Inflammation, Not Obesity, Cause of Insulin Resistance

[ATHLETIC EDGE NUTRITION]

UCSD Researchers Discover Inflammation, Not Obesity, Cause of Insulin Resistance

SAN DIEGO, CA -- November 6, 2007 -- Researchers at the University of California, San Diego (UCSD) School of Medicine have discovered that inflammation provoked by immune cells called macro****es leads to insulin resistance and Type 2 diabetes. Their discovery may pave the way to novel drug development to fight the epidemic of Type 2 diabetes associated with obesity, the most prevalent metabolic disease worldwide.

In recent years, it has been theorized that chronic, low-grade tissue inflammation related to obesity contributes to insulin resistance, the major cause of Type 2 diabetes. In research done in mouse models, the UCSD scientists proved that, by disabling the macro****e inflammatory pathway, insulin resistance and the resultant Type 2 diabetes can be prevented.

The findings of the research team, led by principle investigators Michael Karin, PhD, Professor of Pharmacology in UCSD's Laboratory of Gene Regulation and Signal Transduction, and Jerrold Olefsky, Distinguished Professor of Medicine and Associate Dean for Scientific Affairs, will be published as the feature article of the November 7 issue of Cell Metabolism.

"Our research shows that insulin resistance can be disassociated from the increase in body fat associated with obesity," said Olefsky.

Macro****es, found in white blood cells in the bone marrow, are key players in the immune response. When these immune cells get into tissues, such as adipose (fat) or liver tissue, they release cytokines, which are chemical messenger molecules used by immune and nerve cells to communicate. These cytokines cause the neighboring liver, muscle or fat cells to become insulin resistant, which in turn can lead to Type 2 diabetes.

The UCSD research team showed that the macro****e is the cause of this cascade of events by knocking out a key component of the inflammatory pathway in the macro****e, JNK1, in a mouse model. This was done through a procedure called adoptive bone marrow transfer, which resulted in the knockout of JNK1 in cells derived from the bone marrow, including macro****es.

With this procedure, bone marrow was transplanted from a global JNK1 knockout mouse (lacking JNK1 in all cell types) into a normal mouse that had been irradiated to kill off its endogenous bone marrow. This resulted in a chimeric mouse in which all tissues were normal except the bone marrow, which is where macro****es originate. As a control, the scientists used normal, wild-type mice as well as mice lacking JNK1 in all cell types. These control mice were also subjected to irradiation and bone marrow transfer.

The mice were all fed a high-fat diet. In regular, wild-type mice, this diet would normally result in obesity, leading to inflammation, insulin resistance and mild Type 2 diabetes. The chimeric mice, lacking JNK1 in bone marrow-derived cells, did become obese; however, they showed a striking absence of insulin resistance ? a pre-condition that can lead to development of Type 2 diabetes.


"If we can block or disarm this macro****e inflammatory pathway in humans, we could interrupt the cascade that leads to insulin resistance and diabetes," said Olefsky. "A small molecule compound to block JNK1 could prove a potent insulin-sensitizing, anti-diabetic agent."

The research also proved that obesity without inflammation does not result in insulin resistance. Olefsky explained that when an animal or a human being becomes obese, they develop steatosis, or increased fat in the liver. The steatosis leads to liver inflammation and hepatic insulin resistance.

The chimeric mice did develop fatty livers, but not inflammation. "Their livers remained normal in terms of insulin sensitivity," said Olefsky, adding that this shows that insulin resistance can also be disassociated from fatty liver.

"We aren't suggesting that obesity is healthy, but indications are promising that, by blocking the macro****e pathway, scientists may find a way to prevent the Type 2 diabetes now linked to obesity and fatty livers," Olefsky said.

Co-first authors of the paper are Giovanni Solinas, UCSD Department of Pharmacology and Cristian Vilcu, UCSD Division of Endocrinology and Metabolism.

This research was supported by National Institutes of Health grants ES004151, ES006376, DK033651 and DK074868. Additional funding was provided by a fellowship from the Swiss National Science Foundation, a University of California Discovery Grant and Mentor-Based Postdoctoral Fellowships from the American Diabetes Association. Michael Karin is an American Cancer Society Research Professor.
SOURCE: University of California - San Diego



JNK1 in Hematopoietically Derived Cells Contributes to Diet-Induced Inflammation and Insulin Resistance without Affecting Obesity.
Solinas G, Vilcu C, Neels JG, Bandyopadhyay GK, Luo JL, Naugler W, Grivennikov S, Wynshaw-Boris A, Scadeng M, Olefsky JM, Karin M.

Laboratory of Metabolic Stress Biology, Division of Physiology, Department of Medicine, University of Fribourg, Chemin du Mus?e 5, CH-1700 Fribourg, Switzerland; Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

Cell Metab. 2007 Nov 7;6(5):386-397. Links



Obesity-induced insulin resistance is a major factor in the etiology of type 2 diabetes, and Jun kinases (JNKs) are key negative regulators of insulin sensitivity in the obese state.

Activation of JNKs (mainly JNK1) in insulin target cells results in phosphorylation of insulin receptor substrates (IRSs) at serine and threonine residues that inhibit insulin signaling. JNK1 activation is also required for accumulation of visceral fat. Here we used reciprocal adoptive transfer experiments to determine whether JNK1 in myeloid cells, such as macro****es, also contributes to insulin resistance and central adiposity. Our results show that deletion of Jnk1 in the nonhematopoietic compartment protects mice from high-fat diet (HFD)-induced insulin resistance, in part through decreased adiposity.

By contrast, Jnk1 removal from hematopoietic cells has no effect on adiposity but confers protection against HFD-induced insulin resistance by decreasing obesity-induced inflammation.

[NO HYPE]

Great find.... I'll be adding it to my inflammation files.

These results just re-enforce my opinion that excessive inflammational response/ROS generation, are the primary causes for even more diseases than we are currently aware of.

[leonidas300]

Great find.... I'll be adding it to my inflammation files.

These results just re-enforce my opinion that excessive inflammational response/ROS generation, are the primary causes for even more diseases than we are currently aware of.

So my inevitable question is, how does this relate to X-factor?

[G.W. Hayduke]

This is a chicken and egg question. Which came first? Good article though. And I'm not trying to sound like a know it all, but I really thought this was understood for quite some time. At least, that's how I understood it. It's also why I almost always recommend a low carb intake. Carbs, insulin, inflammation, aging, obesity are all very interrelated.

So my inevitable question is, how does this relate to X-factor?

It doesn't. It doesn't really apply to our demographic.

[Insulin Ihsaan]

perphaps a misplaced post? lol

[G.W. Hayduke]

CHEST

Dumbbell Bench Press
80's x 6 (rest 30)
80's x 4 (rp)
80's x 4

DB Incline Press
65's x 9
75's x 5 (rest 30 seconds)
75's x 4

Decline Bench Press
205 x 6 (RP)
205 x 4

Ab Work
Roman Chair Situps x 50
Leg Raises x 35

Cardio
Time 21 minutes
Distance - 1.6 miles
Incline - 5
Calories - 303

Rotator Cuff Work

lmao

[DaveGabe24]

Well Leo obviously just answered any and all questions regarding inflammation

[GeneGnomeX]

What do you know, a potential use for glutamine.


1: Diabetologia. 2007 Jun 29; [Epub ahead of print] Links
L: -glutamine supplementation induces insulin resistance in adipose tissue and improves insulin signalling in liver and muscle of rats with diet-induced obesity.
Prada PO, Hirabara SM, Souza CT, Schenka AA, Zecchin HG, Vassallo J, Velloso LA, Carneiro E, Carvalheira JB, Curi R, Saad MJ.

Departamento de Cl?nica M?dica da Universidade Estadual de Campinas, Rua Tess?lia Viera de Camargo 126, Campinas, San Paulo, 13083-887, Brazil, msaad@fcm.unicamp.br.

AIMS/HYPOTHESIS: Diet-induced obesity (DIO) is associated with insulin resistance in liver and muscle, but not in adipose tissue. Mice with fat-specific disruption of the gene encoding the insulin receptor are protected against DIO and glucose intolerance. In cell culture, glutamine induces insulin resistance in adipocytes, but has no effect in muscle cells. We investigated whether supplementation of a high-fat diet with glutamine induces insulin resistance in adipose tissue in the rat, improving insulin sensitivity in the whole animal. MATERIALS AND METHODS: Male Wistar rats received standard rodent chow or a high-fat diet (HF) or an HF supplemented with alanine or glutamine (HFGln) for 2 months. Light microscopy and morphometry, oxygen consumption, hyperinsulinaemic-euglycaemic clamp and immunoprecipitation/immunoblotting were performed. RESULTS: HFGln rats showed reductions in adipose mass and adipocyte size, a decrease in the activity of the insulin-induced IRS-phosphatidylinositol 3-kinase (PI3-K)-protein kinase B-forkhead transcription factor box 01 pathway in adipose tissue, and an increase in adiponectin levels. These results were associated with increases in insulin-stimulated glucose uptake in skeletal muscle and insulin-induced suppression of hepatic glucose output, and were accompanied by an increase in the activity of the insulin-induced IRS-PI3-K-Akt pathway in these tissues. In parallel, there were decreases in TNFalpha and IL-6 levels and reductions in c-jun N-terminal kinase (JNK), IkappaB kinase subunit beta (IKKbeta) and mammalian target of rapamycin (mTOR) activity in the liver, muscle and adipose tissue. There was also an increase in oxygen consumption and a decrease in the respiratory exchange rate in HFGln rats. CONCLUSIONS/INTERPRETATION: Glutamine supplementation induces insulin resistance in adipose tissue, and this is accompanied by an increase in the activity of the hexosamine pathway. It also reduces adipose mass, consequently attenuating insulin resistance and activation of JNK and IKKbeta, while improving insulin signalling in liver and muscle.

PMID: 17604977 [PubMed - as supplied by publisher]

[GeneGnomeX]

JNK also in the myostatin cascade



1: Cell Signal. 2007 Aug 7; [Epub ahead of print]
Links
Regulation of myostatin signaling by c-Jun N-terminal kinase in C2C12 cells.
Huang Z, Chen D, Zhang K, Yu B, Chen X, Meng J.

Institute of Animal Nutrition, Sichuan Agricultural University, Yaan, Sichuan 625014, PR China.

Myostatin, a member of the transforming growth factor beta (TGF-beta) superfamily, is a negative regulator of skeletal muscle growth. We found that myostatin could activate c-Jun N-terminal kinase (JNK) signaling pathway in both proliferating and differentiating C2C12 cells. Using small interfering RNA (siRNA) mediated activin receptor type IIB (ActRIIB) knockdown, the myostatin-induced JNK activation was significantly reduced, indicating that ActRIIB was required for JNK activation by myostatin. Transfection of C2C12 cells with TAK1-specific siRNA reduced myostatin-induced JNK activation. In addition, JNK could not be activated by myostatin when the expression of MKK4 was suppressed with MKK4-specific siRNA, suggesting that TAK1-MKK4 cascade was involved in myostatin-induced JNK activation. We also found that blocking JNK signaling pathway by pretreatment with JNK specific inhibitor SP600125, attenuated myostatin-induced upregulation of p21 and downregulation of the differentiation marker gene expression. Furthermore, it was also observed that the presence of SP600125 almost annulled the growth inhibitory role of myostatin. Our findings provide the first evidence to reveal the involvement of JNK signaling pathway in myostatin's function as a negative regulator of muscle growth.

PMID: 17689926 [PubMed - as supplied by publisher]

[Phosphate bond]

So my inevitable question is, how does this relate to X-factor?

I know the Inflammatory response caused by IL-6 (from adipocytes) has detrimental consequences with regard to regulation of insulin secretion(at the pancreas). This inturn can cause an oversecretion of insulin further potentiating more excessive insulin release.

Hyper-secretion of insulin is what causes obesity and insulin resistance.

X factor can lower IL-6 (and more than likely excessive insulin release) if a person exercises with it.

Remember arachidonic acid is a key essential fatty acid and we were evolved to use it. But remember we also evolved in the setting of labor of physical activity (not modern conveniences).

[GeneGnomeX]

Published online before print October 18, 2006, 10.1073/pnas.0607626103
PNAS | October 31, 2006 | vol. 103 | no. 44 | 16454-16459

BIOLOGICAL SCIENCES / MEDICAL SCIENCES
Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates

Giovanni Solinas*, Willscott Naugler*, Francesco Galimi, Myung-Shik Lee, and Michael Karin*,

*Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive, MC 0723, La Jolla, CA 92093-0723; Department of Biomedical Sciences/Instituto Nazionale di Biostrutture e Biosistemi, University of Sassari Medical School, 07100 Sassari, Italy; and Department of Medicine, Samsung Medical Center, 50 Irwon-dong Kangnam-ku, Seoul 135-710, Korea

Contributed by Michael Karin, September 1, 2006


JNKs are attractive targets for treatment of obesity and type-2 diabetes. A sustained increase in JNK activity was observed in dietary and genetic models of obesity in mice, whereas JNK deficiency prevented obesity-induced insulin resistance. A similar insulin-sensitizing effect was seen upon treatment of obese mice with JNK inhibitors. We now demonstrate that treatment with the saturated fatty acid palmitic acid results in sustained JNK activation and insulin resistance in primary mouse hepatocytes and pancreatic -cells. In the latter, palmitic acid treatment inhibits glucose-induced insulin gene transcription, in part, by interfering with autocrine insulin signaling through phosphorylation of insulin-receptor substrates 1 and 2 at sites that interfere with binding to activated insulin receptors. This mechanism may account for the induction of central insulin resistance by free fatty acids.


diabetes | insulin gene expression | lipotoxicity | obesity

Author contributions: G.S. and M.K. designed research; G.S. and W.N. performed research; G.S., W.N., F.G., and M.-S.L. contributed new reagents/analytic tools; G.S. and M.K. analyzed data; and G.S. and M.K. wrote the paper.

The authors declare no conflict of interest.

To whom correspondence should be addressed. E-mail: karinoffice@ucsd.edu

[Phosphate bond]

This is a chicken and egg question. Which came first?

Good point. Yeah I know obesity directly results in more IL-6 release (from fat cells) and this in effect "potentiates" a slippery slope effect that results in even more insulin secretion.

Most people (in this forum) should consider themselves fortunate that they keep themselves physically fit so this systemic inflammatory response doesn't start to rear its ugly head.

[leonidas300]

Good point. Yeah I know obesity directly results in more IL-6 release (from fat cells) and this in effect "potentiates" a slippery slope effect that results in even more insulin secretion.

Most people (in this forum) should consider themselves fortunate that they keep themselves physically fit so this systemic inflammatory response doesn't start to rear its ugly head.

Does MN ever plan to test X-factor regarding c-reactive protein levels. I think that would pretty much put a stake through the heart of any criticisms regarding x-factor and inflammation.

For those who are not aware, c-reactive protein = bad for you.

[G.W. Hayduke]

There will be more clinical trials on XF in the future. That is something we can all look forward to.

[Phosphate bond]

Does MN ever plan to test X-factor regarding c-reactive protein levels. I think that would pretty much put a stake through the heart of any criticisms regarding x-factor and inflammation.

For those who are not aware, c-reactive protein = bad for you.

We hope to do this in the future (as far as I know).

Just to let you know IL-6 levels and C-reactive protein levels appear to be positively correlated (this in part because Il-6 stimulates C-reactive protein production in the liver). That being said we would still like a direct measurement.

[NO HYPE]

Most people (in this forum) should consider themselves fortunate that they keep themselves physically fit so this systemic inflammatory response doesn't start to rear its ugly head.

Just as a reminder, some people within this forum (including myself), keep themselves very fit.... and yet, still experience symptoms of systemic inflammatory response.

[Peter LeDrew]

This is a chicken and egg question. Which came first? Good article though. And I'm not trying to sound like a know it all, but I really thought this was understood for quite some time. At least, that's how I understood it. It's also why I almost always recommend a low carb intake. Carbs, insulin, inflammation, aging, obesity are all very interrelated.


It doesn't. It doesn't really apply to our demographic.

From what I'm getting really the point of this study is to help lead to a better understanding of insulin resistance, especially in the obese. If your looking at it as saying obesity, inflammation and insulin resistance are interrelated then of course, this is not new, but I don't think that is their point.

IMO, this quote helps sum up their main findings...
"Our research shows that insulin resistance can be disassociated from the increase in body fat associated with obesity," said Olefsky.
The key word being 'can', not is.

Of course increase in body fat and obesity can lead to insulin resistance, but... this is where the can comes into play.
another important quote:
"If we can block or disarm this macro****e inflammatory pathway in humans, we could interrupt the cascade that leads to insulin resistance and diabetes," said Olefsky.
So while the true answer is to address obesity, unfortunately we currently suffer an obesity epidemic, developing a treatment could help the obese avoid the usual accompanying insulin resistance and the ravages of diabetes. I think this is their intention.

Like you say, there are many interrelated factors, I agree... Insulin function is highly correlated to aging and disease. I don't think the answer is simply to address inflammation as some may think that is where this study is going... it's just a link in the process of insulin resistance and diabetes. The mice still became obese remember... despite the lack of insulin resistance and diabetes, still not exactly the epitomy of optimum health.

IMO, Better to address insulin resistance first and improve insulin function, then you will positively affect inflammation, diabetes and obesity. I think there's plenty of research that proves this with drugs such as metformin and nutraceuticals such as cinnulin-pf, corosolic acid, R-Lipoic acid, hops isohumulones, chromium, etc...

[Peter LeDrew]

What do you know, a potential use for glutamine.


1: Diabetologia. 2007 Jun 29; [Epub ahead of print] Links
L: -glutamine supplementation induces insulin resistance in adipose tissue and improves insulin signalling in liver and muscle of rats with diet-induced obesity.
Prada PO, Hirabara SM, Souza CT, Schenka AA, Zecchin HG, Vassallo J, Velloso LA, Carneiro E, Carvalheira JB, Curi R, Saad MJ.

Departamento de Cl?nica M?dica da Universidade Estadual de Campinas, Rua Tess?lia Viera de Camargo 126, Campinas, San Paulo, 13083-887, Brazil, msaad@fcm.unicamp.br.

AIMS/HYPOTHESIS: Diet-induced obesity (DIO) is associated with insulin resistance in liver and muscle, but not in adipose tissue. Mice with fat-specific disruption of the gene encoding the insulin receptor are protected against DIO and glucose intolerance. In cell culture, glutamine induces insulin resistance in adipocytes, but has no effect in muscle cells. We investigated whether supplementation of a high-fat diet with glutamine induces insulin resistance in adipose tissue in the rat, improving insulin sensitivity in the whole animal. MATERIALS AND METHODS: Male Wistar rats received standard rodent chow or a high-fat diet (HF) or an HF supplemented with alanine or glutamine (HFGln) for 2 months. Light microscopy and morphometry, oxygen consumption, hyperinsulinaemic-euglycaemic clamp and immunoprecipitation/immunoblotting were performed. RESULTS: HFGln rats showed reductions in adipose mass and adipocyte size, a decrease in the activity of the insulin-induced IRS-phosphatidylinositol 3-kinase (PI3-K)-protein kinase B-forkhead transcription factor box 01 pathway in adipose tissue, and an increase in adiponectin levels. These results were associated with increases in insulin-stimulated glucose uptake in skeletal muscle and insulin-induced suppression of hepatic glucose output, and were accompanied by an increase in the activity of the insulin-induced IRS-PI3-K-Akt pathway in these tissues. In parallel, there were decreases in TNFalpha and IL-6 levels and reductions in c-jun N-terminal kinase (JNK), IkappaB kinase subunit beta (IKKbeta) and mammalian target of rapamycin (mTOR) activity in the liver, muscle and adipose tissue. There was also an increase in oxygen consumption and a decrease in the respiratory exchange rate in HFGln rats. CONCLUSIONS/INTERPRETATION: Glutamine supplementation induces insulin resistance in adipose tissue, and this is accompanied by an increase in the activity of the hexosamine pathway. It also reduces adipose mass, consequently attenuating insulin resistance and activation of JNK and IKKbeta, while improving insulin signalling in liver and muscle.

PMID: 17604977 [PubMed - as supplied by publisher]

Nice find!

[Peter LeDrew]

It'd be nice to know the dose of glutamine used and how that relates to humans.

[G.W. Hayduke]

IMO, Better to address insulin resistance first and improve insulin function, then you will positively affect inflammation, diabetes and obesity.

I think I have to agree with that.

[Peter LeDrew]

I think I have to agree with that.

Having your intellectual agreement means alot Aeternitatis!

[Doughboy]

Just as a reminder, some people within this forum (including myself), keep themselves very fit.... and yet, still experience symptoms of systemic inflammatory response.

Would love to hear your thoughts on how to deal with this, a new thread or a PM would be super

[Phosphate bond]

Just as a reminder, some people within this forum (including myself), keep themselves very fit.... and yet, still experience symptoms of systemic inflammatory response.

Thats true, but its just higher in obese people.

Definitely having good insulin sensitivity results in much lower inflammatory markers.

Now that doesn't mean you still can't hurt your knee, but your general organs such as your heart or kidneys are under much less sustained inflammatory stress.

[G.W. Hayduke]

Definitely having good insulin sensitivity results in much lower inflammatory markers.

This is very important and very tricky in practice. I've stated before that I can predictably manipulate the degree of systemic inflammatory symptoms experienced while using X-Factor simply by modifying my diet and exercise patterns. This leads me to believe, with regard to inflammation, that diet/exercise is foremost, with individual differences being secondary.

To give an example of the insulin connection in practice: I normally do not experience any side effects from AA supplementation even at high doses for extended periods. I also get ZERO results from insulin enhancing supplements such as the currently popular Anabolic Pump/P-slin.

I think these little clues can point us all in the right direction.

[hjayss]

UCSD Researchers Discover Inflammation, Not Obesity, Cause of Insulin Resistance

SAN DIEGO, CA -- November 6, 2007 -- Researchers at the University of California, San Diego (UCSD) School of Medicine have discovered that inflammation provoked by immune cells called macro****es leads to insulin resistance and Type 2 diabetes. Their discovery may pave the way to novel drug development to fight the epidemic of Type 2 diabetes associated with obesity, the most prevalent metabolic disease worldwide.

In recent years, it has been theorized that chronic, low-grade tissue inflammation related to obesity contributes to insulin resistance, the major cause of Type 2 diabetes. In research done in mouse models, the UCSD scientists proved that, by disabling the macro****e inflammatory pathway, insulin resistance and the resultant Type 2 diabetes can be prevented.

The findings of the research team, led by principle investigators Michael Karin, PhD, Professor of Pharmacology in UCSD's Laboratory of Gene Regulation and Signal Transduction, and Jerrold Olefsky, Distinguished Professor of Medicine and Associate Dean for Scientific Affairs, will be published as the feature article of the November 7 issue of Cell Metabolism.

"Our research shows that insulin resistance can be disassociated from the increase in body fat associated with obesity," said Olefsky.

Macro****es, found in white blood cells in the bone marrow, are key players in the immune response. When these immune cells get into tissues, such as adipose (fat) or liver tissue, they release cytokines, which are chemical messenger molecules used by immune and nerve cells to communicate. These cytokines cause the neighboring liver, muscle or fat cells to become insulin resistant, which in turn can lead to Type 2 diabetes.

The UCSD research team showed that the macro****e is the cause of this cascade of events by knocking out a key component of the inflammatory pathway in the macro****e, JNK1, in a mouse model. This was done through a procedure called adoptive bone marrow transfer, which resulted in the knockout of JNK1 in cells derived from the bone marrow, including macro****es.

With this procedure, bone marrow was transplanted from a global JNK1 knockout mouse (lacking JNK1 in all cell types) into a normal mouse that had been irradiated to kill off its endogenous bone marrow. This resulted in a chimeric mouse in which all tissues were normal except the bone marrow, which is where macro****es originate. As a control, the scientists used normal, wild-type mice as well as mice lacking JNK1 in all cell types. These control mice were also subjected to irradiation and bone marrow transfer.

The mice were all fed a high-fat diet. In regular, wild-type mice, this diet would normally result in obesity, leading to inflammation, insulin resistance and mild Type 2 diabetes. The chimeric mice, lacking JNK1 in bone marrow-derived cells, did become obese; however, they showed a striking absence of insulin resistance ? a pre-condition that can lead to development of Type 2 diabetes.


"If we can block or disarm this macro****e inflammatory pathway in humans, we could interrupt the cascade that leads to insulin resistance and diabetes," said Olefsky. "A small molecule compound to block JNK1 could prove a potent insulin-sensitizing, anti-diabetic agent."

The research also proved that obesity without inflammation does not result in insulin resistance. Olefsky explained that when an animal or a human being becomes obese, they develop steatosis, or increased fat in the liver. The steatosis leads to liver inflammation and hepatic insulin resistance.

The chimeric mice did develop fatty livers, but not inflammation. "Their livers remained normal in terms of insulin sensitivity," said Olefsky, adding that this shows that insulin resistance can also be disassociated from fatty liver.

"We aren't suggesting that obesity is healthy, but indications are promising that, by blocking the macro****e pathway, scientists may find a way to prevent the Type 2 diabetes now linked to obesity and fatty livers," Olefsky said.

Co-first authors of the paper are Giovanni Solinas, UCSD Department of Pharmacology and Cristian Vilcu, UCSD Division of Endocrinology and Metabolism.

This research was supported by National Institutes of Health grants ES004151, ES006376, DK033651 and DK074868. Additional funding was provided by a fellowship from the Swiss National Science Foundation, a University of California Discovery Grant and Mentor-Based Postdoctoral Fellowships from the American Diabetes Association. Michael Karin is an American Cancer Society Research Professor.
SOURCE: University of California - San Diego



JNK1 in Hematopoietically Derived Cells Contributes to Diet-Induced Inflammation and Insulin Resistance without Affecting Obesity.
Solinas G, Vilcu C, Neels JG, Bandyopadhyay GK, Luo JL, Naugler W, Grivennikov S, Wynshaw-Boris A, Scadeng M, Olefsky JM, Karin M.

Laboratory of Metabolic Stress Biology, Division of Physiology, Department of Medicine, University of Fribourg, Chemin du Mus?e 5, CH-1700 Fribourg, Switzerland; Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

Cell Metab. 2007 Nov 7;6(5):386-397. Links



Obesity-induced insulin resistance is a major factor in the etiology of type 2 diabetes, and Jun kinases (JNKs) are key negative regulators of insulin sensitivity in the obese state.

Activation of JNKs (mainly JNK1) in insulin target cells results in phosphorylation of insulin receptor substrates (IRSs) at serine and threonine residues that inhibit insulin signaling. JNK1 activation is also required for accumulation of visceral fat. Here we used reciprocal adoptive transfer experiments to determine whether JNK1 in myeloid cells, such as macro****es, also contributes to insulin resistance and central adiposity. Our results show that deletion of Jnk1 in the nonhematopoietic compartment protects mice from high-fat diet (HFD)-induced insulin resistance, in part through decreased adiposity.

By contrast, Jnk1 removal from hematopoietic cells has no effect on adiposity but confers protection against HFD-induced insulin resistance by decreasing obesity-induced inflammation.

Love this post bro good research....

[bgnb]

my two cents:

insulin resistance is related to low levels of testosterone in men ...

http://men.webmd.com/news/20070605/l...wnl_men_072407

higher levels of estrogen in males tends to block insulin uptake
which leads to increased levels of blood sugar which is then
deposited as fat (typically belly fat) ...

the more belly fat, the more aromatase and the more testosterone
is converted to estrogen and the less insulin taken up and so on ...

it may also explain the inflammation because any sugar NOT taken
into cells binds to the cells themselves as scar tissue ...

particularly hard hit are your testicles which are damaged by high
sugar levels which is why erectile dysfunction is considered the
first sign of Type ll diabetes.

rather than treating the 'insulin resistance' problem with gluco****e,
it would be more efficient and effective to lower estrogen in men
who have metabolic syndrome (which includes insulin resistance)

[Peter LeDrew]

my two cents:

insulin resistance is related to low levels of testosterone in men ...

http://men.webmd.com/news/20070605/l...wnl_men_072407

higher levels of estrogen in males tends to block insulin uptake
which leads to increased levels of blood sugar which is then
deposited as fat (typically belly fat) ...

the more belly fat, the more aromatase and the more testosterone
is converted to estrogen and the less insulin taken up and so on ...

it may also explain the inflammation because any sugar NOT taken
into cells binds to the cells themselves as scar tissue ...

particularly hard hit are your testicles which are damaged by high
sugar levels which is why erectile dysfunction is considered the
first sign of Type ll diabetes.

rather than treating the 'insulin resistance' problem with gluco****e,
it would be more efficient and effective to lower estrogen in men
who have metabolic syndrome (which includes insulin resistance)

I tend to believe and that study also hints that insulin resistance leads to low testosterone levels so anything to improve insulin sensitivity could also assist in having an indirect effect on raising test levels.
It really takes a multi-factorial approach as you look at more and more studies and see how complicated it can be... addressing insulin resistance is certainly very high on this list as it seems to affect so many of the other issues, but then you have to also think about ways to improve inflammation, keep test high, estrogen, esp. bad estrogen down, etc...
There is never one simple answer to the often unsolved puzzles of the human body. This is where medicine led us astray in the one disease-one drug cure approach.

[G.W. Hayduke]

IMO, the quickest way to achieve what you just mentioned is to strictly control insulin by severely limiting carb intake. The virtues of carb restriction are quite impressive.

[Peter LeDrew]

IMO, the quickest way to achieve what you just mentioned is to strictly control insulin by severely limiting carb intake. The virtues of carb restriction are quite impressive.

Yes.

[labradarep]

IMO, the quickest way to achieve what you just mentioned is to strictly control insulin by severely limiting carb intake. The virtues of carb restriction are quite impressive.

X2

Inflammation is just 1 piece in the puzzle( an important piece).

2 supplements that I have found most beneficial in controlling inflammation.
A) Fish oil ( where do you start with the virtues of this product)
B) Sorenzyme( please don`t flame me for this) I know it works first hand. My wife has used it with tons of success.