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,
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.
RESEARCH DESIGN AND METHODS:
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
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
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.
RESEARCH DESIGN AND METHODS:
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
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,
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
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,
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
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
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
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):
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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