Re: Use your muscles or ....

"GysdeJongh" <jongh711@xxxxxxxxx> wrote in message
news:46a9ed8f$0$25476$ba620dc5@xxxxxxxxxxxxxxxxxxxxxx


Proc Natl Acad Sci U S A. 2007 Jul 18
The role of skeletal muscle insulin resistance in the pathogenesis of the
metabolic syndrome.

PMID: 17640906



I posted this article because of the very nice nmr technique which allowed
the scientists to see the destination of the ingested meal in "real time"
and because of my personal interest in the subject.

For me I think that there are a lot of "causes" for T2D and I won't be
susrprised if , in a few years , we have a number of deseases that don't
even have the word "diabetes" in their name.Having said that , I think that
one of the causes may lie in the way the muscle works.

Here is my theory.
The bad news :
1) The mitochondrions in the muscle are the powerplants .Like a powerplant
converts oil in electricity the mitochondrion converts carbohydrate and/or
fat to ATP.Both for the same reason : electricity and ATP are much more
easily transportable energy carriers.

2) The muscle can choose between carbohydrate and fat.This is called
substrate switching.If you have the wrong genes than the substrate switching
in the muscle is impaired and if you ingest too much food glucose is not
stored by the muscle as glycogen but diverted to the liver and stored as
fat.

3) If you ingest too much food than a very intriguing mechanism protects the
muscle.In the menbrane of the mitochondrion are uncoupling proteins : UCP2
and UCP3.They short circuit the powerplant and the energy is just converted
to heat.If you want to know more than look for "non-shivering thermogenesis"
..If you have the wrong genes the uncoupling proteins are impaired

4) The fat in the muscle and various other organs will activate an
inflammatory pathway which will phosphorilate the insuline receptor , via
TNF-a , in the wrong place causing insuline resistance.

The good news:
1) If you exercise you get more muscle mass.More muscle mass means more
GLUT4 receptors.A working muscle can take up glucose without insulin.The
GLUT4 receptors are than allocated to the menbrane by an ATP activated
protein kinase.

2) If you create more muscle mass than the new muscle cells were "born"
under your new tight glucose control so their mitochondrions have better
substrate switching and working uncoupling proteins.

3) You now have a diet with good fats .The essential fats linoleic and
linolenic acid .Long chain omega-3 EPA , DHA from fish .Now this type of fat
in your muscle _can_ be used in beta oxidation as a substrate for the
generation of energy (instead of inflamation).You now have abandoned the
western diet with too much saturated- and transfat and far too much energy.

4) Your insulin resistance will diminish :)

Here is some literature to backup my theory :

========================================

Am J Physiol Endocrinol Metab. 2006 May;290(5)
Exercise training restores uncoupling protein-3 content in limb muscles of
patients with chronic obstructive pulmonary disease.

Oxidative capacity and uncoupling protein-3 (UCP3) content are reduced in
limb muscles of patients with chronic obstructive pulmonary disease (COPD).
It has been hypothesized that the physiological role of UCP3 is to protect
mitochondria against lipotoxicity in cases where fatty acid influx exceeds
the capacity to oxidize them. Exercise training improves oxidative capacity
and reduces UCP3 protein content in healthy subjects, but the response of
UCP3 to training in COPD is unknown. We studied the effect of exercise
training on UCP3 content in limb muscles of COPD patients. For this, seven
healthy age-matched subjects and thirteen patients with COPD were studied.
All patients were admitted to an 8-wk exercise training intervention.
Exercise capacity was assessed by means of an incremental cycle ergometry
test. Biopsies were taken from the vastus lateralis in which UCP3 and lipid
peroxidation levels were determined by Western blotting. Citrate synthase
and 3-hydroxyacyl-CoA dehydrogenase (HAD; an enzyme involved in fatty acid
oxidation) were measured as indexes of muscle oxidative capacity. UCP3 in
COPD was approximately 50% lower compared with healthy age-matched controls.
In COPD, training induced upregulation of UCP3 [from 67.7 (SD 41.8) to 113.8
(SD 104.2) arbitrary units (AU), P = 0.062], especially in the patients who
showed no increase in HAD activity [from 80.9 (SD 52.6) to 167.9 (SD 109.1)
AU, P = 0.028], whereas lipid peroxidation levels remained unaltered. We
conclude that exercise-training can restore muscle UCP3 protein level in
COPD, and the nature of this response complies with the hypothesis that UCP3
may protect against lipotoxicity.

PMID: 16352674

========================================

Am J Clin Nutr. 2007 Mar;85(3):662-77.
Skeletal muscle lipid deposition and insulin resistance: effect of dietary
fatty acids and exercise.

Mounting evidence indicates that elevated intramyocellular triacylglycerol
concentrations are associated with diminished insulin sensitivity in
skeletal muscle. This lipid accumulation is most likely due to enhanced
fatty acid uptake into the muscle coupled with diminished mitochondrial
lipid oxidation. The excess fatty acids are esterified and either stored or
metabolized to various molecules that may participate or interfere with
normal cellular signaling, particularly insulin-mediated signal
transduction, thus altering cellular and, subsequently, whole-body glucose
metabolism. Impaired insulin responsiveness, if not managed, can further
progress to type 2 diabetes mellitus, an all too common condition. For most
of the human population this is avoidable, given that causes of
intramyocellular lipid deposition are predominantly lifestyle-mediated.
Chronic overconsumption of calories coupled with deleterious intakes of
saturated or trans-unsaturated fatty acids inconsistent with the
recommendations outlined in the Dietary Guidelines for Americans have been
shown to increase the risk of insulin resistance. Furthermore, lack of
exercise, which can have a profound effect on skeletal muscle lipid
turnover, is implicated in this lipid-induced insulin resistance. This
review summarizes the current understanding of the effects of elevated
intramyocellular lipids on insulin signaling and how these effects may be
altered by varying dietary fat composition and exercise.

PMID: 1734448

========================================

J Appl Physiol. 2006 May;100(5):1467-74. Epub 2005 Dec 15.
Saturated, but not n-6 polyunsaturated, fatty acids induce insulin
resistance: role of intramuscular accumulation of lipid metabolites.

Consumption of a Western diet rich in saturated fats is associated with
obesity and insulin resistance. In some insulin-resistant phenotypes this is
associated with accumulation of skeletal muscle fatty acids. We examined the
effects of diets high in saturated fatty acids (Sat) or n-6 polyunsaturated
fatty acids (PUFA) on skeletal muscle fatty acid metabolite accumulation and
whole-body insulin sensitivity. Male Sprague-Dawley rats were fed a chow
diet (16% calories from fat, Con) or a diet high (53%) in Sat or PUFA for 8
wk. Insulin sensitivity was assessed by fasting plasma glucose and insulin
and glucose tolerance via an oral glucose tolerance test. Muscle ceramide
and diacylglycerol (DAG) levels and triacylglycerol (TAG) fatty acids were
also measured. Both high-fat diets increased plasma free fatty acid levels
by 30%. Compared with Con, Sat-fed rats were insulin resistant, whereas
PUFA-treated rats showed improved insulin sensitivity. Sat caused a 125%
increase in muscle DAG and a small increase in TAG. Although PUFA also
resulted in a small increase in DAG, the excess fatty acids were primarily
directed toward TAG storage (105% above Con). Ceramide content was
unaffected by either high-fat diet. To examine the effects of fatty acids on
cellular lipid storage and glucose uptake in vitro, rat L6 myotubes were
incubated for 5 h with saturated and polyunsaturated fatty acids. After
treatment of L6 myotubes with palmitate (C16:0), the ceramide and DAG
content were increased by two- and fivefold, respectively, concomitant with
reduced insulin-stimulated glucose uptake. In contrast, treatment of these
cells with linoleate (C18:2) did not alter DAG, ceramide levels, and glucose
uptake compared with controls (no added fatty acids). Both 16:0 and 18:2
treatments increased myotube TAG levels (C18:2 vs. C16:0, P < 0.05). These
results indicate that increasing dietary Sat induces insulin resistance with
concomitant increases in muscle DAG. Diets rich in n-6 PUFA appear to
prevent insulin resistance by directing fat into TAG, rather than other
lipid metabolites.

PMID: 16357064

========================================

Am J Physiol. 1993 Jun;264(6 Pt 1):E855-62.
Exercise increases muscle GLUT-4 levels and insulin action in subjects with
impaired glucose tolerance.

A decline in insulin sensitivity is associated with aging, inactivity, and
obesity. The effects of exercise training on glucose homeostasis independent
of weight loss in older glucose-intolerant individuals are not well
established. We examined the effects of exercise training on oral glucose
tolerance, insulin action, and concentration of the GLUT-4 glucose
transporters in skeletal muscle. Exercise training at 50 and 75% of heart
rate reserve was performed for 12 wk in 18 individuals (age = 64 +/- 2, body
fat = 37.0 +/- 1.5%). Peripheral insulin action was determined 96 h after
the last exercise bout using a two-step hyperinsulinemic-euglycemic glucose
clamp (insulin = 192 and 708 pmol/l). Percent body fat and fat-free mass
(FFM) were unchanged with training. Diet composition, assessed by diet
record, did not change over the 12 wk. Improved oral glucose tolerance was
observed, as exhibited by lower plasma glucose concentrations after training
(P < 0.05), whereas plasma insulin response remained unchanged. The rate of
glucose disposal was unchanged during the low insulin concentration but
increased 11.0% at the high insulin concentration (P < 0.05) after training
(54.4 +/- 4.4 vs. 60.4 +/- 5.5 mumol.kg FFM-1.min-1). Skeletal muscle
glycogen and GLUT-4 concentration increased 24 and 60%, respectively, with
training. There was no direct relationship between the change in GLUT-4
protein and the change in glucose disposal rate. These findings demonstrate
that chronic exercise training without changes in body composition improves
peripheral insulin action in subjects with impaired glucose
tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID: 8333511

========================================

Diabetes. 1999 May;48(5):1113-9.
Association of increased intramyocellular lipid content with insulin
resistance in lean nondiabetic offspring of type 2 diabetic subjects.

Insulin resistance plays an important role in the pathogenesis of type 2
diabetes; however, the multiple mechanisms causing insulin resistance are
not yet fully understood. The aim of this study was to explore the possible
contribution of intramyocellular lipid content in the pathogenesis of
skeletal muscle insulin resistance. We compared insulin-resistant and
insulin-sensitive subjects. To meet stringent matching criteria for other
known confounders of insulin resistance, these individuals were selected
from an extensively metabolically characterized group of 280 first-degree
relatives of type 2 diabetic subjects. Some 13 lean insulin-resistant and 13
lean insulin-sensitive subjects were matched for sex, age, BMI, percent body
fat, physical fitness, and waist-to-hip ratio. Insulin sensitivity was
determined by the hyperinsulinemic-euglycemic clamp method (for
insulin-resistant subjects, glucose metabolic clearance rate [MCR] was
5.77+/-0.28 ml x kg(-1) x min(-1) [mean +/- SE]; for insulin-sensitive
subjects, MCR was 10.15+/-0.7 ml x kg(-1) x min(-1); P<0.002). Proton
magnetic resonance spectroscopy (MRS) was used to measure intramyocellular
lipid content (IMCL) in both groups. MRS studies demonstrated that in soleus
muscle, IMCL was increased by 84% (11.8+/-1.6 vs. 6.4+/-0.59 arbitrary
units; P = 0.008 ), and in tibialis anterior muscle, IMCL was increased by
57% (3.26+/-0.36 vs. 2.08+/-0.3 arbitrary units; P = 0.017) in the
insulin-resistant offspring, whereas the extramyocellular lipid content and
total muscle lipid content were not statistically different between the two
groups. These data demonstrate that in these well-matched groups of lean
subjects, IMCL is increased in insulin-resistant offspring of type 2
diabetic subjects when compared with an insulin-sensitive group matched for
age, BMI, body fat distribution, percent body fat, and degree of physical
fitness. These results indicate that increased IMCL represents an early
abnormality in the pathogenesis of insulin resistance and suggest that
increased IMCL may contribute to the defective glucose uptake in skeletal
muscle in insulin-resistant subjects.

PMID: 10331418

Type 2 diabetes is characterized by impaired beta cell function and a
decrease in insulin-stimulated glucose uptake, predominantly of skeletal
muscle (1). Insulin resistance is thought to play an important role in the
development of type 2 diabetes (1,2). This alteration can already be
demonstrated in a large proportion of asymptomatic offspring of patients
with type 2 diabetes, a group of normoglycemic subjects known to be at high
risk to develop type 2 diabetes (1,3-5).

To minimize the influence of other confounding variables,such as
hyperglycemia or vascular alterations (7-12), that may contribute to the
pathogenesis of insulin resistance in later stages of the development toward
clinically overt type 2 diabetes, it seems appropriate to focus on the group
of asymptomatic and normoglycemic but insulin-resistant subjects (3,4) to
study the role of intramyocellular lipid content on the pathogenesis of
skeletal muscle insulin resistance. Besides genetic traits, insulin
resistance is affected by acquired factors such as obesity (13), body fat
distribution (5,14-16), smoking (17), physical activity level (18,19), and
dietary habits (20,21). In this regard, not only the amount of calories but
also the composition of the diet seems to be important. Epidemiologic
studies indicate that a high intake of saturated fat is associated with
insulin resistance (22,23) and a higher risk to develop type 2 diabetes
(21). Moreover, in animal studies, insulin resistance can be induced by
highfat feeding (24-26). This manipulation also results in an augmented
content of lipids in the muscle, and the latter was found to be closely
correlated to the degree of insulin resis-tance (24,25,27). These
observations suggest that an oversupply of dietary fat resulting in an
increased lipid accumulation in the muscle could play an important role in
the pathogenesis of type 2 diabetes (28,29).

TABLE 1
Characteristic of the study population
Insulin-sens Insulin-res P v a l u e
Sex (M/F) 7/6 7/6 N S
Age (years) 31.8 29.4 N S
BMI (kg/m2) 22.9 23.4 N S

TABLE 2
Glucose and lipid measures of the study population
Insulin-sens Insulin-res P v a l u e
MCR 10.15 5.77 0.0001
Fast gluc 4.82 4.75 N S
Fast insul 5.45 7.83 0.04
Triglyc 0.8 1.25 N S
HDL chol 1.54 1.69 N S


========================================

Acta Physiol Scand. 2003 Aug;178(4):405-12.
The role of uncoupling proteins in the regulation of metabolism.

Investigations of variations in metabolic efficiency and thermogenesis have
a short and turbulent history. In small animals, non-shivering thermogenesis
and diet-induced thermogenesis have a great impact on overall body weight,
and the question is whether mechanisms to waste energy have evolved also in
human energy metabolism. The candidate molecules for this adaptive
thermogenesis are the uncoupling proteins. This is a newly discovered family
of proteins, consisting of at least five proteins, namely UCP1, UCP2, UCP3,
UCP4 and UCP5. Although a role for UCP1 in thermogenesis is unequivocal, the
physiological function of the newer uncoupling proteins is as yet unclear.
UCP1 is present in brown adipose tissue and has a well-documented role in
cold-induced thermogenesis. The targeted disruption of the UCP1-gene
rendered animals that were cold sensitive, but not obese. UCP2 mRNA has a
ubiquitous distribution in tissue, namely, in skeletal muscle, white and
brown adipose tissue, the gastro-intestinal tract, the lung and the spleen.
By targeting the UCP2-gene there was no effect on whole body energy
metabolism, but instead, a reduced ability to protect against free-radical
oxygen species. UCP2 has also been shown to act as a negative regulator for
insulin secretion. UCP3 is present in skeletal muscle. Targeted disruption
of the UCP3-gene gave no effect on whole body energy metabolism, but showed
the mitochondria in muscle to be more coupled. In conclusion, the uncoupling
proteins may be important in various specific ways, as protectors of free
radical oxygen species and as regulators of ATP-dependent processes.

PMID: 12864746

========================================

hth
Gys



















.

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