Cause of Diabetes: References (For the Table too)


Diabetes. 2010 Mar;59(3):662-9.
Oxygen tension regulates pancreatic beta-cell differentiation through hypoxia-inducible factor 1alpha.
Heinis M, Simon MT, Ilc K, Mazure NM, Pouyssugur J, Scharfmann R, Duvilli B.
INSERM U845, Research Center Growth and Signalling, Universitu Paris Descartes, Hopital Necker, Paris, France.
Recent evidence indicates that low oxygen tension (pO2) or hypoxia controls the differentiation of several cell types during development. Variations of pO2 are mediated through the hypoxia-inducible factor (HIF), a crucial mediator of the adaptative response of cells to hypoxia. The aim of this study was to investigate the role of pO2 in beta-cell differentiation.
We analyzed the capacity of beta-cell differentiation in the rat embryonic pancreas using two in vitro assays. Pancreata were cultured either in collagen or on a filter at the air/liquid interface with various pO2. An inhibitor of the prolyl hydroxylases, dimethyloxaloylglycine (DMOG), was used to stabilize HIF1alpha protein in normoxia.
When cultured in collagen, embryonic pancreatic cells were hypoxic and expressed HIF1alpha and rare beta-cells differentiated. In pancreata cultured on filter (normoxia), HIF1alpha expression decreased and numerous beta-cells developed. During pancreas development, HIF1alpha levels were elevated at early stages and decreased with time. To determine the effect of pO2 on beta-cell differentiation, pancreata were cultured in collagen at increasing concentrations of O2. Such conditions repressed HIF1alpha expression, fostered development of Ngn3-positive endocrine progenitors, and induced beta-cell differentiation by O2 in a dose-dependent manner. By contrast, forced expression of HIF1alpha in normoxia using DMOG repressed Ngn3 expression and blocked beta-cell development. Finally, hypoxia requires hairy and enhancer of split (HES)1 expression to repress beta-cell differentiation.
These data demonstrate that beta-cell differentiation is controlled by pO2 through HIF1alpha. Modifying pO2 should now be tested in protocols aiming to differentiate beta-cells from embryonic stem cells.

J Clin Invest. 2010 Jun 1;120(6):2171-83. doi: 10.1172/JCI35846.
Hypoxia-inducible factor-1alpha regulates beta cell function in mouse and human islets.
Cheng K, Ho K, Stokes R, Scott C, Lau SM, Hawthorne WJ, O'Connell PJ, Loudovaris T, Kay TW, Kulkarni RN, Okada T, Wang XL, Yim SH, Shah Y, Grey ST, Biankin AV, Kench JG, Laybutt DR, Gonzalez FJ, Kahn CR, Gunton JE.
Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, New South Wales, Australia.
Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that regulates cellular stress responses. While the levels of HIF-1alpha protein are tightly regulated, recent studies suggest that it can be active under normoxic conditions. We hypothesized that HIF-1alpha is required for normal beta cell function and reserve and that dysregulation may contribute to the pathogenesis of type 2 diabetes (T2D)... Increasing HIF-1alpha levels markedly increased expression of ARNT and other genes in human T2D [type 2 diabetes] islets and improved their function...

Cancer Res. 2006 Jun 15;66(12):6264-70.
Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway.
Carroll VA, Ashcroft M.
Cell Growth Regulation and Angiogenesis Laboratory, Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, United Kingdom.

Diabetes. 2009 Jan;58(1):95-103.
Hypoxia decreases insulin signaling pathways in adipocytes.
Regazzetti C, Peraldi P, Grumeaux T, Najem-Lendom R, Ben-Sahra I, Cormont M, Bost F, Le Marchand-Brustel Y, Tanti JF, Giorgetti-Peraldi S.
Team Cellular and Molecular Physiopathology of Obesity and Diabetes, Institut National de la Sante et de la Recherche Modicale U 895, Mediterranean Research Centre for Molecular Medicine, Nice, France.
Obesity is characterized by an overgrowth of adipose tissue that leads to the formation of hypoxic areas within this tissue. We investigated whether this phenomenon could be responsible for insulin resistance by studying the effect of hypoxia on the insulin signaling pathway in adipocytes.
The hypoxic signaling pathway was modulated in adipocytes from human and murine origins through incubation under hypoxic conditions (1% O(2)) or modulation of hypoxia-inducible factor (HIF) expression. Insulin signaling was monitored through the phosphorylation state of several key partners of the pathway and glucose transport.
In both human and murine adipocytes, hypoxia inhibits insulin signaling as revealed by a decrease in the phosphorylation of insulin receptor. In 3T3-L1 adipocytes, this inhibition of insulin receptor phosphorylation is followed by a decrease in the phosphorylation state of protein kinase B and AS160, as well as an inhibition of glucose transport in response to insulin. These processes were reversible under normoxic conditions. The mechanism of inhibition seems independent of protein tyrosine phosphatase activities. Overexpression of HIF-1alpha or -2alpha or activation of HIF transcription factor with CoCl(2) mimicked the effect of hypoxia on insulin signaling, whereas downregulation of HIF-1alpha and -2alpha by small interfering RNA inhibited it.
We have demonstrated that hypoxia creates a state of insulin resistance in adipocytes that is dependent upon HIF transcription factor expression. Hypoxia could be envisioned as a new mechanism that participates in insulin resistance in adipose tissue of obese patients.

Mol Cell Biol. 2009 Aug;29(16):4467-83.
Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue.
Halberg N, Khan T, Trujillo ME, Wernstedt-Asterholm I, Attie AD, Sherwani S, Wang ZV, Landskroner-Eiger S, Dineen S, Magalang UJ, Brekken RA, Scherer PE.
Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Adipose tissue can undergo rapid expansion during times of excess caloric intake. Like a rapidly expanding tumor mass, obese adipose tissue becomes hypoxic due to the inability of the vasculature to keep pace with tissue growth. Consequently, during the early stages of obesity, hypoxic conditions cause an increase in the level of hypoxia-inducible factor 1alpha (HIF1alpha) expression. Using a transgenic model of overexpression of a constitutively active form of HIF1alpha, we determined that HIF1alpha fails to induce the expected proangiogenic response. In contrast, we observed that HIF1alpha initiates adipose tissue fibrosis, with an associated increase in local inflammation. "Trichrome- and picrosirius red-positive streaks," enriched in fibrillar collagens, are a hallmark of adipose tissue suffering from the early stages of hypoxia-induced fibrosis. Lysyl oxidase (LOX) is a transcriptional target of HIF1alpha and acts by cross-linking collagen I and III to form the fibrillar collagen fibers. Inhibition of LOX activity by beta-aminoproprionitrile treatment results in a significant improvement in several metabolic parameters and further reduces local adipose tissue inflammation. Collectively, our observations are consistent with a model in which adipose tissue hypoxia serves as an early upstream initiator for adipose tissue dysfunction by inducing a local state of fibrosis.

Am J Physiol Endocrinol Metab. 2007 Dec;293(6):E1590-6.
HIF-1 regulates hypoxia- and insulin-induced expression of apelin in adipocytes.
Glassford AJ, Yue P, Sheikh AY, Chun HJ, Zarafshar S, Chan DA, Reaven GM, Quertermous T, Tsao PS.
Department of Medicine, Stanford University Medical Center, Stanford, CA, USA.
Apelin, a novel peptide with significant cardioactive properties, is upregulated by insulin in adipocytes. However, the mechanism by which insulin promotes apelin production is unknown. Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor involved in the angiogenic and metabolic responses to tissue hypoxia, has been shown to be activated by insulin in various settings. We therefore hypothesized that HIF-1 regulates insulin-mediated apelin expression in adipocytes. 3T3-L1 cells were differentiated into adipocytes in culture. For experiments, serum-starved 3T3-L1 cells were exposed to insulin and/or a 1% O(2) environment. Apelin expression was assessed using quantitative real-time PCR and ELISA. To directly assess the role of HIF-1 in apelin production, we differentiated mouse embryonic fibroblasts (MEFs) containing a targeted deletion of the HIF-1alpha gene into adipocytes and measured their response to insulin and hypoxia. Apelin expression in mature 3T3-L1 adipocytes was increased significantly by insulin and was attenuated by pharmacological inhibition of insulin signaling. Exposure of cells to either hypoxia or the chemical HIF activators cobalt chloride (CoCl(2)) and dimethyloxaloylglycine (DMOG) resulted in significant upregulation of apelin, consistent with a role for HIF in apelin induction. Moreover, hypoxia-, CoCl(2)-, DMOG-, and insulin-induced apelin expression were all attenuated in differentiated HIF-1alpha-deficient MEFs. In summary, in cultured 3T3-L1 adipocytes and differentiated MEFs, HIF-1 appears to be involved in hypoxia- and insulin-induced apelin expression.

Biochem Biophys Res Commun. 2006 Mar 10;341(2):549-56.
Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes.
Chen B, Lam KS, Wang Y, Wu D, Lam MC, Shen J, Wong L, Hoo RL, Zhang J, Xu A.
Department of Medicine, University of Hong Kong, Hong Kong, China.
Low plasma levels of adiponectin (hypoadiponectinemia) and elevated circulating concentrations of plasminogen activator inhibitor (PAI)-1 are causally associated with obesity-related insulin resistance and cardiovascular disease. However, the mechanism that mediates the aberrant production of these two adipokines in obesity remains poorly understood. In this study, we investigated the effects of hypoxia and reactive oxygen species (ROS) on production of adiponectin and PAI-1 in 3T3-L1 adipocytes. Quantitative PCR and immunoassays showed that ambient hypoxia markedly suppressed adiponectin mRNA expression and its protein secretion, and increased PAI-1 production in mature adipocytes. Dimethyloxallyl glycine, a stabilizer of hypoxia-inducible factor 1alpha (HIF-1alpha), mimicked the hypoxia-mediated modulations of these two adipokines. Hypoxia caused a modest elevation of ROS in adipocytes. However, ablation of intracellular ROS by antioxidants failed to alleviate hypoxia-induced aberrant production of adiponectin and PAI-1. On the other hand, the antioxidants could reverse hydrogen peroxide (H2O2)-induced dysregulation of adiponectin and PAI-1 production. H2O2 treatment decreased the expression levels of peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer binding protein (C/EBPalpha), but had no effect on HIF-1alpha, whereas hypoxia stabilized HIF-1alpha and decreased expression of C/EBPalpha, but not PPARgamma. Taken together, these data suggest that hypoxia and ROS decrease adiponectin production and augment PAI-1 expression in adipocytes via distinct signaling pathways. These effects may contribute to hypoadiponectinemia and elevated PAI-1 levels in obesity, type 2 diabetes, and cardiovascular diseases.

FASEB J. 2002 May;16(7):745-7.
Apoptosis in hypoxic human pancreatic islets correlates with HIF-1alpha expression.
Moritz W, Meier F, Stroka DM, Giuliani M, Kugelmeier P, Nett PC, Lehmann R, Candinas D, Gassmann M, Weber M.
Clinic for Visceral and Transplant Surgery, University Hospital Zurich, CH-8091 Zurich, Switzerland.
To become insulin independent, patients with type 1 diabetes mellitus require transplantation of at least two donor pancreata because of massive beta-cell loss in the early post-transplantation period. Many studies describing the introduction of new immunosuppressive protocols have shown that this loss is due to not only immunological events but also nonimmunological factors. To test to what extent hypoxia may contribute to early graft loss, we analyzed the occurrence of apoptotic events and the expression of hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor consisting of an oxygen-dependent alpha subunit and a constitutive beta subunit. Histological analysis of human and rat islets revealed nuclear pyknosis as early as 6 h after hypoxic exposure (1% O2). Moreover, immunoreactivity to activated caspase-3 was observed in the core region of isolated human islets. Of note, both of these markers of apoptosis topographically overlap with HIF-1alpha immunoreactivity. HIF-1alpha mRNA was detected in islets from human and rat as well as in several murine beta-cell lines. When exposed to hypoxia, mouse insulinoma cells (MIN6) had an increased HIF-1alpha protein level, whereas its mRNA level did not alter. In conclusion, our data provide convincing evidence that reduced oxygenation is an important cause of beta-cell loss and suggest that HIF-1alpha protein level is an indicator for hypoxic regions undergoing apoptotic cell death. These observations suggest that gene expression under the control of HIF-1 represents a potential therapeutic tool for improving engraftment of transplanted islets.

References for the Table

Bottini et al, 2003

Bottini P, Dottorini ML, M. Cordoni MC, Casucci G, Tantucci C, Sleep-disordered breathing in nonobese diabetic subjects with autonomic neuropathy, Eur Respir J 2003; 22: p. 654–660.

Dept of Internal Medicine and Endocrine-Metabolic Sciences, University of Perugia, Perugia, Italy

Tantucci et al, 2001

Tantucci C, Bottini P, Fiorani C, Dottorini ML, Santeusanio F, Provinciali L, Sorbini CA, Casucci G, Cerebrovascular reactivity and hypercapnic respiratory drive in diabetic autonomic neuropathy, J Appl Physiol 2001, 90: p. 889–896.

Clinica di 1Semeiotica e Metodologia Medica and Neurologia e Neuroriabilitazione, University of Ancona, and Dipartimento di Medicina Interna e Scienze Endocrino-Metaboliche, University of Perugia, Italy.

Mancini et al, 1999

Mancini M, Filippelli M, Seghieri G, Iandelli I, Innocenti F, Duranti R, Scano G, Respiratory Muscle Function and Hypoxic Ventilatory Control in Patients With Type I Diabetes, Chest 1999; 115; p.1553-1562.

Tantucci et al, 1997

Tantucci C, Scionti L, Bottini P, Dottorini ML, Puxeddu E, Casucci G, Sorbini CA, Influence of autonomic neuropathy of different severities on the hypercapnic drive to breathing in diabetic patients, Chest. 1997 Jul; 112(1): p. 145-153.

Clinica di Semeiotica e Metodologia Medica, University of Ancona, Italy.

Tantucci et al, 1996

Tantucci C, Bottini P, Dottorini ML, Puxeddu E, Casucci G, Scionti L, Sorbini CA, Ventilatory response to exercise in diabetic subjects with autonomic neuropathy, J Appl Physiol 1996, 81(5): p.1978–1986.

Clinica di Semeiotica Metodologia Medica, University of Ancona, Ospedale Regionale Torrette, Ancona 60020; and Istituto di Medicina Interna e Scienze Endocrine e Metaboliche, University of Perugia, Perugia 06100, Italy.

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