Consequences of insulin resistance, PCOS, ovarian and pregnancy

Question 1

What does maternal insulin resistance during pregnancy cause?

Answer 1

Maternal insulin resistance and obesity leads to foetal MACROSOMIA and large for gestational size. Larger babies more likely to injure themselves during birth. Increased risk of morbidity such as 3rd degree tear, obstructed labour, Caesarian section.

Question 2

What is macrosomia defined as?

Answer 2

Generally greater than 4 kg ( absolute) or centile birthweight (90%

Question 3

What are the main predictors of macrosomia?

Answer 3

GDM, DM and BMI

Question 4

What can normal pregnancy be defined as?

Answer 4

A profoundly insulin resistant state (as measured by euglycaemic hyperinsulinaemic state). this can precipitate insulin secretion deficits.

Question 5

What does maternal hyperglycaemia lead to?

Answer 5

Higher foetal omental fat

Question 6

What are the mechanisms behind gestational DM?

Answer 6

adipocytokines, fatty acid metabolic and hormonal effects

Question 7

What is the most important pregnancy hormone?

Answer 7

Human placental lactogen (v. important high secretion – but poorly understood seems to be imp in driving insulin resistance in mothers which allows calories to be given to the fetus)

Question 8

What other hormones are affected? and another factor

Answer 8

In gestational diabetes, you get low adiponectin, not low Leptin and certain fatty acids. Beta cell failure

Question 9

What do fatty acids do in pregnancy?

Answer 9

Free fatty acids increase insulin resistance in pregnancy: glucose tolerant women underwent euglycemic hyperinsulinemic clamp and received either lipid and heparin or saline infusions. Rates of total glucose disposal and carb and FO oxidation was measured. This showed that elevating FFA during pregnancy inhibits total body glucose uptake and oxidation. Elvated plasma FFA can contribute to peripheral insulin resistance seen in late pregnancy

Question 10

What suggests beta cell failure?

Answer 10

The increased pro-insulin to insulin ratio, which predicts GDM

Question 11

What happens to insulin secretion in GDM?

Answer 11

1996) In ladies with GDM they have lost their 1st phase insulin secretion but make more 2nd phase – but the failed 1st phase is what is crutial. After 3 hours they may have normal glucoe levels but they still had higher levels of glucose to start with

Question 12

Why is the baby initially hyperinsulinaemic?

Answer 12

PEDERSON: glucose easily crosses the placenta but then can only get into adipocytes in the presence of insulin. The hyper glycaemia stimulates the fetal pancreas causing hyperinsulinaemia. After birth the baby keeps making insulin at the same rate leading to hyperglycaemia and feeding through a also gastric tube for a couple days.

Question 13

How do triglycerides fit into GDM?

Answer 13

Triglyceride is a good predictor of macrosomia but it is not used clinically (does not cross placenta but can when hydrolysed to NEFAs). Amino acids can easily cross the placenta. Babies can grow not only by inc glucose but due to increase AA and TG/NEFA in the maternal circulation. Amino acid concs are inc when there is less insulin so in diabetes you get high gluc and high AA. AA are potent insulin secretogoes just like glucose. NEFA need to be broken down by placental lipase to become FA to pass through theplacenta and in excess can contribute to the fuel uptake

Question 14

For fetal macrosomia is it just hyperglycaemia that matters?

Answer 14

HAPO study: associations with maternal BMI (controlled for confounders) looked at highest BMI and lowest. saw that obese mothers have higher birthweight babies, higher % fat in baby, inc risk of C section – so its not just sugar its obesity as well that matters.

Question 15

What happens to the fat ratio of GDM mothers

Answer 15

Women with GDM were shown to have a lower polyunsaturated:saturated fat ratio

Question 16

What is given for GDM?

Answer 16

Metformin is used in the treatment as it is just as effective often (some patients needed insulin) and reduced the risk of hypos (i.e. safer). The women on metformin also tended to have better weight lost post partum and the ladies prefered the treatment

Question 17

What happens to the thermogenesis of GDM

Answer 17

Lean body mass is positively proportional to resting energy expenditure, GDM have reduced post prandial thermogenesis. Women before and after GDM have reduced insulin sensitive and PPT
22% of the extra energy required for pregnancy
This may form the benefit of the predisposition to NIDDM as it helps conserve energy

Question 18

What about TG in GDM?

Answer 18

Maternal Tg (as NEFA) may be a source of energy through the haemochorial placenta
The insulin resistance of normal pregnancy and the increased [Tg] can increase energy delivery to the fetus
The higher [Tg] in the diabetic mother is associated with fetal weight gain sufficient to increase the chances of survival

Question 19

Describe the main features of PCOS. Characterised by, prevalence, onset

Answer 19

Characterised by anovulation with clinical (hirsutism/acne) and/or biochemical evidence of androgen excess
Typically presents during adolescence
Affects >5% women of reproductive age
Commonest cause of menstrual dysfunction (>80% cases of anovulatory infertility) and hirsutism

Question 20

What are the main biochemical findings?

Answer 20

Typical endocrine features are raised testosterone and LH

Question 21

What is PCOS associated with in the context of metabollic abnormalities

Answer 21

Also associated with metabolic abnormalities and increased risk of type 2 diabetes

Question 22

What are the Rotterdam criteria for diagnosis?

Answer 22

Diagnosis of PCOS. oligo-and or anovulation clinical and or biochem signs of hyperandrogenism PCO (2/3)

Question 23

What occurs in both obese and lean women with PCOS

Answer 23

Insulin sensitivity is reduced, obesity amplifies insulin resistance in PCOS ladies

Question 24

What is the difference between ovulatory and anovulatory PCOS?

Answer 24

Ovulatory you have high LH and testosterone but you are still insulin sensitive.
Anovulatory you have high LH and testosterone BUT INSULIN INSENSITIVE

Question 25

What does the difference between anovulatory and ovulatory PCOS show?

Answer 25

Ovulation and insulin resistance are linked

Question 26

What happens in terms of follicle development

Answer 26

There is arrested antral follicle development, LH too high and FSH too low. IN PCOS women, their follicles stop growing at 5-8mm so don’t undergo the final stage of maturation before ovulation.

Question 27

What evidence is there for insulin’s actions on LH

Answer 27

Insulin amplifies LH-induced progesterone production by granulosa cells

Question 28

What is important in terms of follicle growth and signalling pathways?

Answer 28

In a normal cycle your follicles make a certain amount of camp which increases due to FSH and the follicle grows – at 10mm when the follicle is dominant it presents LH receptors in its granulosa cells so now FSH and LH can act on these cells, when the LH surger occurs it causes increased size (20mm) and increased cAMP which is called terminal differentiation and this causes the follicle to stop growing as it is now differentiating.

Question 29

What happens in follicular growth in PCOS?

Answer 29

If you have LH and insulin in the first stage (seen in PCOS) this causes very high cAMP levels which causes the follicles to terminally differentiate too early causing premature arrest of the follicle before the LH surge. so the follicle stops growing but it is still able to make progesterone and estradiol which suppresses FSH. You can give FSH to patients to help their healthy follicles grow.

Question 30

What is PCOS highly associated with?

Answer 30

30-40% of PCOS have metabolic syndrome

Question 31

What is the prevalence of IGT and PCOS

Answer 31

Prevalence of IGT and diabetes in young women with PCOS: in people with low BMI they have 7% prevalence of IGT
in larger BMI populations theyhave upto 35% IGT and 10% diabetes Looking at the same cohort 2-3 years later saw that inc incidence of IGT and DM in them

Question 32

What is often linked to PCOS?

Answer 32

Gestational diabetes

Question 33

What proportion of PCOS go on to develop T2DM

Answer 33

People with PCOS had higher chance of t2dm when adjusted for BMI (not significant) OR 2.2 (0.9 – 5.2) If obese subjects with PCOS was included OR: 2.8 (1.5-5.5)

Question 34

What does PCOS have a slight degree of those who are affected?

Answer 34

Evidence for genetic basis of PCOS: familial clusting, concordance > in identical than non identical twins, heritability of endocrine and metabolic features, mode of inheritance uncertain. complex endocrine disorder like T2DM likely to be oligogenic or polygenic

Question 35

Which genes are likely to be involved in PCOS?

Answer 35

steroid hormone production and metabolism metabolic: insulin secretion and action - obesity Insulin resistance: IR, PPARy Obesity: FTO Androgen action androgen receptor Ovarian follicle development Follistatin: FBN3

Question 36

What are problems with looking at familial PCOS?

Answer 36

Familial PCOS:
hard to do genetic studies due to the fact it is only in women of reproductive age, cant tell in older women if they had it – no male phenotype, large affected families uncommon, heterogeneity of phenotype and disagreement about diagnostic criteria

Question 37

What did they discover looking at the sisters of those with PCOS?

Answer 37

Affected sister pairs with PCO: looked at women with PCO on US if positive = proband, then looked at their sisters they saw what symptoms the PCO proband had – oligomen, hirsutiism, achne, alopecia they then compared this to the sisters of the proband They saw that the serum test in affected sisters was the same as in proband but unaffected sisters had lower testosterone also saw that insulin levels were similar in affected sisters and proband but lower in unaffected sisters.

Question 38

What currently does not occur for the diagnosis of PCOS

Answer 38

No test of insulin resistance needed to make PCOS diagnosis or for treatment selction

Question 39

How do you prevent those with PCOS getting t2DM

Answer 39

Prevention of T2D in PCOS: make an early diagnosis lean women with PCOS should not get fat obese women with PCOS should be adviced on diet and lifestyle factors those at high risk may need medication. Effect of diet/lifestyle on insulin and fertility in obese women with PCOS: showed a 5% weigh reduction is associated with improvements in metabolic indicies such as fasting insulin.

Question 40

What is the role of metformin in PCOS?

Answer 40

Small number of studies conducted – significant but very modest inc in ovulation rate q benfit thought to be over estimated Not useful for infertility or menstrual disturbances, or effective treatment of hirsutism but does have a place in management of women at high risk of developing diabetes

Question 41

What was an interesting observation concerning offsprings future life?

Answer 41

Wu et al found an increased risk of cardiovascular disease in offsprings of father’s with DM

Question 42

What is another way that contributes to insulin resistance?

Answer 42

The ability of insulin to suppress whole-body lipolysis is also reduced during late pregnancy (3), and this is further reduced in GDM subjects (4), contributing to greater postprandial increases in FFAs, increased hepatic glucose production, and severe insulin resistance (2,5–7).

Question 43

What is insulin mediated glucose transport like?

Answer 43

Freshly isolated skeletal muscle fibers were obtained from obese GDM women during elective cesarean delivery and compared with muscle fibers from obese pregnant subjects with normal glucose tolerance matched for BMI, age, and ethnicity (90% Caucasian). We demonstrated directly in skeletal muscle fibers that pregnancy alone was associated with a marked reduction (40%) in insulin-stimulated glucose transport, and this impairment in insulin action was significantly worse in GDM subjects (65% reduced) compared with obese pregnant subjects