Global Deletion of the Prolactin Receptor Aggravates Streptozotocin-Induced Diabetes in Mice

Abstract

Prolactin (PRL) levels are reduced in the circulation of rats with diabetes or obesity, and lower circulating levels of PRL correlate with increased prevalence of diabetes and a higher risk of metabolic alterations in the clinic. Furthermore, PRL stimulates β-cell proliferation, survival, and insulin production and pregnant mice lacking PRL receptors in β-cells develop gestational diabetes. To investigate the protective effect of endogenous PRL against diabetes outside pregnancy, we compared the number of cases and severity of streptozotocin (STZ)-induced hyperglycemia between C57BL/6 mice null for the PRL receptor gene (Prlr-/-) and wild-type mice (Prlr+/+). STZ-treated diabetic Prlr-/- mice showed a higher number of cases and later recovery from hyperglycemia, exacerbated glucose levels, and glucose intolerance compared to the Prlr+/+ mice counterparts. Consistent with the worsening of hyperglycemia, pancreatic islet density, β-cell number, proliferation, and survival, as well as circulating insulin levels were reduced, whereas α-cell number and pancreatic inflammation were increased in the absence of PRL signaling. Deletion of the PRL receptor did not alter the metabolic parameters in vehicle-treated animals. We conclude that PRL protects whole body glucose homeostasis by reducing β-cell loss and pancreatic inflammation in STZ-induced diabetes. Medications elevating PRL circulating levels may prove to be beneficial in diabetes.

Dopamine D2 receptor antagonist counteracts hyperglycemia and insulin resistance in diet-induced obese male mice

“…Sulpiride improved glucose tolerance and reduced glycemia independently of alterations in body weight and caloric intake in both lean and obese mice. Even if these data are consistent with the beneficial metabolic actions of prolactin [ 13 , 43 ], here we demonstrated that the effects of sulpiride, at least reducing hyperglycemia are independent from PRL actions on its classical receptors, this was concluded because sulpiride reduced glucose levels and improved glucose tolerance in obese mice that are knockout for the prolactin receptors.…”

Astragalus polysaccharide promotes autophagy and alleviates diabetic nephropathy by targeting the lncRNA Gm41268/PRLR pathway

“…PRLR belongs to the cytokine receptor superfamily and has been demonstrated to bind to at least three different ligands, namely prolactin, placental lactogen, and growth hormone, thereby complicating the investigation of its role [ 37 ]. Several studies have investigated the function of PRLR in the regulation of glucose homeostasis, β-cell proliferation, and survival and found that STZ-treated diabetic Prlr–/– mice showed increased glucose levels and impaired glucose intolerance [ 38 , 39 ]. However, the role of PRLR in DN remains to be elucidated.…”

Hormonal Determinants of Growth and Weight Gain in the Human Fetus and Preterm Infant

“…Prolactin and placental lactogen stimulate beta cell proliferation and glucose-stimulated insulin secretion and inhibit beta cell apoptosis in rodent islets in vivo and in vitro [ 158 , 159 ] and in some studies of human islets [ 160 , 161 ]. Moreover, lactogen signaling is required for pregnancy-dependent increases in beta cell mass in the mouse and maintenance of maternal glucose tolerance [ 162 , 163 , 164 ]. The effects of prolactin and placental lactogen are mediated through binding to prolactin receptors (PRLRs), which are detected in a wide array of human fetal tissues [ 165 ] including the liver, lung, duodenal villi, adrenocortical cells, renal tubular epithelial cells, skeletal myocytes, and chondrocytes of developing bones.…”