >140 mg/dl with 75g oral glucose -GDM
( irrespective of the time last meal was consumed)
Definitive test: 75gm 2 hour OGTT ( ADA Criteria)
If negative rescreen at 24 weeks /32 weeks
If positive proceed to treatment

17. Gestational DM-Revised ADA criteria (2011) 75 g OGTT at 24-28 wks of gestation
Fasting
> 92 mg/dl
1 hr
>180 mg/dl
2 hr
> 153 mg/dl _ _ _
ANY 1 ABNORMAL VALUE - GDM
100 g OGTT – O,I,2,3 hr values …. 95,180,155,140 …2 abnormal values

18. “Abnormal” Plasma Glucose during Pregnancy
The occurrence of macrosomia was continuum as the 2 hr plasma glucose increased from 120 mg/dl (adjusted odds ratio 3.02 [ 95% CI 1.30 – 7.00], P < 0.05])
Balaji V, Balaji MS, Seshiah V, Mukundan S, Datta M.Diabetes Res Clin Pract Aug;73(2):223-4.
Occurrence of birth weight of new born > 90th percentile was continuum as FPG increased from 80 mg/dl and was significant above 90 mg/dl (adjusted odds ratio 2.08 [ 95% CI 1.24 – 3.48], P = 0.005])
V Seshiah, V Balaji, Madhuri S Balaji, A Paneerselvam. Abnormal Fasting Plasma Glucose during Pregnancy. Diabetes Care vol 31 (12): e92, December 2008
Abnormal : FPG > 90 & PPG > 120 mg/dl

19. TARGET BLOOD GLUCOSE LEVELS
Fasting PG
80 mg %
90 mg %
PPG
110 mg %
120 mg %
Mean PG level
95 mg %
105 mg %
Balaji V, Balaji MS, Seshiah V, Mukundan S, Datta M.Diabetes Res Clin Pract Aug;73(2):223-4.
V. Seshiah, AK Das, Balaji V, Shashank Joshi, MN Parikh, Sunil Gupta for DIPSI. GDM- Guidelines. JAPI vol 54, 2006,
Oded Langer. Maternal glycemic criteria for insulin therapy in GDM. Diabetes care, vol 21 (2), August B91-98.
Birth weight between
2.5 and 3.5 Kg
Vinod K Paul, Ashok K Deorari, Meharban Singh. Management of Low Birth Weight Babies. In: IAP Textbook of Pediatrics. 2nd ed. A. Parthasarathy, editor. Jaypee publications, 2002, p60.

20. GDM – Fetal Morbidity Macrosomia of the baby CPD – Shoulder Dystocia
Intrapartum Trauma – Feto-maternal
Neonatal Hypoglycemia
Neonatal Hypocalcemia
Neonatal Hyperbilirubinemia
Respiratory Distress Syndrome (RDS)
Polycythemia (secondary) in the new born

21. Fetal Morbidity

22. Maternal Morbidity Hypertension/Preeclampsia and Eclampsia
Cesarean delivery; Pre term labour
Polyhydramnios – fluid > 2000 ml
Post-partum uterine atony
Abruptio placenta
40-60% risk of DM (screen 6 wk/6 mths after delivery)

23. MANAGEMENT
Aim To maintain plasma glucose values as to that of non diabetic pregnancy #

24. How to treat?
Medical nutrition therapy (MNT)
Exercise
Insulin

25. MNT
2 wk trial – if uncontrolled switch over to insulin
30 kcal/kg/day for 60 kg
BMI>30- 25kcal/kg/day
300 extra calories for 2 & 3 trimester
3 meals & 3 snacks - avoid hypoglycemia
40 – 50% of calories as CHO,25% each as fat and protein

26. Exercise
Women with GDM often need regular, moderate physical activity to help control their blood sugar levels by allowing insulin to work better.
Examples include:
Walking
Prenatal aerobics classes
Swimming
Keep in mind that it may take 2 to 4 weeks before physical activity has an effect on blood sugar levels.

27. Insulin therapy Safe ,Effective, time tested Human Insulin preferred
Short acting analogues – good option
May need short term hospitalization
Monitoring fasting, premeals & post meal

29. Insulin secretion defect in diabetes
25/03/2017
Insulin secretion defect in diabetes
Normal
Diabetes
Plasma-immunoreactive
Insulin (µU/mL)
Plasma-immunoreactive
Insulin (µU/mL)
120
1ste fase
(acute afgifte)
120
100
100 80 80 60 60
As a person deteriorates from having a normal insulin profile to having increasingly severe type 2 diabetes, the insulin response to glucose becomes both delayed and blunted. 40 40
2e fase
This slide shows one of the key physiological differences between healthy individuals and those with type 2 diabetes: insulin secretion following an increase in blood glucose.
In healthy individuals, normal insulin response to an intravenously administered glucose bolus is biphasic.1 The first phase is a sharp release of insulin, which begins within 1–2 minutes after glucose administration and lasts approximately 10 minutes. This is followed by a more prolonged second phase, which starts at approximately 10 minutes and lasts 1–2 hours.
The acute first phase of insulin release inhibits hepatic glucose production and is critical to the regulation of prandial and postprandial glycaemia; the second phase of insulin release promotes glucose uptake by the peripheral tissues, attenuating postprandial excursions.1–3
As a person deteriorates from having a normal insulin profile to having increasingly severe type 2 diabetes, the insulin response to glucose becomes both delayed and blunted. Eventually, it is completely lost.
First-phase insulin secretion is an early casualty in this process.3,4 Defects in first-phase secretion would be expected to contribute significantly to postprandial hyperglycaemia, and this is indeed observed, even in individuals who are not yet overtly diabetic.4,5 This is shown in the next slide.
1. Fonseca V. Clinical significance of targeting postprandial and fasting hyperglycaemia in managing type 2 diabetes mellitus. Curr Med Res Opin 2003;49:635–641.
2. Pfeiffer MA, Halter JB & Porte D, Jr. Insulin secretion in diabetes mellitus. Am J Med\ 1981;70:579–588.
3. Pratley RE & Weyer C. The role of impaired early insulin secretion in the pathogenesis of type ll diabetes mellitus. Diabetologia 2001;44:929–945.
4. Coates PA, Ollerton RL, Luzio SD, Ismail I & Owens DR. A glimpse of the ‘natural history’ of established type 2 diabetes mellitus from the spectrum of metabolic and hormonal responses to a mixed meal at the time of diagnosis. Diabetes Res Clin Pract 1994;26:177–187. 20 20
Time (min)
Time (min)
Fonseca V. Curr Med Res Opin 2003;19:635–641.

30. Insulin Therapy- Physician Expectations
Insulin therapy should closely mimic normal insulin physiology
Basal needs: Intermediate-/long-acting insulins (NPH, ILPS, detemir, glargine)
Bolus needs: Rapid-/short-acting insulins given with meals
(lispro, aspart, glulisine, human regular insulin)
This slide discusses normal physiology of insulin action.
The ideal insulin regimen should strive to match normal insulin secretion patterns
The combination of a long-acting insulin to cover the basal dose with rapid-acting insulin to cover the bolus doses may be the best regimen by which to mimic the normal secretion of insulin
Patients are reluctant to take multiple injections daily; when starting therapy, dramatic effects may be observed with a once-daily dose of mixed-action insulin
ILPS = insulin lispro protamine suspension
Meal
Meal
Meal
Expected insulin changes during the day for individuals without diabetes
Insulin effect images are theoretical representations and are not derived from clinical trial data.
Normal insulin physiology is matched by multiple insulin injections

31. Comparison of Human insulins/Analogs
Title
Subtitle
Insulin Onset Peak Duration
Short acting
Regular min h 4-6 h
Lispro/aspart min h h
Glulisine
Intermediate acting
NPH 1-4 h h h
Long acting
Glargine 1-2 h Flat ~24 h
Detemir Flat

32. So, Why Modern Insulins ?

33. Û Û Dissociation of Insulins Û Û Û 10-3 M 10-3 M 10-5 M 10-8 M 10-3 M
Regular Human Insulin
Peak time
2-4 hr
10-3 M
10-3 M
10-5 M
10-8 M Û Û Û
Formulation
Capillary membrane
Analogs
Peak time
1 hr
10-3 M
10-3 M
10-3 M Û Û
Formulation
Transient

34. Limitations of conventional soluble human insulin
Inability of s.c. injected soluble insulin to mimic the physiological pattern
Delayed onset of action (30-60 min after injection) i.e. should be injected min prior to a meal
Prolonged duration of action (6-8 hrs after injection)
Inadequate insulin when in need
Insulin when not needed
Presentation title

35. The shortcomings of conventional insulin (regular)
Presentation title
Date
The shortcomings of conventional insulin (regular)
Physiological insulin profile:
basal component
meal-related peaks
Regular insulin fails to match normal insulin peak
Fails to match the physiology

36. Shortcomings of human insulin
Presentation title
Date
Shortcomings of human insulin
Physiological insulin
profile: basal component
meal-related peaks
Period of unwanted hyperglycemia
Period of unwanted hypoglycemia
Mixtard fails to re-create the physiological insulin profile
When patient is takes premix insulin, there is a late peak and delayed trough. So this does not match the physiological insulin profile (as you can see in the red colored graph). This leads to inadequate control of hyperglycemia and unwanted hypoglycemia.
So this is the short coming of human Mixtard. Can we do something better, an insulin which is more close to a physiological one ?

37. What is premixed insulin?
Premixed is a suspension of:
Soluble insulin analogue
30%
30%
Soluble
human insulin
Protamine-crystallised
insulin
NPH
This is a simple diagramatic presentation showing the formulation of premixes. Mixtard, i.e., human insulin premix contains 30% soluble human insulin and 70% NPH, where as NovoMix30 contains 30% soluble insulin aspart (the rapid acting insulin analogue for post-prandial glucose control) and 70% protaminated insulin aspart for basal glucose control
Presentation title
Date

38. 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

39. INSULIN TACTICS Multiple Daily Injections (MDI):NPH + Mealtime Lispro
NPH at AM and HS + Lispro AC
NPH at HS + Lispro AC
Insulin Effect B S L HS
Lispro
NPH
Slide 6-29
INSULIN TACTICS
Multiple Daily Injections (MDI)
NPH + Mealtime Lispro
This schematic slide shows the profiles resulting from two kinds of multiple-injection regimens in which insulin lispro is substituted for human regular insulin. The peaks of lispro more closely match the normal profile, but the 4-hour duration of lispro leaves lunch and late evening poorly covered by insulin with the two-mealtime-injection regimen on the left. With NPH at bedtime and lispro with meals, as shown on the right, clear gaps of coverage of basal requirements are evident as well.
6-29

40. Insulin Regimen If MNT fails after 2 wks of trial initiate Insulin
Dose: 0.7, 0.8 and 0.9 u/kg – 1, 2 & 3 trim.
Eg. 1st trim – 64 kg = 0.7 x 64 = 45 units
Give 2/3 before BF = 30 units of 30:70 mix
Give 1/3 before supper = 15 u of 30:70 mix
Increase total dose by 2-4 units based on BG

41. Oral agents -GDM Glibenclamide ( Currently not recommended)
Metformin – Select group ( pre GDM/PCOS)
ADVANTAGES
Easy to take
Need far less education
Affordable
No social stigma
Not endorsed by any formal recommendations apart from NICE Guidelines

43. Original Article Metformin versus Insulin for the Treatment of Gestational Diabetes
Janet A. Rowan, M.B., Ch.B., William M. Hague, M.D., Wanzhen Gao, Ph.D., Malcolm R. Battin, M.B., Ch.B., M. Peter Moore, M.B., Ch.B., for the MiG Trial Investigators
N E J M.358(19):
May 8, 2008

44. Monitoring HbA1c Levels
HbA1c in early pregnancy - differentiates between a pre gestational diabetic and GDM. If the HbA1c level is more than 6%, she is likely to be a pre GDM.
HbA1c is useful in monitoring the glucose control during pregnancy, but not for the day to day management. Estimation of fructosamine during pregnancy is less frequently used.

45. Conclusions Universal screening ideal for our women
2 hour 75 gm screening is cost effective
2 hour 75 gm – GTT ( Definitive test)
Diet and exercise provides good control in many
Insulin analogues are safe and very effective
Oral agents are an alternative – in select situations
Postpartum follow-up is an integral part of GDM management

46. Richard S. Hollis President ACOG
Remember how fortunate we are to be included in the lives of our patients at the most precious times of their lives
Richard S. Hollis President ACOG

47. ILLNESS
WELLNESS

48. THANK YOU