Extrapancreatic insulin-producing cells in multiple organs in diabetes

Abstract

Insulin-producing cells normally occur only in the pancreas and thymus. Surprisingly, we found widespread insulin mRNA and protein expression in different diabetic mouse and rat models, including streptozotocin-treated mice and rats, ob͞ob mice, and mice fed high-fat diets. We detected in diabetic mice proinsulinand insulin-positive cells in the liver, adipose tissue, spleen, bone marrow, and thymus; many cells also produced glucagon, somatostatin, and pancreatic polypeptide. By in situ nucleic acid hybridization, diabetic, but not nondiabetic, mouse liver exhibited insulin transcript-positive cells, indicating that insulin was synthesized by these cells. In transgenic mice that express GFP driven by the mouse insulin promoter, streptozotocin-induced diabetes led to the appearance of GFP-positive cells in liver, adipose tissue, and bone marrow; the fluorescent signals showed complete concordance with the presence of immunoreactive proinsulin. Hyperglycemia produced by glucose injections in nondiabetic mice led to the appearance of proinsulin-and insulin-positive cells within 3 days. Bone marrow transplantation experiments showed that most of the extrapancreatic proinsulin-producing cells originated from the bone marrow. Immunoreactive proinsulin-and insulin-positive cells were also detected in the liver, adipose tissue, and bone marrow of diabetic rats, indicating that extrapancreatic, extrathymic insulin production occurs in more than one species. These observations have implications for the regulation of insulin gene expression, modulation of selftolerance by insulin gene expression, and strategies for the generation of insulin-producing cells for the treatment of diabetes.pancreatic islets ͉ hyperglycemia ͉ ob͞ob ͉ obesity ͉ bone marrow transplantation I nsulin is normally produced in highly specialized cells of the endocrine pancreas. The tissue-specific expression of insulin is tightly regulated at the transcriptional level, and the major regulatory elements are located in the 5Ј flanking region of the insulin gene (1). Insulin expression is specific to ␤ cells in the pancreatic islets, although proinsulin has also been detected in the fetal and postnatal thymus and spleen͞lymphoid tissues (2, 3), a pattern of promiscuous expression of normally tissuerestricted ''peripheral'' proteins in these tissues (4, 5). Immunoreactivity to insulin plays a key role in autoimmune diabetes in NOD mice (6, 7) and in type 1 diabetes in humans (7); expression of minute amounts of insulin in the thymus is believed to be important in the induction of tolerance to insulin and other ''self-antigens '' (8-11). In this study, we found insulin gene transcription and protein expression in multiple tissues outside the pancreas and thymus in mice and rats with diabetes. The widespread occurrence of extrapancreatic, extrathymic insulin gene products in diabetic animals is surprising; it suggests that we should revise our thinking on the regulation of insulin gene expression, the mechanism of immune tolerance to insulin, the pathophysi...

Blastema cells derived from New Zealand white rabbit’s pinna carry stemness properties as shown by differentiation into insulin producing, neural, and osteogenic lineages representing three embryonic germ layers

“…In this regard, we have previously reported that SLCs, obtained from the New Zealand white rabbit's pinnas, showed SC characteristics such as high proliferation ability and expression of pluripotency markers Oct4 and Sox2 (Mahmoudi et al 2011). In the present study, the capacity of SLCs to differentiate into cells derived It has been shown that serum-free medium (Zalzman et al 2003) and b-mercaptoethanol (Kojima et al 2004) promote the expression of Nestin, a pancreatic precursor marker, in SCs. Several studies have also indicated that high glucose concentration (25 mM) facilitates differentiation of SCs toward pancreatic (Sun et al 2007;Neshati et al 2010).…”

“…Several studies have also indicated that high glucose concentration (25 mM) facilitates differentiation of SCs toward pancreatic (Sun et al 2007;Neshati et al 2010). Moreover, it has also been demonstrated that combination of b-mercaptoethanol with serum-free medium or nicotinamide increases the efficiency of differentiation to IPCs (Kojima et al 2004;Sun et al 2007;Neshati et al 2010). Based on above mentioned reports, we induced the differentiation of SLCs using a combined protocol, which includes nicotinamide and b-mercaptoethanol in a high glucose serum-free medium.…”

Streptozotocin-induced diabetes can be reversed by hepatic oval cell activation through hepatic transdifferentiation and pancreatic islet regeneration

“…8 In this study, we have demonstrated that the oval-cell-activated livers transcribed major pancreatic mRNAs and readily produced significant amount of insulin during the hyperglycemic stage. It has been reported that amelioration of hyperglycemia such as insulin supplementation after STZ injection could accelerate the regeneration of b-cells.…”

“…6,7 Although insulin is primarily produced in the pancreatic islets, a previous study has revealed the existence of extrapancreatic insulin-producing cells in multiple organs such as liver, spleen, bone marrow and adipose in hyperglycemic conditions. 8 However, the newly emerged insulin-producing cells in the pancreas and other organs are not sufficient in number as well as in insulin production ability to reverse the diabetic condition. 9 Although hyperglycemia is detrimental to islet bcells, high glucose is a very efficient signal in vitro for differentiation of stem cells into insulin-producing cells.…”

Fusion of proinsulin-producing bone marrow-derived cells with hepatocytes in diabetes

“…Our laboratory recently reported the appearance of proinsulin-producing (Proins-P) cells in the bone marrow of diabetic rats and mice (6). The Proins-P BMDC migrate out of the bone marrow and populate different organs and tissues, including liver and fat.…”