Insulin in Brain and Other Extrapancreatic Tissues of Vertebrates and Nonvertebrates

Roith, Derek Le; Hendricks, Sharief; Lesniak, Maxine A.; Rishi, Surendra; Becker, Kenneth L.; Havránková, Jana; Rosenzweig, James L.; Brownstein, Michael J.; Roth, Jesse

doi:10.1016/b978-0-12-027310-2.50017-7

Cited by 53 publications

(28 citation statements)

References 41 publications

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“…We previously described a line of mice [C57BL6-TgN9(Ins2Cre)25Mgn] in which a 668 bp promoter fragment of the rat insulin II (RIP2) gene was used to direct Cre expression in mice Kulkarni et al, 1999). While insulin promoter fragments of this size are thought to direct expression only to the pancreatic ␤ cell, we detected RIP2-Cre expression in the brain of five different lines of mice, perhaps consistent with reports describing insulin in the brain (Havrankova et al, 1981;Le Roith et al, 1983). The line we further characterize here showed the highest levels of transgene expression within pancreatic ␤ cells and the lowest levels of expression in brain tissue ; data not shown).…”

supporting

confidence: 57%

Analysis of the Cre-mediated recombination driven by rat insulin promoter in embryonic and adult mouse pancreas

Gannon

Shiota

Postic

et al. 2000

genesis

165

151

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supporting

confidence: 57%

Analysis of the Cre-mediated recombination driven by rat insulin promoter in embryonic and adult mouse pancreas

Gannon

Shiota

Postic

et al. 2000

genesis

165

151

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“…The presence of insulin-related material in the brain and other extrapancreatic tissues of adult nondiabetic vertebrates was reported 20 years ago (reviewed in ref. 29). The nature of the insulin-related material was unclear, and by immunohistochemical staining we failed to detect any immunoreactive proinsulin or insulin-positive cells in brain or other extrapancreatic, extrathymic tissues in nondiabetic mice.…”

Section: Discussionmentioning

confidence: 98%

Extrapancreatic insulin-producing cells in multiple organs in diabetes

Kojima

Fujimiya

Matsumura

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

192

183

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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, 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...

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“…Demonstration of insulin synthesis in brain or elsewhere would strongly imply as yet undescribed functions for this peptide. There are no data to answer this question, except reports of increased levels of insulin in brain compared with plasma under various conditions [4][5][6]. The low abundance of insulin in brain precludes the use of radiolahelled amino-acid incorporation to document synthesis directly [7].…”

mentioning

confidence: 92%

“…Others, such as insulin, are present at levels 1000-fold less in brain than in pancreas [4,5]. The identification of pg quantities of less abundant peptides per g of brain has been facilitated by radioimmunoassays and by localization with immunocytochemical techniques [1][2][3][4][5].…”

mentioning

confidence: 99%

Evaluation of rat insulin messenger RNA in pancreatic and extrapancreatic tissues

1985

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Summary. The purpose of these studies was to determine whether insulin detected immunochemically in extrapancreatic tissues of the adult rat is synthesized in situ by quantitating mRNA in these tissues. A blot hybridization assay was utilized with cloned 32p-proinsulin cDNA. The lower limit of detection was estimated to be 3pg. Proinsulin mRNA concentration was found to be 1000-1500 p~g in isolated pancreatic islets and was easily detected in total pancreatic RNA at 10-15 pg/ ~tg. Proinsulin mRNA was quantitated in rat insulinoma cells adapted to culture at levels 1 : 50 those in normal islets. Samples of RNA (20-50 p~g) enriched about 50-fold for mRNA sequences by repeated oligo-deoxythymidylate chromatography were assayed. No insulin mRNA was detected in 50 ~tg samples of RNA from brain or in 20 ~tg samples from subsections of brain or other extrapancreatic tissues. RNA samples were undegraded as assessed by ability to stimulate protein synthesis in a cell-free system. Proinsulin mRNA from pancreas was added to brain homogenates and recovered intact. Brain RNA samples with insulin mRNA levels 1:1000 that of pancreas would be predicted to have 50-75 pg proinsulin mRNA/50 ~tg sample assayed if present. Because none was found, brain must have a concentration < 1 : 6,000 that of pancreas. These findings suggest that immunoassayable insulin detected in extrapancreatic tissues of the adult rat is synthesized by the pancreas.Keywords: RNA blot hybridization, rat, proinsulin mRNA, brain mRNA, pancreatic islets.A number of peptides originally described as hormones from gut have been identified in brain [1,2]. Some are present in approximately equal concentrations in hypothalamus and gut (e. g. somatostatin) [3]. Others, such as insulin, are present at levels 1000-fold less in brain than in pancreas [4,5]. The identification of pg quantities of less abundant peptides per g of brain has been facilitated by radioimmunoassays and by localization with immunocytochemical techniques [1][2][3][4][5].The immunochemical detection of hormones in brain leaves unanswered the important question of their origin. Demonstration of insulin synthesis in brain or elsewhere would strongly imply as yet undescribed functions for this peptide. There are no data to answer this question, except reports of increased levels of insulin in brain compared with plasma under various conditions [4][5][6]. The low abundance of insulin in brain precludes the use of radiolahelled amino-acid incorporation to document synthesis directly [7].Using an RNA blot hybridization technique, we have assayed for proinsulin I and II mRNA's (which are 93% homologous) in brain and several other tissues of the adult rat, using a cloned 32p-labelled probe complementary to rat insulin I mRNA [8]. ProinsulinI cDNA hybridizes readily to both genes under the conditions of hybridization employed [9]. The presence of proinsulin mRNA in extrapancreatic tissues would provide an independent line of evidence for synthesis. The present limit of sensitivity of this assay is about 5 p...

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Insulin in Brain and Other Extrapancreatic Tissues of Vertebrates and Nonvertebrates

Cited by 53 publications

References 41 publications

Analysis of the Cre-mediated recombination driven by rat insulin promoter in embryonic and adult mouse pancreas

Analysis of the Cre-mediated recombination driven by rat insulin promoter in embryonic and adult mouse pancreas

Extrapancreatic insulin-producing cells in multiple organs in diabetes

Evaluation of rat insulin messenger RNA in pancreatic and extrapancreatic tissues

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