Pathogenesis of gestational DM
Gestational diabetes (GDM) describes a heterogeneous group of hyperglycemic metabolic disorders detected in pregnancy. The majority of women with GDM are overweight or obese, and many have latent metabolic syndrome, a genetic predisposition to type 2 diabetes, a physically inactive lifestyle and unhealthy eating habits prior to pregnancy. The risk factors for GDM are similar to those of type 2 diabetes: increased waist circumference, dyslipidemia, hypertension, polycystic ovary syndrome, increasing age, family history of diabetes and ethnicity (Asian, Hispanic). Prenatal programming may also contribute to GDM whereby nutritional stress induced by both maternal undernutrition and overnutrition or maternal hyperglycemia during pregnancy persistently alter metabolism of the offspring. A minority of women develop type 1 diabetes in pregnancy, and clinicians should be alert to this possibility, but GDM may in general be regarded as pre-type 2 diabetes.
Gestational diabetes is diabetes first detected in pregnancy. Although type 1 diabetes is more likely to develop in pregnancy, the great majority of women have pre-type 2 diabetes, and many will go on to develop permanent diabetes later in life. If type 1 diabetes is suspected during pregnancy or after delivery, autoimmunity should be confirmed by measurement of antibodies against islet cell antigens (antibodies directed against glutamic acid decarboxylase [GADA], islet antigen-2 [IA-2A]). MODY may also present in pregnancy, and genetic testing is recommended when family history suggests that this phenotype may be present. However, in general GDM can be regarded as pre-Type 2 diabetes.
Physiology of Normal Pregnancy
Pregnancy is a state of physiological insulin resistance, and therefore represents a physiological model of beta-cell stress. In normal pregnancy insulin sensitivity emerges in the second trimester and progresses over the late third trimester, thereby increasing maternal glucose, free fatty acids and amino acids in order to provide adequate energy to the fetus. In normal pregnancy, insulin resistance leads to an appropriate increase of insulin secretion, and blood glucose levels remain in the normal range. Due to the increasing demand of the developing fetus and increased transplacental nutrition transfer, maternal glucose levels are even lower than in healthy non-pregnant women. Healthy pregnant women have peak glucose levels (70 min postprandially) of approximately 120 mg/dl (6.7 mmol/l).
Polymorphisms of susceptible genes of type 2 diabetes such as transcription factor 7-like 2 (TCF7L2), potassium channel voltage-gate KQT-like subfamily member 1 (KCNQ1) and cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) gene have been shown to relate to development of GDM. Although genetic risk mainly relates to impaired insulin secretion, GDM is also characterised by coincident insulin resistance. The pathophysiological changes responsible for insulin resistance in GDM are nor fully clarified but seem to be at a postreceptor level in the insulin signaling pathway. These changes are accompanied by distinct changes of insulin secretion patterns and kinetics.
A heterogeneous condition?
The use of different diagnostic criteria, differing ethnicity and different time points during pregnancy, together with varying follow-up periods postpartum further complicates the comparability and generalizability of studies. Therefore screening and policy varied widely in European countries . The introduction of universal diagnostic criteria by the IADPSG and dissociation of GDM from overt type 2 diabetes first detected early in pregnancy (up to 20 gestational weeks) will hopefully help to enhance reproducibility of results, better clarify the pathophysiologic mechanisms in distinct GDM subgroups and pave the way to personalized therapy and evidence-based recommendations in the future. In 2013 the WHO adopted these new universal criteria including distinction of diabetes in pregnancy and GDM (PDF).
Insulin secretion and insulin sensitivity
The metabolic/endocrine changes accompanying the second half of gestation and inducing physiological pregnancy-related insulin resistance unmask and worsen the underlying pre-existing metabolic disturbances (pre-gestational insulin resistance and relative insulin secretion defect), leading to the full clinical picture of GDM.
Impaired first phase insulin secretion, prolonged and increased second phase insulin release, reduced inulinogenic indices, increased hepatic glucose output (relative to prevailing hyperinsulinemia), changes in insulin kinetics, reduced glucose absorption from the gut and varying degrees of insulin resistance have been described. These abnormalities have been described in women with GDM, as compared to pregnant women with normal glucose tolerance, based upon fasting or dynamic tests (oral and intravenous glucose tolerance tests or clamp studies).
Other Metabolic Changes
Increased fractional release of amylin and proinsulin relative to insulin secretion may be a cause or consequence of dysfunctional insulin secretion and action. In addition, increased ectopic fat mass (intramyocellular and intrahepatic fat) and a slightly impaired flux through myocellular ATP synthase, the final step of mitochondrial oxidative phosphorylation, has also been found in women with GDM. Impaired lipid metabolism with increased FFA concentrations (insulin resistance of the adipose tissue with increased lipolysis) is also characteristic of the condition.
Decreased GLUT-4 transporter levels have been reported in adipocytes but not in muscle of women with GDM, and no significant insulin receptor defect or decrease in insulin binding to the skeletal muscle insulin receptor is present in women with GDM as compared with non-diabetic pregnancy. Impaired insulin receptor autophoshorylation has however been reported, and increased plasma cell membrane glycoprotein-1 content associated with reduced insulin receptor phosphorylation and insulin receptor tyrosine kinase activity has also been described. Decreased IRS-1 but increased p85 protein levels in adipose tissue and their association with impaired lipid metabolism may further contribute to the metabolic disturbances of GDM.
Many studies have set out to characterize women with GDM in terms of potential causes or factors contributing to its pathophysiology. These investigated plasma levels and expression of adipokines and cytokines that might potentially play a role in induction of pregnancy-related normal and pathological insulin resistance or changes in lipid and glucose metabolism.
At present changes of adiponectin and leptin appear to be the most important disturbances, although an increase of TNFα and plasma cortisol levels also parallel the increase of insulin resistance during pregnancy. TNFα may impair the postreceptor insulin signaling cascade in skeletal muscle by activating pathways that increase sphingomyelinases and ceramides.
A decrease of adiponectinand increase of leptin has consistently been described, with; changes in resistin, visfatin, chemerin, vaspin, fetuin-A and many other proteins released from adipose tissue, the liver or the gastrointestinal tract have also been described, but with inconsistent results.
Cytokines, inflammatory and vascular parameters
Inflammatory markers such as CRP, IL-6 and soluble adhesion molecules (ECAM, VCAM, ICAM) and vascular markers (e.g. ADMA) were found to be increased in some studies. In women with GDM or in those with a history of GDM, early endothelial dysfunction associates with the development of glucose dysregulation and other risk factors for atherosclerosis.
Another interesting association can be seen between bone markers and insulin secretion and sensitivity in GDM. Increased osteocalcin and CTX levels in GDM could be regarded as compensatory mechanisms which try to cope with increased demand on insulin secretion, while decreased osteopontin levels may relate to insulin resistance in GDM.
Future studies should extend our current knowledge on pregnancy-associated changes in glucose and lipid metabolism to include new biomarkers which are really able to predict increased risk of perinatal complications at an early stage, and to predict cardiovascular disease and diabetes in mother and offspring over the longer term. We also need evidence of specific screening and treatment strategies that are able to reduce complications during pregnancy and postpartum including obesity, diabetes and cardiovascular disease at follow-up.
Personalized medicine should be available for all women with the heterogeneous entity we refer to as GDM. Important research topics will include studies of offspring of women with a history of GDM, and fetal programming research to increase understanding of the impact of the intrauterine environment on fetal, neonatal and long-term outcomes, and epigenetic studies. More knowledge on sex-differences in fetal programming effects and impact of lactation on health of the offspring and mother will also be important.
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^ Prikoszovich T et al. Body and liver fat mass rather than muscle mitochondrial function determine glucose metabolism in women with a history of gestational diabetes mellitus. Diabetes Care. 2011;34:430-6
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^ Winhofer Y et al. CTX (crosslaps) rather than osteopontin is associated with disturbed glucose metabolism in gestational diabetes. PLoS One. 2012, 7:e40947