Transcript Insulins in Diabetic Pregnancy by Dr Sarma

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Glucose Challenge Test (GCT)
An excellent screening test is to obtain plasma glucose level one
hour after a 50 g glucose load administered at any time of the day
without regard to the time since the last meal. It is a well validated
and widely applied screening procedure for women between 24 -28
weeks of gestation.
Cut-off value > 140 mg/dl identifies 80% women with GDM
Cut-off value > 130 mg/dl identifies 90% women with GDM
GCT is elevated, do a diagnostic oral glucose tolerance test
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Timing of
measurement
National Diabetes
Data Group (1979)
Carpenter and
Coustan (CC) 1982
Fasting
105 mg/dl
95 mg/dl
1 hour
190 mg/dl
180 mg/dl
2 hour
165 mg/dl
155 mg/dl
3 hour
145 mg/dl
140 mg/dl
2 or more values must be abnormal; for at least 3 days prior to the test, the
patient should have an unrestricted diet and unlimited physical activity. The
patient should fast for 8 hours before the test. The CC criteria detects 54%
more women with GDM than NDDG criteria
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Diabetes 1979;28:1039–1057; Am J OBG. 1982;144:768-73
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Test sample timing
Plasma Glucose value
Fasting (mg%)
95
1 hour (mg%)
180
2 hour (mg%)
155
3 hour (mg%)
140
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Tight glycemic control can reduce fetal risk. But, stringent
glycemic control puts the mother at increased risk of
hypoglycemic events and the fetus at risk of being smallfor-gestational age.
American Diabetes Association (ADA) Recommendations:
Fasting whole blood glucose
<95 mg/dl
1 hr postprandial blood glucose <140 mg/dl
2 hr postprandial blood glucose <120 mg/dl
Hb A1C (for GDM)
< 6.0 %
These are venous plasma targets, not glucometer targets
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HbA1C – not ideal for screening of GDM
May used for screening of T2DM
Patients with excessive fetal growth - Insulin
Those who don’t achieve targets in 1w- Insulin
Target values
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Hb A1c < 6%; Pre pregnancy Hb A1c < 7%
Fasting – < 95 mg%
Post prandial 1 hour – < 120 mg %
Post prandial 2 hours – < 140 mg%
Urine ketones should be negative
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Diabetes Care 21(2):B161–B167, 1998, Diabetes Care 2010; 33: 676–682
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At Birth
After Birth
Macrosomia
Obesity
Hypoglycemia
Placenta
Maternal DM
Uterine
AA, Fat
CHO
Metabolic Syndrome
 Insulin
IGT/DM
Fetus
CVD
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Barker’s Hypothesis
Low birth weight
Pederson’s hypothesis
Macrosomia
HTN, IGT
Type 2 DM
Optimal Nutrition + Optimal Glycemic Control
Results in optimal birth weight of 3–3.5 kg.
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• First Half of Pregnancy (Anabolic)
– Pancreatic beta-cell hyperplasia  hyper insulinemia
– Increased uptake and storage of glucose
• Second Half of Pregnancy (Catabolic)
– Placental hormones block glucose receptors and cause
insulin resistance
• Increased lipolysis
• Increased gluconeogenesis
• Decreased glycogenesis
– Increased glucose and amino acids for the fetus
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• Pregnancy is Diabetogenic condition
• A Wonderful Metabolic Stress Test
• Placental Diabetogenic Hormones
– Progesterone, Cortisol, GH
– Human Placental Lactogen (HPL), Prolactin
• Insulin Resistance (IR), ↑  cell stimulation
• Reduced Insulin Sensitivity up to 80%
• Impaired 1st phase insulin, Hyperinsulinemia
• Islet cell auto antibodies (2 to 25% cases)
• Glucokinase mutation in 5% of cases
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The hormones of pregnancy cause IR
They also cause direct hyperglycemia
But, the basic defect is
The maternal pancreatic  cells are unable to compensate
for this increased demand
• Plasma Glucose in pregnancy hangs on a delicate balance
• If the Mean Plasma Glucose (MPG) is
– Less than 87 mg% - IUGR of fetus
– More than 104 mg% - LGA of fetus
• It is important to screen for hypothyroidism
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• Does GDM pose serious risks to offspring?
• Does treatment reduce those risks?
• Does treatment reduce other risks associated
with GDM (obesity/diabetes in offspring)?
• Does reducing hyperglycemia reduce risks?
(macrosomia & cesarean delivery)
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• Poor Pregnancy outcomes and mortality
• High maternal & perinatal morbidity
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• High risk of future onset of diabetes in mothers
• A good primary prevention opportunity
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• Metabolic problems in the offspring
• Including high incidence of diabetes
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Mean glucose is >150 – PN Mortality is 24%
Mean glucose is 100-150 - PN Mortality is 15%
Mean glucose is <100 – PN Mortality is 4%
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Maternal HbA1c levels
< 7.2
Nil
7.2-9.1
14%
9.2-11.1
23%
> 11.2
25%
Critical periods - 3-6 weeks post conception
Need preconception metabolic care
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Complication
Mean blood glucose
Spontaneous abortion
160 mg%
Congenital anomalies
140 mg%
Still births
140 mg&
Lung maturation
140 mg%
Metabolic complication
110 mg%
Macrosomia or LGA
110 mg%
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• 1922- Insulin discovery by Banting and Best
• 1923- Commercial insulin with impurities
• 1975- Higher quality Bovine and Porcine Insulin
• 1978- Synthetic Human Insulin
• 1982- Synthetic human insulin approved
• 1983- Synthetic recombinant human insulin
• 1985- Sequencing the human insulin receptor
• 1996- Lispro insulin (Lilly) analogue
• 2003- Glargine insulin (Sanofi Aventis) analogue
• 2004- Glulisine (Sanofi Aventis) analogue
• 2006- Detemir insulin (Novo Nordisk) analogue
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• Mimic physiological control
• No adverse effect upon maternal and fetal outcome.
• No interfere with antenatal, perinatal & post natal care
• IgG bound insulin can cross placenta. So insulin
should not induce antibody generation
• Insulin Analogues fulfills all the criteria
• Mimic physiological insulin secretion
• Does not cross placenta
• No mitogenic potential
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Analogue
Change in amino acid sequence
Type
Lispro
28-29 Proline and Lysine are interchanged
Rapid
Aspart
Proline at 28 replaced by Aspartic acid
Rapid
Glulisine
3 Lysine by Asparagine; 29 Lysine by Glutamine
Rapid
Glargine
A21 Asparagine by Glycine; 2 Arginine to C terminal B
Long
Detemir
B 30 Threonine by Myristic acid a C-14 Fatty acid
Long
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Analogue
Brand Name
Manufacturer
Lispro
HUMALOG
Eli Lilly
B
Aspart
NOVOLOG
Novo Nordisk
B
Glulisine
APIDRA
Sanofi Aventis
C
Glargine
LANTUS(R)
Sanofi Aventis
C
Detemir
LEVEMIR
Novo Nordisk
B
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FDA
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Batch to Batch consistency
No allergy, antibody formation
No immune mediated lipoatrophy
Glucose control is similar in endogenous insulin
production
• Pre prandial hypoglycemia and postprandial
hyperglycemia are well controlled.
• Mealtime flexibility is possible with analogues.
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Maternal
Fetal
More physiological profile
Low fetal hypoglycemia risk
Better glycemic control
Less Macrosomia, defects
Minimum hypoglycemia risk
Fewer C-sections
Greater meal time flexibility
Better pregnancy outcomes
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Brunzell JD et al. J Clin Endocrio Metab. 1976; 42:222-229
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Barnett AH, Owens DR, Lancet 1977; 349:97-99 and 1997,101:60-70
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Basal
Basal Plus
Basal Bolus
Spilt Mix
AM+PM
CSII + CGMS
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• Two parameters – Weight and Gestational age
• The level of blood sugar is not the criterion
• Insulin requirements increase rapidly,
especially from 28 to 32 weeks of gestation
– 1st trimester: 0.7-0.8 U/kg/day
– 2nd trimester: 0.8-1.0 U/kg/day
– 3rd trimester: 0.9-1.2 U/kg/day
• Increase every 3 days by 2 units based on BGM
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Titrate insulin based on SMBG values:
• Fasting 60-90
• Pre-meal <95
• 2 hour post-meal <120
• Bedtime <120
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NICE Clinical Guideline 63 March 2008
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Blood Glucose
IV Fluid with or without Insulin
60-90 mg%
5% DNS – 100 ml/hr
90-120 mg%
NS or RL – 100 ml/hr
120-140 mg%
NS or RL – 100 ml/hr + 4 U R Insulin
140-180 mg%
NS or RL – 100 ml/hr + 6 U R Insulin
> 180 mg%
NS or RL – 100 ml/hr + 8 U R Insulin
In GDM Insulin requirement precipitously drops after placental expulsion
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Total 24 hour Insulin requirement in 60 kg 1st Trimester
60 x 0.7 = 42 units – 2/3 pre BF = 28 U, 1/3 = 14 U evening
Of the 28U – 2/3 NPH and 1/3 Regular = (19 + 9) in one inj.
Of the 14U – ½ Regular pre supper (7U) and ½ NPH at bed
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• Patient Resistance: (Psychological Insulin Resistance)
– Compliance issues, Needle phobia
– Fear of scarring, Fear of wrong dosage
– Financial, Difficulties in administration
• Physician Resistance (Clinician Inertia)
– Lack of resources and knowledge of Insulins
– Lack of time to plan/follow/educate intensive regimen
• Perceived and real adverse effects
– Weight gain; Hypoglycemia
– Optimal control requires multiple injections
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• Crowther et al – Multicenter – 1000 pts.
• Langer et all – 1100 GDM, 1100 Normal
• HAPO: 28,000 women
(Hyperglycemia And Adverse Pregnancy Outcome)
• ACHOIS
(Australian Carbohydrate Intolerance Study)
• MFMU
Maternal and Fetal Medicine Unit (NICHD) GDM Trial
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Int J Gynecology & Obstetrics. 2002,78, (1);69-77
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Langer et al - NEJM 2000: 1343-1138, Oct 19
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OAD in Pregnancy: The Other Alternative, O. Langer,
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OAD in Pregnancy: The Other Alternative, O. Langer,
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Glibenclamide – Class B, may be other SUs
Metformin – Class B ( No statins, No ACEi, ARB)
TZD – Not to be used, AGI – Class B
GLP-1, DPP IV Inhibitors – More studies needed
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Current Diabetes Reviews, 2009, 5, 252-258
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• New generation of oral hypoglycemic agents
glyburide does not cross the placenta and may
be used to replace insulin between 11-33 wks.
• Metformin can be used in P.C.O. patients during
the whole pregnancy. It showed that it reduces
miscarriages and the incidence of GDM
• TZDs not studied in pregnancy – not a choice
• AGIs – weak drugs – GI side effects -local action
• GLP-1 and DPP IV Inhibitors not studied yet
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Selective v/s Universal screening
Single 50g GCT v/s 100g OGTT
OADs – Poor Women’s Insulin
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Expert Rev. Endocrinol. Metab. 7(2), 165–167 (2012)
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Abstract
Diabetes in pregnancy is associated with risks to the woman and to the developing
fetus. Miscarriage, pre-eclampsia, preterm labour and congenital malformations in
fetus are more common in women with pre-existing diabetes. Insulin requirement
increases with each trimester of pregnancy in diabetic females. Treatment of
gestational diabetes consists of medical nutrition therapy but insulin treatment forms
the mainstay of the therapy. Monitoring glycemic control is essential in treatment of
gestational diabetes. HbA1c level is helpful to differentiate between a pre-GDM and
GDM. Majority of pregnant women with diabetes fail to achieve optimum glycemic
control, mostly the postprandial plasma glucose with conventional insulin. In them, the
best option is to administer ultra-short-acting analogs, insulin Lispro or insulin Aspart.
These analogs improve the postprandial glucose control during pregnancy in both type
1 and type 2 diabetes and are considered safe and effective.
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Supplement to JAPI • April 2011 • VOL. 59
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NICE Clinical Guideline 63 March 2008
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• Blood glucose levels monitored continuously
• Pre specified insulin dose is s/c delivered by pump
• This minimized timing and dosing errors.
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Blood glucose is assessed periodically
Insulin dose is calculated
CGMS is integrated with a delivery device – blue tooth
Hence round the clock blood glucose is controlled.
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When used within ADI
• Aspartame (NutraSweet)
– does not cross placenta;
– No adverse effects
• Sucralose (Equal) – acceptable
• Acesulfame K (Sunnet) – acceptable
• Saccharin (Nectra Sweet, Sweet Twin)
– Crosses placenta; not acceptable
• Cyclamate (Sucril) – not acceptable
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