Exam 4 - Gestational Diabetes

Question 1

What is gestational diabetes?

Answer 1

glucose intolerance with onset or first recognition during pregnancy
characterized by insufficient pancreatic B-cell function to meet the body’s insulin needs

Question 2

What is insulin resistance like before and after pregnancy for women who have gestational diabetes?

Answer 2

Insulin resistance exists before pregnancy in women with history of GDM but worsens during gestation

Most women with GDM go on to develop diabetes outside of pregnancy

Question 3

What might gestational diabetes be caused by?

Answer 3

insulin resistance (progression to Type 2 Diabetes, most common form)

autoimmune disease (progression to Type 1 Diabetes, less common)

monogenic causes (single gene defects, very rare)

Question 4

How has the incidence of gestational diabetes changed over the last 6-8 years?

Answer 4

it has doubled and is paralleling the obesity epidemic

Question 5

What are possible explanations for the rise in GDM?

Answer 5

increased screening (more women being screened, and undiagnosed diabetes is first found in pregnancy)

changes in diagnostic criteria (changed in the 1990s resulting in inclusion of more women)

Question 6

What was the mean GDM in 1991 and 2000?

Answer 6

1991 - 5.1%
2000 - 6.9%

Question 7

What is normal range for fasting glucose? What ranges determine hypoglycemia and hyperglycemia?

Answer 7

70-99 mg/100 ml, or 3.9-5.5 mmol/L

hypoglycemia: <2.7 mmol/L
hyperglycemia: >14 mmol/L

Question 8

What symptoms can happen with hyperglycemia, hypoglycemia, and severe hypoglycemia?

Answer 8

hyperglycemia: frequent urination, sugar in urine, frequent thirst and hunger, ketoacidosis, and coma

hypoglycemia: nervousness, sweating, intense hunger, trembling, weakness, irregular heart rate, and difficulty speaking

severe hypo: confusion, drowsiness, coma, and seizure

Question 9

What factors increase blood glucose to maintain homeostasis?

Answer 9

diet (absorption from digestive tract)

mobilization (hepatic glucose production through glycogenolysis and gluconeogenesis)

Question 10

What factors decrease blood glucose to maintain homeostasis?

Answer 10

utilization/storage (utilize for energy production or store through glycogenesis or triglycerides)

excretion (unusual, only excreted through urine and blood glucose is so high that it exceeds the reabsorptive capacity of the kidney tubules)

Question 11

What are the 3 basic functions of insulin in maintaining blood glucose homeostasis?

Answer 11

promote cellular uptake of glucose from the blood

promotes energy storage

promotes utilization for energy production

Question 12

What body structures are involved in insulin release?

Answer 12

pancreatic B-cells in the islets of Langerhans sense blood glucose levels

when blood glucose rises, the B-cells secrete insulin into the systemic circulation

Question 13

Describe the process of glucose stimulated insulin release (on a cellular level)

Answer 13

• glucose flows down its concentration gradient into the B-cell through a GLUT2 transporter
• phosphorylation of glucose causes a rise in the ATP:ADP ratio
• rise in ratio inactivates the potassium channels
• membrane polarizes, opening the voltage gated calcium channel
• calcium ions flow in
• rise in calcium triggers exocytosis of insulin from storage granules

Question 14

Describe the structure of insulin

Answer 14

peptide hormone, derived from proinsulin
C peptide is cleaved off during processing, and it remains with insulin in the storage granules and when it is released from the B-cells

Question 15

Where does most glucose uptake occur?

Answer 15

mostly in skeletal muscle, but adipose tissue is also important

Question 16

Where is GLUT4 when insulin levels are low?

Answer 16

stored in intracellular vesicles

Question 17

Describe the process of insulin stimulated glucose uptake (on a cellular level)

Answer 17

• GLUT-4 is stored in intracellular vesicles.
• Insulin binds to extracellular part of receptor in the plasma membrane, causing phosphorylation of the
  intracellular portion (a tyrosine kinase).
• activated tyrosine kinase phosphorylates insulin-receptor substrates (IRS)
• insulin-receptor substrates form complexes with docking proteins such as phosphoinositide-3 kinase (PI-3K) at its regulatory 85-kd subunit (p85)
• p85 binds to the catalytic subunit (p110)
• Activation of PI-3K phosphorylates membrane-bound phosphoinositol-3,4,5-phosphate (PIP3)
• PIP3 activates phosphoinositide-dependent kinases that activate protein kinase B (also known as Akt) and atypical forms of protein kinase C (PKC)
• GLUT-4 is translocated to cell membrane, where it can facilitate glucose uptake

Question 18

GLUT4 vs. GLUT2

Answer 18

GLUT2 is how glucose enters the pancreatic B-cells to trigger insulin release

GLUT4 is how glucose enters the skeletal muscle/adipose cells during insulin stimulated glucose uptake

Question 19

How does exercise affect glucose uptake?

Answer 19

Exercise stimulates glucose transport by pathways that are independent of phosphoinositide-3 kinase and that may involve 5’-AMP–activated kinase

Question 20

How is GDM diagnosed? Describe the test and normal vs abnormal responses?

Answer 20

oral glucose test in the 24-28th weeks of pregnancy
measures the level of glucose in the mother’s blood following the ingestion of a sugary drink containing 100 g of dextrose

In GDM patients, the blood glucose is significantly higher at 1, 2, and 3 hours than in the non-GDM patients. In normal results, the blood glucose should return to the fasting level after about 3 hours, but in GDM patients the glucose was still significantly elevated.

Question 21

How is euglycemia achieved in non-GDM pregnant women?

Answer 21

50% decrease in insulin-mediated glucose uptake byt a 200-250% increase in insulin secretion to maintain euglycemia

Question 22

What factors may cause insulin resistance and increased insulin secretion in a non-GDM pregnancy?

Answer 22

insulin resistance:
- increased maternal adiposity
- insulin desensitizing effects of placental hormones (like human placental lactogen and human placental growth hormone) which is likely because insulin resistance resolves rapidly after delivery

increased insulin secretion:
- pancreatic B-cells increase secretion to compensate for insulin resistance

Question 23

How does the rate of insulin secretion contribute to GDM?

Answer 23

rate of insulin secretion (insulin secretion rate, ISR) is significantly lower in women with GDM than women without

Question 24

Describe the study by Homko. What did it indicate?

Answer 24

Insulin Secretion Expmnt:
- set blood glucose at about 8.9 mmol/L (a hyperglycemic clamp)
- as blood glucose increased to the clamp level, so did the ISR
- when blood glucose was held constant, the ISR of women with GDM was lower than the controls

Insulin Resistance Expmnt:
- glucose infusion rate (GIR) was higher for controls than for GDM patients (indicating the glucose is not being taken up as fast)

Question 25

What is the proposed cellular mechanism for GDM?

Answer 25

• decreased insulin receptor pY (less tyrosine phosphorylation), decreased IRS-1 protein, more IRS degradation
• increased human placental growth hormone (hPGH) increases p85, inhibits PI3K association with IRS1 which reduces PIP3, Akt, aPKC, and GLUT4 transport to the membrane which decreases glucose uptake into cells. Leaves more glucose in the blood available to the fetus through the placenta.
• increased placental factors (TNF a/cytokines) increase PKC/JNK/NFkB which increases insulin receptor pS and IRS-1 pS; leads to decreased glucose uptake
• increased pregnancy-related adiposity decreases adiponectin and AMPK activity (also excess circulating nutrients) increase mTOR activity, which increases IR pS and IRS-1 pS; leads to decreased glucose uptake

Question 26

What are the risk factors for GDM and which are most modifiable?

Answer 26

modifiable: obesity, physical inactivity, diet high in saturated fat, smoking, and advanced maternal age

also, family history of diabetes

Question 27

Describe the Barbour study. What did it indicate?

Answer 27

In all races and birth cohort ranges, as maternal age increased there was an increased rate of GDM.

Question 28

What is the treatment for GDM?

Answer 28

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

Question 29

How does GDM affect offspring?

Answer 29

leads to fetal hyperglycemia, fetal pancreatic islet cell hypertrophy and B-cell hyperplasia, causing fetal hyperinsulinemia which leads to…

• neonatal hypoglycemia
• childhood obesity, glucose intolerance, and Type 2 Diabetes
• fetal substrate uptake (fat synthesis) that causes macrosomia, adiposity, and visceromegaly

Question 30

What is macrosomia?

Answer 30

abnormally large body

Question 31

What is visceromegaly?

Answer 31

enlarged internal organs

Question 32

Why does high fetal insulin cause abnormal growth?

Answer 32

fetal insulin acts as a fetal growth hormone