2Watching TV for 2 hours/day increases Risk of diabetes by 20%....JAMA,June 2011
3ARETAEUS(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”
4DefinitionGestational 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.
5The 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.1Compensatory hyperinsulinaemia due to insulin resistance.Failure of beta cells secretion to overcome the insulin resistance leads to GDM.
6Diabetes and Pregnancy – Why it is relevant? Hyperglycaemia during pregnancy is associated with high risk of maternal and perinatal morbidity and mortalityMaternal hyperglycaemia is associated with development of type 2 diabetes in the offspringDiagnosis of GDM identifies women at high risk of future diabetes, offers opportunity of primary prevention
7GDM……… Pregnancy – diabetogenic condition (metabolic stress test) Unmasks a compensated metabolic abnormalityA direct consequence of the altered maternal metabolismstemming from the changing hormonal milieu.
8GDM prevalence linked to background IGT rates 2%Agarwal S, Gupta AN. Gestational Diabetes. J Assoc Physicians India 1982;30:203Ramachandran A, et .al., High prevalence of diabetes in an urban population in south India. BMJ 1988;3; 297(6648):587-901980s7.6%Narendra J, Munichoodappa C, et al, Prevalence of glucose intolerance during pregnancy. Int J Diab Dev Countries 1991;11:2-48.2%Ramachandran A, Snehalatha c, Dharmaraj D, Viswanathan M. Prevalence of glucose intolerance in Asian Indians. Diabetes Care 1992; 15:1990s16.6%V Seshiah, V Balaji, Madhuri S Balaji, CB Sanjeevi, A. Green. Gestational Diabetes Mellitus in India. J Assoc Physicians India 2004;52:70714.5%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;44:2000s8
9FREINKEL HYPOTHESIS Uterine At Birth After Birth placenta Macrosomia ObesityHypoglycemiaMaternal DMMetabolic syndromeAmniotic Fluid InsulinIGT/DMA.AFatCHOFetusCVD
10Pathophysiology Human Placental Lactogen (HPL) Produced by syncytiotrophoblasts of placenta.Acts to promote lipolysis increased Free fatty acids contributing to tissue insulin resistance.Estrogen and ProgesteroneInterfere with insulin-glucose relationship.InsulinasePlacental product that may play a minor role.
11Pathophysiology 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”
12GDM –POSTPRANDIAL HYPERGLYCEMIA IS MORE RELEVANT Fetal renal thershold for glucose < 110 mg/dlMaternal hyperglycemia (>110 mg/dl) – increased iv glucose load to the fetus producing fetal glycosuriaFetal polyuria - polyhyramnios20 wks GA – fetus ingests glucose rich amniotic fluidGut stimulus to insulin secretion is more potent than transient iv hyperglycemiaIV + Oral route (glucose) – overfed,fat fetus
13INDIAN - ETHNICITY Risk Factors Age 35 years Obesity (BMI 30 kg/m2)Family historyPrevious delivery of a macrosomic infantMember of a high-risk populationPolycystic ovarian syndromePrevious abnormal glucose toleranceINDIAN - ETHNICITY
14GDM dilemmas Early or late sreening? To treat or not ? WHO or ADA criteriaOne 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?
15Who & When to screen? UNIVERSAL First booking – Differentiates pre GDM from GDM24-28 weeks [ Repeat - GTT]weeks [ Repeat -GTT]
16How 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 weeksIf positive proceed to treatment
17Gestational DM-Revised ADA criteria (2011) 75 g OGTT at 24-28 wks of gestation Fasting> 92 mg/dl1 hr>180 mg/dl2 hr> 153 mg/dl___ANY 1 ABNORMAL VALUE - GDM100 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 2008Abnormal : FPG > 90 & PPG > 120 mg/dl
19TARGET BLOOD GLUCOSE LEVELS Fasting PG80 mg %90 mg %PPG110 mg %120 mg %Mean PG level95 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 between2.5 and 3.5 KgVinod 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.
20GDM – Fetal Morbidity Macrosomia of the baby CPD – Shoulder Dystocia Intrapartum Trauma – Feto-maternalNeonatal HypoglycemiaNeonatal HypocalcemiaNeonatal HyperbilirubinemiaRespiratory Distress Syndrome (RDS)Polycythemia (secondary) in the new born
22Maternal Morbidity Hypertension/Preeclampsia and Eclampsia Cesarean delivery; Pre term labourPolyhydramnios – fluid > 2000 mlPost-partum uterine atonyAbruptio placenta40-60% risk of DM (screen 6 wk/6 mths after delivery)
23MANAGEMENTAim To maintain plasma glucose values as to that of non diabetic pregnancy#
24How to treat?Medical nutrition therapy (MNT)ExerciseInsulin
25MNT2 wk trial – if uncontrolled switch over to insulin30 kcal/kg/day for 60 kgBMI>30- 25kcal/kg/day300 extra calories for 2 & 3 trimester3 meals & 3 snacks - avoid hypoglycemia40 – 50% of calories as CHO,25% each as fat and protein
26ExerciseWomen with GDM often need regular, moderate physical activity to help control their blood sugar levels by allowing insulin to work better.Examples include:WalkingPrenatal aerobics classesSwimmingKeep in mind that it may take 2 to 4 weeks before physical activity has an effect on blood sugar levels.
27Insulin therapy Safe ,Effective, time tested Human Insulin preferred Short acting analogues – good optionMay need short term hospitalizationMonitoring fasting, premeals & post meal
29Insulin secretion defect in diabetes 25/03/2017Insulin secretion defect in diabetesNormalDiabetesPlasma-immunoreactiveInsulin (µU/mL)Plasma-immunoreactiveInsulin (µU/mL)1201ste fase(acute afgifte)12010010080806060As 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.40402e faseThis 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.1–3As 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;26:177–187.2020Time (min)Time (min)Fonseca V. Curr Med Res Opin 2003;19:635–641.
30Insulin Therapy- Physician Expectations Insulin therapy should closely mimic normal insulin physiologyBasal 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 patternsThe 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 insulinPatients are reluctant to take multiple injections daily; when starting therapy, dramatic effects may be observed with a once-daily dose of mixed-action insulinILPS = insulin lispro protamine suspensionMealMealMealExpected insulin changes during the day for individuals without diabetesInsulin effect images are theoretical representations and are not derived from clinical trial data.Normal insulin physiology is matched by multiple insulin injections
31Comparison of Human insulins/Analogs TitleSubtitleInsulin Onset Peak DurationShort actingRegular min h 4-6 hLispro/aspart min h hGlulisineIntermediate actingNPH 1-4 h h hLong actingGlargine 1-2 h Flat ~24 hDetemir Flat
33Û Û Dissociation of Insulins Û Û Û 10-3 M 10-3 M 10-5 M 10-8 M 10-3 M Regular Human InsulinPeak time2-4 hr10-3 M10-3 M10-5 M10-8 MÛÛÛFormulationCapillary membraneAnalogsPeak time1 hr10-3 M10-3 M10-3 MÛÛFormulationTransient
34Limitations of conventional soluble human insulin Inability of s.c. injected soluble insulin to mimic the physiological patternDelayed onset of action (30-60 min after injection) i.e. should be injected min prior to a mealProlonged duration of action (6-8 hrs after injection)Inadequate insulin when in needInsulin when not neededPresentation title
35The shortcomings of conventional insulin (regular) Presentation titleDateThe shortcomings of conventional insulin (regular)Physiological insulin profile:basal componentmeal-related peaksRegular insulin fails to match normal insulin peakFails to match the physiology
36Shortcomings of human insulin Presentation titleDateShortcomings of human insulinPhysiological insulinprofile: basal componentmeal-related peaksPeriod of unwanted hyperglycemiaPeriod of unwanted hypoglycemiaMixtard fails to re-create the physiological insulin profileWhen 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 ?
37What is premixed insulin? Premixed is a suspension of:Soluble insulin analogue30%30%Solublehuman insulinProtamine-crystallisedinsulinNPHThis 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 controlPresentation titleDate
38INSULIN TACTICS Twice-daily Split-mixed Regimens RegularNPHInsulin EffectSlide 6-23INSULIN TACTICSTwice-daily Split-mixed RegimensTwice-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:BLSHSB6-23
39INSULIN TACTICS Multiple Daily Injections (MDI):NPH + Mealtime Lispro NPH at AM and HS + Lispro ACNPH at HS + Lispro ACInsulin EffectBSLHSLisproNPHSlide 6-29INSULIN TACTICSMultiple Daily Injections (MDI)NPH + Mealtime LisproThis 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
40Insulin 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 unitsGive 2/3 before BF = 30 units of 30:70 mixGive 1/3 before supper = 15 u of 30:70 mixIncrease total dose by 2-4 units based on BG
41Oral agents -GDM Glibenclamide ( Currently not recommended) Metformin – Select group ( pre GDM/PCOS)ADVANTAGESEasy to takeNeed far less educationAffordableNo social stigmaNot endorsed by any formal recommendations apart from NICE Guidelines
43Original 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 InvestigatorsN E J M.358(19):May 8, 2008
44Monitoring 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.
45Conclusions Universal screening ideal for our women 2 hour 75 gm screening is cost effective2 hour 75 gm – GTT ( Definitive test)Diet and exercise provides good control in manyInsulin analogues are safe and very effectiveOral agents are an alternative – in select situationsPostpartum follow-up is an integral part of GDM management
46Richard 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 livesRichard S. Hollis President ACOG