High concentration of thyrotropin-releasing hormone in pancreatic islets.

Martino, Enio; Lernmark, Åke; Seo, Hisao; Steiner, Donald F.; Refetoff, Samuel

doi:10.1073/pnas.75.9.4265

Cited by 115 publications

(56 citation statements)

References 32 publications

(21 reference statements)

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“…TRH content in the pancreas has been reported to drastically change during the prenatal and postnatal periods (8,9). This suggests that TRH deficiency may affect fetal development of the pancreas, but our observations did not support this hypothesis.…”

Section: Discussioncontrasting

confidence: 57%

“…Second, although isolated deficiency of TRH has been suggested to be the cause of tertiary (hypothalamic) hypothyroidism, there is neither direct clinical evidence nor an animal model to support this hypothesis. In the pancreas, TRH exists in the islets of Langerhans and more specifically within the ␤ cells producing insulin (6)(7)(8)(9). However, due to technical difficulties associated with selective depletion of TRH in the ␤ cells, it has been difficult to discern its role in insulin physiology.…”

mentioning

confidence: 99%

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Tertiary hypothyroidism and hyperglycemia in mice with targeted disruption of the thyrotropin-releasing hormone gene

Yamada

Saga

Shibusawa

et al. 1997

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

197

105

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Thyrotropin-releasing hormone (TRH) is a brain hypothalamic hormone that regulates thyrotropin (TSH) secretion from the anterior pituitary and is ubiquitously distributed throughout the brain and other tissues including pancreas. To facilitate studies into the role of endogenous TRH, we have used homologous recombination to generate mice that lack TRH. These TRH ؊͞؊ mice are viable, fertile, and exhibit normal development. However, they showed obvious hypothyroidism with characteristic elevation of serum TSH level and diminished TSH biological activity. Their anterior pituitaries exhibited an apparent decrease in TSH immunopositive cells that was not due to hypothyroidism. Furthermore, this decrease could be reversed by TRH, but not thyroid hormone replacement, suggesting a direct involvement of TRH in the regulation of thyrotrophs. The TRH ؊͞؊ mice also exhibited hyperglycemia, which was accompanied by impaired insulin secretion in response to glucose. These findings indicate that TRH ؊͞؊ mice provide a model of exploiting tertiary hypothyroidism, and that TRH gene abnormalities cause disturbance of insulin secretion resulting in marked hyperglycemia.Thyrotropin-releasing hormone (TRH) was originally isolated as the first hypothalamic hormone (1, 2) and has been shown to be present in many organs, including the central nervous system, reproductive system, and gastrointestinal tract (3, 4). Administration of exogenous TRH to animals and humans has been observed to cause a variety of endocrine and nonendocrine biological activities (3-5). The results of these studies have led to the suggestion that TRH may act as a neurotransmitter or neuromodulator in many organs.Because of the ubiquitous distribution of TRH in many organs and the lack of a suitable method to produce selective changes in in vivo TRH level, it has been difficult to examine the mechanism by which TRH regulates different biological activities. For example, TRH is the major regulator of synthesis and secretion of thyrotropin (TSH) in the anterior pituitary and, thus, it plays a pivotal role in the regulation of the hypothalamic-pituitary-thyroid axis. However, the contribution of TRH in the functional maturation of pituitary thyrotrophs during development remains obscure. Second, although isolated deficiency of TRH has been suggested to be the cause of tertiary (hypothalamic) hypothyroidism, there is neither direct clinical evidence nor an animal model to support this hypothesis. In the pancreas, TRH exists in the islets of Langerhans and more specifically within the ␤ cells producing insulin (6-9). However, due to technical difficulties associated with selective depletion of TRH in the ␤ cells, it has been difficult to discern its role in insulin physiology.In view of the aforementioned observations, it is clear that the availability of a TRH-deficient animal model will greatly enhance our ability to clarify the precise role of the peptide in many organ functions.We recently cloned and characterized a mouse hypothalamic cDNA and genomic DNA...

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Section: Discussioncontrasting

confidence: 57%

mentioning

confidence: 99%

Tertiary hypothyroidism and hyperglycemia in mice with targeted disruption of the thyrotropin-releasing hormone gene

Yamada

Saga

Shibusawa

et al. 1997

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

197

105

View full text Add to dashboard Cite

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“…4, nZ5): these included several novel candidates (Gap43, Nrep, Egln3, and Racgap1) that were strongly (5-to 25-fold, P!0.05, nZ5) downregulated upon b cell maturation, as well as several genes that were previously reported to mark more immature b cell stages, and thus serve as positive controls: Dlk1 and Pref1 (Carlsson et al 1997), Mafb (Nishimura et al 2006), thyrotropin-releasing hormone (Trh) (Martino et al 1978, Dolva et al 1983, and Npy (Myrsen-Axcrona et al 1997). Npy mRNA was 5G1 times (P!0.05, nZ5) higher in neonatal b cells but could still confidently be detected in 10-week-old b cells.…”

Section: Candidate Markers For Residual Developmental Immaturitymentioning

confidence: 99%

Functional characteristics of neonatal rat β cells with distinct markers

Martens¹,

Motté²,

Kramer³

et al. 2013

Journal of Molecular Endocrinology

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Neonatal b cells are considered developmentally immature and hence less glucose responsive. To study the acquisition of mature glucose responsiveness, we compared glucose-regulated redox state, insulin synthesis, and secretion of b cells purified from neonatal or 10-week-old rats with their transcriptomes and proteomes measured by oligonucleotide and LC-MS/MS profiling. Lower glucose responsiveness of neonatal b cells was explained by two distinct properties: higher activity at low glucose and lower activity at high glucose. Basal hyperactivity was associated with higher NAD(P)H, a higher fraction of neonatal b cells actively incorporating 3 H-tyrosine, and persistently increased insulin secretion below 5 mM glucose. Neonatal b cells lacked the steep glucose-responsive NAD(P)H rise between 5 and 10 mM glucose characteristic for adult b cells and accumulated less NAD(P)H at high glucose. They had twofold lower expression of malate/aspartate-NADH shuttle and most glycolytic enzymes. Genome-wide profiling situated neonatal b cells at a developmental crossroad: they showed advanced endocrine differentiation when specifically analyzed for their mRNA/protein level of classical neuroendocrine markers. On the other hand, discrete neonatal b cell subpopulations still expressed mRNAs/proteins typical for developing/proliferating tissues. One example, delta-like 1 homolog (DLK1) was used to investigate whether neonatal b cells with basal hyperactivity corresponded to a more immature subset with high DLK1, but no association was found. In conclusion, the current study supports the importance of glycolytic NADH-shuttling in stimulus function coupling, presents basal hyperactivity as novel property of neonatal b cells, and provides potential markers to recognize intercellular developmental differences in the endocrine pancreas.

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“…In addition to the hypothalamus, TRH has been identified in many systemic organs including the pancreas (Martino et al 1978, Koivusalco & Leppaluoto 1979, Morley et al 1979, Engler et al 1982, Aratan-Spire et al 1984, Leduque et al 1985, Fuse et al 1990). In the pancreas, TRH expression is at its peak during the neonatal period and gradually declines after birth (Martino et al 1978, Basmaciogullari et al 2000. The distribution of TRH in the pancreas has been localized in both the islet -cells and other pancreatic cells (Basmaciogullari et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Expression of thyrotropin-releasing hormone receptor in immortalized beta-cell lines and rat pancreas

Luo

Yano²

2004

Journal of Endocrinology

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Thyrotropin-releasing hormone (TRH), a hypothalamic tripeptide, is expressed in pancreatic islets at peak levels during the late gestation and early neonate period. TRH increases insulin production in cultured -cells, suggesting that it might play a role in regulating pancreatic -cell function. However, there is limited information on TRH receptor expression in the pancreas. The aim of the present study was to explore the distribution of the TRH receptor in the pancreas and its function in pancreatic -cells. TRH receptor type 1 (TRHR1) gene expression was detected by RT-PCR and verified by Northern blotting and immunoblotting in the -cell lines, INS-1 and TC-6, and the rat pancreatic organ. The absence of TRH receptor type 2 expression in the tissue and cells indicated the tissue specificity of TRH receptor expression in the pancreas. The TRHR1 signals (detected by in situ hybridization) were distributed not only in islets but also in the surrounding areas of the pancreatic ductal and vasal epithelia. The apparent dissociation constant value for the affinity of [ 3 H]3-methyl-histidine TRH (MeTRH) is 4·19 in INS-1 and 3·09 nM in TC-6. In addition, TRH induced epidermal growth factor (EGF) receptor phosphorylation with a half-maximum concentration of approximately 50 nM, whereas the high affinity analogue of TRH, MeTRH, was 1 nM. This suggested that the affinity of TRH ligands for the TRH receptor influences the activation of EGF receptor phosphorylation in TC-6 cells. Our observations suggested that the biological role of TRH in pancreatic -cells is via the activation of TRHR1. Further research is required to identify the role of TRHR1 in the pancreas aside from the islets.

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High concentration of thyrotropin-releasing hormone in pancreatic islets.

Cited by 115 publications

References 32 publications

Tertiary hypothyroidism and hyperglycemia in mice with targeted disruption of the thyrotropin-releasing hormone gene

Tertiary hypothyroidism and hyperglycemia in mice with targeted disruption of the thyrotropin-releasing hormone gene

Functional characteristics of neonatal rat β cells with distinct markers

Expression of thyrotropin-releasing hormone receptor in immortalized beta-cell lines and rat pancreas

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