Gestational Diabetes Flashcards
1
Q
Gestational Diabetes Mellitus
A
- Glucose intolerance with onset of first recognition during pregnancy
- Characterized by insufficient pancreatic β-cell function to meet body’s insulin needs
- Insulin resistance exits before pregnancy in women with history of GDM, but worsens during gestation
- Most, but not all, woman with GDM go on to develop diabetes outside of pregnancy
2
Q
GDM Causes
A
- Insulin resistance- progression to type 2 diabetes
- Most common form
- Autoimmune disease-progression to type 1 diabetes
- Less common
- Monogenic causes- single gene defect
- Rare
3
Q
Incidence
A
- Incidence of GDM has doubled over the last 6-8 years
- It parallels the obesity epidemic
- Causes of rise
- Increased keening during pregnancy
- More women are being screened
- Undiagnosed diabetes is being diagnosed first during pregnancy
- Changes in diagnosis criteria
- Criteria in the 1990s resulting in inclusion of more women
- Increased keening during pregnancy
4
Q
Blood Glucose Homeostasis
A
- Maintained within a narrow range
- Normal range fasting- 70-100mg/100ml or 3.9-5.5mmol/L
- Insulin decreases blood glucose
5
Q
Hypoglycemia
A
- <2.7 mmol/L
- Nervousness
- Sweating
- Intense hunger
- Trembling
- Weakness
- Irregular heart rate
- Difficulty speaking
- <2.5 mmol/L
- Confusion
- Drowsiness
- Coma
- Seizure
6
Q
Hyperglycemia
A
- >14 mmol/L
- Frequent urination
- Sugar in urine
- Frequent thirst
- Frequent hunger
- Ketoacidosis
- Coma
7
Q
Factors that increase blood glucose
A
- Diet
- Glucose absorption from digestive tract
- Mobilization
- Hepatic glucose production
- Through glycogenolysis of stored glucose
- Through gluconeogenesis
- Hepatic glucose production
8
Q
Factors that decrease blood glucose
A
- Utilization or storage
- Transport of glucose into cells
- For utilization for energy production
- For storage
- As glycogen through glycogenesis
- As triglycerides
- Transport of glucose into cells
- Excretion
- Urinary excretion of glucose
- Occurs only abnormally, when blood glucose levels become so high it exceed the reabsorption capacity of kidney tubules during urine ormation
9
Q
Insulin and Blood Glucose
A
- Only hormone capable of lowering blood glucose
- Promotes cellular uptake of glucose from the blood
- Promotes energy storage
- Promotes utilization for energy production
10
Q
Glucose-stimulated insulin release
A
- Pancreatic β-cells in Islets Langerhans sense blood glucose levels
- When blood glucose rises, β-cells secrete insulin into systemic circulation
- Insulin secretion by β-cells triggered by rising blood glucose levels
- Starting with the uptake of glucose by the GLUT2 transporter, the phosphorylation of glucose causes a rise in the ATP:ADP ratio
- This rise inactivates the K+ channel that depolarizes the membrane, causing Ca2+ channels to open up allowing Ca2+ ions to flow inward
- The ensuing rise in levels of Ca2+ leads to exocytosis of insulin from storage granules
11
Q
Insulin Structure
A
- Insulin is a peptide hormone derived from proinsulin
- C-peptide is cleaved off during processing and packaged along with insulin in storage granules
- C-peptide is released along with insulin form pancreatic β-cells
12
Q
Insulin-stimulated Glucose Uptake
A
- Skeletal muscle is the principal site of whole-body glucose disposal
- Less glucose is transported into adipose tissue than into skeletal muscle but adipose is still an important tissue for glucose uptake
- GLUT-4 is the main insulin-responsive glucose transported
- It is expressed in skeletal muscle and adipose
- When insulin level are low, GLUT-4 is stored in intracellular vesicles
13
Q
Steps of glucose uptake
A
- GLUT-4 is stored in intracellular vesicles.
- Insulin binds to the extracellular domain of its receptor in the plasma membrane, resulting in phosphorylation of the intracellular portion of the receptor (a tyr kinase).
- The activated tyr kinase phosphorylates insulin-receptor substrates such as the IRS molecules (IRS-1, IRS-2, IRS-3 and IRS-4).
- These insulin-receptor substrates form complexes with docking proteins such as phosphoinositide-3 kinase (PI-3K) at its regulatory 85-kd subunit (p85) by means of SH2 (Scr homology region 2) domains.
- p85 is then constitutively bound to the catalytic subunit (p110).
- Activation of PI-3K is a major pathway in the mediation of insulin stimulated glucose transport and metabolism.
- Exercise stimulates glucose transport by pathways that are independent of phosphoinositide-3 kinase and that may involve 5’-AMP–activated kinase.
14
Q
Diagnosis of GDM
A
- Screening conducted on otherwise healthy pregnant women
- Usually conducted in 24-28 weeks of pregnancy
- End of second trimester
- Measures levels of sugar in the mother’s blood following ingestion of sugary drink- 100g dextrose
- Abnormal glucose levels may indicate gestational diabetes
15
Q
Oral Glucose Tolerance Test
A
- No significant difference between groups for basal blood glucose concentration
- Blood glucose was significantly higher in GDM group than in controls at 1, 2, and 3 hours indicating inadequate insulin action
- Postpartum blood glucose in GDM group was similar to pregnant controls- inadequate action resolves after delivery of baby
16
Q
Normal glucose regulation during prenancy
A
- Normal pregnancy is characterized by a 50% decrease in insulin-mediated glucose uptake and 200-250% increase in insulin secretion to maintain euglycemia (normal blood glucose)
- Progressive insulin resistance begins near mid-pregnancy and progresses through third trimester to levels that approximate insulin resistance seen in type 2 diabetes
- Pancreatic β-cells normally increase insulin secretion to compensate for insulin resistance of pregnancy
- Changes in circulating glucose levels over course of pregnancy are quite small compared with large changes in insulin sensitivity
17
Q
Causes of Insulin Resistance in Normal Pregnancy
A
- Increased maternal adiposity
- Insulin-desensitizing effects of placental hormones
- Human placental lactogen-AKA human chorionic somatomammotopin
- Rapid abatement of insulin resistance after delivery suggests major contribution from placental hormones
18
Q
Abnormal Glucose Regulation with GDM
A
- Insulin secretion is inadequate to compensate for the insulin resistance, leading to hyperglycemia that is detected by routine glucose screening in pregnancy
- Gestational diabetes results in inability of pancreatic β-cells to make enough insulin to respond to tissue insulin demand
- Defective insulin secretion in women with GDM
- Defective insulin action – in all women but is even worse in GDM
19
Q
Decreases Insulin Secretion Test
A
- Both groups had blood glucose levels set at ~8.9 mmol/L during experiment- hyperglycemic clamp
- As blood glucose increased, so did insulin secretory rate (ISR) in both pregnancy and postpartum women
- ISRs are higher during pregnancy than after deliver indicating inulin resistance during pregnancy
- During last 3 hours of study, ISR was 19% lower in pregnant women with GDM indicating reduced ability to secrete insulin in response to hyperglycemia
20
Q
Insulin Resitance Test
A
- Glucose infusion rate (GIR) is higher in pregnant controls than in women with GDM
- Need to add glucose at faster rate in controls than GDM group to replace glucose that is being taken up by muscle and adipose
- 30-40% lower GIR in women with GDM indicates less glucose uptake and therefore more insulin resistance
- Women who had GDM are still more insulin resistant postpartum
21
Q
Proposed Mechanism of Insulin Resitance Both
A
- Pathway for inulin stimulation o glucose transport in muscle incolces activation of insulin receptor which phosphorylates IRS-1 and IRS-2 on tyrosine residues
- IRS-1 recruit p85α regulatory subunit of PI#-Kinase resulting in phosphorylation of membrane bound phospholipids at 3’ poition (PIP3)
- Production of PIP3 is required for activation of Akt and signaling for GLUT4 translocation
- Similaritie between non-pregnant and pregnant subjects
- Some amount of IR protein
- Same amount of GLUT-4 intracellular stores
- Differences between non-pregnant and pregnant subjects
- The degree of insulin resiance is more pronounced with GDM
22
Q
Proposed mechanism for insulin resistance without GDM
A
- Decreased tyr phosphorylation
- Decreased IRS-1 protein increased degradation
- Increased TNFα/cytokines act via increased PKC/JNK/NFκB serine kinase activity to increase IR serine phosphorylation
- Decreases adiponectin acts via decreased AMPK activity to increase mTOR activity and increase IR and IRS-1 serine phosphorylation
- Increased placental hormones increase p85 which inhibits PI3K activity
- Excess p85 association o PI3k with IRS-1 thereby reduces PIP3 production
23
Q
Proposed Mechanism of Insulin Resitance with GDM
A
- Further decrease in IR tyr phosphorylation
- Further decrease in IRS-1 protein and futher degradation
- Further decrease in adiponectin
- Excess nutrients (glucose, amino acids), which further stimulates mTOR acticity
- Increased basal 970S6K phosphorylation, which in turn contributes to increased IR and IRS-1 phosphorylation
24
Q
Risk Factors for GDM
A
- Obesity
- Physical inactivity
- Diet high in saturated fat
- Smocking
- Advanced maternal age
- worse in Asians and hispanics
- Family history of diabetes
25
Q
How obesity increases risk of GDM
A
- Many biochemical mediators of insulin resistance that occur in obesity have been identified in studies of women with GDM
- Increased circulating levels of leptin
- Inflammatory markers TNFα and C-reactive protein
- Decreased levels of adiponectin
- Increased fat in liver and muscle
- Abnormal subcellular localization of GLUT-4 transporters
26
Q
Treatment of GDM
A
- Low-carb diet
- Exercise
- Maintain healthy pregnancy weight
- Monitor glucose levels
- If necessary, take daily insulin injections
27
Q
Risk of GDM to offspring
A
- Exposure to excess glucose during pregnancy causes permanent fetal changes that extend though childhood and adulthood
- Greater birth weight (macrosomia)
- Obesity
- Increased risk of type 2 diabetes
28
Q
Risk to offspring mechanism
A
Maternal hyperglycemia -> fetal hyperglycemia -> fetal pancreatic islet cell hypertrophy and β-cell hyperplasia -> fetal hyperinsulinemia
- Fetal hyperinsulinemia leads to
- Neonatal hypoglycemia
- Fetal substrate uptake
- Leads to marosomia, adiposity, and visceromegaly
- Childhood and adult risk factors
- Glucose can cross the placenta but insulin cannot
- Fetal insulin acts as a fetal growth hormone
29
Q
Obesity and Diabetes Epidemic
A
- Insulin resistance, which develop as a result of both genetic and environmental factors, is associated with obesity
- Obesity is the most important risk factor for development of type 2 diabetes in youth
- Obesity has led to a dramatic increase in type 3 diabetes among children and adolescent over the past 2 decades
