What is the cause of insulin resistance in the elderly?
tmatth at netcom.ca
Sat Mar 21 22:20:18 EST 1998
Aubrey de Grey wrote:
> Hang-Jun Jang wrote:
> > As far as I know, early glycosylation products are reversible, but if once
> > formed, advanced glycosylation end products(AGEs) are not reversible
> > You said we currently have mechanisms for removing/repairing/undoing
> > glycation. Could you let me know them?
> I don't know whether this is what Tom was referring to, but there was an
> articly in Nature two years ago reporting this in rats:
> Nature 1996 Jul 18;382(6588):275-278
> An agent cleaving glucose-derived protein crosslinks in vitro and in vivo.
> Vasan S, Zhang X, Zhang X, Kapurniotu A, Bernhagen J, Teichberg S, Basgen J,
> Wagle D, Shih D, Terlecky I, Bucala R, Cerami A, Egan J, Ulrich P
> The only followup article I have come across (which I haven't read) is:
> Diabetologia 1997 Jul;40 Suppl 2:S157-S159
> Pharmacological reversal of advanced glycation end-product-mediated protein
> Ulrich P, Zhang X
Thanks Aubrey, for supplying those. By searching Pubmed, I had found
However, besides several agents which are known to inhibit AGE
formation, aminoguanidine, alpha lipoic acid, pyridoxamine, thiamine
pyrophosphate, etc., I was simply referring to the body's own
degradation and removal system (see the following abstracts) which
presumably declines in efficiency with age.
Kidney Int 1998 Feb;53(2):416-422
Renal catabolism of advanced glycation end products: the fate of
Miyata T, Ueda Y, Horie K, Nangaku M, Tanaka S, van Ypersele de Strihou
C, Kurokawa K
Department of Medicine, Tokai University School of Medicine, Isehara,
Advanced glycation end products (AGEs) generated through the Maillard
reaction significantly alter protein characteristics. Their accumulation
has been incriminated in tissue injury associated with aging, diabetes,
and renal failure. However, little is known about their clearance from
the body. The present study delineates the catabolic pathway of a
well-defined AGE product, pentosidine. Synthesized pentosidine given
intravenously in rats with normal renal function was rapidly eliminated
from the circulation through glomerular filtration, but was undetectable
in the urine by chemical analysis. Immunohistochemistry with
anti-pentosidine antibody disclosed that pentosidine accumulated
transiently in the proximal renal tubule one hour after its
administration, but had disappeared from the kidney at 24 hours. After
an intravenous load of radiolabeled pentosidine, radioactivity peaked in
the kidney at one hour and subsequently decreased, whereas it rose
progressively in the urine. Over 80% of the radioactivity was recovered
in the 72-hour collected urine. However, only 20% of urine radioactivity
was associated with intact pentosidine chemically or immunochemically.
In gentamicin-treated rats with tubular dysfunction, up to 30% of the
pentosidine load was recovered as intact pentosidine in the urine. The
present study suggests that free pentosidine (and possibly other AGEs)
is filtered by renal glomeruli, reabsorbed in the proximal tubule where
it is degraded or modified, and eventually excreted in the urine. Kidney
thus plays a key role in pentosidine disposal.
Biochem J 1997 Mar 1;322( Pt 2):567-573
Advanced glycation end products are eliminated by
scavenger-receptor-mediated endocytosis in hepatic sinusoidal Kupffer
and endothelial cells.
Smedsrod B, Melkko J, Araki N, Sano H, Horiuchi S
Department of Experimental Pathology, University of Tromso, Norway.
Long-term incubation of proteins with glucose leads to the formation of
advanced glycation end products (AGE). Physiological aspects of the
catabolism of non-enzymically glycated proteins were studied in vivo and
in vitro. AGE-modified BSA (AGE-BSA) was a mixture of high-Mr
(cross-linked), monomeric and low-Mr (fragmented) AGE-BSA. After
intravenous administration in rat, all three fractions of AGE-BSA
accumulated extremely rapidly and almost exclusively in liver. Uptake in
liver endothelial, Kupffer and parenchymal cells accounted for approx.
60%, 25% and 10-15% respectively of hepatic elimination. Both
cross-linked and monomeric AGE-BSA were efficiently taken up and
degraded in cultures of purified liver endothelial and Kupffer cells.
Endocytosis of AGE-BSA by these cells was inhibited by several ligands
for the scavenger receptor. Although 125I-Hb was not endocytosed in
vitro, 125I-AGE-Hb was effectively endocytosed by a mechanism that was
subject to inhibition by AGE-BSA. Endocytosis of N-terminal propeptide
of type I procollagen, a physiological ligand for the scavenger
receptor, was effectively inhibited by AGE-Hb and AGE-BSA. We conclude
that AGE-modification renders
macromolecules susceptible for elimination via the scavenger receptor of
both liver endothelial and Kupffer cells.
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