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Reproductive physiology > Gestational Diabetes > Flashcards

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
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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
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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
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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
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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
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6
Q

Hyperglycemia

A
  • >14 mmol/L
    • Frequent urination
    • Sugar in urine
    • Frequent thirst
    • Frequent hunger
    • Ketoacidosis
    • Coma
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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
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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
  • 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
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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
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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
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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
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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
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13
Q

Steps of glucose uptake

A
  1. GLUT-4 is stored in intracellular vesicles.
  2. 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).
  3. The activated tyr kinase phosphorylates insulin-receptor substrates such as the IRS molecules (IRS-1, IRS-2, IRS-3 and IRS-4).
  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.
  5. p85 is then constitutively bound to the catalytic subunit (p110).
  6. Activation of PI-3K is a major pathway in the mediation of insulin stimulated glucose transport and metabolism.
  7. Exercise stimulates glucose transport by pathways that are independent of phosphoinositide-3 kinase and that may involve 5’-AMP–activated kinase.
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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
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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
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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
  1. Pathway for inulin stimulation o glucose transport in muscle incolces activation of insulin receptor which phosphorylates IRS-1 and IRS-2 on tyrosine residues
  2. IRS-1 recruit p85α regulatory subunit of PI#-Kinase resulting in phosphorylation of membrane bound phospholipids at 3’ poition (PIP3)
  3. Production of PIP3 is required for activation of Akt and signaling for GLUT4 translocation
  4. Similaritie between non-pregnant and pregnant subjects
    1. Some amount of IR protein
    2. Same amount of GLUT-4 intracellular stores
  5. Differences between non-pregnant and pregnant subjects
    1. The degree of insulin resiance is more pronounced with GDM
22
Q

Proposed mechanism for insulin resistance without GDM

A
  1. Decreased tyr phosphorylation
  2. Decreased IRS-1 protein increased degradation
  3. Increased TNFα/cytokines act via increased PKC/JNK/NFκB serine kinase activity to increase IR serine phosphorylation
  4. Decreases adiponectin acts via decreased AMPK activity to increase mTOR activity and increase IR and IRS-1 serine phosphorylation
  5. Increased placental hormones increase p85 which inhibits PI3K activity
    1. Excess p85 association o PI3k with IRS-1 thereby reduces PIP3 production
23
Q

Proposed Mechanism of Insulin Resitance with GDM

A
  1. Further decrease in IR tyr phosphorylation
  2. Further decrease in IRS-1 protein and futher degradation
  3. Further decrease in adiponectin
  4. Excess nutrients (glucose, amino acids), which further stimulates mTOR acticity
  5. 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

Reproductive physiology (8 decks)

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