Re: Researchers discover how a high-fat diet causes type 2 diabetes

On Wed, 20 Sep 2006 14:09:58 +0300, Matti Narkia <mna@xxxxxxxx> wrote:

On Wed, 20 Sep 2006 03:31:21 +0300, Matti Narkia <mna@xxxxxxxx> wrote:

When I fed lipotoxicity to google, the first hit was

Sivitz WI.
Lipotoxicity and glucotoxicity in type 2 diabetes. Effects on
development and progression.
Postgrad Med. 2001 Apr;109(4):55-9, 63-4. Review.
PMID: 11317469 [PubMed - indexed for MEDLINE]
<http://www.postgradmed.com/issues/2001/04_01/sivitz.htm>

It seems to define lipotoxicity as the diabetogenic effect of
increased circulating free fatty acids or increased cellular fat
content. The excess circulating free fatty acids seem mostly arise
from obesity. A few citations:

"Lipotoxicity is the diabetogenic effect of increased circulating
free fatty acids or increased cellular fat content. This condition
is manifest in several tissues, most notably the liver, muscle,
and pancreatic islet

[...]

It also is thought that excess fuel in the form of fat may be
responsible for raising blood glucose concentrations to those seen
in diabetes. The association between diabetes and obesity is well
established.

[...]

The prevalence of obesity among diabetic patients and observations
that plasma levels of free fatty acids are elevated in most obese
persons suggest that free fatty acids themselves might induce
hyperglycemia."


Other related articles:

Below some citations from these articles.

Diabetes & Free Fatty Acids, on MedicineNet.com
<http://www.medicinenet.com/script/main/art.asp?articlekey=52045>>

"So what are free fatty acids? During the process of lipolysis
-- the breakdown of fat stored in fat cells -- free fatty acids
are released into the bloodstream and circulate throughout the
body. Naturally, people who are obese have larger reservoirs of
fat cells that can potentially become free fatty acids. When
free fatty acid levels are too high, there's evidence they
cause a number of problems.

[...]

High free fatty acid levels decrease the ability of the liver
to store sugars -- keeping sugars in the blood and away from
muscles that use them for energy. They may also directly affect
the functioning of beta cells in the pancreas, the cells that
produce insulin. How free fatty acids do this is the subject of
some debate.

One widely accepted hypothesis that goes back 40 years is that
an excess of free fatty acids in the bloodstream blocks the
normal absorption of glucose by other cells. However, that
idea, called the Randle hypothesis, has been under scrutiny
recently.

A different hypothesis is that an excess of fat cells results
in fat being stored in places that it shouldn't, such as in the
liver, skeletal muscles, and in the beta cells. This improper
storage could result in insulin resistance. Another potentially
complimentary hypothesis is that the excretion of other
endocrine hormones -- such as leptin and resistin -- from fat
tissue could have a marked effect on the body's metabolism,
causing dysfunction."

Koutsari C, Jensen MD.
Thematic review series: patient-oriented research. Free fatty acid
metabolism in human obesity.
J Lipid Res. 2006 Aug;47(8):1643-50. Epub 2006 May 9.
PMID: 16685078 [PubMed - in process]
<http://www.jlr.org/cgi/content/short/R600011-JLR200v1> (abstract)
<http://www.jlr.org/cgi/reprint/R600011-JLR200v1> (full text PDF)

"Adipose tissue lipolysis provides circulating free-fatty acids
(FFA) to meet the body's lipid fuel demands. FFA release is
well-regulated in normal-weight individuals, however, in upper-
body obesity excess lipolysis is commonly seen. This
abnormality is considered a cause for at least some of the
metabolic defects (dyslipidemia, insulin resistance) associated
with upper-body obesity. ?Normal? lipolysis is sex-specific and
largely determined by the individual?s resting metabolic rate.
Women have greater FFA release rates than men without higher
FFA concentrations or greater fatty acid oxidation, indicating
they have greater non-oxidative FFA disposal, although the
processes and tissues involved in this phenomenon are unknown.
Therefore, women have the advantage of having greater FFA
availability without exposing their tissues to higher and
potentially harmful FFA concentrations. Upper-body fat is more
lipolytically active than lower-body fat in both women and men.
FFA released by the visceral fat depot contributes only a small
percentage of systemic FFA delivery. Upper-body subcutaneous
fat is the dominant contributor to circulating FFA and the
source of the excess FFA release in upper-body obesity. We
believe abnormalities in subcutaneous lipolysis could be more
important than those in visceral lipolysis as a cause of
peripheral insulin resistance. Understanding the regulation of
FFA availability will help to discover new approaches to treat
FFA-induced abnormalities in obesity."

Here's another interesting sstudy with selected citations:

Sandu O, Song K, Cai W, Zheng F, Uribarri J, Vlassara H. Insulin
resistance and type 2 diabetes in high-fat-fed mice are linked to high
glycotoxin intake.
Diabetes. 2005 Aug;54(8):2314-9.
PMID: 16046296 [PubMed - indexed for MEDLINE]
<http://diabetes.diabetesjournals.org/cgi/content/full/54/8/2314>

"Dietary advanced glycosylation end products (AGEs) have been
linked to insulin resistance in db/db(++) mice. To test whether
dietary AGEs play a role in the progression of insulin
resistance in normal mice fed high-fat diets, normal C57/BL6
mice were randomly assigned to high-fat diets (35% g fat),
either high (HAGE-HF group; 995.4 units/mg AGE) or low (by 2.4-
fold LAGE-HF group; 329.6 units/mg AGE) in AGE content for 6
months. Age-matched C57/BL6 and db/db(++) mice fed regular diet
(5% g fat, 117.4 units/mg AGE) served as controls. After 6
months, 75% of HAGE-HF mice were diabetic and exhibited higher
body weight (P < 0.001), fasting glucose (P < 0.001), insulin
(P < 0.001), and serum AGEs (P < 0.01) than control mice, while
none of the LAGE-HF mice were diabetic despite a similar rise
in body weight and plasma lipids. The HAGE-HF group displayed
markedly impaired glucose and insulin responses during glucose
tolerance tests and euglycemic and hyperglycemic clamps and
altered pancreatic islet structure and function compared with
those of LAGE-HF mice, in which findings resembled those of
control mice. The HAGE-HF group had more visceral fat (by two-
and fourfold) and more AGE-modified fat (by two- and fivefold)
than LAGE-HF and control mice, respectively. In the HAGE-HF
group, plasma 8-isoprostane was higher (P < 0.01) and
adiponectin lower (P < 0.001) than control mice, while in the
LAGE-HF group, these were more modestly affected (P < 0.05).
These results demonstrate that the development of insulin
resistance and type 2 diabetes during prolonged high-fat
feeding are linked to the excess AGEs/advanced lipoxidation end
products inherent in fatty diets.

[...]

Advanced glycation end products (AGEs) as well as advanced
lipoxidation end products (ALEs) are prooxidant and
proinflammatory compounds that have recently been linked to
impaired insulin sensitivity (8). These compounds continuously
form in the body from the reaction of reducing sugars and
reactive carbonyls with free amino groups (9), while amine-
containing lipids are also generators of lipid peroxidation
products (10?12). AGEs/ALEs can also originate exogenously,
during heat processing of food (13?16), and become incorporated
in body components after intestinal absorption (17). It has now
become apparent that dietary AGEs represent a significant
source of circulating and tissue AGEs, manifesting similar
pathogenic properties to their endogenous counterparts (17?24).
The restriction of the AGE content in standard mouse diets was
found, among other effects, to markedly improve insulin
resistance in obese db/db(++) mice (8).

Because fat-rich foods are also particularly rich in AGEs/ALEs
(16), we postulated that the insulin resistance observed after
chronic high-fat feeding (25) is related to the obligatory
intake of large amounts of AGEs inherent in these diets. To
test this hypothesis, we evaluated glucose and insulin
responses, visceral adiposity, pancreatic islet morphology, and
type 2 diabetes incidence in mice subjected to long-term
feeding on high-fat diets but with either high or low AGE/ALE
content. We also measured plasma 8-isoprostane as an index of
systemic oxidant stress and plasma adiponectin as a molecule
that has been found to be inversely correlated with insulin
resistance.

[...]

The studies presented demonstrate that in normal mice exposed
to a high-fat diet, the metabolic changes, which lead to weight
gain, glucose intolerance, insulin resistance, and type 2
diabetes are linked to the AGEs/ALEs present in the diet. In
addition, the studies illustrate that visceral adiposity and
systemic indicators of oxidative stress or inflammation, such
as 8-isoprostane and adiponectin, can be differentially linked
to the ingested AGEs beyond the excess of fat. Furthermore,
pancreatic islet structure and function, which are affected
negatively during prolonged exposure to a fat-rich diet, appear
to be linked to the dietary content of glycoxidants and can
thus be spared by a diet comparatively low in AGEs, even if it
is fat rich. These observations differ significantly from
previous observations on the role of dietary AGEs in
genetically type 2 diabetes?prone mice (8), the key difference
here being the induction of insulin resistance and type 2
diabetes in normal mice exposed to excess fat, a dietary
condition resembling that of many healthy humans.

In the present studies, high dietary fat intake by normal mice
for the period between 1 and 7 months of age led to an increase
in body weight of both high- and low-AGE groups, which was
modest yet significantly higher in the HAGE-HF than in the
LAGE-HF mice. Interestingly, a major proportion (~75%) of the
mice fed a HAGE-HF diet were diabetic by the end of the study
compared with none of those exposed to the LAGE-HF diet, based
on a fasting blood glucose level >130 mg/dl. The AGE-rich fatty
diet resulted in a pattern of profound abnormalities in glucose
tolerance, glucose disposal rate, and insulin responses closely
resembling those of the diabetic db/db(++) mice (8). In
contrast, exposure to the low-AGE fatty diet led to a pattern
comparable with the normal metabolic profile associated with
the standard (low-fat) diet. These findings suggest that
dietary factors other than high fat content contribute to these
metabolic changes.

[...]

In summary, during prolonged high-fat feeding, the AGE/ALE
content of food may exert significant influence on the
regulation of insulin secretion and action and visceral
adiposity and may ultimately lead to type 2 diabetes. These
results, taken together with previous work (8) on the effects
of a high-in-AGE-but-low-in-fat diet on insulin resistance
support the view that in addition to the fat, the high AGE/ALE
content of food is significantly linked to the insulin-
resistant state. While the mechanisms linking AGEs and the
related deleterious metabolic effects are likely to be complex,
the evidence indicates that lowering AGE/ALE content in fatty
foods might be an intervention to control insulin resistance
and prevent diabetes. Further long-term studies in humans are
needed."



--
Matti Narkia
.

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