Modulation of pancreatic islets-stress axis by hypothalamic releasing hormones and 11β-hydroxysteroid dehydrogenase

Schmid, Janine; Ludwig, Barbara; Schally, Andrew V.; Steffen, Anȷa; Ziegler, Christian; Block, Norman L.; Koutmani, Yassemi; Brendel, Mathias D.; Karalis, Katia; Simeonovic, Charmaine J.; Licinio, Júlio; Ehrhart‐Bornstein, Monika; Bornstein, Stefan R.

doi:10.1073/pnas.1110965108

Cited by 45 publications

(35 citation statements)

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“…Studies have shown that CRHR1 exists in human, mouse, and rat islets (15,16) and that CRH enhances calcium influx (17), increases insulin content, and elevates insulin secretion in a glucose-dependent manner in cultured islets (15,16,18). Furthermore, CRH modulates development, proliferation, and antiapoptosis in islets (15,16,19). These findings suggest that CRH and CRHR1 play significant roles in regulating insulin release under normal conditions.…”

mentioning

confidence: 71%

“…Insulin, the hypoglycemic hormone, is only secreted from pancreatic islet b-cells and is mainly regulated by glucose and neuroendocrine inputs (11,13). There have been reports that CRHR1 is expressed in human, mouse, and rat islets (15,16), which upon activation by CRH, increases calcium influx (17) and stimulates insulin secretion in a glucose-dependent manner (15,16,18). The current study demonstrates a 24-h persistent insulinotropic role of CRH under normoxia, depending on both glucose and CRHR1 signaling pathways, namely PKA and L-type calcium channel-mediated calcium influx (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, CRH is the key regulator of the hypothalamic-pituitary-adrenal (HPA) axis; is activated by a variety of stressors, including hypoxia; and mediates a variety of neural and endocrine response to stress (14). Studies have shown that CRHR1 exists in human, mouse, and rat islets (15,16) and that CRH enhances calcium influx (17), increases insulin content, and elevates insulin secretion in a glucose-dependent manner in cultured islets (15,16,18). Furthermore, CRH modulates development, proliferation, and antiapoptosis in islets (15,16,19).…”

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confidence: 99%

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Inactivation of Corticotropin-Releasing Hormone–Induced Insulinotropic Role by High-Altitude Hypoxia

et al. 2014

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We have shown that hypoxia reduces plasma insulin, which correlates with corticotropin-releasing hormone (CRH) receptor 1 (CRHR1) in rats, but the mechanism remains unclear. Here, we report that hypobaric hypoxia at an altitude of 5,000 m for 8 h enhances rat plasma CRH, corticosterone, and glucose levels, whereas the plasma insulin and pancreatic ATP/ADP ratio is reduced. In islets cultured under normoxia, CRH stimulated insulin release in a glucose-and CRH-level-dependent manner by activating CRHR1 and thus the cAMP-dependent protein kinase pathway and calcium influx through L-type channels. In islets cultured under hypoxia, however, the insulinotropic effect of CRH was inactivated due to reduced ATP and cAMP and coincident loss of intracellular calcium oscillations. Serum and glucocorticoid-inducible kinase 1 (SGK1) also played an inhibitory role. In human volunteers rapidly ascended to 3,860 m, plasma CRH and glucose levels increased without a detectable change in plasma insulin. By contrast, volunteers with acute mountain sickness (AMS) exhibited a marked decrease in HOMA insulin sensitivity (HOMA-IS) and enhanced plasma CRH. In conclusion, hypoxia may attenuate the CRH-insulinotropic effect by reducing cellular ATP/ADP ratio, cAMP and calcium influx, and upregulated SGK1. Hypoxia may not affect HOMA-IS in healthy volunteers but reduces it in AMS volunteers.To enjoy social activities, millions of people travel to high altitudes every year. High-altitude hypoxia often induces dysfunction and illness, particularly acute mountain sickness (AMS) (1). During the construction of the QinghaiTibet railway (at altitudes of 3,000-5,000 m) in China, .100,000 construction workers were involved, and 51% of them developed AMS (2). Moreover, since the railway began service, .10 million travelers have visited the Tibet region in 2012, of whom 31% developed AMS despite traveling with an oxygen supply on the train (3). Increasing evidence in both humans and animals suggests that exposure to either high-altitude or hypobaric hypoxia influences plasma insulin levels and glucose homeostasis, depending on the oxygen level and duration of exposure (4-9). We previously showed that subacute hypoxia at an altitude of 5,000 m for 5 days reduces plasma insulin in rats, and this effect is blocked by a corticotropin-releasing hormone (CRH) receptor 1 (CRHR1) antagonist in vivo (10). However, the underlying mechanisms have not been clearly addressed.Insulin, the unique hypoglycemic hormone, plays a crucial role in maintaining glucose sensing in pancreatic b-cells and regulating glucose uptake in a variety of tissues and cells during health and disease (11,12). Apart from glucose, many neural and endocrine hormones regulate pancreatic insulin release (13). In particular, CRH is the key regulator of the hypothalamic-pituitary-adrenal (HPA) axis; is activated by a variety of stressors, including hypoxia; and mediates a variety of neural and endocrine

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confidence: 71%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Inactivation of Corticotropin-Releasing Hormone–Induced Insulinotropic Role by High-Altitude Hypoxia

et al. 2014

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“…Upon binding, these ligands increases cell proliferation and decreases βcells apoptotic rate. Both peptides also change the intracellular balance bet ween the active and inactive glucocorticoid molecules in favor of the inactive form, thereby increasing insulin sensitivity [191] . We tested one of these effectors in diabetic rats using the βAir BAP.…”

Section: Controlling Apoptosismentioning

confidence: 99%

Survival of encapsulated islets: More than a membrane story

Barkai¹,

Rotem²,

Vos³

2016

WJT

114

109

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“…Liu et al make several comments and suggestions (1) on our publication (2) in which we studied primarily the role of hypothalamic releasing hormones corticotropin-releasing hormone (CRH) and growth hormone-releasing hormone on islet function. The occurrence of HSD enzymes in rodent and human pancreatic islets has been shown by various groups.…”

mentioning

confidence: 99%

Reply to Liu et al.: Hypothalamic control of islets

Schmid¹,

Ludwig²,

Schally³

et al. 2011

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

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Liu et al. make several comments and suggestions (1) on our publication (2) in which we studied primarily the role of hypothalamic releasing hormones corticotropin-releasing hormone (CRH) and growth hormone-releasing hormone on islet function. The occurrence of HSD enzymes in rodent and human pancreatic islets has been shown by various groups. Although most of these groups have studied and discussed the role of 11β-HSD1 and steroid action with respect to β-cell function and insulin release, one study suggests a primary role of α-cells in pancreatic islets (3). Our study (2) demonstrated mRNA and protein expression of 11β-HSD1 in rodent and human islets and in β-cell line INS-1, as well as steroid regulation in INS-1 cells. Analysis of expression of mRNA for human and rat 11β-HSD1 and 11β-HSD2 was performed with sequence-specific primers and further quantified by real-time PCR.In addition, we analyzed expression of protein by using the anti-HSD1 antibody marketed by Abcam and detected a clear protein product for 11β-HSD1 in human and rat islets and a thin but detectable protein product in INS-1 cells. This protein was confirmed by immunohistochemistry. In further studies, we also could demonstrate a time-dependent down-regulation of the distinct 11β-HSD1 protein product in INS-1 cells treated with CRH in contrast to control cells. Previous studies of other groups [e.g., Liu et al. (4)] that used several cell lines such as the preadipocyte, 3T3-L1, cell line with an acknowledged role of 11β-HSD1 have shown a very low, but detectable, expression of 11β-HSD1 protein; small changes of 11β-HSD correlated with an increase of more than 100% of the classical adipocyte cell differentiation markers, LPL or aP2. Therefore, with the 11β-HSD1 enzyme, low expression levels do correlate with highly significant physiological and pathophysiological responses.The 11β-HSD1 activity assay used in our study (2) is established and has been used by many other research groups to measure the conversion of cortisone added to cortisol, and corresponds to other radiolabel methods (5). The cross-reactivity of this immunoassay with cortisone is lower than 0.1%. Altogether, this part of our study confirms previous work of Oppermann and coworkers (5), demonstrating 11β-HSD1 in β-cells and establishing a role of glucocorticoid conversion by local 11β-HSD as well as its function in the regulation of insulin secretion in β-cells. An additional influence of CRH on 11β-HSD1 in α-cells is suggested by the work of Swali et al. (3). However, to our knowledge, no functional studies of 11β-HSD1 in α-cell lines, such as α-TC1, have been performed. Furthermore, there is an obvious natural and well established link of the key central stimulator of peripheral cortisol, CRH, to the 11β-HSD1 in various peripheral cell systems, including adipocytes and skin cells. Importantly in this context, CRH receptors were primarily expressed in β-cell lines and, to a lesser extent, in α-cell lines (6). Nevertheless, given the newly recognized role of α-cell/β-cell crossta...

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Modulation of pancreatic islets-stress axis by hypothalamic releasing hormones and 11β-hydroxysteroid dehydrogenase

Cited by 45 publications

References 31 publications

Inactivation of Corticotropin-Releasing Hormone–Induced Insulinotropic Role by High-Altitude Hypoxia

Inactivation of Corticotropin-Releasing Hormone–Induced Insulinotropic Role by High-Altitude Hypoxia

Survival of encapsulated islets: More than a membrane story

Reply to Liu et al.: Hypothalamic control of islets

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