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REPRO > 4.22 - Gestational diabetes > Flashcards

4.22 - Gestational diabetes Flashcards

1
Q

Describe gestational diabetes mellitus (GDM). Indicate when it is diagnosed, what
causes it, and what happens after pregnancy.

A
  • glucose intolerance with onset or first recognition during pregnancy
  • characterized by insufficient pancreatic B-cell function to meet body’s insulin needs
    -insulin resistance exists before pregnancy in females with history of GDM but worsens during gestation
    -most, but not all, females with GDM go on to develop GDM outside of pregnancy
    –
    may be caused by:
    -insulin resistance, progression to type 2 diabetes (most common)
    -autoimmune disease (less common)
    -monogenic causes (single gene defects (rare)
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2
Q

Describe the incidence of GDM in the United States from 1990-2010.

A

doubled in the last 6-8years and is paralleling obesity epidemic

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3
Q

Explain possible explanations for the observed rise in GDM.

A
  • increased screening during pregnancy
    -more females being screened
    -undiagnosed diabetes is being diagnosed first in pregnancy
    -changes in diagnostic criteria
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4
Q

Explain how the Ferrara (2007) paper supports the increasing prevalence of GDM

A
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5
Q

Describe the normal limits for fasting blood glucose and describe the consequences of
hypo- and hyper-glycemia

A

hypoglycemia
<2.5 mmol/L: confusion, drowsiness, coma, seizure
<2.7 mmol/L: nervousness, sweating, intense hunger, trembling, weakness, irregular HR, difficulty speaking
–
hyperglycemia
> 14 mmol/L: frequent urination, sugar in urine, frequent thirst, frequent hunger, ketoacidosis, coma

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6
Q

Explain how blood glucose is maintained within narrow limits. Include mention of
factors that increase and decrease blood glucose

A

factors that increase blood glucose:
-diet, glucose absorption from digestive tract
-mobilization, hepatic glucose production: through glycogenolysis of stored glycogen, through gluconeogenesis
-
factors that decrease blood glucose:
-utilization or storage, transport of glucose into cells: for utilization for energy production
-for storage as glycogen through glycogenesis, as triglycerides
-excretion (unusual): urinary excretion of glucose (occurs only abnorally, when blood glucose levels become so high it exceeds the reabsorptive capacity of kidney tubules during urine formation)
–
role of insulin in glucose homeostasis: decreases blood glucose, 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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7
Q

Distinguish between pathways that mobilize, use or store blood glucose.

A

mobilization - hepatic glucose production
utilization - transport glucose into cells
storage - as glycogen through glycogenesis, or as triglycerides

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8
Q

Explain the role of insulin in glucose homeostasis. Indicate overall pathways stimulated
by insulin.

A

insulin decreases blood glucose
-only hormone capable of lowering blood glucose
-promotes energy storage
-promotes utilization for energy production

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9
Q

Explain role of pancreatic b-cells in responding to changes in blood glucose with changes
in insulin secretion.

A
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10
Q

Describe the sequence of events that starts with the rise in blood glucose and ends with
the release of insulin from pancreatic beta-cells. Include mention of GLUT2, glucokinase,
ATP synthesis, the ATP/ADP ratio, the ATP-sensitive potassium channel, membrane
depolarization, the voltage-gated calcium channel and the release of insulin from
storage granules

A

rise in blood glucose -> glucose follows concentration gradient + enters pancreatic B-cell via the GLUT2 transporter –> phosphorylation of glucose causes rise in the ATP-ADP ratio –> this rise inactivates (closes) the potassium channel that depolarizes the membrane –> this causes the calcium channel to open and allows calcium ions to flow inward –> rise in calcium levels leads to exocytosis of insulin from storage granules

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11
Q

Explain the significance of C-peptide

A
  • insulin is a peptide hormone derived from proinsulin
    -C-petide is cleaved off during processing and packaged along with insulin in storage granules
    -C-peptide is released along with insulin from pancreatic B-cells
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12
Q

Describe two key tissues involved in insulin-stimulated glucose uptake

A

skeletal muscle and adipose tissue
-skeletal muscle is principal site of whole-body glucose disposal (uptake)
-less glucose is transported into adipose tissue than into skeletal muscle but adipose is still important

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13
Q

Explain the role of GLUT-4 in glucose transport.

A

*main insulin-responsive glucose transporter
-it is expressed in skeletal muscle and adipose tissue
-when insulin levels are low, GLUT-4 is stored in intracellular vesicles

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14
Q

Describe the sequence of events that starts with the rise in blood insulin and ends with
the uptake of glucose by muscle and adipose cells. Include mention of the insulin
receptor, tyrosine kinase, IRS, p85, p110, PIP3, phosphoinositide-dependent kinases (PI-
3K), protein kinase B (Akt), atypical protein kinase C (aPKC), and GLUT-4 translocation to
the cell membrane.

A
  1. Glut-4 is stored in intracellular vesicles
  2. Insulin binds to the extracellular domain or its receptor in the plasma membrane, resulting in phosphorylation of the intracellular portion of the receptor (a tyrosine kinase)
  3. The activated tyrosine kinase phosphorylates insulin-receptor substrates (IRS)
  4. The IRS forms complexes with docking proteins such as phosphoinositide-3 kinase (PI-3K) at its regulatory 85-kd subunit (p85)
  5. p85 is then consititutively 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
    –> PI-3K phosphorylates PIP3, PIP3 activates phosphoinositide-dependent kinases that participate in the activation of PKB (akt) and atypical forms of PKC
  7. GLUT-4 is translocated to cell membrane, where it can facilitate glucose uptake
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15
Q

Indicate the effect of exercise on glucose uptake (via 5’-AMP-activated kinase; AMPK).

A

exercise stimulates glucose transport by pathways that are independent of PI-3K and that may involve 5’-AMP-activated kinase (AMPK)

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16
Q

______ cells are stimulated by an increase in blood _______ to release _________

A

pancreatic beta; glucose; insulin

17
Q

glucose enters _______ cells via _______ in response to _________
2 answers

A

adipose; GLUT4, elevated insulin
skeletal muscle; GLUT-2, a concentration gradient

18
Q

Explain how GDM is diagnosed. Include a description of the oral glucose tolerance test
and distinguish between normal and GDM responses.

A

oral glucose tolerance test
-screening conducted on otherwise healthy pregnant females
-usually conducted in the 24th to 28th weeks of pregnancy (end of 2nd trimester)
-measures levels of sugar (glucose) in the mother’s blood following ingestion of sugary drink (100g dextrose)
abnormal glucose levels may indicate gestational diabetes

19
Q

Explain how euglycemia is achieved in a normal (non-GDM) pregnant mother through a
combination of insulin resistance and increased insulin secretion.

A

-normal pregnancy is characterized by 50% decrease in insulin-mediated glucose uptake (i.e. insulin resistance) and 200-250% increase in insulin secretion to maintain euglycemia (normal blood glucose levels) in the pregnant mother
–> progressive insulin resistance begins near mid-pregnancy and progresses through third trimester to levels that approximate insulin resistance seen in type 2 diabetes
–> pancreatic B-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

20
Q

Name two factors that may cause insulin resistance and increased insulin secretion in a normal (non-GDM) pregnancy.

A

-increased maternal adiposity
-insulin-desensitizing effects of placental hormones
–rapid abatement of insulin resistance after delivery suggests major contribution from placental hormones

21
Q

blood glucose remains elevated longer in females with GDM, indicating a problem with:

A

either insulin resistance or secretion

22
Q

If we set blood glucose at a high level, insulin secretion should:

A

increase

23
Q

Explain how inadequate insulin secretion in females with GDM causes hyperglycemia.

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 from inability of pancreatic B-cells to make enough insulin to respond to tissue insulin demand
–>defective insulin secretion (in females with GD) as well as defective insulin action (i.e. resistance, in all pregnant females but even worse with GDM)

24
Q

A higher glucose infusion rate (GIR) indicates:

A

faster glucose uptake

25
Q

Faster glucose uptake indicates:

A

less insulin resistance

26
Q

Explain how the study by Homko and co-workers (2001) provides evidence for
decreased insulin secretion and increased insulin resistance in females with GDM.
Include mention of the significance of hyperglycemic clamp, C-peptide kinetics, the
insulin secretory rate, and the glucose infusion rate.

A

Both groups (pregnant, glucose tolerant and GDM) had blood glucose levels set at ~8.9 mmol/L during experiment (hyperglycemic clamp)
-as blood glucose increased so did insulin secretory rate in both pregnant and postpartum females
-*ISRs are higher during pregnancy than after delivery (indicating insulin resistance during pregnancy)
-during the last 3 hours of the study the insulin secretory rate was ~ 19% lower in pregnant females with GDM
*insulin secretory rate (ISR) is estimated from C-peptide kinetics

27
Q

What does it mean if females with GDM have a smaller increase in blood insulin after having their blood glucose set at 9 mmol/L?

A

a problem with insulin secretion

28
Q

similarities and differences between non-pregnant and pregnant patients (with or without GDM)

A

similarities:
-same amount of IR protein
-same amount of glut4 intracellular stores
differences:
-pregnant pts (with or without GDM) are insulin-resistant and have impaired GU

29
Q

Proposed cellular mechanism for insulin resistance in pregnancy (w/o GDM)

A
  1. Decreased IR pY (less tyrosine phosphorylation)
  2. Decreased IRS-1 protein (increased degradation)
  3. Increased human placental growth hormone hPGH increases amount of p85, which in turn inhibits PI3K activity (excess p85 blocks association of PI3K (p85-p110) with IRS-1, thereby reducing PIP3 production); result is reduced glucose transport into skeletal muscle, which makes glucose more available to fetus
  4. Increased placental factors (TNFa/cytokines) act via increased PKC/JNK/NKkB serine kinase activity to increase IR pS and IRS-1 pS; leads to decreased glucose uptake
  5. Decreased adiponectin (as a result of increased pregnancy-related adiposity) acts via decreased AMPK activity to permit increased MTOR activity, which increases IR pS and IRS-1 pS; leads to decreased glucose uptake
30
Q

Describe the proposed cellular mechanisms for insulin resistance with pregnancy and
GDM. Include mention of pY, pS, IRS, PI 3-kinase (p85-p110), PIP3, Akt, aPKC, GLUT-4,
hPGH, p85 excess, placental factors (cytokines, TNF-a), pregnancy-associated adiposity
(decreased adiponectin), mTOR, AMPK, and excess nutrients (with GDM)

A
  1. Further decrease in IR pY
  2. Further decrease in IRS-1 protein (further increase in degredation)
  3. Further decrease in adiponectin (as a result of increased adiposity), which acts via decreased AMPK activity to permit increased MTOR activity, which increases IR pS and IRS-1 pS; further decreases GU
  4. Excess circulating nutrients (glucose, amino acids) stimulate mTOR activity, which further decreases GU
31
Q

phosphorylation of tyrosine residues on the insulin receptor will increase skeletal muscle glucose __________

A

uptake

32
Q

Pregnancy is associated with increased adiposity, which ___________ MTOR activity

A

-AMPK senses AMP-ATP ratio
-when energy in cell is high (as with adiposity), low AMP relative to ATP inhibits AMPK activity
-AMPK inhibition permits a rise in mTOR
-stimulation of mTOR promotes serine phosphorylation (pS) in skeletal muscle, which in turn will decrease glucose uptake
-inhibition of mTOR reduces cell growth, etc.

33
Q

If mTOR activity increases with an increase in pregnancy-associated adiposity, then glucose uptake will _______

A

mTOR increases IR pS and IRS-1 pS, which leads to decreased GU

34
Q

List the risk factors for GDM and indicate which are modifiable

A

modifiable:
obesity
physical inactivity
diet high in saturated fat
smoking
advanced maternal age
not:
family history of diabetes

35
Q

Explain how Barbour and co-workers (2007) data show that advanced maternal age
increases the risk for GDM.

A
36
Q

Describe the treatment for GDM

A

-eat low-carb diet
-exercise
-maintain healthy pregnancy weight
-monitor glucose levels
-if necessary, take daily insulin injections

37
Q

Describe how GDM affects offspring and explain how maternal hyperglycemia can result
in fetal hyperinsulemia, increased fetal fat synthesis, neonatal hypoglycemia, and
metabolic imprinting.

A
38
Q

Define macrosomia and visceromegaly

A

macrosomia - abnormally large body
visceromegaly - enlarged internal organs

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