Differential Effects of Chronic Pulsatile versus Chronic Constant Maternal Hyperglycemia on Fetal Pancreaticβ-Cells

Mackenzie S Frost,Sean W Limesand,William W Hay,Paul J Rozance,Aqib H Zehri

doi:10.1155/2012/812094

Mackenzie S Frost, Sean W Limesand + Show 3 more

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https://doi.org/10.1155/2012/812094

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Abstract

Constant maternal hyperglycemia limits, while pulsatile maternal hyperglycemia may enhance, fetal glucose-stimulated insulin secretion (GSIS) in sheep. However, the impact of such different patterns of hyperglycemia on the development of the fetal β-cell is unknown. We measured the impact of one week of chronic constant hyperglycemia (CHG, n = 6) versus pulsatile hyperglycemia (PHG, n = 5) versus controls (n = 7) on the percentage of the fetal pancreas staining for insulin (β-cell area), mitotic and apoptotic indices and size of fetal β-cells, and fetal insulin secretion in sheep. Baseline insulin concentrations were higher in CHG fetuses (P < 0.05) compared to controls and PHG. GSIS was lower in the CHG group (P < 0.005) compared to controls and PHG. PHG β-cell area was increased 50% (P < 0.05) compared to controls and CHG. CHG β-cell apoptosis was increased over 400% (P < 0.05) compared to controls and PHG. These results indicate that late gestation constant maternal hyperglycemia leads to significant β-cell toxicity (increased apoptosis and decreased GSIS). Furthermore, pulsatile maternal hyperglycemia increases pancreatic β-cell area but did not increase GSIS, indicating decreased β-cell responsiveness. These findings demonstrate differential effects that the pattern of maternal hyperglycemia has on fetal pancreatic β-cell development, which might contribute to later life limitation in insulin secretion.

Highlights

Fetuses exposed to chronic hyperglycemia secondary to maternal diabetes are prone to develop β-cell hyperplasia and increased insulin secretion that underlie increased postnatal risk of exaggerated glucose-stimulated insulin secretion (GSIS) and hyperinsulinemic hypoglycemia [1,2,3,4,5,6]
Previous studies in pregnant sheep have tested the impact of chronic hyperglycemia on fetal β-cell function, using controlled experimental manipulation of maternal and fetal glucose concentrations and in vivo measurement of fetal insulin secretion to begin to determine mechanisms responsible for the impact of different patterns of maternal and fetal glucose concentration, as occur in diabetic pregnancies, on fetal GSIS [7,8,9,10,11]
Maternal arterial plasma glucose concentrations were significantly increased in the CHG and PHG groups compared to controls throughout the infusion (P < 0.0001, Figure 1(a))

Summary

Introduction

Fetuses exposed to chronic hyperglycemia secondary to maternal diabetes are prone to develop β-cell hyperplasia and increased insulin secretion that underlie increased postnatal risk of exaggerated glucose-stimulated insulin secretion (GSIS) and hyperinsulinemic hypoglycemia [1,2,3,4,5,6]. Previous studies in pregnant sheep have tested the impact of chronic hyperglycemia on fetal β-cell function, using controlled experimental manipulation of maternal and fetal glucose concentrations and in vivo measurement of fetal insulin secretion to begin to determine mechanisms responsible for the impact of different patterns of maternal and fetal glucose concentration, as occur in diabetic pregnancies, on fetal GSIS [7,8,9,10,11] Such studies demonstrated that constant maternal hyperglycemia produced an initial increase in fetal glucose and insulin concentrations [9], but over eight to ten days of constant high maternal and fetal glucose concentrations the fetal insulin concentrations returned to normal [8, 9]. After ten days of constant maternal hyperglycemia, fetal GSIS and arginine-stimulated insulin secretion (ASIS) were decreased compared to normal fetuses [8, 9]

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