Change from physiology to pathophysiology

Identification of the primary metabolic disturbance in GDM would facilitate the development of interventions aimed at prevention as well as treatment. Gestational diabetes mellitus may provide the ideal model for investigating the primary defect which leads to the development of Type 2 diabetes.

Human pregnancy is an insulin-resistant condition. Although there is a 4- to 5-fold range of insulin resistance in the general population, there is a relatively uniform 40-50% increase (from the pregravid condition) in insulin resistance and increase in insulin secretion in obese patients of 60% in the first phase of secretion and 130% in the second phase.7 These alterations in insulin have been previously ascribed to a variety of reproductive hormones such as human placental lactogen, cortisol, progesterone and estrogen.8

More recent data have implicated adypocyte/placental secreted factors such as cytokines, in particular tumor necrosis factor alfa (TNF-a) and leptin as active candidates in the alteration of insulin sensitivity in pregnancy. Adiponectin belongs to the family of adipocytokines which also includes leptin, TNF-a, resistin, interleukin-6 (IL-6), and others.8,9 Adiponectin is associated with obesity, diabetes, cardiovascular disease and dyslipidemia.10-12 From a metabolic standpoint, adiponectin produces an insulin-sensitizing effect on skeletal muscle, adipose tissue a and liver. It has been demonstrated that the level of adiponectins in class A2 and B gestational diabetes are associated with suppressed levels of adiponectins, similar to that found in other insulin-resistant states (Type 2 diabetes and obesity.)

Retnakaran et al.13 reported that C-reactive protein (CRP) levels in late pregnancy relate to pregravid BMI and not to GDM per se. Assuming that the CRP concentrations in late gestation are a marker of insulin resistance, then a woman's pregravid BMI may be the strongest clinical indicator of the degree of her insulin resistance, even in late gestation. The lack of a relationship between CRP and GDM may reflect the wide variation of pregravid BMI to inflammation/insulin resistance rather than the relative uniform decreases observed during pregnancy.14

It has been shown that total oxidative and non-oxidative glucose metabolism is inversely related to increased visceral-to-subcutaneous fat ratio in obese women and to total fat content in lean women. Others have demonstrated decreased insulin sensitivity in subjects with a central pattern of fat distribution. Whatever the cause for increased insulin resistance during pregnancy, in women who maintain normal glucose tolerance, it is offset by a 3- to 3.5-fold increase in insulin secretion.17 The degree of insulin resistance during late gestation appears to be dependent primarily on pregravid maternal insulin resistance, which is quite variable, and secondarily on the 40-50% increases mediated through placental factors.

It is not too surprising that GDM develops in genetically susceptible women when they become pregnant. They probably have some degree of insulin resistance prior to pregnancy and normal pregnancy is associated with severe insulin resistance. Catalano et al.15 found an approximate 21% decrease in insulin sensitivity occurring by 12-14 weeks of gestation and a 56% decrease in insulin sensitivity occurring by 34-36 weeks. Others have found similar results.16-18

In summary, gestational diabetes is characterized by patho-genesis deviating from the normal physiology of pregnancy which involves insulin resistance and decreased insulin secretion. Furthermore, similarity exists between the pathogen-esis of GDM and Type 2 diabetes which are probably one disease at different stages on the spectrum of glucose intolerance.

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