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Endocrinology

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Intradialytic parenteral nutrition improves protein and energy homeostasis in chronic hemodialysis patients
Lara B. Pupim, … , Raymond M. Hakim, T. Alp Ikizler
Lara B. Pupim, … , Raymond M. Hakim, T. Alp Ikizler
Published August 15, 2002
Citation Information: J Clin Invest. 2002;110(4):483-492. https://doi.org/10.1172/JCI15449.
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Intradialytic parenteral nutrition improves protein and energy homeostasis in chronic hemodialysis patients

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Abstract

Research Article

Authors

Lara B. Pupim, Paul J. Flakoll, John R. Brouillette, Deanna K. Levenhagen, Raymond M. Hakim, T. Alp Ikizler

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Thrombopoietin expands hematopoietic stem cells after transplantation
Norma Fox, … , Thalia Papayannopoulou, Kenneth Kaushansky
Norma Fox, … , Thalia Papayannopoulou, Kenneth Kaushansky
Published August 1, 2002
Citation Information: J Clin Invest. 2002;110(3):389-394. https://doi.org/10.1172/JCI15430.
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Thrombopoietin expands hematopoietic stem cells after transplantation

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Abstract

Research Article

Authors

Norma Fox, Greg Priestley, Thalia Papayannopoulou, Kenneth Kaushansky

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Identification of a biochemical link between energy intake and energy expenditure
Silvana Obici, … , Kimyata Morgan, Luciano Rossetti
Silvana Obici, … , Kimyata Morgan, Luciano Rossetti
Published June 15, 2002
Citation Information: J Clin Invest. 2002;109(12):1599-1605. https://doi.org/10.1172/JCI15258.
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Identification of a biochemical link between energy intake and energy expenditure

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Abstract

Obesity is the result of an imbalance between energy intake and energy expenditure. Using high-density DNA microarrays and Northern analyses, we demonstrated that the activation of a nutrient-sensing pathway, the hexosamine biosynthesis pathway (HBP), rapidly decreased the expression of a cluster of nuclear-encoded mitochondrial genes involved in skeletal muscle oxidative phosphorylation. Conversely, the expression of uncoupling protein-1 and of the same mitochondrial genes was increased in brown adipose tissue. Most important, these transcriptional changes were accompanied by a marked decrease in whole-body energy expenditure. Short-term overfeeding replicated this transcriptional pattern, suggesting that this adaptation to nutrient abundance occurs under physiological conditions. Thus, the activation of the HBP by nutrients represents a biochemical link between nutrient availability, mitochondrial proteins, and energy expenditure, and it is likely to play an important role in the regulation of energy balance.

Authors

Silvana Obici, Jiali Wang, Rahena Chowdury, Zhaohui Feng, Uma Siddhanta, Kimyata Morgan, Luciano Rossetti

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Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity
Yujin Shuto, … , Shinichi Oikawa, Ichiji Wakabayashi
Yujin Shuto, … , Shinichi Oikawa, Ichiji Wakabayashi
Published June 1, 2002
Citation Information: J Clin Invest. 2002;109(11):1429-1436. https://doi.org/10.1172/JCI13300.
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Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity

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Abstract

Growth hormone secretagogues (GHSs) stimulate GH secretion and food intake. GHS receptor (GHS-R) mRNA has been identified mainly in the arcuate nucleus (Arc) and ventromedial nucleus of the hypothalamus and in the pituitary. Ghrelin, an endogenous ligand for GHS-R, has recently been purified from rat stomach. Although ghrelin is also expressed in the hypothalamus, the physiological significance of the ghrelin/GHS-R system is still unknown. We have created transgenic (Tg) rats expressing an antisense GHS-R mRNA under the control of the promoter for tyrosine hydroxylase (TH), thus selectively attenuating GHS-R protein expression in the Arc. Tg rats had lower body weight and less adipose tissue than did control rats. Daily food intake was reduced, and the stimulatory effect of GHS treatment on feeding was abolished in Tg rats. GH secretion and plasma insulin-like growth factor-I levels were reduced in female Tg rats. These results suggest that GHS-R in the Arc is involved in the regulation of GH secretion, food intake, and adiposity.

Authors

Yujin Shuto, Tamotsu Shibasaki, Asuka Otagiri, Hideki Kuriyama, Hisayuki Ohata, Hideki Tamura, Jun Kamegai, Hitoshi Sugihara, Shinichi Oikawa, Ichiji Wakabayashi

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Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor
Koji Nakabayashi, … , Sheau Yu Hsu, Aaron J.W. Hsueh
Koji Nakabayashi, … , Sheau Yu Hsu, Aaron J.W. Hsueh
Published June 1, 2002
Citation Information: J Clin Invest. 2002;109(11):1445-1452. https://doi.org/10.1172/JCI14340.
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Thyrostimulin, a heterodimer of two new human glycoprotein hormone subunits, activates the thyroid-stimulating hormone receptor

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Abstract

Human thyrotropin (TSH), luteotropin (LH), follitropin (FSH), and chorionic gonadotropin are members of the heterodimeric glycoprotein hormone family. The common α subunit forms noncovalent heterodimers with different β subunits. Two novel human glycoprotein hormonelike genes, α2 (A2) and β5 (B5), recently have been identified. Using a yeast two-hybrid assay, the two subunits were found as potential heterodimerization partners. Immunological analyses confirmed the heterodimerization of A2 and B5 in transfected cells and their colocalization in the anterior pituitary. Recombinant A2/B5 heterodimeric glycoproteins, purified using cation exchange and size fractionation chromatography, activated human TSH receptors, but not LH and FSH receptors, and showed high affinity to TSH receptors in a radioligand receptor assay. The heterodimer also stimulated cAMP production and thymidine incorporation by cultured thyroid cells and increased serum thyroxine levels in TSH-suppressed rats in vivo. This new heterodimeric glycoprotein hormone was named as thyrostimulin based on its thyroid-stimulating activity. The expression of thyrostimulin in the anterior pituitary known to express TSH receptors suggested a paracrine mechanism. The present discovery of a new ligand based on genomic approaches could facilitate the understanding of the physiological roles of extra-thyroid TSH receptor systems and the structural-functional basis of receptor signaling by related glycoprotein hormones.

Authors

Koji Nakabayashi, Hirotaka Matsumi, Alka Bhalla, Jeehyeon Bae, Sietse Mosselman, Sheau Yu Hsu, Aaron J.W. Hsueh

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Paracrine regulation of fat cell formation in bone marrow cultures via adiponectin and prostaglandins
Takafumi Yokota, … , Yuji Matsuzawa, Paul W. Kincade
Takafumi Yokota, … , Yuji Matsuzawa, Paul W. Kincade
Published May 15, 2002
Citation Information: J Clin Invest. 2002;109(10):1303-1310. https://doi.org/10.1172/JCI14506.
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Paracrine regulation of fat cell formation in bone marrow cultures via adiponectin and prostaglandins

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Abstract

Adiponectin, an adipocyte-derived hormone, was recently shown to have potential therapeutic applications in diabetes and obesity because of its influence on glucose and lipid metabolism. We found that brown fat in normal human bone marrow contains this protein and used marrow-derived preadipocyte lines and long-term cultures to explore potential roles in hematopoiesis. Recombinant adiponectin blocked fat cell formation in long-term bone marrow cultures and inhibited the differentiation of cloned stromal preadipocytes. Adiponectin also caused elevated expression of cyclooxygenase-2 (COX-2) by these stromal cells and induced release of prostaglandin E2 (PGE2). The COX-2 inhibitor Dup-697 prevented the inhibitory action of adiponectin on preadipocyte differentiation, suggesting involvement of stromal cell–derived prostanoids. Furthermore, adiponectin failed to block fat cell generation when bone marrow cells were derived from B6,129SPtgs2tm1Jed (COX-2+/–) mice. These observations show that preadipocytes represent direct targets for adiponectin action, establishing a paracrine negative feedback loop for fat regulation. They also link adiponectin to the COX-2–dependent PGs that are critical in this process.

Authors

Takafumi Yokota, C.S. Reddy Meka, Kay L. Medina, Hideya Igarashi, Phillip C. Comp, Masahiko Takahashi, Makoto Nishida, Kenji Oritani, Jun-ichiro Miyagawa, Tohru Funahashi, Yoshiaki Tomiyama, Yuji Matsuzawa, Paul W. Kincade

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Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes
Ripudaman S. Hundal, … , Steven E. Shoelson, Gerald I. Shulman
Ripudaman S. Hundal, … , Steven E. Shoelson, Gerald I. Shulman
Published May 15, 2002
Citation Information: J Clin Invest. 2002;109(10):1321-1326. https://doi.org/10.1172/JCI14955.
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Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes

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Abstract

Recent studies have implicated fatty acid-dependent activation of the serine kinase IKKβ, which plays a key role in tissue inflammation, in the pathogenesis of insulin resistance. High doses of salicylates have recently been shown to inhibit IKKβ activity and might therefore ameliorate insulin resistance and improve glucose tolerance in patients with type 2 diabetes. To test this hypothesis, we studied nine type 2 diabetic subjects before and after 2 weeks of treatment with aspirin (∼7 g/d). Subjects underwent mixed-meal tolerance tests and hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose to assess glucose turnover before and after treatment. High-dose aspirin treatment resulted in a ∼25% reduction in fasting plasma glucose, associated with a ∼15% reduction in total cholesterol and C-reactive protein, a ∼50% reduction in triglycerides, and a ∼30% reduction in insulin clearance, despite no change in body weight. During a mixed-meal tolerance test, the areas under the curve for plasma glucose and fatty acid levels decreased by ∼20% and ∼50%, respectively. Aspirin treatment also resulted in a ∼20% reduction in basal rates of hepatic glucose production and a ∼20% improvement in insulin-stimulated peripheral glucose uptake under matched plasma insulin concentrations during the clamp. In conclusion, these data support the hypothesis that IKKβ represents a new target for treating type 2 diabetes mellitus.

Authors

Ripudaman S. Hundal, Kitt F. Petersen, Adam B. Mayerson, Pritpal S. Randhawa, Silvio Inzucchi, Steven E. Shoelson, Gerald I. Shulman

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Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy
Kitt Falk Petersen, … , Phillip Gorden, Gerald I. Shulman
Kitt Falk Petersen, … , Phillip Gorden, Gerald I. Shulman
Published May 15, 2002
Citation Information: J Clin Invest. 2002;109(10):1345-1350. https://doi.org/10.1172/JCI15001.
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Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy

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Abstract

Lipodystrophy is a rare disorder that is characterized by selective loss of subcutaneous and visceral fat and is associated with hypertriglyceridemia, hepatomegaly, and disordered glucose metabolism. It has recently been shown that chronic leptin treatment ameliorates these abnormalities. Here we show that chronic leptin treatment improves insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients. This improvement in insulin action was associated with a marked reduction in hepatic and muscle triglyceride content. These data suggest that leptin may represent an important new therapy to reverse the severe hepatic and muscle insulin resistance and associated hepatic steatosis in patients with lipodystrophy.

Authors

Kitt Falk Petersen, Elif Arioglu Oral, Sylvie Dufour, Douglas Befroy, Charlotte Ariyan, Chunli Yu, Gary W. Cline, Alex M. DePaoli, Simeon I. Taylor, Phillip Gorden, Gerald I. Shulman

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Anabolic effects of a G protein–coupled receptor kinase inhibitor expressed in osteoblasts
Robert F. Spurney, … , Farshid Guilak, L. Darryl Quarles
Robert F. Spurney, … , Farshid Guilak, L. Darryl Quarles
Published May 15, 2002
Citation Information: J Clin Invest. 2002;109(10):1361-1371. https://doi.org/10.1172/JCI14663.
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Anabolic effects of a G protein–coupled receptor kinase inhibitor expressed in osteoblasts

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Abstract

G protein–coupled receptors (GPCRs) play a key role in regulating bone remodeling. Whether GPCRs exert anabolic or catabolic osseous effects may be determined by the rate of receptor desensitization in osteoblasts. Receptor desensitization is largely mediated by direct phosphorylation of GPCR proteins by a family of enzymes termed GPCR kinases (GRKs). We have selectively manipulated GRK activity in osteoblasts in vitro and in vivo by overexpressing a GRK inhibitor. We found that expression of a GRK inhibitor enhanced parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor-stimulated cAMP generation and inhibited agonist-induced phosphorylation of this receptor in cell culture systems, consistent with attenuation of receptor desensitization. To determine the effect of GRK inhibition on bone formation in vivo, we targeted the expression of a GRK inhibitor to mature osteoblasts using the mouse osteocalcin gene 2 (OG2) promoter. Transgenic mice demonstrated enhanced bone remodeling as well as enhanced urinary excretion of the osteoclastic activity marker dexoypyridinoline. Both osteoprotegrin and OPG ligand mRNA levels were altered in calvaria of transgenic mice in a pattern that would promote osteoclast activation. The predominant effect of the transgene, however, was anabolic, as evidenced by an increase in bone density and trabecular bone volume in the transgenic mice compared with nontransgenic littermate controls.

Authors

Robert F. Spurney, Patrick J. Flannery, Sanford C. Garner, Krairerk Athirakul, Shiguang Liu, Farshid Guilak, L. Darryl Quarles

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β cell expression of IGF-I leads to recovery from type 1 diabetes
Mónica George, … , Jean Christophe Devedjian, Fatima Bosch
Mónica George, … , Jean Christophe Devedjian, Fatima Bosch
Published May 1, 2002
Citation Information: J Clin Invest. 2002;109(9):1153-1163. https://doi.org/10.1172/JCI12969.
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β cell expression of IGF-I leads to recovery from type 1 diabetes

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Patients with type 1 diabetes are identified after the onset of the disease, when β cell destruction is almost complete. β cell regeneration from islet cell precursors might reverse this disease, but factors that can induce β cell neogenesis and replication and prevent a new round of autoimmune destruction remain to be identified. Here we show that expression of IGF-I in β cells of transgenic mice (in both C57BL/6–SJL and CD-1 genetic backgrounds) counteracts cytotoxicity and insulitis after treatment with multiple low doses of streptozotocin (STZ). STZ-treated nontransgenic mice developed high hyperglycemia and hypoinsulinemia, lost body weight, and died. In contrast, STZ-treated C57BL/6–SJL transgenic mice showed mild hyperglycemia for about 1 month, after which they normalized glycemia and survived. After STZ treatment, all CD-1 mice developed high hyperglycemia, hypoinsulinemia, polydipsia, and polyphagia. However, STZ-treated CD-1 transgenic mice gradually normalized all metabolic parameters and survived. β cell mass increased in parallel as a result of neogenesis and β cell replication. Thus, our results indicate that local expression of IGF-I in β cells regenerates pancreatic islets and counteracts type 1 diabetes, suggesting that IGF-I gene transfer to the pancreas might be a suitable therapy for this disease.

Authors

Mónica George, Eduard Ayuso, Alba Casellas, Cristina Costa, Jean Christophe Devedjian, Fatima Bosch

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Dynamin 2 prevents insulin granule traffic jams
Fan Fan and colleagues demonstrate that dynamin 2 is important for maintaining insulin secretion dynamics in β cells…
Published September 28, 2015
Scientific Show StopperEndocrinology

UPR stress gets β cells going
Rohit Sharma and colleagues reveal that insulin demand-induced β cell proliferation is regulated by the unfolded protein response…
Published September 21, 2015
Scientific Show StopperEndocrinology

Restricting β cell growth
Sung Hee Um and colleagues reveal that S6K1-dependent alterations of β cell size and function are independent of intrauterine growth restriction…
Published June 15, 2015
Scientific Show StopperEndocrinology

Insight into Kallmann syndrome
Anna Cariboni and colleagues demonstrate that dysfunctional SEMA3E results in gonadotropin-releasing hormone neuron deficiency…
Published May 18, 2015
Scientific Show StopperEndocrinology

L cells to the rescue
Natalia Peterson and colleagues demonstrate that increasing L cell populations in the gut improves insulin responses and glucose tolerance in a murine type 2 diabetes model…
Published December 15, 2014
Scientific Show StopperEndocrinology
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