Defective Insulin Secretion

Decreased insulin secretion in offspring of mothers with diabetes has been reported in both animal studies involving the GK rat (48, 69), as well as human studies (29, 43, 70). It is thought that exposure to excess maternal fuels during critical periods in fetal development may lead to permanent changes in physiology, referred to as "programming." In the course of fetal development, the endocrine pancreas begins developing at around 7-8 weeks of gestation, with evidence of insulin, glucagon and somatastatin coproduction (71). Insulin and glucagon are produced by differentiated pancreatic islet cells during the second half of gestation (72). The differentiation, proliferation, innervation and vascularization of the pancreatic islet cells, therefore, could be affected by an altered intrauterine environment during the second half of gestation.

The b-cell mass may be altered in the offspring of mothers with diabetes, dependent on the severity of the hyperglycemia. From animal studies, moderate maternal hyperglycemia has been demonstrated to increase proliferation of b cells, leading to enhanced b-cell mass. Severe hyperglycemia in sheep, on the other hand, is associated with degranulation of the b cell, decreased insulin content and reduced glucose-stimulated insulin secretion (72).

Pancreatic angiogenesis and innervation may also be affected by maternal diabetes in utero. Pancreatic islet development is dependent on a number of growth factors, and vascularization of the islet cells is controlled by vascular endothelial growth factors (VEGFs) expressed by newly differentiated islet cells. Reduced angiogenesis in response to excess maternal fuels is a possible mechanism for reduced b-cell mass, since pancreatic growth is dependent on adequate vascularization. VEGF is regulated by glucose, and there is evidence from animal studies that maternal hyperglycemia can cause defects in angiogenesis in mouse embryos (73). Similarly, the innervation of the pancreas may be altered by the intrauterine fuel availability, leading to changes in the function of the islet cells (72) such as glucose-stimulated insulin secretion. A number of other possible mechanisms could be involved in reduced insulin secretion in response to glucose, including altered ion channels, changes in glucokinase and GLUT 2, and reduced prohormone convertase 2 activity.

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