Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 101, Issue 8, Pages 2458-2463Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0308690100
Keywords
pancreatic islets; hyperglycemia; ob/ob; obesity; bone marrow transplantation
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Funding
- NHLBI NIH HHS [HL16512, R01 HL016512] Funding Source: Medline
- NIDDK NIH HHS [R01 DK068037, P30 DK020595, DK068037, P60 DK020595, U19 DK061245, DK20595, DK61245] Funding Source: Medline
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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, ob/ob mice, and mice fed high-fat diets. We detected in diabetic mice proinsulin-and 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 self-tolerance by insulin gene expression, and strategies for the generation of insulin-producing cells for the treatment of diabetes.
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