Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 179–193

Contents lists available at SciVerse ScienceDirect

Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

Metabolic complications of obesity

Dr. Sue D. Pedersen MD, FRCPC, Specialist in Endocrinology &
Metabolism *
C-ENDO Endocrinology Centre Calgary, Suite 240, 1016 – 68th Avenue SW, Calgary, AB T2V 4J2, Canada

Keywords:
Obesity is a risk factor for several metabolic complications, with
obesity insulin resistance being the common denominator in these con-
type 2 diabetes mellitus ditions. Impaired blood glucose regulation is one of the most
prediabetic state important of these complications, and includes type 2 diabetes
gestational diabetes mellitus (T2DM), prediabetes, and gestational diabetes. Metabolic
metabolic syndrome X syndrome describes a constellation of features including insulin
polycystic ovary syndrome resistance, hypertension, dyslipidemia, and abdominal obesity.
Polycystic ovary syndrome is a condition characterized by ovula-
tory dysfunction and clinical evidence of hyperandrogenism. As
many of these complications can go unnoticed for years without
overt clinical complications, awareness of both patients and health
care professionals is essential such that appropriate screening and
diagnostic strategies can be undertaken. Aggressive management
strategies of diabetic and prediabetic states are essential for pre-
vention of complications over time. Strategies for identification of
vascular risk factors must be implemented such that appropriate
risk reduction strategies can be undertaken to minimize the risk of
development of cardiovascular complications.
Ó 2013 Elsevier Ltd. All rights reserved.

Introduction

This chapter will focus on three main metabolic complications of obesity, namely, diabetes and
dysglycemia; metabolic syndrome; and polycystic ovary syndrome. A focus on hypertension and
dyslipidemia will be provided in chapter 6.

* Tel.: þ1 403 705 3636; Fax: þ1 403 705 2636.

E-mail address: drsuepedersen@gmail.com.

URL: http://www.drsue.ca/

1521-690X/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.beem.2013.02.004
180 S.D. Pedersen / Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 179–193

Glycemic disturbances

Diabetes mellitus

In parallel with the rise in obesity prevalence, so too have we seen a marked increase in the
prevalence of type 2 diabetes mellitus (T2DM) globally. The World Health Organization has predicted a
global increase in the prevalence of diabetes of 39% between year 2000 and 2030, with 366 million
people estimated to be affected by 2030.1 Type 2 diabetes mellitus is a condition that arises when the
pancreas does not produce enough insulin to overcome the insulin resistance in the peripheral tissues,
leading to hyperglycemia. Type 2 diabetes is distinguished from type 1 diabetes, which is an auto-
immune disease characterized by absolute failure of pancreatic insulin production.
The rise in T2DM parallels the global increase in the prevalence of obesity. Ninety percent of pa-
tients with T2DM are overweight or obese, and over 60% of cases of type 2 diabetes can be attributed
directly to excess body weight.2 Outcomes are significantly worse in type 2 diabetic patients who are
also obese, including an increased risk of cardiovascular disease and all-cause mortality of 44% and 71%,
respectively.3
The diagnosis of T2DM can be based on fasting blood glucose (BG), random BG, BG following a 75 g
oral glucose tolerance test, or a hemoglobin A1C above the diagnostic threshold (Table 1).4

Etiology of T2DM
The etiology of type 2 diabetes is complex, and is the product of a combination of genetic predis-
position and often, excess body weight. Overweight and obesity are the major causes of the devel-
opment of type 2 diabetes, though individuals with normal body weight but a high genetic
susceptibility toward insulin resistance can develop type 2 diabetes as well. The genetic predisposition
is an important determinant as to whether an obese individual develops type 2 diabetes or not, and
many morbidly obese subjects without the genetic predisposition maintain normoglycemia
throughout life.
As the genome-wide search began for genes predisposing to T2DM in 2007, over 40 susceptibility
loci have been identified, and this number continues to grow.5 These loci may be involved in any of
several pathways leading to diabetes, including pancreatic beta cell growth and development, insulin
synthesis, insulin secretion, and insulin action (post-receptor defects). Amongst the insulin action
defects, obesity dependent and independent mechanisms may exist.
Obesity is a clear risk factor for T2DM, with the risk of T2DM increasing with increasing body weight.
The association of diabetes and body weight, however, is modified by a number of factors, including
genetic predisposition and age. Excess adipose tissue increases the risk of T2DM by increasing resistance
to insulin-mediated peripheral glucose uptake. The mechanisms by which this occurs are complex,
involving a host of adipokines and inflammatory mediators (see Chapter 8). The distribution of body fat
is an important determinant of the risk of insulin resistance and T2DM, with excess visceral adiposity
being associated with the highest risk. Waist circumference and waist-to-hip ratio are two easily
obtainable clinical measures which reflect visceral adiposity, and are good markers of metabolic risk.
Birth weight is also an important risk factor for future development of T2DM, with both low birth
weight and high birth weight being associated with increased risk. The increased risk of T2DM with

Table 1
Diagnostic criteria for diabetes mellitus.a

1. Fastingb BG  7.0 mmol/L

OR
2. Random BG  11.1 mmol/L with symptoms of diabetes (polyuria, polydipsia, unexplained weight loss)
OR
3. 2h BG in a 75 g OGTT  11.1 mmol/L
OR
4. HbA1c  6.5%
a
A confirmatory laboratory glucose test (an fasting plasma glucose (FPG), a random BG or a 2hPG in a 75-g OGTT) must be
done in all cases on another day in the absence of unequivocal hyperglycemia accompanied by acute metabolic decompensation.
b
Fasting ¼ no caloric intake for 8 h.
 S.D. Pedersen / Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 179–193 181

low birth weight may be due to a ‘thrifty phenotype’ being established via epigenetic effects of caloric
deprivation in utero.6 The association between high birth weight (>4.0 kg) and T2DM may be related to
maternal hyperglycemia during pregnancy.
There are a host of other risk factors for the development of T2DM, including impaired fasting
glucose, impaired glucose tolerance, prior history of gestational diabetes, smoking, sedentary lifestyle,
poor diet, low fiber intake, and possibly environmental exposures such as bisphenol A.7

Health impact of T2DM

Chronic hyperglycemia is associated with an increased risk of development of microvascular
complications in T2DM, with the primary manifestations being diabetic retinopathy, nephropathy, and
neuropathy. These complications are often subclinical at the onset, being detected through regular
screening, which is an important part of overall diabetes management. However, in more severe cases,
these complications can progress to cause end organ damage, and as such, diabetes is a leading cause of
blindness, kidney failure, and peripheral limb amputation. The time from the onset of disease to end
stage complications varies, being accelerated by poor glycemic control; with good control, it is entirely
possible to have a lifetime of diabetes without developing clinically relevant complications. It is
important to note that good blood pressure control, lipid control, and abstinence from smoking are also
critically important in decreasing the risk or progression of microvascular complications.
Chronic hyperglycemia is also associated with an increased risk of macrovascular complications,
namely, ischemic heart disease, stroke, and peripheral vascular disease. Patients with diabetes are at
increased risk of dying from cardiovascular disease, and have a life expectancy six to eight years shorter
than people without diabetes.8,9 Many patients with T2DM also have several additional risk factors for
macrovascular disease, including hypertension and dyslipidemia (see Metabolic Syndrome below). As
for microvascular complications, good glycemic control, blood pressure control, lipid management, and
abstinence from smoking are key factors in preventing or delaying the onset or progression of mac-
rovascular disease.
It is of critical importance that individuals with risk factors for T2DM are identified, such that
appropriate screening for the diagnosis can be undertaken. T2DM can be present for years without
overt clinical features, with subclinical complications developing as hyperglycemia continues unno-
ticed. Early diagnosis of T2DM allows the opportunity to establish good glycemic control and prevent
or delay progression to micro- and macrovascular complications.

Management of T2DM
This section focuses on the management of hyperglycemia in T2DM; lipid and blood pressure
management are discussed elsewhere in this textbook.
The foundation of diabetes management is lifestyle alteration, with a focus on healthy eating and
exercise, and with the additional goal of weight loss in type 2 diabetics who are overweight. Not only
does lifestyle alteration improve the course of T2DM, it can also prevent the onset of T2DM in pa-
tients who are at risk (see Management of Prediabetes below). In addition to weight management
strategies (see Section 3), a focus is placed on consumption of lower glycemic index foods and intake
of carbohydrates spread throughout the day, which can help to decrease postprandial glycemic
excursions.
It is possible to put diabetes into remission with weight loss in some cases, though this is less likely
if the genetic predisposition to T2DM is strong, or the diabetes has been present for a longer period of
time, as the natural history of T2DM is that of a progressive decline in beta cell function with time. In
the latter cases, there is still an improvement in the severity of T2DM with weight loss in overweight
patients, by virtue of a concomitant decrease in the degree of peripheral insulin resistance. Patients
who experience T2DM remission with lifestyle alteration must be followed carefully and long term for
possible recurrence of T2DM.
Unfortunately, it has evaded the medical profession to establish a universally successful long term
effective lifestyle management strategy for T2DM. This is likely due to a multitude of factors, including
poor patient compliance over time, the natural history of gradual decline of beta cell function with
time, as well as the tendency of weight to increase with time. As such, medications are most often
required in addition to lifestyle intervention to treat T2DM.
182 S.D. Pedersen / Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 179–193

There are several agents available for T2DM treatment (Table 2), and the choice of agent is patient
specific and depends on a number of factors, including pattern of hyperglycemia, A1C lowering
required, patient comorbidities, effect on weight, risk of hypoglycemia, and cost considerations.
Metformin is the first line drug therapy for type 2 diabetes.10–12 It works by decreasing insulin
resistance, thereby decreasing hepatic glucose output and increasing insulin-medicated glucose uti-
lization in peripheral tissue. Metformin has been shown to decrease microvascular and macrovascular
complications associated with T2DM.13,14 Metformin therapy can be associated with a small amount of
weight loss, and does not cause hypoglycemia.
Many traditionally available antihyperglycemic agents, such as sulfonylureas, thiazolidinediones,
and insulin, are accompanied by weight gain as an unwanted side effect.15 This creates a paradox in
management, in that with weight gain, insulin resistance worsens, and while diabetes control may
initially improve, the underlying insulin resistance progresses, potentially paving the way for an
increased need for diabetes medications in the future.16 Each 1 lb increase in body weight has been
associated with a 2% increased odds of progression of diabetes.17 Patients’ desire to avoid weight gain
may also compromise compliance with treatment.18
While insulin causes weight gain, it is often a necessary treatment agent in type 2 diabetes, partic-
ularly in patients who present with severe hyperglycemia, and for patients in later stages or more severe
cases of the disease. Insulin and sulfonylureas can also cause hypoglycemia, which can be dangerous;
careful counseling must be provided to educate the patient on avoidance of hypoglycemia with appro-
priate use and adjustment of these medications. A hypoglycemic event requires the immediate ingestion
of carbohydrate calories, which may precipitate weight gain, particularly if it is a recurrent phenomenon.
The incretin based therapies represent a newer treatment option for type 2 diabetes which are
associated with weight loss (in the case of glucagon-like peptide-1 (GLP-1) agonists) or weight
neutrality (in the case of dipeptidyl peptidase-4 (DPP-4) enzyme inhibitors).19,20 Patients with T2DM
produce lower levels of GLP-1, a hormone that stimulates insulin release and suppresses glucagon
production in response to a meal, slows gastric emptying, and stimulates the central satiety center in
the paraventricular nucleus of the hypothalamus.21 The insulinotropic and glucagon suppressive ef-
fects of GLP-1 are only active in the presence of hyperglycemia; the clinical implication of this is that
incretin therapies do not cause hypoglycemia.
DPP-4 inhibitors work by slowing the degradation of endogenous GLP-1, thereby providing pro-
longation of physiologic levels of GLP-1. GLP-1 receptor agonists (GLP-1 RAs) provide exogenous GLP-1
by way of subcutaneous injection. As they provide supraphysiologic GLP-1 activity, GLP-1 RAs are more
potent than DPP-4 inhibitors, both in terms of A1C reduction (though this varies by agent) and in terms
of weight loss. In the early phases of treatment with GLP-1 RAs, nausea may be experienced due to the
effect to slow gastric emptying; the proportion of patients who experience this side effect varies by
agent, but does tend to improve with time for most patients. The weight loss seen with GLP-1 RAs is
independent of the nausea effect in most cases, and the weight loss is sustained despite resolution of
nausea symptoms. The weight loss seen with GLP-1 RAs is approximately 3–5 kg over 6 months, though
the results vary from patient to patient.
While all antihyperglycemic agents improve glycemic control, it remains unknown for most of these
agents as to whether they actually decrease the risk of diabetes complications. Hard outcome trials are
currently underway for all of the incretin therapies, with the first results expected in year 2014. It

Table 2
Treatment options for type 2 diabetes mellitus, effect on body weight, and risk of hypoglycemia.

Medication A1C reduction Effect on weight Risk of hypoglycemia?

Metformin Z Neutral to slight Z No
Alpha glucosidase inhibitors Small Z Neutral to slight Z No
DPP-4 inhibitors Z Neutral No
GLP-1 analogs ZZ Z to ZZ No
Insulin ZZZ \ to \\ Yes
Meglitinides Z \ Yes
Sulfonylureas Z \ Yes
Thiazolidinediones Z \ No
 S.D. Pedersen / Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 179–193 183

remains unclear whether a number of the traditional agents, including sulfonylureas and thiazolidi-
nediones, reduce the risk of macrovascular complications.

Practice points: type 2 diabetes mellitus

 T2DM can be diagnosed using fasting BG, random BG, oral glucose tolerance test, or hemo-
globin A1C.
 Identification of patients at risk of T2DM is essential such that appropriate screening can be
undertaken.
 Lifestyle management is the cornerstone of treatment.
 Metformin is the first line agent for treatment of T2DM. Several second line agents exist; the
choice of agent should be tailored to the individual patient.

Prediabetes: impaired glucose tolerance and impaired fasting glucose

The term ‘prediabetes’ refers to a state of dysglycemia which is above normal but below the
diagnostic threshold for diabetes. Prediabetes can refer to either impaired fasting glucose (IFG),
impaired glucose tolerance (IGT), or a combination of both. In the United States, it is estimated that 35%
of American adults have prediabetes.22
Impaired fasting glucose is defined by the World Health Organization as a fasting blood glucose
between 6.1 and 6.9 mmol/L,23 while the American Diabetes Association defines IFG between 5.6 and
6.9 mmol/L.24
Impaired glucose tolerance is defined uniformly by both organizations as a 2-h blood glucose be-
tween 7.8 and 11.0 mmol/L on the 75 g oral glucose tolerance test.
Both IFG and IGT are risk factors for the development of T2DM, with the risk being higher for pa-
tients with higher body mass index (BMI), higher waist-to-hip ratio, higher waist circumference, and
non-Caucasian ethnicity. For patients with both IFG and IGT, the risk of progression to T2DM is very
high, at about 25% over the ensuing 3–5 years.25
Both IFG and IGT are also associated with an increased risk of development of cardiovascular dis-
ease,26 even in the absence of development of T2DM. The pathophysiology of IGT is thought to be
distinct from that of IFG. Specifically, IGT is more strongly associated with cardiovascular disease (CVD)
risk than is IFG, with cardiovascular risk of IGT approaching that of a type 2 diabetic.27 As such, IGT is
often approached more aggressively than IFG from a management perspective.

Management of prediabetes
As IGT and IFG identify patients with an increased risk of developing T2DM, prevention of T2DM in
this population is paramount. As prediabetes is associated with increased health risk, the ideal man-
agement goal is reversion to complete euglycemia. Lifestyle management strategies are the corner-
stone of diabetes prevention.
An intensive combination of dietary and exercise interventions has shown the best success in
preventing progression to T2DM. The Finnish Diabetes Prevention Study was a landmark randomized
clinical study of patients with IGT, that found that a combined diet and exercise weight reduction plan
reduced the 4-year cumulative incidence of diabetes by 58% (diabetes mellitus (DM) incidence 11% vs
23% in controls).28 At three years after study completion, there was some persistence of reduction in
T2DM risk, though not as powerful during the trial itself, with a 36% reduced incidence of T2DM.29 The
Diabetes Prevention Program was another landmark study that randomized over 3000 patients with
both IFG and IGT to placebo, metformin 850 mg twice daily, or an intensive lifestyle intervention.30 At
an average follow up of 3 years, the intensive lifestyle group showed a significantly lower risk of
developing diabetes (14%) compared to the metformin group or the placebo group (22% and 29%,
respectively, with differences between all groups being statistically significant). The number needed to
treat for three years to prevent one case of diabetes in this study was 6.9 persons for the lifestyle
intervention program, and 13.9 for metformin.
184 S.D. Pedersen / Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 179–193

A recent meta-analysis of seven randomized controlled trials examining the effect of lifestyle
intervention on diabetes incidence amongst patients with IGT (including the two above). While all
studies showed a reduction in the incidence of diabetes, the range in longitudinal incidence of DM was
wide, ranging between 3% and 46% in the intervention groups, vs 9.3%–67.7% in the control groups in
these studies.31 This wide range of results highlights a number of important points. Firstly, there is
great variability from study to study as to the design of the lifestyle interventions, including specific
dietary and exercise advice (ranging from information brochures to personalized education by diabetes
specialists). Secondly, there are differences in follow up frequency and intensity, which may be
important in maintaining compliance with the lifestyle intervention. Thirdly, the populations in each
study were variable in terms of ethnicity, age, BMI, and other factors.
Importantly, this meta-analysis also showed that the effect of lifestyle intervention decreases with
time. One of the studies examined showed a reduction in diabetes incidence only in the first follow up
year,32 with others showing reduction in relative risk reduction over time. One possible reason for this
observation is that long term compliance may be poor; it has been well documented that patient
compliance with lifestyle intervention is generally poor.31 This may also reflect the natural history of
insulin resistance and beta cell dysfunction, which is that of overall deterioration over time.
Metformin has been shown to be of benefit in preventing progression of prediabetes to T2DM. This
was demonstrated in the DPP trial noted above, though it’s important to note that metformin was less
effective than lifestyle intervention.30 A meta analysis of randomized trials of metformin for diabetes
prevention in individuals at high risk of DM found that metformin reduced the incidence of new onset
DM by 40%,33 with modest improvements in BMI and lipid profile as well. Based on the evidence,
metformin is indicated in some countries for the prevention of progression to T2DM in patients with
IGT; in other countries, both IFG and IGT are required to be present for the use of metformin.
Other diabetes medications, including thiazolidinediones and acarbose, have also been shown to
decrease the risk of progression to T2DM, but the side effect potential and compliance issues are such
that the risk is thought to exceed the benefit of these medications in DM prevention, and therefore
neither medication is recommended for this indication.
The weight loss medication, orlistat, has been found to decrease the risk of incident T2DM in pa-
tients with IGT compared to placebo.34,35 However, the use of orlistat is limited by gastrointestinal side
effects and the absence of long term sustainability of weight loss.

Practice points: prediabetes

 Prediabetes is diagnosed using the oral glucose tolerance test.

 Identification of patients with prediabetes is essential so that a focus can be placed on pre-
vention of T2DM.
 Lifestyle management is the cornerstone of treatment.
 Metformin can be used to prevent progression to T2DM in patients with impaired glucose
tolerance.

Gestational diabetes

In pregnancy, a number of metabolic changes take place which affect glucose homeostasis. Normal
pregnancy is characterized by an early increase in insulin sensitivity followed by progressive insulin
resistance, with the insulin resistance being mediated by production of diabetogenic hormones such as
growth hormone, corticotropin-releasing hormone (CRH), and others from the growing placenta.
Placental hormones stimulate progressive maternal pancreatic beta cell hyperplasia, with the exact
mechanisms being incompletely delineated. Gestational diabetes occurs when the woman’s pancreas
is not able to produce sufficient insulin to overcome the insulin resistant state.
Gestational diabetes (GDM) has traditionally been defined as hyperglycemia with onset or first
recognition during pregnancy.36 Historically, most of these cases were truly gestational in nature
(meaning that the diabetes was induced by metabolic changes in pregnancy, and the patient returned
 S.D. Pedersen / Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 179–193 185

to normoglycemia postpartum), with only a small proportion being incidentally diagnosed with type 1
diabetes mellitus (T1DM) or T2DM during pregnancy. However, in parallel with the increase in prev-
alence of type 2 diabetes and obesity, an increasing proportion of young women are being diagnosed
with type 2 diabetes at the time of pregnancy, with the condition being previously unrecognized due to
the lack of screening in this age group.
The importance of detection and management of hyperglycemia before and during pregnancy
cannot be overstated. Hyperglycemia in the first trimester of pregnancy is associated with an increased
risk of congenital malformations and spontaneous abortion. As organogenesis is nearly complete by 7
weeks postconception, women who have diabetes undiagnosed or poorly controlled prior to preg-
nancy are at increased risk of these complications. Hyperglycemia later in pregnancy is associated with
fetal macrosomia, which increases the risk of birth injury and complications to both baby and mother.
Screening for GDM is typically undertaken at 24–28 weeks’ gestation, though earlier and repeated
screening is recommended in patients who have risk factors for GDM, starting at the presentation of
pregnancy, and repeated every trimester after that. While there are no worldwide standards for the
screening protocol, a 50 g glucose screen is often performed as the initial screening test. A patient can
be diagnosed with GDM based on this screen, or, if blood sugar is impaired but not clearly GDM range
on this test, the patient then progresses to a 75 g oral glucose tolerance test (OGTT).
The criteria for diagnosis of GDM based on 75 g OGTT is also widely debated. The International
Association of Diabetes and Pregnancy Study Groups (IADPSG) has recently recommended lower
glycemic thresholds than previously accepted to make the diagnosis (Table 3), with thresholds guided
primarily by the risk of giving birth to offspring with high birth weight, high body fat percent, and high
cord C-peptide levels (as a marker of fetal hyperinsulinemia).37
The prevalence of GDM is population-specific, and depends upon the criteria used to make the
diagnosis. Using the above criteria would double the prevalence of GDM to about 18%, with the number
varying depending on the ethnicity and geographic area of the population.38 Whether these diagnostic
criteria for GDM should be universally adopted is currently a topic of intense international debate, as it
is not clear if adopting these lower glycemic thresholds is associated with substantially better maternal
and neonatal outcomes, nor whether adopting these criteria represents appropriate allocation of
already overburdened health care resources.39

Risk factors for GDM

Maternal adiposity is a risk factor for the development of GDM, due to the associated increase in
insulin resistance. One study found that for every increase in prepregnancy BMI of 1 kg/m2, the odds
ratio of developing GDM was 1.08, and for every 5 kg/m2 increase, the odds ratio was 1.48.40 Weight
gain in the years prior to pregnancy has been found to be associated with increased GDM risk; women
who gained 2.3–10 kg per year in the 5 years before pregnancy had a 2.6 fold increased risk of
developing GDM.41 Excessive weight gain in pregnancy is also associated with increased GDM risk,
particularly if the excess weight is accumulated in the first trimester.
Other risk factors for GDM are listed in Table 4.

Treatment of GDM
The management of GDM begins with lifestyle strategies to achieve euglycemia if possible. This in-
cludes evaluation by a registered dietitian to ensure that nutritional therapy promotes euglycemia while
ensuring appropriate weight gain and adequate nutritional intake. Moderate carbohydrate restriction
while ensuring adequate intake is emphasized, and carbohydrate intake is distributed over several small

Table 3
International Association of Diabetes and Pregnancy Study
Groups (IADPSG) criteria for diagnosis of gestational diabetes
on 75 g oral glucose tolerance test.

Time Blood glucose

Fasting 5.1 mmol/L; OR
One hour 10.0 mmol/L; OR
Two hour 8.5 mmol/L
186 S.D. Pedersen / Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 179–193

Table 4
Risk factors for gestational diabetes.

Maternal obesity
Age >25 years
Prior history of GDM
Prior history of giving birth to an infant weighing over 4.1 kg
Personal history of abnormal glucose tolerance
Smoking
Strong family history of T2DM
Ethnicity (especially Native American, Hispanic, African-American, South Asian, East Asian, Pacific Islander)
Polycystic ovary syndrome
Maternal birth weight >4.1 kg or <2.7 kg

meals and snacks through the day. Desired weight gain in pregnancy is similar to goals in women who do
not have GDM, with less weight gain advised for those with higher starting BMI (Table 5).42
In women who are unable to meet glycemic targets with lifestyle management, insulin is utilized to
achieve glycemic control. Whether any oral hypoglycemic medications are safe for use in pregnancy is
still unknown; study of metformin in pregnancy is currently underway. Use of oral hypoglycemic
agents in pregnancy is currently not recommended.
Following delivery, it is paramount to test for persistent T2DM, as approximately 10% of patients
with GDM will have persistent T2DM postpartum,43 with the exact number being variable depending
on the criteria for GDM diagnosis utilized. Testing is typically done at 6 weeks postpartum with a 75 g
OGTT, with nonpregnant criteria being applied (see Diabetes diagnosis above). Women who go on to
have T2DM immediately postpartum may have a higher degree of insulin resistance postpartum (for
example, due to increased adipose tissue postpartum compared to prepregnancy), or they may have
had undiagnosed T2DM prior to pregnancy. Long term, as many as 40% of patients who had GDM will
eventually go on to develop T2DM. The diagnosis of GDM provides an opportunity to identify a woman
at increased lifelong risk of developing T2DM, and this opportunity to identify and screen her longi-
tudinally must not be missed.

Practice points: gestational diabetes

 Screening for the diagnosis of diabetes must be undertaken in women at risk PRIOR to
conception, for identification of women with preexisting diabetes.
 Screening for gestational diabetes must be undertaken to prevent complications of hyper-
glycemia to both fetus and mother.
 Lifestyle management is the cornerstone of therapy for GDM, with insulin utilized in those
who are not able to control hyperglycemia with appropriate lifestyle strategies.

Metabolic syndrome

An abundance of literature points to the existence of a particular metabolic syndrome encom-

passing insulin resistance, hypertension, dyslipidemia, and abdominal obesity. This syndrome is also

Table 5
Recommendations for total weight gain during pregnancy by prepregnancy BMI.

Prepregnancy BMI Total weight gain recommended in pregnancy

Underweight (<18.5 kg/m2) 12.5–18 kg (28–40 lb)
Normal weight (18.5–24.9 kg/m2) 11.5–16 kg (25–35 lb)
Overweight (25.0–29.9 kg/m2) 7–11.5 kg (15–25 lb)
Obese (30 kg/m2) 5–9 kg (11–20 lb)
 S.D. Pedersen / Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 179–193 187

known as insulin resistance syndrome, since the underlying pathophysiology is that of reduced
sensitivity to the action of insulin. Several definitions for the metabolic syndrome have been proposed,
with the most commonly utilized criteria presented in Table 6.44,45
Obesity is a clear risk factor for development of the metabolic syndrome, with National Health and
Nutrition Examination Survey (NHANES) data revealing that the condition was present in approximately
5% of people with normal body weight, 22% of people who are overweight, and 60% of people with obesity
by BMI criteria.46 Weight gain over time portends an increased risk of developing metabolic syndrome, as
does a larger waist circumference,47 lower level of physical activity, and genetic predisposition.
Other risk factors for metabolic syndrome include family history of metabolic syndrome, smoking,
physical inactivity, high carbohydrate diet, ethnicity (especially Native American, Hispanic, African-
American, South Asian, East Asian, Pacific Islander), and older age.

Clinical implications of the metabolic syndrome

The importance of identification of patients who have metabolic syndrome cannot be overstated, as
patients with this condition are at increased risk of developing type 2 diabetes and cardiovascular
disease. It has been recommended that any patient with one or more risk factors for metabolic syn-
drome should be evaluated for development of this condition at least every three years, or more often
as needed.48
The risk of developing T2DM is increased 2- to 4-fold in patients with metabolic syndrome
(depending on the criteria utilized for diagnosis and the population under study), and the risk is also
increased with an increasing number of components of the metabolic syndrome. The metabolic syn-
drome is associated with a 1.5- to 2-fold increase in the risk of incident cardiovascular disease, as well
as an increased risk of all-cause mortality. The increased cardiovascular (CV) risk appears to be related
to the risk factor clustering or insulin resistance associated with the metabolic syndrome, rather than
with obesity per se (see Chapter 6).
Patients with the metabolic syndrome are also at increased risk of a host of other obesity-related
conditions, including obstructive sleep apnea, fatty liver disease, gout, polycystic ovary syndrome,
and chronic kidney disease.
Treatment of the metabolic syndrome includes weight loss in patients with excess adiposity, an
increase in physical activity, and close attention toward cardiovascular risk stratification and reduction
(see Section 3).

Practice points: metabolic syndrome

 All components of metabolic syndrome should be evaluated in patients at risk.

 Lifestyle strategies are the cornerstone of management of the metabolic syndrome.
 Attention to cardiovascular risk reduction is an essential component of therapy.

Polycystic ovarian syndrome

Polycystic ovary syndrome (PCOS) consists of a constellation of clinical features including ovulatory
dysfunction, clinical evidence of hyperandrogenism (hirsutism and/or acne), and subfertility. PCOS is
the most common endocrinopathy in reproductive aged women, affecting between 6.5% and 8% of
women overall.49
PCOS develops in the context of a complex interplay between genetic predisposition similar to that
of T2DM and metabolic syndrome, where multiple genetic and environmental factors interact to
facilitate the development of the condition. Heritability of PCOS is strong, with well documented fa-
milial clustering of PCOS.50 Over a dozen genes have been implicated in PCOS, with this number
growing from genome-wide association studies. These genes are involved in a variety of elements,
including the androgen receptor, synthesis of sex hormone binding globulin, the insulin receptor, and
others.
188 S.D. Pedersen / Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 179–193

Table 6
Diagnostic criteria for the metabolic syndrome.

Parameter NCEPa criteria IDFb criteria

Required Waist 94 cm (men) or 80 cm (women)c
Number of 3 of: And 2 of:
abnormalities required
Glucose 5.6 mmol/L or drug treatment for 5.6 mmol/L or diagnosed diabetes
elevated blood glucose
HDL cholesterol <1.0 mmol/L (men); <1.3 mmol/L <1.0 mmol/L (men); <1.3 mmol/L (women);
(women); or drug treatment for or drug treatment for low HDL
low HDL
Triglycerides 1.7 mmol/L (150 mg/dL) or drug 1.7 mmol/L (150 mg/dL) or drug treatment
treatment for elevated triglycerides for elevated triglycerides
Obesity Waist 102 cm (men) or 88 cm
(women)
Hypertension 130/85 mmHg or drug treatment 130/85 mmHg or drug treatment for
for hypertension hypertension
a
NCEP ¼ National Cholesterol Education Program.44
b
IDF ¼ International Diabetes Federation.45
c
For South Asian and Chinese patients, waist 90 cm (men) or 80 cm (women); for Japanese patients, waist 90 cm (men)
or 80 cm (women).

The predominant underlying pathophysiologic defect in PCOS is insulin resistance, with the devel-
opment of compensatory hyperinsulinemia in many patients with the disorder. The hyperinsulinemia
leads to increased testosterone production by the theca cells of the ovaries51 and also inhibits pro-
duction of sex hormone binding globulin, leading to increased levels of circulating free androgens.52
Increased luteinizing hormone (LH) pulse frequency, amplitude, and action at the ovary may be
involved in the pathogenesis of PCOS as well.53 Together, these metabolic changes result in the net effect
of impairment of the normal ovulatory cycle, resulting in oligomenorrhea and subfertility. The increased
free circulating androgen levels result in the hirsutism and acne that characterize the disorder.
The diagnosis of PCOS is clinical, and does not have rigorous biochemical criteria.54 A slightly
elevated serum testosterone can be seen, though most PCOS women have normal serum total
testosterone but elevated circulating free androgen levels. Polycystic ovaries on ultrasound are often
seen, but are not necessary to make the diagnosis. Exclusion of other causes of hyperandrogenism and
oligomenorrhea (for example, hyperprolactinemia, congenital adrenal hyperplasia, and androgen
producing tumors) is mandatory before diagnosing PCOS.

Influence of obesity on PCOS

Obesity is a risk factor for the development of PCOS, as insulin resistance and hyperinsulinemia
increase with higher BMI. Weight gain is also known to exacerbate clinical features in preexisting PCOS
by the same mechanisms.
However, it is important to note that a significant proportion of patients with PCOS are lean by BMI
criteria, with one study from United States of America (USA) demonstrating that 40% of PCOS women
were not obese.55 That being said, it is possible that some non-obese women with PCOS may be normal
weight by BMI criteria but obese by body fat percentage criteria. Non-obese patients are likely to have a
stronger genetic predisposition toward PCOS, acquiring the clinical manifestations of the disorder at a
lower BMI than a woman who develops PCOS at a higher BMI. It is also possible that the PCOS genotype
may be associated with a greater propensity for obesity and weight gain, which is a topic currently
under active investigation.

Metabolic comorbidities of PCOS

In light of the hyperinsulinemia and obesity that is often associated with PCOS, it does not come as a
surprise that PCOS is associated with an increased risk of metabolic perturbations. PCOS women are at
 S.D. Pedersen / Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 179–193 189

a higher risk of developing prediabetes or T2DM, dyslipidemia, subclinical vascular disease, and
vascular dysfunction, independent of BMI.
There is about a two-fold increased prevalence of both IGT and T2DM in patients with PCOS
compared to age and BMI comparable women without PCOS.56 Most women with PCOS who develop
T2DM have a BMI 30 kg/m2. PCOS women also have about a 10 fold increased risk of developing
GDM.57 Thus, screening for dysglycemia is of paramount importance in the longitudinal management
of PCOS.
Dyslipidemia is the most common metabolic abnormality in PCOS, with the typical lipid profile
including decreased HDL cholesterol, elevated triglycerides, and sometimes higher LDL cholesterol.
Epidemiologic studies have shown a higher prevalence of hypertension amongst women with PCOS,
particularly systolic hypertension.
There is a significantly higher prevalence of non-alcoholic fatty liver disease (NAFLD) in PCOS
women, found to range from 27% to as high as 62% compared with weight and age matched non-PCOS
women.58,59 Importantly, the prevalence of progression to advanced liver disease (non-alcoholic
steatohepatitis (NASH) with fibrosis) in women with PCOS is remarkably high,60,61 perhaps related to
more severe insulin resistance in these patients. This is important as it carries the risk of progressive
liver injury and cirrhosis as well as increased risk of development of DM, atherosclerosis, and CVD.
The prevalence of obstructive sleep apnea (OSA) is elevated in women with PCOS by 5 fold to as
much as 30-fold compared to women without PCOS,57,62 with a persistently increased risk after
adjustment for age and BMI. The prevalence of IGT is two-fold higher in PCOS women with OSA
compared to those without OSA; further, treatment of OSA in obese women with PCOS improves in-
sulin sensitivity and cardiovascular risk factors, independent of changes in body weight.63
It is unclear whether women with PCOS are at increased risk of cardiovascular events or mortality.
Studies that have suggested an increased risk have also found that risk to be attenuated after adjusting
for traditional CV risk factors, suggesting that these risk factors do at least in part account for the in-
crease in risk seen. Due to young age and female gender, even if there is an increased risk of cardio-
vascular events, the absolute risk remains very low.

Treatment of PCOS

Treatment of PCOS depends upon the goals of the patient. For some women, the primary goal is
fertility, whereas for others, hirsutism or acne may be the predominant concern.
The foundation of PCOS management is focused on decreasing insulin resistance, as this is the
foundation of the pathogenesis of the disorder. Amongst overweight or obese women, the primarily
goal is weight loss, particularly loss of abdominal fat, as this is associated with a reduction in circulating
free androgen levels, resumption of ovulation, and fertility.57
Metformin can be of use to lower serum insulin concentrations and increase insulin sensitivity in
patients with PCOS of normal or increased body weight, with the goal being improved frequency/
regularity of menstruation and ovulation. Metformin increases ovulation and pregnancy rates,64 but
whether metformin increases live birth rates is controversial. Clomiphene citrate can also be employed
to induce ovulation and improve fertility in women with PCOS. Addition of metformin can be of benefit
in PCOS women who do not have successful treatment with clomiphene alone.
In a PCOS patient with oligomenorrhea, it is essential that strategies are employed to prevent
endometrial hyperplasia, which can occur in the context of oligomenorrhea. If a PCOS patient is
menstruating less than every 3 months, progesterone induced withdrawal bleeds can be employed to
prevent endometrial hyperplasia. Oral contraceptive therapy can be used to achieve this goal,
depending on whether fertility is currently desired.
Hirsutism and acne often improves with weight loss in overweight PCOS patients, but usually only
partial improvement is noted. Metformin is of little to no benefit in managing hirsutism.65 The oral
contraceptive reduces hyperandrogenism by a number of mechanisms, including suppression of
ovarian androgen production, and increasing sex hormone-binding globulin (SHBG) levels, thereby
decreasing circulating free androgen levels.
Other medications such as spironolactone or cyproterone can be used for management of hirsutism,
with availability varying by country. As no medication is effective to completely ameliorate hirsutism,
190 S.D. Pedersen / Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 179–193

most PCOS women turn to mechanical means of hair removal, either as monotherapy or as additional
therapy to the above options. Options include shaving, waxing, plucking, chemical depilation, elec-
trolysis, and photoepilation.
Screening for, and treatment of, comorbidities of PCOS are a critical component of comprehensive
PCOS management and must not be overlooked. This includes periodic screening for dysglycemia,
hypertension, dyslipidemia, liver dysfunction, as well as OSA assessment.

Practice points: polycystic ovary syndrome

 PCOS is prevalent, and should be suspected in women with oligomenorrhea, subfertility,

hirsutism and/or acne.
 The exclusion of other possible causes of the clinical presentation is an ESSENTIAL component
of establishing the diagnosis of PCOS.
 Treatment strategies are geared toward the clinical concerns of the patient.
 Patients with PCOS are at risk of a host of comorbidities, and screening and management of
these is essential.

Research agenda

 Identification of weight management interventions with sustained efficacy are desperately

needed.
 A better understanding of the genetic contributions to metabolic complications of obesity is
needed.
 Evidence for improvement in hard outcomes of T2DM with various medications is lacking.

Summary

A number of metabolic complications of obesity exist. With the high prevalence of obesity globally,
it is essential that health care providers are aware of these potential complications, such that
appropriate screening and management can be undertaken. Awareness of dysglycemia is ideal at as
early a stage as possible, such that preventive strategies to prevent progression to diabetes can be
undertaken aggressively. The diagnosis of T2DM is essential as early in the natural history of the
disease as possible such that appropriate strategies for prevention of complications can be under-
taken. Metabolic syndrome should be identified such that vascular risk reduction strategies can be
implemented. A high suspicion of PCOS should exist for women with weight struggles and repro-
ductive concerns. Prevention of all of the above on a global level, through identification and
implementation of successful population based weight management strategies is paramount. Much
remains to be understood regarding the genetic contributors to these disease processes, and this is
the subject of much active investigation. A better understanding of the genetic contributions to these
disease processes may facilitate improvements in directed therapy to optimize the health of the
individual patient.

Conflict of interest

Dr Pedersen has conducted research on behalf of Eli Lilly, Novo Nordisk, Sanofi Aventis, Astra
Zeneca, and Boehringer-Ingelheim. Dr Pedersen has received speaking honoraria from Novo Nordisk,
Bristol Myers Squibb, Merck, Sanofi, Eli Lilly, and Boehringer-Ingelheim. Dr Pedersen has participated
on advisory boards for Sanofi, Novo Nordisk, and Merck.
 S.D. Pedersen / Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 179–193 191

Role of the funding source

A small honorarium was provided by the publishers of this textbook for the preparation of this
manuscript.

References

1. Wild S, Roglic G, Green A et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.
Diabetes Care 2004; 27: 1047–1053.
2. Hu FB, Manson JE, Stampfer M et al. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. New England Journal
of Medicine 2001; 345: 790–797.
3. Eeg-Olofsson K, Cederholm J, Nilsson PM et al. Risk of cardiovascular disease and mortality in overweight and obese
patients with type 2 diabetes: an observational study in 13,087 patients. Diabetologia 2009; 52: 65–73.
4. Goldenberg RM, Cheng AYY, Punthakee Z et al. Use of glycated hemoglobin (A1C) in the diagnosis of type 2 diabetes
mellitus in adults. Canadian Journal of Diabetes 2011 July: 247–249.
5. McCarthy I. Genomics, type 2 diabetes, and obesity. New England Journal of Medicine 2010; 363(24): 2339–2350.
6. Vaag AA, Grunnet LG, Arora GP et al. The thrifty phenotype hypothesis revisited. Diabetologia 2012; 55(8): 2085–2088.
7. Alonso-Magdalene P, Quesada I & Nadal A. Endocrine disruptors in the etiology of type 2 diabetes mellitus. Nature Reviews
Endocrinology 2011; 7(6): 346–353.
8. Franco OH, Steyerberg EW, Hu FB et al. Associations of diabetes mellitus with total life expectancy and life expectancy with
and without cardiovascular disease. Archives of Internal Medicine 2007; 167(11): 1145–1151.
9. Seshasai SR, Kaptoge S, Thompson A, et alEmerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, and risk
of cause-specific death. New England Journal of Medicine 2011; 364(9): 829–841.
10. American Diabetes Association. Standards of medical care in diabetes – 2010. Diabetes Care 2010; 33(Suppl. 1): S11–S61.
11. Rydén L, Standl E, Bartnik M et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary.
The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European
Association for the Study of Diabetes (EASD). European Heart Journal 2007; 28: 88–136.
12. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2008 clinical
practice guidelines for the prevention and management of diabetes in Canada. Canadian Journal of Diabetes 2008;
32(Suppl. 1): S1–S201.
13. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared
with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;
352(9131): 837–853.
14. Holman RR, Paul SK, Bethel MA et al. Ten-year follow-up of intensive glucose control in type 2 diabetes. New England
Journal of Medicine 2008; 359(15): 1577–1589.
*15. Meneghini LF, Orozco-Beltran D, Khunti K et al. Weight beneficial treatments for type 2 diabetes. Journal of Clinical
Endocrinology and Metabolism 2011; 96(11): 3337–3353.
16. Schmid C, Krayenbühl P & Wiesli P. Increased insulin dose requirement of long-acting insulin analogues in obese patients
with type 2 diabetes. Diabetologia 2009; 52: 2668–2669.
17. Pani LN, Nathan DM & Grant RW. Clinical predictors of disease progression and medication initiation in untreated patients
with type 2 diabetes and A1C less than 7%. Diabetes Care 2008; 31: 386–390.
18. Hermansen K & Mortensen LS. Body weight changes associated with antihyperglycaemic agents in type 2 diabetes
mellitus. Drug Safety 2007; 30: 1127–1142.
19. Lind M. Incretin therapy and its effect on body weight in patients with diabetes. Primary Care Diabetes 2012; 6(3): 187–191.
20. Cornell S. Differentiating among incretin therapies: a multiple-target approach to type 2 diabetes. Journal of Clinical
Pharmacy and Therapeutics 2012; http://dx.doi.org/10.1111/j.1365-2710.2012.01342.x.
21. Williams DL. Minireview: finding the sweet spot: peripheral versus central glucagon-like peptide 1 action in feeding and
glucose homeostasis. Endocrinology 2009; 150: 2997–3001.
22. National Diabetes Statistics. Fast facts on diabetes. National Institute of Diabetes and Digestive and Kidney Diseases of the
National Institutes of Health, 2011, http://diabetes.niddk.nih.gov/dm/pubs/statistics/ [accessed online 08.09.12].
23. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications: report of a
WHO consultation. Part 1. Diagnosis and classification of diabetes mellitus. [accessed online 10.11.12].
24. American Diabetes, Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2005; 28(Suppl. 1): S37–S42.
25. Nathan DM, Davidson MB, DeFronzo RA, et al, American Diabetes Association. Impaired fasting glucose and impaired
glucose tolerance: implications for care. Diabetes Care 2007; 30(3): 753–759.
26. Coutinho M, Gerstein HC, Wang Y et al. The relationship between glucose and incident cardiovascular events. A meta-
regression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 1999;
22: 233–240.
27. Tominaga M, Eguchi H, Manaka H et al. Impaired glucose tolerance is a risk factor for cardiovascular disease, but not
impaired fasting glucose. Diabetes Care 1999; 22: 920–924.
28. Tuomilehto J, Lindstrom J, Eriksson JG, et al, Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes
mellitus by changes in lifestyle among subjects with impaired glucose tolerance. New England Journal of Medicine 2001;
344: 1343–1350.
29. Lindström J, Ilanne-Parikka P, Peltonen M, et al, Finnish Diabetes Prevention Study Group. Sustained reduction in the
incidence of type 2 diabetes by lifestyle intervention: follow up of the Finnish Diabetes Prevention Study. Lancet 2006;
368(9548): 1673–1679.
30. Knowler WC, Barrett-Connor E, Fowler SE, et al, Diabetes Prevention Program Research Group. Reduction in the incidence
of type 2 diabetes with lifestyle intervention or metformin. New England Journal of Medicine 2002; 246: 393–403.
192 S.D. Pedersen / Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 179–193

*31. Yoon U, Kwok LL & Magkidis A. Efficacy of lifestyle interventions in reducing diabetes incidence in patients with impaired
glucose tolerance: a systematic review of randomized controlled trials. Metabolism 2012 Sept [Epub ahead of print].
32. Lindahl B, NilssoÅNn TK, Borch-Johnsen K et al. A randomized lifestyle intervention with 5-year follow-up in subjects with
impaired glucose tolerance: pronounced short-term impact but long-term adherence problems. Scandinavian Journal of
Public Health 2009; 37(4): 434–442.
33. Salpeter SR, Buckley NS, Kahn JA et al. Meta-analysis: metformin treatment in persons at risk for diabetes mellitus.
American Journal of Medicine 2008; 121(2): 149–157.e2.
34. Torgerson JS, Hauptman J, Boldrin MN et al. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a
randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients.
Diabetes Care 2004; 27(1): 155–161.
35. Heymsfield SB, Segal KR, Hauptman J et al. Effects of weight loss with orlistat on glucose tolerance and progression to type
2 diabetes in obese adults. Archives of Internal Medicine 2000; 160(9): 1321–1326.
36. Metzger BE & Coustan DR. Summary and recommendations of the Fourth International Workshop – Conference on
Gestation Diabetes Melitus. Diabetes Care 1998; 21(Suppl. 2): B161–B167.
*37. Metzger BE, Gabbe SG, Persson B, et al, International Association of Diabetes and Pregnancy Study Groups Consensus
Panel. International association of diabetes and pregnancy study groups recommendations on the diagnosis and classi-
fication of hyperglycemia in pregnancy. Diabetes Care 2010; 33(3): 676–692.
38. Ryan EA. Diagnosing gestational diabetes. Diabetologia 2011; 54(3): 480–486.
39. Langer O, Umans JG & Miodovnik M. Perspectives on the proposed gestational diabetes mellitus diagnostic criteria. Ob-
stetrics and Gynecology 2012 Oct 19 [Epub ahead of print].
40. Singh J, Huang CC, Driggers RW et al. The impact of pre-pregnancy body mass index on the risk of gestational diabetes.
Journal of Maternal, Fetal, and Neonatal Medicine 2012; 25(1): 5–10.
41. Hedderson MM, Williams MA, Holt VL et al. Body mass index and weight gain prior to pregnancy and risk of gestational
diabetes mellitus. American Journal of Obstetrics and Gynecology 2008; 198(4): 409.e1.
42. Institute of Medicine (US) and National Research Council (US) Committee to Reexamine IOM Pregnancy Weight Guide-
lines. Weight gain during pregnancy: reexamining the guidelines. Rasmussen KM, Yaktine AL, editors. National Academies
Press (US), The National Academies Collection. Available at: http://www.nap.edu/catalog/12584.html.
43. Buchanan TA & Xiang AH. Gestational diabetes mellitus. Journal of Clinical Investigation 2005; 115(3): 485.
44. Grundy SM, Cleeman JI, Daniels SR, et al, American Heart Association, National Heart, Lung, and Blood Institute. Diagnosis
and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute
Scientific Statement. Circulation 2005; 112(17): 2735.
45. International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome 2006, http://www.idf.
org/webdata/docs/MetS_def_update2006.pdf [Accessed on 30.10.12].
46. Park YW, Zhu S, Palaniappan L et al. The metabolic syndrome: prevalence and associated risk factor findings in the US
population from the Third National Health and Nutrition Examination Survey, 1988–1994. Archives of Internal Medicine
2003; 163(4): 427–436.
47. Palaniappan L, Carnethon MR, Wang Y et al. Predictors of the incident metabolic syndrome in adults: the Insulin Resistance
Atherosclerosis Study. Diabetes Care 2004; 27(3): 788–793.
*48. Rosenzweig JL, Ferrannini E, Grundy SM et al. Primary prevention of cardiovascular disease and type 2 diabetes in patients
at metabolic risk: an endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2008;
93(10): 3671–3689.
49. Azziz R, Woods KS, Reyna R et al. The prevalence and features of the polycystic ovary syndrome in an unselected pop-
ulation. Journal of Clinical Endocrinology and Metabolism 2004; 89(6): 2745–2749.
50. Kosova G & Urbanek M. Genetics of the polycystic ovary syndrome. Molecular and Cellular Endocrinology 2012; http://dx.
doi.org/10.1016/j.mce.2012.10.009.
51. Nestler JE, Jakubowicz DJ, de Vargas AF et al. Insulin stimulates testosterone biosynthesis by human thecal cells from
women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal
transduction system. Journal of Clinical Endocrinology and Metabolism 1998; 83(6): 2001–2005.
52. Nestler JE, Powers LP, Matt DW et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in
obese women with the polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 1991; 72(1): 83–89.
53. Jakimiuk AJ, Weitsman SR, Navab A et al. Luteinizing hormone receptor, steroidogenesis acute regulatory protein, and
steroidogenic enzyme messenger ribonucleic acids are overexpressed in thecal and granulosa cells from polycystic ovaries.
Journal of Clinical Endocrinology and Metabolism 2001; 86(3): 1318–1323.
54. * Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria
and long-term health risks related to polycystic ovary syndrome. Fertility and Sterility 2004; 81: 19–25.
55. Azziz R, Sanchez LA, Knochenhauer ES et al. Androgen excess in women: experience with over 1000 consecutive patients.
Journal of Clinical Endocrinology and Metabolism 2004; 89(2): 453–462.
56. Legro RS, Kunselman AR, Dodson WC et al. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired
glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. Journal of Clinical
Endocrinology and Metabolism 1999; 84: 165–169.
*57. Randeva HS, Tan BK, Weikert MO et al. Cardiometabolic aspects of the polycystic ovary syndrome. Endocrinology Reviews
2012; 33(5): 812–841.
58. Tan S, Bechmann LP, Benson S et al. Apoptotic markers indicate nonalcoholic steatohepatitis in polycystic ovary syndrome.
Journal of Clinical Endocrinology and Metabolism 2010; 95: 343–348.
59. Gutierrez-Grobe Y, Ponciano-Rodríguez G, Ramos MH et al. Prevalence of non alcoholic fatty liver disease in premenopausal,
postmenopausal and polycystic ovary syndrome women. The role of estrogens. Annals of Hepatology 2010; 9: 402–409.
60. Brzozowska MM, Ostapowicz G & Weltman MD. An association between non-alcoholic fatty liver disease and polycystic
ovarian syndrome. Journal of Gastroenterology and Hepatology 2009; 24: 243–247.
61. Setji TL, Holland ND, Sanders LL et al. Nonalcoholic steatohepatitis and nonalcoholic fatty liver disease in young women
with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2006; 91: 1741–1747.
 S.D. Pedersen / Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 179–193 193

62. Vgontzas AN, Legro RS, Bixler EO et al. Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime
sleepiness: role of insulin resistance. Journal of Clinical Endocrinology and Metabolism 2001; 86: 517–520.
63. Tasali E, Chapotot F, Leproult R et al. Treatment of obstructive sleep apnea improves cardiometabolic function in young
obese women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2011; 96: 365–374.
64. Misso ML, Teede HJ, Hart R et al. Status of clomiphene citrate and metformin for infertility in PCOS. Trends in Endocrinology
and Metabolism 2012; 23(10): 533–543.
65. Martin KA, Chang RJ, Ehrmann DA et al. Evaluation and treatment of hirsutism in premenopausal women: an endocrine
society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2008; 93(4): 1105–1120.