Consequences of insulin resistance, PCOS, ovarian and pregnancy Flashcards

1
Q

What does maternal insulin resistance during pregnancy cause?

A

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.

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2
Q

What is macrosomia defined as?

A

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

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3
Q

What are the main predictors of macrosomia?

A

GDM, DM and BMI

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4
Q

What can normal pregnancy be defined as?

A

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

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5
Q

What does maternal hyperglycaemia lead to?

A

Higher foetal omental fat

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6
Q

What are the mechanisms behind gestational DM?

A

adipocytokines, fatty acid metabolic and hormonal effects

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7
Q

What is the most important pregnancy hormone?

A

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)

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8
Q

What other hormones are affected? and another factor

A

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

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9
Q

What do fatty acids do in pregnancy?

A

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

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10
Q

What suggests beta cell failure?

A

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

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11
Q

What happens to insulin secretion in GDM?

A

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

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12
Q

Why is the baby initially hyperinsulinaemic?

A

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.

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13
Q

How do triglycerides fit into GDM?

A

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

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14
Q

For fetal macrosomia is it just hyperglycaemia that matters?

A

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.

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15
Q

What happens to the fat ratio of GDM mothers

A

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

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16
Q

What is given for GDM?

A

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

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17
Q

What happens to the thermogenesis of GDM

A

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

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18
Q

What about TG in GDM?

A
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
19
Q

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

A

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

20
Q

What are the main biochemical findings?

A

Typical endocrine features are raised testosterone and LH

21
Q

What is PCOS associated with in the context of metabollic abnormalities

A

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

22
Q

What are the Rotterdam criteria for diagnosis?

A

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

23
Q

What occurs in both obese and lean women with PCOS

A

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

24
Q

What is the difference between ovulatory and anovulatory PCOS?

A

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

25
Q

What does the difference between anovulatory and ovulatory PCOS show?

A

Ovulation and insulin resistance are linked

26
Q

What happens in terms of follicle development

A

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.

27
Q

What evidence is there for insulin’s actions on LH

A

Insulin amplifies LH-induced progesterone production by granulosa cells

28
Q

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

A

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.

29
Q

What happens in follicular growth in PCOS?

A

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.

30
Q

What is PCOS highly associated with?

A

30-40% of PCOS have metabolic syndrome

31
Q

What is the prevalence of IGT and PCOS

A

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

32
Q

What is often linked to PCOS?

A

Gestational diabetes

33
Q

What proportion of PCOS go on to develop T2DM

A

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)

34
Q

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

A

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

35
Q

Which genes are likely to be involved in PCOS?

A

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

36
Q

What are problems with looking at familial PCOS?

A

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

37
Q

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

A

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.

38
Q

What currently does not occur for the diagnosis of PCOS

A

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

39
Q

How do you prevent those with PCOS getting t2DM

A

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.

40
Q

What is the role of metformin in PCOS?

A

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

41
Q

What was an interesting observation concerning offsprings future life?

A

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

42
Q

What is another way that contributes to insulin resistance?

A

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).

43
Q

What is insulin mediated glucose transport like?

A

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