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Presentation on theme: "GESTATIONAL DIABETES MELLITUS - CURRENT CONCEPTS"— Presentation transcript:

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 rates
2% 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”

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

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




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