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Br J Nutr 2001 Oct;86(4):515-9
Low iron status and enhanced insulin sensitivity in lacto-ovo vegetarians.
Hua NW, Stoohs RA, Facchini FS
Department of Medicine, Division of Nephrology, San Francisco General
Hospital, San Francisco, CA, USA.
[Medline record in process]
The efficacy of insulin in stimulating whole-body glucose disposal
(insulin sensitivity) was quantified using direct methodology in
thirty lacto-ovo vegetarians and in thirty meat-eaters. All subjects
were adult, lean (BMI <23 kg/m2), healthy and glucose tolerant.
Lacto-ovo vegetarians were more insulin sensitive than meat-eaters,
with a steady-state plasma glucose (mmol/l) of 4.1 (95 % CI 3.5, 5.0)
v. 6.9 (95 % CI 5.2, 7.5; respectively. In addition, lacto-ovo
vegetarians had lower body Fe stores, as indicated by a serum ferritin
concentration (mg/l) of 35 (95 % CI 21, 49) compared with 72 (95 % CI
45, 100) for meat-eaters To test whether or not Fe status might
modulate insulin sensitivity, body Fe was lowered by phlebotomy in six
male meat-eaters to levels similar to that seen in vegetarians, with a
resultant approximately 40 % enhancement of insulin-mediated glucose
disposal Our results demonstrate that lacto-ovo vegetarians are more
insulin sensitive and have lower Fe stores than meat-eaters. In
addition, it seems that reduced insulin sensitivity in meat-eaters is
amenable to improvement by reducing body Fe. The latter finding is in
agreement with results from animal studies where, no matter how
induced, Fe depletion consistently enhanced glucose disposal.
PMID: 11591239, UI: 21475355
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Subject: diabetes
from the Journal of Clinical Investigation, April 2001
Transition metals redox: reviving an old plot for diabetic vascular disease
Vincent M. Monnier
Case Western Reserve University, Institute of Pathology, Cleveland, Ohio
44106, USA.
Phone: (216) 368-6613; Fax: (216) 368-0495; E-mail: vmm3@po.cwru.edu.
Considerable effort over the past 25 years has focused on the role of
oxidant stress in aging and in the pathogenesis of age-related diseases -
diabetes, Alzheimer's disease, end-stage renal disease, and atherosclerosis,
among others. Research on redox signaling and the chemistry of the aging
process has led to major insights, including the identification of oxidant
stress-responsive transcription factors, such as NF-B, which regulate tissue
remodeling and therefore control the progression of pathological lesions;
the role of mitochondria in generating reactive oxygen species and
activating apoptotic pathways; the role of sulfhydryl homeostasis in redox
signaling; and the development of mass spectrometry methods to identify and
quantify protein damage in aging or stressed tissues.
Because of the prevalence and the dire consequences of the diseases
involved, the stakes in this field are high. However, despite the great
interest in developing drugs that might block oxidant or carbonyl stress,
clinical studies involving antioxidant or carbonyl-trapping agents have had
mixed success, suggesting a greater degree of complexity than anticipated.
Thus, in the diabetic rat, treatment with various antioxidants or
carbonyl-trapping agents has had impressive effects in delaying, if not
altogether preventing, complications of diabetes such as cataracts,
retinopathy, nephropathy, vascular abnormalities, nerve conduction velocity,
plasma lipid oxidation, and fetal malformations. In the diabetic human,
conversely, while intra-arterial infusion of vitamin C improved
endothelium-dependent vasodilation (1) and oral intake of vitamin E improved
retinal blood flow and creatinine clearance (2), chronic treatment with
vitamin E did not reduce cardiovascular risk (3). Similarly, the
antioxidant -lipoic acid decreased plasma hydroperoxides in diabetic
subjects but had equivocal efficacy in polyneuropathy and cardiac autonomic
neuropathy (4, 5). A similar "antioxidant paradox" has also been observed in
other diseases associated with oxidant stress (6).
Protein oxidation in diabetes
In diabetes, the controversy has focused on the origin, the type, the
magnitude, and the localization of oxidant stress in relation to
hyperglycemia, and how this combination promotes the progression of micro-
and macrovascular disease. For example, high glucose levels were associated
early on with an altered cellular redox state, aldose reductase activation,
and impaired glutathione homeostasis in selected tissues. In experimental
diabetes, antioxidants or transition metal chelators can ameliorate
retinopathy and neuropathy, suggesting that oxidant stress contributes to
this condition (7, 8). On the other hand, Williamson et al., noting an
increased cellular NADH/NAD ratio (9), have proposed that diabetes is a
state of "reductive" stress and "pseudohypoxia," raising the question of how
oxidative damage might arise in a reducing environment.
As the glycation theory of diabetic complications unfolded, metal-catalyzed
glucose autooxidation and oxidation of glycated residues emerged as potent
sources of free radicals and were proposed as the primary culprits in tissue
damage (10, 11). In vitro, exposing proteins to high levels of glucose
causes oxidative protein fragmentation and damage to amino acid residues,
with the accumulation of methionine sulfoxide, o-tyrosine, m-tyrosine, and
other modifications. Many of the glucose-associated oxidative modifications
have been attributed to Fenton chemistry carried out by transition metals
like copper and iron, which are normally present in phosphate buffer (11).
Wolff et al. and Baynes therefore proposed a key role for oxidation and
glycoxidation chemistry in the pathogenesis of diabetic complications (10,
11). More recently, however, the model of generalized oxidant stress lost
support because of a lack of evidence for increased levels of oxidized skin
collagen in diabetic individuals (reviewed in ref. 12). Instead, Baynes and
Thorpe propose a greater role for overload of metabolic pathways as the
primary culprit in oxidant and carbonyl stress in diabetes: "Treatment of
diabetes with antioxidant therapy," they write, "is like applying water to a
burning house, certainly helpful in limiting the conflagration, but also a
little bit late in the process" (12).
Oxidative damage in atherosclerosis research has also focused investigators
on the effects of transition metals. Cu2+-catalyzed LDL oxidation has become
a useful and widely studied, albeit controversial, model for oxidative
events in the arterial wall. Coincubation of LDL with glucose or glycated
proteins significantly increases lipoprotein oxidation by adventitious
transition metals, thus offering a potential explanation for the
acceleration of atherosclerosis in diabetes (13). In this context, the
useful terms "glycoxidation" and "lipoxidation" have found their way in the
literature (12).
However, another potentially relevant mechanism of oxidation emerged with
the exciting discovery that myeloperoxidase, derived from macrophages of the
arterial wall, potently oxidizes LDL to generate the same oxidative
modifications found in LDL isolated from atheromatous plaques. Both
Cu2+-mediated and myeloperoxidase-mediated oxidation lead to an increase in
o-tyrosine and m-tyrosine, but only the latter selectively generates
dityrosine from tyrosine radical (reviewed in ref. 14). The finding that
dityrosine was selectively increased in fatty streaks and intermediate
atheromatous lesions, whereas hydroxyl radical damage was elevated only in
more advanced lesions, led Semenkovich and Heinecke (15) to propose "a new
plot" for oxidative events in diabetes and atherosclerosis, in which
myeloperoxidase, rather than transition metals and hydroxyl radicals,
initiates the oxidant cascade.
Yet a third potential mechanism of oxidation arose from observations that
endothelium-derived nitric oxide together with superoxide might lead to
increased levels of the highly oxidizing and atherogenic molecule
peroxynitrite (reviewed in ref. 14). Whereas peroxynitrite has hydroxyl
radical-like properties and can generate o- and m-tyrosine from
phenylalanine, it also generates the highly specific 3-nitrotyrosine, which
is increased 80-fold in atherosclerotic lesions compared with plasma LDL,
and can serve as a marker for the reactive nitrogen pathway (14).
Hydroxyl radicals revisited
Many of the data implicating myeloperoxidase in early atherosclerotic
lesions were limited to nondiabetic tissue. In this issue of the JCI,
Pennathur et al. (16) have now examined the oxidative chemistry occurring in
early atherosclerosis in Cynomologus monkeys after 6 months of
streptozotocin-induced diabetes and feeding of a Western-type diet. Working
with a protein-rich extract from thoracic aorta, these authors quantified o-
and m-tyrosine, o,o'-dityrosine, and 3-nitrotyrosine as markers of damage
from hydroxyl radical, myeloperoxidase activity, and peroxynitrite,
respectively. They report that o-, m-, and dityrosine, but not
3-nitrotyrosine, are significantly elevated in diabetic aortae, indicating
that peroxynitrite is an unlikely source of damage. To test the correlation
of the data from these chemical analyses with the extent of hyperglycemia,
the authors also quantified glycated hemoglobin. They report that two of the
oxidative products, o- and m-tyrosine, are tightly correlated with this
physiological parameter, but that dityrosine levels are not, consistent with
hydroxyl radical-mediated damage but not with a principle role for
myeloperoxidase. They further show that glucose autoxidation does not
explain their data. Thus, in all likelihood, redox-active transition metals
are involved in this form of atherosclerosis.
Figure 1 summarizes one possible sequence of events that may explain how
diabetes initiates atherosclerotic lesions without involving inflammatory
cells. First, diabetes-associated hyper- and dyslipidemia are expected to
accelerate LDL deposition in the arterial wall, while hyperglycemia promotes
the formation of the highly reducing Amadori products in both LDL and
collagen. Hyperglycemia also leads to the conversion of methylglyoxal to
carboxyethyl-lysine (CEL) (reviewed in refs. 11, 17). All these processes
occur nonoxidatively. Oxidation of polyunsaturated fatty acids in LDL,
mediated by high glucose-driven superoxide formation by mitochondria and
NADH oxidase (18, 19), will yield glyoxal, a potent precursor of
N-carboxymethyl-lysine (CML) (17). Indeed, CML has been detected
immunochemically in early atheromatous lesions (20). Evidence for the
presence of CEL in such lesions is still pending, but it is expected based
on findings of elevated CEL in diabetic tissues (17).
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Figure 1. Proposed sequence of events leading to hydroxyl
radical-mediated protein damage in early atherosclerosis in diabetes. The
data from Pennathur et al. (16) show a strong relationship between hydroxyl
radical damage and hemoglobin glycation. Because these authors found no
evidence for increased nitration-mediated damage, it appears that formation
of the initial lesion does not involve inflammatory cells. A likely scenario
involves increased glycation and the formation of the redox-active center
due to the formation of carboxymethyl-lysine (CML) and carboxyethyl-lysine
(CEL), which can bind redox-active copper and perhaps iron. Amadori products
and ceruloplasmin (not shown) are also expected to be potent precursors of
oxidative damage. Hyperglycemia-catalyzed superoxide formation from
mitochondrial and cytoplasmic sources is expected to initiate the
lipoxidation cascade and release of glyoxal, a potent CML precursor. PUFA,
polyunsaturated fatty acid.
The strong relationship observed between glycated hemoglobin and hydroxyl
radical damage suggests a concomitant process in which CML originates from
Amadori products through hydroxyl radical-mediated oxidation (21). Proteins
rich in CML (22) and methylglyoxal-treated proteins (R. Subramaniam and V.M.
Monnier, unpublished results) have been found to bind redox-active Cu2+,
providing a possible mechanism for the protein damage reported by Pennathur
et al. (16). Of major interest in this context is the recent suggestion of
Saxena et al. (23) that ascorbic acid, which is also found in atheromatous
plaques, can generate CML and become a pro-oxidant in the presence of
transition metals.
Still unclear is the exact source of the transition metals. Possibilities
include the transfer of loosely bound metals to CML/CEL-rich proteins, which
could result from glycation of superoxide dismutase, ceruloplasmin, or
ferritin (24), and the possible binding of redox-active iron by Amadori
products (25). However, intact ceruloplasmin can also oxidize lipoproteins
(26), and its levels are increased in selected patients with diabetes.
The apparent absence of myeloperoxidase- and nitration-mediated oxidation
suggests that inflammatory cells are not involved at the very early stage of
atherogenesis in diabetes. This scenario may be specific for diabetes, since
previous data from apparently nondiabetic individuals suggest the contrary
(14). However, once they become oxidized and accumulate CML and other
advanced glycation products, vessel-associated LDL and other proteins can
act as signals and chemotactic factors for activation of inflammatory cells
by binding to RAGE, CD36, or other receptors (27-29). Once that barrier has
been crossed, it is not surprising that many forms of protein damage ensue.
If the mechanisms put forward in Figure 1 apply to the early phase of
atherosclerosis in diabetes, then therapeutic antioxidants will be needed
much earlier in the process than previously appreciated. Transition
metal-chelating agents and hydroxyl radical scavengers may prove useful as
adjuvants to other forms of therapy.
References
Ting, H.H. et al.1996. Vitamin C improves endothelium-dependent vasodilation
in patients with non-insulin-dependent diabetes mellitus. J. Clin. Invest.
97:22-28.[Medline]
Bursell, S.E. et al.1999. High-dose vitamin E supplementation normalizes
retinal blood flow and creatinine clearance in patients with type 1
diabetes. Diabetes Care. 22:1245-1251.[Medline]
Hoogwerf, B.J., and Young, J.B. 2000. The HOPE study. Ramipril lowered
cardiovascular risk, but vitamin E did not. Cleve. Clin. J. Med.
67:287-293.[Medline]
Reljanovic, M. et al.1999. Treatment of diabetic polyneuropathy with the
antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter
randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic
Acid in Diabetic Neuropathy. Free Radic. Res. 31:171-179.[Medline]
Ziegler, D. et al.1999. Treatment of symptomatic diabetic polyneuropathy
with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized
controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic
Acid in Diabetic Neuropathy. Diabetes Care. 22:1296-301.[Medline]
Halliwell, B. 2000. The antioxidant paradox. Lancet. 355:1179-1180.[Medline]
Cameron, N.E., and Cotter, M.A. 1995. Neurovascular dysfunction in diabetic
rats. Potential contribution of autoxidation and free radicals examined
using transition metal chelating agents. J. Clin. Invest.
96:1159-1163.[Medline]
Kunisaki, M. et al.1995. Vitamin E prevents diabetes-induced abnormal
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Williamson, J.R. et al.1993. Perspectives in diabetes: hyperglycemic
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Wolff, S.P., Jiang, Z.Y., and Hunt, J.V. 1991. Protein glycation and
oxidative stress in diabetes mellitus and ageing. Free Radic. Biol. Med.
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Baynes, J.W. 1991. Role of oxidative stress in development of complications
in diabetes. Diabetes. 40:405-412.[Medline]
Baynes, J.W., and Thorpe, S.R. 1999. Role of oxidative stress in diabetic
complications: a new perspective on an old paradigm. Diabetes.
48:1-9.[Medline]
Mullarkey, C.J., Edelstein, D., and Brownlee, M. 1990. Free radical
generation by early glycation products: a mechanism for accelerated
atherogenesis in diabetes. Biochem. Biophys. Res. Commun.
173:932-939.[Medline]
Heinecke, J.W. 1998. Oxidants and antioxidants in the pathogenesis of
atherosclerosis: implications for the oxidized low density lipoprotein
hypothesis. Atherosclerosis. 141:1-15.[Medline]
Semenkovich, C., and Heinecke, J.W. 1997. The mystery of diabetes and
atherosclerosis: time for a new plot. Diabetes. 46:327-334.[Medline]
Pennathur, S., Wagner, J.D., Leeuwenburgh, C., Litwak, K.N., and Heinecke,
J.W. 2001. A hydroxyl radical-like species oxidizes cynomolgus monkey artery
wall proteins in early diabetic vascular disease. 107:853-860.[Abstract/Full
Text]
Baynes, J.W., and Thorpe, S.R. 2000. Glycoxidation and lipoxidation in
atherogenesis. Free Radic. Biol. Med. 28:1708-1716.[Medline]
Nishikawa, T. et al.2000. Normalizing mitochondrial superoxide production
blocks three pathways of hyperglycaemic damage. Nature.
404:787-790.[Medline]
Ellis, E.A. et al.1998. Increased NADH oxidase activity in the retina of the
BBZ/Wor diabetic rat. Free Radic. Biol. Med. 24:111-120.[Medline]
Imanaga, Y. et al.2000. In vivo and in vitro evidence for the glycoxidation
of low density lipoprotein in human atherosclerotic plaques.
Atherosclerosis. 150:343-355.[Medline]
Nagai, R. et al.1997. Hydroxyl radical mediates Ne-(carboxymethyl)lysine
formation from Amadori product. Biochem. Biophys. Res. Commun.
234:167-172.[Medline]
Saxena, A.K. et al.1999. Protein aging by carboxymethylation of lysines
generates redox active and divalent metal binding sites: relevance to
diseases of glycoxidative stress. Biochem. Biophys. Res. Commun.
260:332-338.[Abstract/Full Text]
Saxena, P. et al.2000. Transition metal-catalyzed oxidation of ascorbate in
human cataract extracts: possible role of advanced glycation end products.
Invest. Ophthalmol. Vis. Sci. 41:1473-1481.[Abstract/Full Text]
Taniguchi, N. et al.1995. Glycation of metal-containing proteins such as
Cu,Zn-superoxide dismutase, ceruloplasmin, and ferritin: possible
implication for DNA damage in vivo. Contrib. Nephrol. 112:18-23.[Medline]
Qian, M., Liu, M., and Eaton, J.W. 1998. Transition metals bind to glycated
proteins forming redox active "glycochelates": implications for the
pathogenesis of certain diabetic complications. Biochem. Biophys. Res.
Commun. 250:385-389.[Medline]
Fox, P.L. et al.2000. Ceruloplasmin and cardiovascular disease. Free Radic.
Biol. Med. 28:1735-1744.[Abstract/Full Text]
Ohgami, N. et al.2001. CD36, a member of class B scavenger receptor family,
as a receptor for advanced glycation end products (AGE). J. Biol. Chem.
276:3195-3202.[Abstract/Full Text]
Schmidt, A.M. et al.1999. Activation of receptor for advanced glycation end
products: a mechanism for chronic vascular dysfunction in diabetic
vasculopathy and atherosclerosis. Circ. Res. 84:489-497.[Full Text]
Stitt, A.W. et al.2000. Advanced glycation end-product receptor interactions
on microvascular cells occur within caveolin-rich membrane domains. FASEB J.
14:2390-2392.[Full Text]
Linköping University Medical Dissertations
No. 599
Insulin-Producing Cells, Iron, Oxidative Stress, and Lysosomal
Pathology
Beata Teresa Olejnicka, MD
Akademisk avhandling
som för avläggande av doktorsexamen i medicinsk vetenskap kommer att
offentligt försvaras i Patologens föreläsningssal, Hälsouniversitetet,
Linköping, onsdagen den 2 juni 1999, kl 13.00.
Fakultetsopponent: Professor Enrique Cadenas, Department of Molecular
Pharmacology & Toxicology, University of Southern California, Los
Angeles, USA.
ABSTRACT
Accumulating evidence suggests that injuries caused by oxygen-derived
radicals contribute to the destruction of pancreatic islet ß-cells in
autoimmune diabetes mellitus (diabetes type I, or IDDM. Oxidative
stress may be caused by an enhanced production of oxygen-derived
radicals, or by a decreased scavenging of such molecules. It was
recently suggested that iron-mediated intralysosomal oxidative
reactions result in the destabilization of lysosomal membranes,
leakage of lysosomal contents to the cytosol, cellular destruction
and, moreover, that such mechanisms may operate in IDDM.
In the present study, we have investigated the mechanisms by which
hydrogen peroxide induces cell damage, and its possible relationship
to intralysosomal iron. The work was done on three insulin-producing
insulinoma cell lines: HIT-T15, NIT-1, and RINmF cells, on mouse
pancreatic islets ß-cells, and the macrophage-like J-774 cells. In
particular, we studied the influence of induced autophagocytosis (by
glucose- and amino acid starvation) on the sensitivity to oxidative
stress; the influence of high-glucose growth media on hydrogen
peroxide cytotoxicity; the protective effects by starvation-stimulated
intracellular ferritin synthesis against oxidative stress; the
possible relationship between oxidative stress, lysosomal
destabilization and apoptotic/necrotic cell death; and the impact of
iron chelation on lysosomal stability, and insulinoma- and ß-cell
survival.
A high susceptibility to oxidative stress was demonstrated for all the
insulin-producing cells. Starvation-induced autophagocytosis increased
the concentration of desferrioxamine-available low-molecular-weight
iron in HIT-T15 cells, as assayed by HPLC. The iron was mainly found
in secondary lysosomes, as shown by the autometallography technique
when applied at electron microscopical level. Starvation enhanced
oxidative stress-induced damage of the HIT-T15, RINm5F and J-774
cells, as assayed by the trypan blue dye exclusion test and tests for
lysosomal stability (the acridine orange relocation/uptake tests). In
contrast, the pronounced starvation-induced autophagocytosis that was
shown by the most vulnerable insulinoma cell line (NIT-1) was
paralleled by enhanced resistance to oxidative stress, and by
increased lysosomal stability as well. A rapid NIT-1 ferritin
synthesis was demonstrated by immunocytochemistry under conditions of
starvation. It is believed that autophagocytotic lysosomal uptake of
non-iron-saturated ferritin will allow such ferritin to act as an iron
chelator and stabilize lysosomes against oxidative stress. NIT-1 and
ß-cells which were subjected to a low level of oxidative stress (30 µM
H2O2, for 15 min) were still largely intact at the light microscopical
level but 10-20% of the cells exhibited nuclear chromatin condensation
as an early sign of apoptosis when examined by the Ho334/PI staining
technique, or by TEM, 0.5-1 h after the insult. At the same point of
time, a decrease in the number of intact lysosomes was also observed.
The rate of oxidative stress-induced lysosomal destabilization
progressed with time, and a widespread apoptotic/necrotic-type
degeneration/fragmentation ensued, as demonstrated by SEM, TEM, and
the TUNEL-reaction. The mitochondria revealed a mixture of lamelliform
and swollen cristae, indicating altered properties of the
mitochondrial membranes. Pre-treatment with the iron chelator
desferrioxamine attenuated the lysosomal destabilization, and
increased cell viability, following exposure to oxidative stress.
At high-glucose conditions, the H2O2-sensitivity of HIT-T15, NIT-1,
and ß-cells was reduced which, was consistent with a moderately
enhanced stability of their lysosomes, as measured by the acridine
orange-relocation test, and with reduced amounts of
desferrioxamine-available iron.
We conclude that the decisive role of free lysosomal iron in oxidative
stress is strongly supported by the following lines of evidence,
provided by the present study (a) glucose- and amino acid-starvation
promotes autophagic/crinophagic activity of the cells, resulting, in
enrichment of intracellular (intralysosomal) desferrioxamine-available
iron; (b) high-glucose conditions depress autophagic/crinophagic
activity and, consequently, the occurrence of intralysosomal iron; (c)
starvation-stimulated ferritin synthesis enhances lysosomal stability
during oxidative stress by limiting lysosomal redox-active iron; (d)
lysosomal destabilization and related apoptotic cell death are
associated with the amounts of intralysosomal iron in redox-active
form,
Keywords: Insulin-producing cells, redox-active iron, oxidative
stress, lysosomes, desferrioxamine
Department of Neuromuscular Science and Locomotion, Division of
Pathology II
and Department of Internal Medicine, Emergency Clinic
Linköping University, Faculty of Health Sciences
S-581 85 Linköping, Sweden
Linköping 1999
ISBN 91-7219-345-X ISSN 0345-0092
(HOME) Subject: iron/diabetes type 1
APMIS 1999 Aug;107(8):747-61
Minute oxidative stress is sufficient to induce apoptotic death of NIT-1
insulinoma cells.
Olejnicka BT, Dalen H, Brunk UT
Division of Pathology II, Faculty of Health Sciences, Linkoping
University, Sweden.
[Medline record in process]
When cultured NIT-1 cells were subjected to a low level of oxidative
stress (30 microM hydrogen peroxide for 15 min at 37 degrees C)
several of their lysosomes ruptured, as demonstrated by intravital
staining with the lysosomotropic weak base acridine orange. Such
rupture is due to intralysosomal, iron-catalyzed oxidative reactions,
since it was largely prevented by previous endocytotic uptake of
desferrioxamine. The resultant limited leakage of lysosomal hydrolytic
enzymes into the cytosol could be important for an apoptotic-type
degradation/fragmentation process within initially intact plasma
membranes. In contrast, extensive lysosomal rupture leads to necrosis.
The development of the damage process was followed by light- and
electron microscopy; and by the TUNEL-reaction. As a result of the
applied oxidative stress, which is comparable to that expected to
occur within the microenvironment surrounding activated macrophages
under oxidative burst (e.g. during autoimmune insulitis), about 90% of
the cells eventually died due to post-apoptotic secondary necrosis.
The few surviving cells phagocytosed the debris from their fragmented
neighbours and began to divide about 24 h after the insult. Thus the
sensitivity to oxidative stress varies, perhaps as a consequence of
varying amounts of intralysosomal redox-active iron, as we have found
to be the case in several other cellular systems. Since the NIT-1
cells are highly differentiated, and in many ways like beta cells, we
consider our result to be of value for the understanding of beta-cell
death during the development of insulin-dependent (Type I) diabetes
mellitus (IDDM).
PMID: 10515125, UI: 99443148
_________________________________________________________________
Subject: diabetic neuropathy/vegan diet
DIABETIC NEUROPATHY/VEGAN DIET
Diabetic neuropathy symptoms of sharp, stabbing, burning and/or
shooting pains were entirely relieved in 17 of 21 patients placed on
an animal-product free (vegan), unrefined diet, and exercise at Weimar
Institute in Weimar, California. Improvement was noticed in four days
in some patients. (American Journal of Clinical Nutrition 48(3)Suppl
926, September 1988)
Vitamin E Works As Anti-Inflammatory Agent In Type II Diabetes
DALLAS, TX -- July 10, 2000 -- A high intake of vitamin E can help
reduce heart disease and stroke risk in type II diabetics, UT
Southwestern researchers have found.
In a study published in the July 11 issue of Circulation, Drs.
Ishwarlal Jialal and Sridevi Devaraj found that increased inflammation
caused by white blood cells -- monocytes -- was reduced when diabetics
were given 1,200 International Units per day of natural vitamin E
(alpha-tocopherol) for three months.
"This is the first study that shows that vitamin E has
anti-inflammatory effects in diabetic patients," said Dr. Jialal,
professor of pathology and internal medicine. "It could be a further
therapy to prevent vascular complications in diabetes since
inflammation seems to be critical as a causative factor in diabetic
vascular disease.''
The main cause of death and morbidity in type II diabetes, also known
as non-insulin dependent diabetes mellitus, are vascular
complications. Previous studies by Dr. Jialal, the principal
investigator in this study and a senior investigator in the Center for
Human Nutrition, have shown that vitamin E is a potent antioxidant.
Type II diabetics with and without macrovascular disease were compared
with nondiabetics.
Twenty-five participants in each of the three groups were given 1,200
IU of vitamin E daily for three months followed by two-months without
the supplement. Blood was taken from all the patients at the beginning
of the study, after three months and again after the washout. The
effect of the vitamin E was similar in all three groups.
The study showed that type II diabetic patients have increased
inflammation, as shown by the activity of a pivotal cell (the
circulating monocyte) in plaque formation on artery walls.
The monocyte is a crucial and the most readily accessible cell
involved in atherogenesis.
Study data showed that the diabetic monocyte was more active and
promoted more inflammation and more free radicals and cytokines, or
messenger molecules. The diabetic monocyte also caused more adhesion
to the lining cells of the artery wall.
"It was very important to elucidate the pivotal role for inflammation
in diabetic vascular disease and examine how it could be modulated,"
said Dr. Devaraj, assistant professor in the clinical biochemistry and
human metabolism division in the Department of Pathology.
Subject: Excess Iron Storage in Patients with Type 2 Diabetes Unrelated to
Primary Hemochromatosis
The New England Journal of Medicine -- September 21, 2000 -- Vol. 343, No.
12
Excess Iron Storage in Patients with Type 2 Diabetes Unrelated to Primary
Hemochromatosis
----------------------------------------------------------------------------
----
To the Editor:
The discovery of mutations in the HFE gene in patients with
hemochromatosis has made possible earlier or more complete ascertainment of
cases of this disease. (1) Diabetes mellitus is one manifestation of
hemochromatosis, but in several studies, the frequency of HFE mutations was
similar in normal subjects and in patients with type 2 diabetes. (2)
We analyzed exons 2 and 4 of the HFE gene by sequencing in 19 patients
with primary hemochromatosis and in the 5 patients, of a total of 551 with
type 2 diabetes, who had a positive biochemical screening test for
hemochromatosis (serum transferrin saturation, greater than or equal to 50
percent; serum ferritin concentration, greater than or equal to 1000 µg per
liter). Liver biopsy was performed in four of the five patients; in Patient
3, the diagnosis was established on the basis of total iron removed (>4 g).
Studies included measurements of glucose, estradiol, testosterone, and
gonadotropins; calculation of hepatic iron storage per gram of dry tissue;
and echocardiography (Table 1). Of the 19 patients with primary
hemochromatosis, 13 (68 percent) had type 2 diabetes mellitus, and 18 (95
percent) were homozygous for the Cys282Tyr mutation in the HFE gene. In
contrast, only one of the five patients with diabetes had this mutation, and
she was a heterozygous carrier.
There was no correlation between the genotype and the clinical
manifestations in any of the patients. The only difference between the two
groups was the age at the time of diagnosis of iron overload: the five
patients with diabetes were significantly older (P=0.03). Thus, iron
accumulation in patients with diabetes is not caused by hemochromatosis
related to mutations in the HFE gene, and although not biochemically
different from hemochromatosis, it develops later in life.
Homozygosity for Cys282Tyr may result in a greater accumulation of iron
in the pancreas in a shorter time than that which occurs in other forms of
hemochromatosis and may therefore result in earlier insulin dependence. To
date, none of the five patients with diabetes has been treated with insulin,
whereas four of the patients with hemochromatosis are receiving insulin
therapy. In these four patients, diabetes is secondary to hemochromatosis,
whereas in the patients with diabetes, the diabetes preceded the
hemochromatosis. High body iron stores are associated with abnormally
altered glucose homeostasis in patients with type 2 diabetes, (3) and serum
ferritin concentrations are higher in patients with diabetes than in the
general population. (4) The development of hemochromatosis in some patients
with type 2 diabetes may be the consequence of an anomalous trend toward
iron accumulation mediated by mechanisms other than mutations in the HFE
gene.
Guiomar Perez de Nanclares, B.Sc.
Luis Castano, M.D., Ph.D.
Sonia Gaztambide, M.D., Ph.D.
Jose Ramon Bilbao, Ph.D.
Hospital de Cruces
Barakaldo-Basque Country E48903, Spain
Javier Pi, M.D.
Maria Luisa Gonzalez, M.D., Ph.D.
Hospital General Yague
Burgos E09006, Spain
Jose Antonio Vazquez, M.D., Ph.D.
Hospital de Cruces
Barakaldo-Basque Country E48903, Spain
References
1. Adams PC, Chakrabarti S. Genotypic/phenotypic correlations in genetic
hemochromatosis: evolution of diagnostic criteria. Gastroenterology
1998;114:319-23.
Return to Text
2. Frayling T, Ellard S, Grove J, Walker M, Hattersley AT. C282Y
mutations in HFE (haemochromatosis) gene and type 2 diabetes. Lancet
1998;351:1933-4.
Return to Text
3. Tuomainen T-P, Nyyssonen K, Salonen R, et al. Body iron stores are
associated with serum insulin and blood glucose concentrations: population
study in 1,013 eastern Finnish men. Diabetes Care 1997;20:426-8.
Return to Text
4. Ford ES, Cogswell ME. Diabetes and serum ferritin concentration among
U.S. adults. Diabetes Care 1999;22:1978-83.
Subject: Re: [P] IRON/diabetes
Diabetes Care 1997 Mar;20(3):426-428
Body iron stores are associated with serum insulin and blood glucose
concentrations. Population study in 1,013 eastern Finnish men.
Tuomainen TP, Nyyssonen K, Salonen R, Tervahauta A, Korpela H, Lakka T,
Kaplan GA, Salonen JT
OBJECTIVE: To study if there is an association between mildly elevated
body iron and glucose homeostasis indexes. RESEARCH DESIGN AND
METHODS: A cross-sectional population study was conducted in 1,013
middle-aged men, and an association of serum ferritin with
concentrations of serum insulin, blood glucose, and serum fructosamine
was tested. RESULTS: The mean concentration of fasting serum insulin
was 21.6% higher (95% CI 7.3-37.9%, P < 0.001) in the 5th quintile of
serum ferritin compared with the 1st quintile. The elevation in blood
glucose was 6.1% (95% CI 2.3-9.9%, P < 0.001) and in serum
fructosamine 3.9% (1.5-6.9%, P < 0.01). CONCLUSIONS: Mildly elevated
body iron stores are associated with statistically significant
elevations in glucose homeostasis indexes.
PMID: 9051399, UI: 97203827
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