Beneficial effects of lipids and prolactin on insulin secretion and beta-cell proliferation: a role for lipids in the adaptation of islets to pregnancy.
To meet the increased demand for insulin during pregnancy, the pancreatic islets undergo adaptive changes including enhanced insulin secretion and beta-cell proliferation. These changes peak in mid-pregnancy and return to control levels by parturition. Because lactogens (placental lactogen and/or prolactin) induce this up-regulation and remain elevated throughout gestation, we examined whether lipids alter the effects of prolactin on islets. In response to prolactin, there was a 2.5-fold increase in insulin secretion when compared with control islets. There was also a 2.5-fold increase in insulin secretion in response to palmitate and a fivefold increase when islets were cultured with a combination of prolactin and palmitate. After culture with prolactin and palmitate, acute stimulation with 10 mM glucose for 1 h showed a suppression of insulin release. However, including palmitate in the stimulation media (a condition similar to late pregnancy in vivo) restored a higher rate of insulin release. This suggests that elevated lipids in late pregnancy lead to enhanced insulin secretion that is increasingly dependent on lipids and less sensitive to glucose. beta-Cell proliferation was also increased sixfold by prolactin and threefold with palmitate. The combination of both was slightly more than additive (11-fold). Similar experiments with oleate had no effect on insulin secretion. However, oleate stimulated beta-cell division by threefold and was synergistic with prolactin (21-fold). These results were repeated in experiments including normal serum. Interestingly, prolactin also blocked the reduction of glucokinase levels observed with fatty acids. Overall, these results suggest that increased lipids during pregnancy likely contribute to the adaptation of islets to pregnancy by further enhancing beta-cell division. In addition, the increase in lipids leads to enhanced insulin secretion that is less sensitive to glucose and more dependent on lipids. This provides a potential mechanism for maintaining elevated insulin secretion until parturition while preparing islets for normal glucose sensitivity post partum.
Brelje
T Clark
TC
Department of Genetics, Cell Biology and Development, University of Minnesota Medical School, 6-160 Jackson Hall, 321 Church Street, SE, Minneapolis, Minnesota 55455, USA.
Bhagroo
Nicholas V
NV
Stout
Laurence E
LE
Sorenson
Robert L
RL
D000222:Adaptation, Physiological; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004305:Dose-Response Relationship, Drug; D005260:Female; D005941:Glucokinase / Q000032:analysis; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D019301:Oleic Acid / Q000494:pharmacology; D019308:Palmitic Acid / Q000494:pharmacology*; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000378:metabolism*; D011388:Prolactin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
C436291:CDKN1B protein, human; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019301:Oleic Acid; D019308:Palmitic Acid; D011388:Prolactin; D005941:Glucokinase; D005947:Glucose