In animal models, pregnancy is associated with distinct morphological and functional adaptations in the endocrine pancreas, particularly characterized by β cell hyperplasia and hypertrophy. Failed islet adaptation to increased metabolic demands in pregnancy contributes to the development of gestational diabetes. However, the effects of pregnancy on the remodeling of human endocrine pancreas remain largely unknown. To address this, we used human pancreatic autopsy specimens from 8 women who died during pregnancy or within 6 weeks postpartum (P/PP) , and 16 women who were matched by age and body mass index (BMI) to serve as controls (CON) who were not pregnant at death. Subjects had a complete autopsy with pancreatic tissue of adequate quality/quantity stored and a corresponding medical record. Consecutive pancreatic sections were co-immunostained for key islet cell markers including Insulin, Glucagon and Glucagon-Like Peptide-1 (GLP-1) as well as a marker of cell proliferation (Ki-67) . Although the pancreatic fractional insulin area (β cell area) was comparable between P/PP and CON groups, the glucagon and the GLP-1 positive areas were substantially increased ∼2-fold in the P/PP group (p<0.05) . Our analysis also revealed an increase in the proportion of GLP-1/glucagondouble positive islet cells (p<0.05) in PP/P subjects, suggesting a modulatory effect of pregnancy in favor of increased islet GLP-1 production in α cells. Consistently, P/PP subjects demonstrated an increase in α cell expression of prohormone convertase 1/3 (PC1/3) (p<0.05) , an enzyme responsible for the proteolytic cleavage of GLP-1 from proglucagon. Finally, the frequency of both β and α cell proliferation was comparable between groups (p>0.05) . While prior pre-clinical studies have focused solely on functional and morphological changes in pancreatic β cells, our data suggest that proglucagon gene products (glucagon and GLP-1) may play an underappreciated role in (or serve as markers of) the metabolic changes impacting human pregnancy.


A.M.Egan: None. T.K.Her: None. A.Vella: Advisory Panel; Crinetics Pharmaceuticals, Inc., Rezolute, Inc., vTv Therapeutics, Zealand Pharma A/S, Other Relationship; Novo Nordisk. A.Matveyenko: None.


National Institutes of Health (K12 HD065987/HD/NICHD)

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