Sage Journals: Discover world-class research

Abstract

In women with previous gestational diabetes (pGDM), the risk of developing Type 2 diabetes is greatly increased, to the point that GDM represents an early stage in the natural history of Type 2 diabetes. In addition, in the years following the index pregnancy, women with pGDM exhibit an increased cardiovascular risk profile and an increased incidence of cardiovascular disease. This paper will review current knowledge on the metabolic modifications that occur in normal pregnancy, underlining the mechanism responsible for GDM, the link between these alterations and the associated long-term maternal complications. In women with pGDM, accurate follow-up and prevention strategies (e.g., weight control and regular physical exercise) are needed to reduce the subsequent development of overt diabetes and other metabolic abnormalities related to cardiovascular disease. Therefore, our paper will provide arguments in favor of performing follow-up programs aimed at modifying risk factors involved in the pathogenesis of Type 2 diabetes and cardiovascular disease.

Keywords

cardiovascular disease gestational diabetes lifestyle metabolic syndrome prevention of diabetes Type 2 diabetes

Gestational diabetes mellitus (GDM), defined as “glucose intolerance of any degree with onset or first recognition during pregnancy,” is a common complication in pregnancy, occurring in 4- –7% of pregnant women; it represents 90% of all cases of diabetes mellitus that are diagnosed during pregnancy [1].

Incidence rates of GDM are increasing in all ethnic groups, reflecting the increased prevalence of obesity and Type 2 diabetes mellitus (T2DM) within the general population. Both obesity and a family history of T2DM represent important risk factors for the development of GDM [2 –4].

In the short term, GDM is associated with an increased risk of adverse obstetrical outcomes, particularly those related to fetal overgrowth, which include macrosomia, shoulder dystocia, birth injury, prematurity and an increased Caesarean section rate [5].

Despite normal glucose tolerance in the imme-diate postpartum, women with GDM are at high risk for subsequent development of metabolic diseases. Development of T2DM, for instance, is much greater among women with previous GDM (pGDM). These women also tend to display features of metabolic syndrome (MS) such as hypertension, dyslipidemia and microalbuminuria, which increase the risk for atherogenic insult [6]. Women with pGDM should, therefore, be enrolled in follow-up programs designed to ensure continuous surveillance with the aim of providing effective prevention of T2DM and cardiovascular diseases (CVD).

This review examines the available evidence with regard to the associations between GDM, T2DM and CVD. We also describe possible strategies to prevent these abnormalities in high-risk women, with a focus on lifestyle modification.

Glucose homeostasis in pregnancy

In order to better evaluate the potential longterm implications of GDM, we first considered the physiology of glucose homeostasis in pregnancy, underlining those modifications that are more likely to lead to the development of GDM.

Pregnancy is characterized by a complex endocrine-metabolic adaptation process including impaired insulin sensitivity, increased β-cell response, moderately increased blood glucose levels (particularly following the ingestion of a meal), and changes in the levels of circulating free fatty acids, triglycerides, cholesterol and phospholipids [7]. These changes do not reflect a pathological condition; rather, they represent a necessary and indispensable adaptation to meet the energy demands of the fetus and to prepare the maternal organism for delivery and lactation. In fact, the insulin resistance developing in pregnancy is likely to be a physiological event favoring glucose supply to the fetus. The reduced insulin-mediated utilization of glucose switches the maternal energy metabolism from metabolizing carbohydrates to lipid substrates (i.e., free fatty acids), redirecting carbohydrates toward the fetal tissues [8].

The insulin resistance that develops during pregnancy is similar to that observed in T2DM, with impaired insulin action mainly as a result of postreceptor alterations involving glucose transport and intracellular metabolism in insulin-sensitive tissues [9]. The degree of insulin resistance seems to be influenced by obesity and inheritance. In fact, in obese women (BMI > 30; or weight > 150% of ideal body weight) the incidence of GDM is 1.4- to 20-fold higher than that in normal weight subjects [10].

Despite insulin resistance, glucose homeostasis is maintained in normal pregnancies by a concomitant compensatory increase in insulin secretion. The intolerance to carbohydrates develops as soon as β-cell secretion is no longer sufficient to compensate for insulin resistance (Figure 1) [11].

Figure 1.

Endocrine–metabolic adaptation to meet the energy demand of the fetus.

Although the specific mechanism(s) of the alteration of insulin secretion and action remain uncertain, a substantial contribution is made by endocrine modifications that accompany pregnancy. Changes in β-cell function occur in parallel with the development of the feto–placental unit and the local production of hormones, such as estrogens, progesterone, cortisol, human chorionic somatotropin, placental lactogen, prolactin and growth hormone (Table 1). These hormones have been shown to induce insulin resistance both in vitro and in vivo [12]. Moreover, the increase of TNF-α, an inflammatory marker, is the strongest predictor of impaired insulin action during pregnancy, far stronger than gestational hormones such as human placental lactogen and steroids [13].

Table 1.

Hormones associated with modification in insulin secretion and action.

Hormone	Modification
Estrogens	↑ Insulin concentration↑ Insulin binding
Progesterone	↓ Glucose transport↓ Insulin binding↓ Suppression of hepatic neoglucogenesis
Cortisol	↑ Insulin resistance↓ Phosporylation of insulin receptor↓ Insulin receptor substrate-1
Placental lactogen(hypothalamo–pituitary–inter-renal, growth hormone and prolactin)	↓ Insulin sensitivity↑ Insulin secretion↑ Insulin synthesis↑ Utilization and glucose oxidation ↑ cAMP metabolism↑ β-cell number↑ β-cell mass
Glucagon	↑ Insulin resistance

Adapted from [7].

In women with GDM, the impaired insulin-mediated glucose utilization and the inadequate increase in first-phase insulin secretion are the initial alterations of glucose homeostasis that cause the plasma glucose excursion after meal ingestion and postoral glucose tolerance test (OGTT) hyperglicemia. The loss of early insulin release in these women is likely to contribute to the glucose intolerance and postprandial hyperglycemia, and is considered to be a marker of glucose homeostasis impairment. Xiang et al. estimated that women with GDM have a 67% reduction in pancreatic β-cell effect as compared with normal pregnant women [14].

GDM: a risk for T2DM

Although glucose tolerance returns to normal levels after delivery in the majority of women with GDM, this condition represents an early stage in the natural history of T2DM to many clinicians [15,16]. The strength of the association between GDM and T2DM, and the knowledge that both conditions have many of the same risk factors (e.g., family history for diabetes, overweight, increased age and ethnic group), suggest a common genetic background for GDM and T2DM. In accordance with this hypothesis, it has been reported that women with pGDM more frequently display some alleles associated with the high risk of T2DM [17,18].

The transition time from GDM to overt T2DM can be shortened as a function of the number of pregnancies. According to Peters et al., a second pregnancy is associated with a threefold increase in the risk of developing T2DM in women with a pGDM [19], suggesting that recurrence of insulin-resistant states can accelerate the decline of β-cell function. Several factors are known to contribute to evolution toward overt T2DM. Indeed, this is more frequent in women for whom (Box 1) [20,21]:

GDM is diagnosed before the 24th week of pregnancy (5-year risk: 80%);

Fasting glucose levels before pregnancy are higher;

A defect in insulin secretion is apparent;

Insulin therapy is indicated during pregnancy;

Obesity precedes pregnancy (risk; 50–75%);

A positive family history of diabetes mellitus exists;

Bodyweight increases excessively in the postpartum;

Ethnicity is non-Caucasian.

The differences of diagnostic tests, of criteria for GDM, of the ethnic groups and of the length of follow-up, do not allow one to assess the true prevalence of T2DM in women with pGDM, nor the rate of conversion from GDM to T2DM.

In the classic studies by O'Sullivan performed 30 years ago, diabetes was diagnosed in 36% of women 22–28 years after pregnancy with GDM [22]. In 2002, Kim and colleagues conducted a systematic literature review of articles published between 1965 and 2001 [23]. A total of 28 follow-up studies, performed between 6 weeks to 28 years postpartum were examined, and the cumulative incidence of diabetes ranged from 2.6% to over 70%. The authors reported that after adjustment for various lengths of follow-up and testing rates, the cumulative incidence of T2DM increased in the first 5 years after delivery and reached a plateau after 10 years.

More recently, in a meta-analysis performed by Cheung and colleagues from six controlled follow-up studies, the overall relative risk for developing diabetes after GDM was calculated to be 6.0 [24]. The authors, estimating that 10–31% of parous women with diabetes have had GDM, underlined the population health significance of GDM.

Our population, including 160 women with pGDM, underwent an OGTT 1–3 years after delivery; five (3.81%) had diabetes and 31 (19.37%) had impaired glucose regulation (i.e., impaired glucose tolerance and/or impaired fasting glucose) [25]. Prepregnancy BMI, fasting and 120-min glucose levels were independent contributors of postpartum diabetes or impaired glucose regulation. Notably, at postpartum follow-up, all women with normal pregnancy were normotolerant and all pGDM women who were found to be normo-tolerant had significantly higher fasting and post-challenge plasma glucose levels compared with control women.

More recently, Bellamy and colleagues performed a new meta-analysis of cohort studies in which women who had developed T2DM after GDM were followed-up between 1965 and 2009 [26]. Their analysis, including 20 studies of 675,455 women and 10,859 cases of T2DM, reported that women with pGDM have at least a 7.5-times increased risk of developing T2DM in the future compared with those with normoglycemic pregnancy. Moreover, the authors reported that within 5 years of a pregnancy complicated by gestational diabetes, women had a relative risk of 4.69, which more than doubled to 9.34 in those who were examined more than 5 years postpartum.

Box 1.

Antepartum predictors of diabetes risk after gestational diabetes mellitus.

Ethnic group

Family history of maternal Type 2 diabetes

BMI at diagnosis of gestational diabetes mellitus

Diagnosis early in pregnancy

Impaired β-cell function

Magnitude of hyperglycemia

Insulin therapy during pregnancy

Increased body weight during pregnancy

GDM: a risk for cardiovascular disease

In addition to T2DM, women with pGDM also tend to display features of the MS, such as hypertension, dyslipidemia and microalbuminuria [6], and they may present an increased cardiovascular risk factor profile (Figure 2) [27,28]. In this context they show elevated total cholesterol, LDL-cholesterol and triglyceride concentrations and low HDL-cholesterol [29,30].

Figure 2.

Gestational diabetes mellitus: a risk for Type 2 diabetes and for cardiovascular disease later in life.

Moreover, other nontraditional cardio-metabolic risk factors, such as higher levels of plasminogen activator type 1, acute-phase inflammatory biomarkers (e.g., leukocyte count, fibrinogen, C-reactive protein and sialic acid) and low circulating levels of adiponectin have been found in women with pGDM [31 –34]. As a consequence, MS prevalence after a GDM- complicated pregnancy is significantly higher than in women with normal pregnancy, in just the first 10 years following the index pregnancy (Figure 3) [35 –37]. In a previous study, we have demonstrated that the rate of MS was 9% in women with pGDM and 1% in the control group in a cohort of women with pGDM 16 months after delivery [34]. Based on this observation, it appears rational to propose that pGDM should be considered a manifestation of this syndrome.

Figure 3.

Follow-up program for the prevention of T2DM in women with previous gestational diabetes mellitus.

The observation that the association between subclinical inflammation and MS occurs more frequently in women with pGDM than in women with normal pregnancy makes plausible the theory that these women may be exposed to a more atherogenic insult [38]. In fact, studies performed in these women have demonstrated increased vascular dysfunction, including impaired endothelium-dependent vasodilatation, increased vessel stiffness, early abnormalities in diastolic function and impaired cardiac autonomic function [33,39 –41]. In this context, we observed that relatively young women, just 2 years after index pregnancy, are at risk for the early onset of subclinical atherosclerosis, as indicated by increased carotid artery intima-media thickness (Table 2) [42]. Therefore, pregnancy offers an important opportunity for assessing the risk of cardiovascular and metabolic disease, and it could be considered as an event with the potential to unveil a pre-existing susceptibility that is higher in women who previously developed GDM.

Table 2.

Vascular function after gestational diabetes mellitus.

Study	Previous GDM (n)	Method of assessment	Results	Ref.
Hu (1988)	17	Echo tracking of aorta	Impaired	[44]
Anastasiou et al. (1998)	33	Flow-mediated dilatation	Impaired	[41]
Honnemann et al. (2002)	17	Flow-mediated dilatation	Normal	[40]
Paradisi et al. (2002)	25	Flow-mediated dilatation	Impaired	[39]
Heitritter et al. (2005)	23	Echo tracking of aorta	Stroke volume: reducedTotal peripheral resistance: increased	[33]
Bo et al. (2006)	82	Intima-media thickness	Higher	[28]
Volpe et al. (2008)	28	Intima-media thickness	Higher	[42]

GDM: Gestational diabetes mellitus.

Recently, this anticipated association between pGDM and subsequent CVD has been confirmed by Shah et al. [43]. Their study included 8191 women with GDM and 81,262 women without GDM in matched cohorts, with mean ages of 31 years at entry and median follow-up of 11.5 years. The hazard ratio for CVD events was 1.71. They concluded that the increased risk was attributable to subsequent development of T2DM. The importance of these data is that cardiovascular events have been registered in young women. This study confirms the previous observation of Carr et al. who, in a retrospective study of premenopausal women with a family history of T2DM, found that women with pGDM had a higher prevalence of CVD risk factors, including MS and T2DM, but also of CVD events at a younger age compared with those without GDM [44].

The potential role of overt T2DM in determining the vascular risk associated with pGDM remains unclear. However, considering the low period of time generally required for the development of CVD in T2DM, it seems unlikely that diabetes precedes the onset of CVD in women with pGDM. T2DM and CVD probably develop in parallel in this patient group.

Prevention of T2DM & CVD

The American Diabetes Association recommends that women with GDM should be reclassified at 6 weeks after the index pregnancy in order to detect persistent glucose abnormalities [45]. For those who maintain impaired fasting glucose or glucose intolerance after the pregnancy, annual OGTTs should be performed. Furthermore, women with pGDM who give normotolerant results at the first evaluation after delivery should have an OGTT with regular intervals, beginning 1 year after pregnancy. Markers of MS, such as abdominal circumferences, blood pressure and lipid profile may be investigated in addition to the OGTT (Figure 3).

Although follow-up recommendations for women with pGDM are well defined, there are numerous citations in the literature documenting a lack of follow-up care during the postpartum period for GDM [46 –48]. A lack of primary care survillance in a relatively young, mobile population that underestimates their risk of T2DM, and the difficulties associated with adherence to diet and exercise in women who are busy providing care for young children, do not easily allow for a high rate of postpartum follow-up that remain only approximately 50% in this population [49].

It is now well documented in different populations, including Americans [50], Finnish [51] and Asians [52] with prediabetes, that lifestyle changes with increased physical activity, weight loss and a healthy diet can reduce the risk of progressing to T2DM. In addition, pharmacological intervention (e.g., with metformin [50]) has been found to reduce progression to T2DM. Although a common characteristic of these studies is that the subjects were seen intensively over a long period of time, it seems rational to consider similar interventions in women with pGDM. Women with self-reported pGDM, who form a subset of the population who enrolled in the Diabetes Prevention Program, experienced a 55% reduction in the development of T2DM with the lifestyle intervention when compared with those in the placebo group [53]. Considering that this study was limited by the self-reporting of pGDM and the fact that diagnosis of GDM was not validated, these results should not be considered conclusive. Other studies on this topic are not available. Therefore, in order to determine the potential benefit of lifestyle modification and in order to evaluate the most effective way to achieve it, postpartum studies of healthy diet and exercise plans should be performed in women with pGDM.

Several randomized clinical trials have specifically studied diabetes prevention with pharmacological intervention in women with pGDM. Buchanan et al., in the Troglitazone in the Prevention of Diabetes (TRIPOD) study [54], found a 55% risk reduction in progression to T2DM in women who received troglitazone when compared with those who received placebo. They reported an improvement of insulin sensitivity that persisted for 8 months after study medication stopped. The Pioglitazone in Prevention of Diabetes (PIPOD) study [55] enrolled women who had completed the previous study without developing T2DM. A 4.6% yearly incidence rate of T2DM was reported in the pioglitazone group, which was significantly lower than that reported in placebo group (12%). Women with pGDM enrolled in the Diabetes Prevention Program and treated with metformin had a 50% reduction of diabetes risk. However, in the same study, treatment with met-formin was associated with a 14% T2DM risk reduction in women without pGDM [56].

Future perspective

Several opportunities exist for the prevention of T2DM and CVD in women with pGDM, such as education regarding risk awareness, implementation of a healthy lifestyle and pharmacological intervention.

Although GDM is a well-established risk factor for T2DM, many women could be unaware of this increased risk. Interventions are clearly needed in order to increase awareness and acceptance of the personal risk of developing T2DM in women with pGDM. Moreover, considering that not only women with GDM, but also those with mild glucose intolerance in pregnancy are at risk of CVD [57], public education campaigns could be performed for all women with any degree of glucose disturbance during pregnancy.

Postpartum studies of healthy diet and exercise plans should now be performed in women with pGDM in order to determine their potential benefits and to evaluate the most effective way to achieve lifestyle modification in this population. Moreover, considering that breastfeeding is associated with a reduced incidence of T2DM among both women with pGDM and women in the general population [58], the promotion of a combination of breastfeeding, diet and physical activity could reduce maternal T2DM risk, and might be particularly important in women with pGDM.

Executive summary

Gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is a common complication in pregnancy, occurring in 4–7% of pregnant women.

GDM develops as soon as β-cell secretion is no longer sufficient to compensate for physiological insulin resistance, which becomes evident in the second half of pregnancy.

Obesity and a positive family history of Type 2 diabetes (T2DM) are the most significant risk factors for the development of GDM.

GDM: a risk factor for T2DM

Although after delivery glucose tolerance returns to normal in the majority of women with GDM, for many clinicians GDM represents an early stage in the natural history of T2DM.

Factors that contribute to evolution toward overt T2DM are: an early diagnosis of GDM, fasting glucose levels before pregnancy, insulin therapy, prepregnancy obesity, positive family history of diabetes mellitus and excessive weight gain.

Cumulative incidence of T2DM increases in the first 5 years after delivery and reaches a plateau after 10 years.

GDM: a risk for cardiovascular disease

Women with previous GDM (pGDM) tend to display features of the metabolic syndrome (MS), such as hypertension, dyslipidemia and microalbuminuria, and they may present an enhanced cardiovascular risk factor profile.

MS prevalence after a GDM-complicated pregnancy is significantly higher than in women with normal pregnancy.

Impaired endothelium-dependent vasodilatation, increased vessel stiffness, early abnormalities in diastolic function and impaired cardiac autonomic function are reported in women with pGDM at a relatively young age.

The hazard ratio for cardiovascular disease (CVD) events in pGDM women is reported to be 1.71.

Prevention of T2DM & CVD

GDM must be reclassified at 6 weeks after the index pregnancy to detect persistent glucose abnormalities; women with pGDM should have an oral glucose tolerance test (OGTT) with regular intervals, beginning 1 year after pregnancy. Markers of the MS, blood pressure and lipid profile may be investigated in addition to the OGTT.

To reduce the risk of progressing to diabetes and other metabolic abnormalities, lifestyle changes with increased physical activity, weight loss and a healthy diet must be recommended to these women.

Several randomized clinical trials, using drugs that ameliorate insulin action, have specifically studied diabetes prevention with a pharmacologic intervention in women with pGDM.

Future perspective

Interventions are needed in order to increase awareness and acceptance of the personal risk for the development of T2DM in women with pGDM. Public education campaigns could help to increase patient risk-awareness.

Additional pharmacological studies are still needed to evaluate the cost-effectiveness of the prevention of both T2DM and CVD.

Long-term, continuous programs specifically addressed to women with pGDM could be performed in order to permit them to regularly check glucose tolerance, lipid profile, blood pressure and other parameters aimed at improving women's health.

Several randomized clinical trials using drugs that improve insulin sensitivity have specifically studied T2DM prevention with pharmacological intervention in women with pGDM [54 –56]. Although the results of these studies are promising, it should be noted that these medications are not currently approved for use in T2DM prevention. Additional studies are still needed to evaluate the cost-effectiveness of these medications for the prevention of both T2DM and CVD, alone or in combination with new medications.

Furthermore, all women with pGDM should be offered regular checkups of their glucose tolerance, lipid profile, weight and blood pressure.

In order to implement these measures, it is necessary to offer a long-term, continuous programs for these women. Based on the available evidence, a major aim during the next decade will be to implement such programs that might have an important effect on women's health.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

References

Papers of special note have been highlighted as:

of interest

of considerable interest

American Diabetes Association: Diagnosis and classification of diabetes mellitus. Diabetes Care 29(Suppl. 1), S43–S48 (2006).

Lawrence

Contreras

Chen

: Trends in the prevalence of pre-existing diabetes and gestational diabetes mellitus among a racially/ethnically diverse population of pregnant women, 1999-2005. Diabetes Care 31, 899–904 (2008).

Ogden

Carroll

Curtin

: Prevalence of overweight and obesity in the United States, 1999-2004. JAMA 295, 1549–1555 (2006).

Mokdad

Ford

Bowman

: Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 289, 76–79 (2003).

Casey

Lucas

Mcintire

: Pregnancy outcomes in women with gestational diabetes compared with the general obstetric population. Obstet. Gynecol. 90, 869–873 (1997).

Buchanan

Xiang

: Gestational diabetes mellitus. J. Clin. Invest. 115, 485–491 (2005).

10.

Excellent general review regarding the pathogenensis of gestational diabetes mellitus (GDM) that underlines the link between GDM and Type 2 diabetes (T2DM).

11.

Di Cianni

Miccoli

Volpe

: Intermediate metabolism in normal pregnancy and in pregnacy complicated by gestational diabetes. Diab. Metab. Res. Rev. 19, 259–270 (2003).

12.

Butte

: Carbohydrate and lipid metabolism in pregnancy: normal compared with gestational diabetes mellitus. Am. J. Clin. Nutr. 71(Suppl. 5), S1256–S1261 (2000).

13.

Landmark review on intermediate metabolism in pregnancy.

14.

Shao

Catalano

Yamashita

: Decreased insulin receptor tyrosine kinase activity and plasma cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women with gestational diabetes mellitus (GDM): evidence for increased serine/threonine phosphorylation in pregnancy and GDM. Diabetes 49(4), 603–610 (2000).

15.

Galtier-Dereure

Boegner

Bringer

: Obesity and pregnancy: complications and cost. Am. J. Clin. Nutr. 71(Suppl. 5), S1242–S1248 (2000).

16.

Buchanan

: Pancreatic B-cell defects in gestational diabetes: implications for the pathogenesis and prevention of Type 2 diabetes. J. Clin. Endocrinol. Metab. 86, 989–993 (2001).

17.

Sorenson

Brelje

Roth

: Effects of steroid and lactogenic hormones on islets of Langerhans: a new hypothesis for the role of pregnancy steroids in the adaptation of islets to pregnancy. Endocrinology 133, 2227–2234 (1993).

18.

Kirwan

Mouzon

Hauguel-De S

Lepercq

: TNF-α is a predictor of insulin resistance in human pregnancy. Diabetes 51, 2207–2213 (2002)

19.

Xiang

Ruth

Trigo

: Multiple metabolic defects during late pregnancy in women at high risk for Type 2 diabetes. Diabetes 48, 848–854 (1999).

20.

Pendergrass

Fazione

De Fronzo

: Non insulindependent diabetes mellitus and gestational diabetes mellitus: same disease, another name? Diabetes Rev. 3, 566–584 (1995).

21.

Ben Haroush

Yogev

Hod

: Epidemiology of gestational diabetes mellitus and its association with Type 2 diabetes. Diabet. Med. 21, 103–113 (2004).

22.

Lauenborg

Grarup

Damm

: Common Type 2 diabetes risk gene variants associate with gestational diabetes. J. Clin. Endocrinol. Metab. 94, 145–150 (2009).

23.

Cho

Kim

Choi

: Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes in the Korean population. Diabetologia 52, 253–261 (2009).

24.

Peters

Kjos

Xiang

: Long term diabetogenic effect of single pregnancy in women with previous gestational diabetes mellitus. Lancet 347, 227–230 (1996).

25.

Lobner

Knopff

Baumgarten

: Predictors of postpartum diabetes in women with gestational diabetes mellitus. Diabetes 55, 792–797 (2006).

26.

Alberg

Jonsonn

Eskilsson

: Predictive factors of developing diabetes mellitus in women with gestational diabetes. Acta Obstet. Gynecol. Scand. 81, 11–16 (2002).

27.

O'Sullivan

: Gestational diabetes: factors influencing the rates of subsequent diabetes. In: Carbohydrate Metabolism in Pregnancy and the Newborn. Sutherland

Stowers

(Eds). Sprinter-Verlag, NY, USA, 425–435 (1979).

28.

Historical study that first reported the high prevalence of T2DM after GDM.

29.

Kim

Newton

Knopp

: Gestational diabetes and the incidence of Type 2 diabetes. Diabetes Care 25, 1862–1868 (2002).

30.

Systematic review examining factors associated with variations in the risk for T2DM in women with previous GDM (pGDM).

31.

Cheung

Byth

: Population health significance of gestational diabetes. Diabetes Care 26, 2005–2009 (2003).

32.

Meta-analysis underlining the public health significance of GDM.

33.

Lencioni

Volpe

Miccoli

: Early impairment of B-cell function and insulin sensitivity characterizes normotolerant Caucasian women with previous gestational diabetes. Nut. Metab. Cardiov. Dis. 16, 485–493 (2006).

34.

Bellamy

Casas

Hingorani

: Type 2 diabetes mellitus after gestational diabetes: a systematic review and meta-analysis. Lancet 373, 1773–1779 (2009).

35.

More recent meta-analysis of a large cohort of women with GDM, finding that they have an increased risk of developing T2DM.

36.

Marshall

Carpenter

: Gestational diabetes, pregnancy hypertension, and late vascular disease. Diabetes Care 30(Suppl. 2), S246–S250 (2007).

37.

Valpreda

Menato

: Should we consider gestational diabetes a vascular risk factor? Atherosclerosis 194(2), 72–79 (2007).

38.

Demonstrates higher values of markers of endothelial dysfunction and intima-media thickness in women with pGDM than controls. This study shows that women with pGDM have higher values of markers of endothelial dysfuction and intima-media thckness than controls.

39.

Meyers-Seifer

Vohr

: Lipid levels in former gestational diabetic mothers. Diabetes Care 19(12), 1351–1356 (1996)

40.

Kousta

Efstathiadou

Lawrence

: The impact of ethnicity on glucose regulation and the metabolic syndrome following gestational diabetes. Diabetologia 49(1), 36–40 (2006).

41.

Winzer

Wagner

Shneider

: Plasma adiponectin, insulin sensitivity, and subclinical inflammation in women with prior gestational diabetes mellitus. Diabetes Care 27(7), 1721–1727 (2004).

42.

Di Benedetto

Russo

Corrado

: Inflammatory markers in women with a recent history of gestational diabetes mellitus. J. Endocrinol. Invest. 28, 34–38 (2005).

43.

Heitritter

Solomon

Mitchell

: Subclinical inflammation and vascular dysfunction in women with previous gestational diabetes mellitus. J. Clin. Endocrinol. Metab. 90, 3983–3988 (2005).

44.

Di Cianni

Lencioni

Volpe

: C-reactive protein and metabolic syndrome in women with previous gestational diabetes. Diabetes Metab. Res. Rev. 23, 135–140 (2007).

45.

Verma

Boney

Tucker

Vohr

: Insulin resistance syndrome in women with prior history of gestational diabetes mellitus. J. Clin. Endocrinol. Metab. 87, 3227–3235 (2002).

46.

Longitudinal study indicating that women with pGDM have a considerably increased risk of developing metabolic syndrome.

47.

Lauenborg

Mathiesen

Hansen

: The prevalence of the metabolic syndrome in a Danish population of women with previous gestational diabetes mellitus is three-fold higher than in the general population. JCEM 90(7), 4004–4010(2005).

48.

Albareda

Caballero

Badell

: Metabolic syndrome at follow-up in women with and without gestational diabetes mellitus in index pregnancy. Metabolism 54(8), 1115–1121 (2005).

49.

Volpe

Di Cianni

Lencioni

: Gestational diabetes, inflammation, and late vascular disease. J. Endocrinol. Invest. 30, 873–879 (2007).

50.

Paradisi

Biaggi

Ferrazzani

De Carolis

Caruso

: Abnormal carbohydrate metabolism during pregnancy: association with endothelial dysfunction. Diabetes Care 25, 560–564 (2002).

51.

Hannemann

Liddell

Shore

: Vascular function in women with previous gestational diabetes mellitus. J. Vasc. Res. 39, 311–319 (2002).

52.

Anastasiou

Lekaris

Alevizaki

: Impaired endothelium-dependent vasodilatiation in women with previous gestational diabetes. Diabetes Care 2, 2111–2115 (1998)

53.

Volpe

Cuccuru

Lencioni

: Early subclinical atherosclerosis in women with previous gestational diabetes mellitus. Diabetes Care 31, E32 (2008).

54.

Shah

Retnakaran

Booth

: Increased risk of cardiovascular disease in young women following gestational diabetes mellitus. Diabetes Care 31, 1668–1669 (2008).

55.

Carr

Utzschneider

Hull

: Gestational diabetes mellitus increases the risk of cardiovascular disease in women with a family history. Diabetes Care 29, 2078–2083 (2006).

56.

First retrospective study demonstrating that women with pGDM have increased cardiovascular disease events.

57.

American Diabetes Association: Position statement. Diagnosis and classification of diabetes mellitus. Diabetes Care 30(Suppl. 1), S4–S47 (2007).

58.

Clark

Walraven

Code

: Did publication of a clinical practice guideline recommendation to screen for Type 2 diabetes in women with gestational diabetes change practice? Diabetes Care 26, 265–268 (2003).

59.

Gabbe

Pratt

Powe

: Management of diabetes mellitus by Ob/GYNs. Obstet. Gynecol. 103, 1229–1234 (2004).

60.

Rumbold

Crowther

: Guideline use for gestational diabetes mellitus and current screening, diagnosis and management practices in Australian hospitals. Aust. NZ J. Obstet. Gynaecol. 41(1), 86–90 (2001).

61.

Lewis

Levkoff

Stuebe

: Gestational diabetes mellitus: postpartum opportunities for the diagnosis and prevention of Type 2 diabetes mellitus. Nat. Clin. Pract. Endocrinol. Metab. 4(10), 552–558 (2008).

62.

Knowler

Barrett-Connor

Fowler

: Reduction in the incidence of Type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393–403 (2002).

63.

Tuomilehto

Lindström

Eriksson

: Prevention of Type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N. Engl. J. Med. 344, 1343–1350 (2001).

64.

Pan

: Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Quing IGT and diabetes study. Diabetes Care 20, 537–544 (1997).

65.

Ratner

: Prevention of Type 2 diabetes in women with previous gestational diabetes. Diabetes Care 30(Suppl. 2), S242–S245 (2007).

66.

Buchanan

Xiang

Peters

: Preservation of pancreatic β-cell function and prevention of Type 2 diabetes by pharmacological treatment of insulin resistance in high risk Hispanic women. Diabetes 51, 2796–2803 (2002).

67.

Randomized clinical trial that found reduced risk of T2DM in women with pGDM who received a drug that meliorates insulin resistance.

68.

Xiang

Peters

Kjos

: Effect of pioglitazone on pancreatic β-cell function and diabetes risk in Hispanic women with prior gestational diabetes. Diabetes 55, 517–522 (2006).

69.

Trial results of interest.

70.

Ratner

Christophi

Metzger

: Prevention of diabetes in women with a history of gestational diabetes: effects of metformin and lifestyle interventions. J. Clin. Endocrinol. Metab. 93, 4774–4779 (2008).

71.

Retnakaran

Shah

: Mild glucose intolerance in pregnancy and risk of cardiovascular disease: a population-based cohort study. CMAJ DOI:10.1503/cmay.090569 (2009) (Epub ahead of print).

72.

Taylor

Kacmar

Nothnagle

: A systematic review of the literature associating breastfeading with Type 2 diabetes and gestational diabetes. J. Am. Coll. Nutr. 24, 320–326 (2005).

Gestational Diabetes Mellitus: An Opportunity to Prevent Type 2 Diabetes and Cardiovascular Disease in Young Women

Abstract

Keywords

Glucose homeostasis in pregnancy

GDM: a risk for T2DM

GDM: a risk for cardiovascular disease

Prevention of T2DM & CVD

Future perspective

Footnotes

References