Effects of pregnancy hormones on pancreatic islets in organ culture

Abstract

Pregnancy is associated with hyperinsulinaemia and decreased glucose tolerance which may lead to gestational diabetes. Sera from pregnant women in the last trimester were found to stimulate insulin secretion of mouse pancreatic islets maintained in organ culture suggesting a direct effect of pregnancy hormones and/or metabolites on the endocrine pancreas. Previous studies have shown that progesterone and human placental lactogen (hPL) had direct effects on isolated islets and in the present study the effects of combined addition of these hormones to the cultured islets were evaluated. hPL, 1 \g=m\g/ml was found to prevent the decrease in the islet insulin content due to progesterone 100 ng/ml, and hPL induced an increase in the DNA\x=req-\ content compared with the progesterone treated islets. The effect of the hormones on the DNA synthesis was evaluated by incorporation of [3H]thymidine into newborn rat islets. Progesterone in a high concentration, 1 \g=m\g/ml, inhibited while 0.1 and 1 \g=m\g/ml hPL stimulated the [3H]thymidine incorporation. These results indicate that progesterone may contribute to the increased glucose-induced insulin release during pregnancy and hPL to the \g=b\-cellhyperplasia. Since progesterone and hPL counteracted each other with regard to both insulin content and DNA-synthesis in the islets, the direct interaction between these two hormones on the \g=b\-cel l may be of importance for the changes in glucose metabolism during pregnancy.Alterations of glucose homeostasis take place dur¬ ing normal pregnancy as expressed by hyperinsulinaemia and decreased glucose tolerance (for a review see Freinkel 1980). Sometimes transient diabetes, gestational diabetes, or persisting insu¬ lin-dependent diabetes may occur (for a review see Kühl 1977). The precipitating factors for the latter pathological development are not known although hormonal disturbances are supposed to play a role (Kühl 1977; Freinkel 1980; Hornnes 1985). The major hormonal changes known to take place during pregnancy are the early transi¬ tional increase in chorionic gonadotrophin and the later increase in oestriol, oestrone, progester¬ one, prolactin and placental lactogen (for a review see Buster & Marshall 1979). In studies of the effects of the individual hormones, progesterone and placental lactogen seem to have profound direct influence on the pancreatic islets (for a review see Nielsen 1985). Therefore the aim of the present study was to compare the effect of pregnant human sera with that of the individual hormones on insulin release, insulin content, and DNA synthesis in isolated pancreatic islets in or¬ gan culture. Materials and MethodsSerum and hormones Serum samples from 10 women in the last trimester of pregnancy-were obtained from the Outpatient Preg¬ nancy Clinic, Rigshospitalet, Copenhagen, Denmark. None were overweight or had glucosuria. The contents of progesterone and placental lactogen were measured by standard methods at Frederiksberg Hospital. Clini¬ cal-Chemical Department, Copenhagen, Denmark. For compar...

Progesterone stimulates pancreatic cell proliferation in vivo

“…of these gonadal factor(s) might also explain the discrepancy between the stimulation of islet-cell proliferation by progesterone in vivo, as shown in the present study, and the inhibitory effects of progesterone on islet-cell proliferation in vitro (12)(13)(14), under which conditions such factors are absent.…”

Growth and Function of the Pancreatic β cell in vitro

“…Studies of 3H-thymidine incorporation into new¬ born rat islets have shown that progesterone is inhibitory in a concentration of 1 pg/ml (Nielsen et al 1981). Neither oestradiol nor testosterone had any effect (unpublished observation) in agreement with the unchanged DNA content in mouse islets cultured in the presence of the hormones (V).…”

“…However, acute experiments on isolated rat islets have failed to show any effect (see Malaisse 1972). In contrast to the effect of hydrocortisone (IV), there was no inhibitory effect of progesterone when the concentration was in¬ creased from 0.1 µg/ml (5 x 10~7 mol/1) to 1 µg/mI (5 x 10-6 mol/1) (Nielsen et al 1981). By the same arguments as above the employment of longterm culture of mouse islets with sub-optimal sup¬ plement of serum (section 4.1) offers a useful approach to study chronic stimulatory effects, and has thus confirmed the stimulatory effect of pro¬ gesterone (V).…”

Role of increased insulin demand in the adaptation of the endocrine pancreas to pregnancy

“…In order to maintain glucose homeostasis the endocrine pancreas undergoes structural and functional changes, including increased glucose-induced insulin secretory responses (Green & Taylor 1972, Moes et al1988, increased synthesis (Bone & Taylor 1976) and storage (Dunger et al 1989) of insulin, b-cell hypertrophy (Hellman 1960, Aerts & Van Assche 1977, Dunger et al 1989) and hyperplasia caused by enhanced b-cell proliferation (Hellman 1960, Aerts & Van Assche 1977. It has been suggested that gestational hormones are involved in these changes, as in vitro hormones of the placental lactogen (PL)-growth hormone (GH)-prolactin (Prl) family induce increased insulin production and release as well as increased cell proliferation in islets of Langerhans (Nielsen 1982, Sorenson & Parsons 1985, Nielsen et al 1986, Parsons et al 1992. Still, gestational hormones are not likely to be the only factors in£uencing endocrine pancreas function during pregnancy.…”