SOCS3 Gene: Insulin Resistance, IFN resistance

For six years, I believed there was a single-source connection between interferon resistance and interferon resistance.  It is, as I suspected, a gene.  The gene is SOCS3 - Suppressor Of Cytokine Signaling-3.  The discovery of this gene also sheds some light on why prior nonresponders have more trouble acheiving SVR.

1. SOCS-3 is elevated by HCV's core protein.

2. SOCS-3 elevation causes interferon resistance.

3. SOCS-3 elevation causes insulin resistance in the liver.

4. SOCS-3 depletion reduces liver insulin resistance, but causes systemic insulin resistance.

5. SOCS-3 is further elevated in people who have treated unsuccessfully.

These findings suggest a new and viable target for therapy.  

[portann]

"For six years, I believed there was a single-source connection between interferon resistance and interferon (sic) resistance."


------------------------------------------------------------
I'm guessing you meant:  For six years, I believed there was a single-source connection between interferon resistance and INSULIN  resistance.

Are you saying that there is only ONE connection between the two, and that it's this gene? Could it be that simple? Who published it?

Thank you.

(Co-writer, please come in!!!)

[MKAndrew]

Sorry, I did mean insulin resistance.  I always get confused.  Both of them are abbreviated IR so that means there is a connection between IR and IR.

[CoWriter]

SOCS-3 is elevated by HCV's core protein and other mediators of insulin resistance such as tumor necrosis factor- (TNF-), interleukin-6, and growth hormone.

SOCS-3 elevation causes insulin resistance in the liver.  And insulin resistance causes hyperinsulinemia....and high levels of insulin make interferon ineffective

Lack of SOCS3 in the liver promotes systemic insulin resistance by mimicking chronic inflammation.

We knew all that.  I believe there are actually 3 genes connected to SOCS3 and one of them is found more on non-responders

Co



The suppressor of cytokine signaling (SOCS) 1 and SOCS3 but not SOCS2 proteins inhibit interferon-mediated antiviral and antiproliferative activities.

Song MM, Shuai K.

Department of Medicine, Molecular Biology Institute, University of California, Los Angeles, California 90095, USA.

The suppressor of cytokine signaling (SOCS) proteins are a family of cytokine-inducible negative regulators of cytokine signaling. Interferon (IFN)-gamma treatment induces the expression of SOCS1, SOCS2, and SOCS3 mRNAs. To examine the effect of SOCS proteins on IFN-mediated Janus-activated kinase/signal transducers and activators of transcription (STAT) signaling, HeLa- and MCF-7-derived stable cell lines expressing SOCS1, SOCS2, and SOCS3 proteins were established. SOCS1 and SOCS3 but not SOCS2 inhibited the tyrosine phosphorylation and nuclear translocation of STAT1 in response to IFN stimulation. The IFN-mediated antiviral and antiproliferative activities were consistently blocked by the constitutive expression of SOCS1 and SOCS3 but not SOCS2 proteins. The maximum inhibitory activities of SOCS1 and SOCS3 proteins toward the activation of STAT1 were observed at very low levels of SOCS protein expression. In addition, SOCS1 exhibited a much stronger inhibitory activity toward the activation of STAT1 than did SOCS3. These results suggest that SOCS1 and SOCS3 but not SOCS2 are inhibitors of IFN-mediated Janus-activated kinase/STAT signaling pathways.

http://www.ncbi.nlm.nih.gov/pubmed/9857039?dopt=Abstract

[MKAndrew]

Actually, the article you reference states, "The IFN-mediated antiviral and antiproliferative activities were consistently blocked by the constitutive expression of SOCS1 and SOCS3," which indicates that the overexpression of these genes directly block the cytokine, IFN-alpha.  As you suggested, hyperinsulemia occurs further down the chain: increased hepatic glucose output--->impaired glucose tolerance--->insulin resistance--->hyperinsulinemia.  

A recent study of pioglitizone + SOC demonstrated that managing insulin resistance via upregulation of PPARy does not increase the efficacy of SOC therapy.  A study with metformin + SOC seemed to indicate a small RVR outcome, but the study was very small and inconclusive.  Because of these results, I tend to view insulin resistance as a symptom of something further upstream, that may need to be addressed upstream, the overexpression of SOCS3.  TNF-alpha plays a vital role in mediating inflammation, but current TNF-alpha inhibitors come with a risk of infection, and possible carcinogenesis.  I am suggesting SOCS genes as a target for therapy.  The hepatitis C virus is well entrenched with a combination of viral and host factors.  I hope medical science should do what it can, not only to address the virus itself, but also manage host factors that mediate viral resistance, as they are identified.

Miles        

[MKAndrew]

I also believe that pre-treatment inhibition of CYP450 isoforms 2E1, 3A4, and 1A1 should be investigated.

[CoWriter]

The Actos study used only 5 patients, all non-responders, genotype 1. At 12 weeks, two patients got a >2 log drop in viral load, one patient got < 1 log drop and the other two patients had poor response and their insulin resistance increased.

The two patients who had the poor response and their insulin resistance increased were both on psych meds that can cause high blood sugar. One was on Olanzapine ...which is famous for causing high blood sugar and the other one was on Zopiclone. And to top it off, when taken together, Actos causes the levels of Zopiclone to go up.

They used non-responders who were probably interferon resistant, they didn't use the best insulin sensitizer and they allowed patients to take meds that could increase their blood sugar (therefore increasing the insulin resistance).   Call me crazy but the only thing that study proved is that it was poorly planned.

The Metformin study showed an RVR 4x higher on the Metformin group and SVR results were not available yet.  But there are a couple of interesting studies using Rosiglitazone and another using Metformin, Rosi or both (the arm using both lowered HOMA more).

Bottom line...we know genetics are a factor ...but we don't have time to wait for something that will fix it (SOCS-3 is implicated in the etiology of diabetis too...so maybe we can borrow some of their studies...LOL). We need to work with what we have/know to increase SVR now.  

Co

[CoWriter]

"I also believe that pre-treatment inhibition of CYP450 isoforms 2E1, 3A4, and 1A1 should be investigated."

Now you're speaking my language.  I totally agree.

Co

[CockSparrow]

Hi Miles
You sure you are not looking too low down Miles. To me it seems that its HCV core that’s leads to IR. Also as you would already know HCV core activates CYP2E1 which is involved in the liver glucose cycle.

HCV Core increases IRS-1 which leads to Insulin Resistance. HCV also activates CYP2E1 which releases glucose, which leads to IR. We then help it out by drinking Alcohol, by putting on weight and eating a high carb diet. Gets a bit circular all this ay.

J Virol. 2007 Dec 26; : 18160431 (P,S,G,E,B)
HEPATITIS C VIRUS CORE PROTEIN UPREGULATES SERINE PHOSPHORYLATION OF IRS-1 AND IMPAIRS DOWNSTREAM AKT/PKB SIGNALING PATHWAY FOR INSULIN RESISTANCE.

Sutapa Banerjee, Kousuke Saito, Malika Ait-Goughoulte, Keith Meyer, Ratna B Ray, Ranjit Ray

Chronic hepatitis C virus (HCV) infection has a significantly increased prevalence of type 2 diabetes mellitus (T2DM). Insulin resistance is a critical component of T2DM pathogenesis. Several mechanisms are likely to be involved in the pathogenesis of HCV related insulin resistance. Since we and others have previously observed that HCV core protein activates c-Jun N-terminal kinase (JNK) and mitogen-activated protein kinase (MAPK), we examined the contribution of these pathways to insulin resistance in hepatocytes.

Our experimental findings suggest that HCV core protein alone or in the presence of other viral proteins increases Ser(312) phosphorylation of the insulin receptor substrate-1 (IRS-1). Hepatocytes infected with cell culture grown HCV genotype 1a or 2a displayed a significant increase in the Ser(473) phosphorylation status of the Ser/Thr kinase protein kinase B (Akt/PKB), while Thr(308) phosphorylation was not significantly altered.

HCV core protein mediated Ser(312) phosphorylation of IRS-1 was inhibited by JNK (SP600125) and phosphatidylinositol-3 kinase (PI-3K) (LY294002) inhibitors. A functional assay also suggested that hepatocytes expressing HCV core protein alone or infected with cell culture grown HCV exhibited a suppression of 2-deoxy-D-[(3)H] glucose uptake.

Inhibition of the JNK signaling pathway significantly restored glucose uptake despite HCV core expression in hepatocytes. Taken together, our results demonstrated that HCV core protein increases IRS-1 phosphorylation at Ser(312) which may contribute in part to the mechanism of insulin resistance.

And this one show the same thing with G1b and G3a
Hepatitis C Virus Core Protein affects Insulin Signalling in a genotype-specific Manner
MW Douglas

The aim of this project is to study the effects of HCV core protein from different virus genotypes on Insulin Signalling.

Increased phosphorylation of Insulin Receptor Substrate (IRS)-1 at inhibitory serines312 and 639 was observed, more with Genotype 1b than with 3a core also preferentially increased phosphorylation of Gab1 and PTEN which inhibit IRS-1 signalling

We conclude that novel genotype-specific differences in Insulin Signalling in response to transfection with HCV core Protein are present in Hepatocyte-derived cell lines.
These differences may account for the genotype-specific influences of CHC on Insulin Signalling.

Hows things with you anyway
CS

[MKAndrew]

Hey CS - all is well here.  Good to see you.

2E1 is a big problem, especially for HCV patients with diabetes, which upregulates 2E1 expression even more.  Unfortunately, most 2E1 inhibitors cause problems with platelet agglutination, with the notable exception of nicotine, which actually promotes agglutination.  I tried garlic oil, which I don't recommend.  Although it cut my need for insulin by 1/3, I noticed bleeding problems after fingerpricks for glucose testing (as in being able to get blood out of the same fingerprick for the entire day).  I haven't tried nicotine gum yet, but I'm considering it.  I also stopped all 3A4 medications, and although I can't correlate it scientifically, my viral load has dropped from a whopping 32 million to 784,000.  I haven't taken anything known to inhibit this isoform.  I just stopped taking inducers/substrates.

Co - There is a lot being done with antisense oligonucleotide therapy in oncology and other medicines.  This kind of therapy may be highly effective in downregulating SOCS3.  It is currently used in lab experiments to block SOCS3.  

[MKAndrew]

I agree with you.  I believe the insulin-sensitizer studies so far have been flawed by sample size, patient criteria, etc.  I must say, I got my best tx response ever when my doctor put me on Avandamet at week 16.  By week 18 I experienced a sudden 1.5 log drop in viral load.  The correlation between IR and IR were unknown at the time.  I stopped taking the drug because of GI side effects and my viral load began to climb again.

[MKAndrew]

When I tried high-dosing IFN, it made my glucose problems worse.

[CockSparrow]

A randomized trial of 24- vs. 48-week courses of PEG interferon a-2b plus ribavirin for genotype-1b-infected chronic hepatitis C patients: a pilot study in Taiwan

Mutations of interferon sensitivity determining region (ISDR) in the HCV-1b NS5A region correlate with SVR to IFN-based antiviral therapy in Japan and Taiwan, but not in Europe.

Geographic differences between mutant-type ISDR strains in HCV-1b may lead to variations in response of HCV-1 to IFN in Western and Eastern countries.

Or it could be different levesl of Insulin Resistance, which is higher in Western countries than in Eastern countries.

Now if IR is such a good predictor of svr, crosses genotypes and is associate with every negative predict although only losely with HVL, wouldn't that be a better place to research than 1b amino acid mutations.
There are a few abstarcts from Japan presented if you still want to go down that path.
I know i was IR. So are you.

Here is an Abtract from AASLD.
Insulin-Resistance in Chronic Hepatitis C patients: New Predictor of Sustained Virological Response Independent of HCV Genotype and Liver Fibrosis Stage

Category: Q07. HCV: Treatment

Session: HCV: Therapy

Author(s): R. Moucari, M. Ripault, M. Martinot-Peignoux, A. Cardoso, T. Asselah, N. Boyer, D. Valla, P. Marcellin, Service d'Hépatologie and INSERM U773, Hôpital Beaujon, Clichy, FRANCE; H. Voitot, M. Vidaud, Service de Biochimie, Hôpital Beaujon, Clichy, FRANCE; S. Maylin, Service de Microbiologie, Hôpital Beaujon, Clichy, FRANCE; P. Bedossa, Service d'Anatomie Pathologique, Hôpital Beaujon, Clichy, FRANCE;

Date: Monday, November 03, 2008

Full Text:

Abstract:
Background & Aim: Insulin-Resistance (IR) has been previously shown to impair sustained virological response (SVR) rate in chronic hepatitis (CHC) patients infected with genotype 1 when treated with pegylated interferon and ribavirin. The aim of this study was to assess the independent impact of IR after adjustment to major predictors of SVR, particularly HCV genotype and liver fibrosis stage. Patients and

Methods:
167 consecutive non-diabetic treatment-naïve CHC patients, treated in our centre with pegylated interferon plus ribavirin, were prospectively assessed. Insulin resistance was assessed using the Homeostasis Model (HOMA-IR). HCV genotype was determined by sequencing. Serum HCV RNA was quantified using bDNA (Bayer Versant HCV RNA 3.0 Assay). Liver histology was assessed using the METAVIR score. SVR was defined as undetectable serum HCV RNA 24 months after treatment stopping.

Results:
Baseline characteristics were: male gender (66%), mean age (46±9 years), mean BMI (24±4 kg/m2), excessive alcohol consumption (9%). Blood transfusion and intravenous drug injection were the principal source of transmission (52%). HCV genotype distribution was: 1 (47%), 2 (7%), 3 (24%), and 4 (22%). Mean serum HCV RNA level was 5.5±0.7 log10 IU/mL, and 42% of patients had high serum HCV RNA level (>600 000 IU/mL). Median value of HOMA-IR was 2.1 (IQL range 1.1-4.6). Liver histology showed moderate-severe necroinflammation (METAVIR score A2-A3) in 46%, severe fibrosis (METAVIR score F3-F4) in 32%, and severe steatosis (>30%) in 29% of patients. By univariate analysis, SVR was associated with HOMA-IR, HCV genotype, serum HCV RNA level, liver fibrosis stage and steatosis. Patients with HOMA-IR 2 (72% vs. 44% respectively, p<0.01). Patients infected with genotypes 2 and 3 achieved higher SVR rates than those infected with genotypes 1 and 4 (79% vs. 46% respectively, p<0.001). Patients with low viral load achieved higher SVR rate than those with high viral load (67% vs. 44% respectively, p<0.01). Patients with mild-moderate fibrosis achieved higher SVR rate than those with severe fibrosis (62% vs. 44% respectively, p<0.05). Patients with mild-moderate steatosis achieved higher SVR rate than those with severe steatosis (62% vs. 42% respectively, p<0.05). By logistic regression, SVR was associated only with HCV genotype 2 and 3 (p<0.001, OR=4.5, CI=2.0-9.8) and with HOMA-IR <2 (p<0.01, OR=2.8, CI=1.4-5.5)

Conclusion:
Insulin-Resistance is a major negative predictor of SVR in CHC patients treated with pegylated interferon plus ribavirin. Impact of IR is independent of HCV genotype and liver fibrosis stage.

[MKAndrew]

Well yes, that's the thing.  Host factors are a huge variant with tx.  I believe more should be done pre-treatment to manage host factors that are predictive of response.  My first hepatologist believed the 1a patients in Europe carried a different 1a strain, but a some of what I read these days suggests that racial host factors may be involved.

[CoWriter]

" I haven't tried nicotine gum yet, but I'm considering it."


The med insert says nicotine gum is a weak 2E1 inhibitor....and it's not recommended for those with hypertension or insulin dependent diabetes.

Plus, you would need to maintain high levels, because at low doses, nicotine increases 2E1.....


"Our findings indicate that nicotine increases CYP2E1 at very low doses and may enhance CYP2E1-related toxicity in people treated with nicotine."

http://jpet.aspetjournals.org/cgi/content/full/306/3/941



If you like spicy food you could try using dihydrocapsaicin (found in red peppers)....it's a good 2E1 inhibitor.

Co

[CoWriter]

These are the final reasults of the Metformin+SOC study....(genotype 1, they all had a HOMA greater than 2 and the study used Metformin 425mg tid for 4 weeks, then increased it to 850mg tid).


"Adding Metformin to Standard Peginterferon alfa-2a/Ribavirin Regimen Improves Insulin Sensitivity in Patients With HCV Infection

SOC+Metformin vs SOC+placebo

SVR  52.5%  vs  42.2%
HOMA-IR less than 2 at Week 24  55% vs 13.6%
SVR for Females 57.7% vs 28.6%


Summary of Key Conclusions:

Metformin added to peginterferon alfa-2a/ribavirin regimen in genotype 1 HCV-infected patients with insulin resistance....
    * Significantly improves insulin sensitivity.
    * Shows trend toward improved sustained virologic response (SVR) rates.
    *  Ad hoc analysis found significant improvement in SVR rates for female patients only.
Treating insulin resistance potential new goal for HCV therapy."



Now they need to stop messing around and quit using suboptimal doses ...and start the Metformin earlier.

Co

[portann]

Co: "SOC+Metformin vs SOC+placebo

      SVR  52.5%  vs  42.2%
      HOMA-IR less than 2 at Week 24  55% vs 13.6%
      SVR for Females 57.7% vs 28.6%"

----------------------------------------------------------------------------------
Did I understand correctly that "SVR for Females 57.7% vs 28.6% " was achieved in SOC and Metaformin compared to those females with SOC and placebo?

I haven't been following the forum much but presumably this relates to females who are insulin-resistant before treatment? This is really astonishing stuff and you'd think it would make giant waves. If I were a female with insulin-resistance, I'd pay close, close attention.

[CoWriter]

"Did I understand correctly that "SVR for Females 57.7% vs 28.6% " was achieved in SOC and Metaformin compared to those females with SOC and placebo?"


That's right.  The women did much better than the men.  

And the SVR  of 52.5%  vs  42.2%  is for ITT.  

They started with 123 patients and 22 of them discontinued because of non-compliance, they chose to stop before week 24, lost to follow-up, etc.

Of the 101 that finished the study, SVR was 67.4% vs 49.1%

(and people may do better if the Metformin is started before tx)



"This is really astonishing stuff and you'd think it would make giant waves. If I were a female with insulin-resistance, I'd pay close, close attention. "


The bad thing is that most doctors don't test patients for insulin resistance.

The info on insulin resistance has been out there for years and docs have done nothing about it.  They kept saying that there was data that proved that insulin resistance lowered SVR but there was no data that proved that improving insulin resistance would increase SVR....

Which drove me absolutely crazy!

Well....there's data now.  Let's see what they'll do with it.

Co

[CockSparrow]

Interesting 1st post.
If by dont push it you mean dont push the Insulin Resistance thing
Then If Co dont push It I will.

Whats your game.
CS

[Proactive]

Think I might have mentioned it this Spring, but my doc made a comment of his involvement with an upcoming Hep C/insulin resistance trial..Might be old news to you, but stumbled on a tiny bit of info, seems it started this Summer..
http://www.dhmc.org/webpage.cfm?site_id=2&org_id=102&morg_id=0&sec_id=0&gsec_id=46442&item_id=46494

[CockSparrow]

Thanks.
I hope they do a better job than this study did. Talk about mess it up.
Pioglitazone (Actos) in chronic hepatitis C not responding to pegylated interferon-a and ribavirin Journal of Hepatology 49 (2008) 295–298

Background/Aims:
Insulin resistance reduces the response to interferon alfa-based therapy of chronic hepatitis C patients. It has been speculated that improvement of insulin sensitivity might increase the chances of responding to treatment of such individuals.

Methods:
We started a multicenter clinical trial of retreatment of chronic hepatitis C patients, who had failed to respond to the pegylated interferon alfa/ribavirin combination, with a triple therapy consisting in these same antivirals plus an insulin-sensitizer (pioglitazone) (The INSPIRED-HCV study).

Results:
None of the first five patients fulfilling the inclusion criteria and included in the trial had a satisfactory virological response after 12 weeks of retreatment, despite the fact that in at least three of them the insulin resistance score improved. As a result, the study was terminated.

Conclusions:
Different schedules are warranted to improve insulin sensitivity prior to attempting retreatment of chronic hepatitis C patients with insulin resistance.

CS

[bajawoman]

I am curious have any studies been done if IR is a leading factor for Non Response to interferon treatment  of all the Non Responders How many are Insulin Resistant? From what I am reading seems Many? I would think Top Heptologists have computer records of their patients  
  Why after all these years of the Interferon treatment  is this only now coming to light??
Diabetics with Chronic HCV  is that different than insulin resistant?  Or are Diabetic conditions the same as Pre Diabetic and do people with Diabetes on tx do they SVR what is their treatment  I do not understand all the technical data much as I am knew to all this but Diabetes is a real factor where I live very high rates due I would think in major part to sugar intake  

[comeagain]

dont say that i´m just sitting here crunching candy reading this !!!

[bajawoman]

I am reading also that smoking is also a factor insulin resistance that is my next to do on my list is to quit smoking as it may also be a factor for me   sorry to ruin your candyfest

[CockSparrow]

Yes there have been studies done. And yes it is associated with non response.
I suspect almost everyone who has a null response is Insulin Restistant
I am, Miles is and so in Bandman to give some examples.

IR is the pre cursor to diabetes. Not everyone who is insulin resistant becomes diabetic.

IR has been known as a negative for quite a while, but there have been no studies that show that improving IR improves svr. Some are starting to come out now that suggest it will.
There have been studies that show reducing weight lowers IR and thus increases svr

CS

[comeagain]

Did you here that your a smoker aint you me my self stopped 17 years ago started when I was 11 though so been smokoing quite a lot.

[jmjm530]

CS: IR has been known as a negative for quite a while, but there have been no studies that show that improving IR improves svr.
--------------------------------------------------------
As I mentioned in the other thread, many liver specialists having been asking patients to lose weight for some time prior to treatment -- so even without specific studies they have been connecting the dots which seems quite logical. BTW what is your position on using first-line measures like diet, exercise, stop smoking, etc, before taking on another drug like Metaformin?

[meki]

Now - explain this:

Mild to moderate Steatosis and IR --- Gained weight on TX --- I did not RVR, in fact LATE response... If there is a word for that... 18th week finally decreased. Did not extend TX - and managed SVR.

Also Moderate Damage to liver now at grade 1 stage 2... (GOING DOWN FOLKS --- so this DOES mean that the LIVER does INDEED heal itself --- and fairly rapidly too...)

So --- You're saying that my instance is unusual based on the fact that I probaly have all three of those jeans.... Oooops... I mean genes.... LOL!

Anyhow -- that's a lot of mouthful there.

I think that it's probable --- that a lot of things can affect --- and effect --- the probability of SVR status....

Like a CodeBreaker - a thief - HCV insinuates itself inside cellular structures and replicates, taking advantage of different elements...

So it thrives in environments that those specific genes produce.

It makes sense...

I'm just more and more amazed that I actually obtained SVR status --- and I'm counting my lucky stars... and feel so very blessed - as I watch more and more folks struggle with the NON RESPONDER status...

Which may very well encompass having these genes --- and other factors which cause them.

So - I'm thinking --- people who seriously want to reach UND - must lose weight, take weight based Riba - eat less fatty foods, maintain non-sugary content eating ---- must exercise to keep everything moving --- and must adapt to a very healthy lifestyle...

For those who are IR --- they must follow through even more so ---- correct?

Now --- let me ask this:

It's going to sound like an extremely STRANGE question.

WOULD HIGH SODIUM INTAKE AFFECT ANYTHING?

Because --- at the middle of my TX --- I started craving --- Unbelievably a HIGH SODIUM diet... I ate everything Salty --- couldn't stand sweet stuff --- except yogurt (vanilla or peach only) --- fresh Canteloupe and popsicles... (occassional binges on Oreos don't count - LOL!)

But at the middle to NOW currently - I've moved from Chocoholic status to SALT FREAK.

Could that have ANY bearing at all on IR or SVR status?

Don't laugh - I'm asking seriously.

The reason I'm asking is because right around when I started eating Salt --- is when I started responding to the medications... And I never thought anything about it...

I know that probiotics are important --- so maybe salt is too?

I mean  - I ate a yogurt a day ---- and at least a half a bag of potato chips (healthier ones, of course --- or when unavailable - I stuffed my face with kettle ones... LOL!)

But seriously --- could sodium or salt content have any bearing on any of this?

I know sugar does -- adversely...

OK - I'm shutting up now... You guys can go ahead and laugh... LOL!

I'll love all of you anyway.

Hugs,

Meki

[meki]

Oh - and Stranger still - with my diet (containing salt products instead of sweets all the time) --- I've dropped 60+ pounds...

And about 10 clothing sizes.

I went from 205 prior to TX --- up to 215 during TX until the end of TX.

And now almost a year and 8 months Post TX I'm down to 145 pounds...

From a size 22 women's plus to a 12 avg.

[bajawoman]

Hey there  very interesting post to me   especially the weight loss and clothing sizes After TX WOW  that is wonderful news you must feel like a new woman and have fun wearing clothes

well what do you attribute losing weight too?

Doesn't sound like you dieted? I didn't hear anything about excercise either after tx and during tx you even gained weight??  And if I am reading it right you went off tx then lost wieght

And is seems you were taken off tx early but yet managed SVR this is great news

And you also said you were IR at the beginning of Tx  so you are one of the exceptions all the way around to the reactions and actions around tx

Another thing is you are saying your liver is healing itself  so your viral load is low what was the grade and stage and your viral load?  when you began tx? you were also IR ? You really are one of the lucky ones  
Not sure how many here smoke that may be a factor in my case with high Viral Load and IR but I am changing my diet and starting to excercise and will quit smoking I am a lot older than you so maybe weaker to the sx of tx and SVR

[epiphiny]

Wow!  That's an impressive weight loss.  

I went the other way on my first tx from 62kg to 72kg (I'm 6'00 so that made me pretty skinny at 62kgs) and despite being skinny had no viral response.

I never lost the additional weight, in fact gained another 5kgs, before I started this tx which makes me a little overweight and this time I'm responding to tx.

I still smoke BUT last time round I was smoking about 25 - 30 a day and this time I smoke between 2 and 8 and I never smoke a full cigarette.

There are so many variables with this virus, I just don't see how we can really predict any outcomes but I think in a strange way it helps us to try.  As humans we are always trying to find patterns and reasons, some kind of order in the chaos.

Sometimes it drives me mad trying to figure it all out but I have developed a taste for Madon Sea Salt and have been dipping my fingertips in it and licking them, so I'll keep on with that!  Incidentally, I was a chocoholic before tx as well.....

Epi.

[bajawoman]

After Jim posted the links from the last Symposium in SF this month I copied many of them for my Doctor this was one on Insulin Resistant as Co Writer mentioned to me it may be an issue with me which is just the info She has given me

AASLD 2008 Annual Meeting

You may print by clicking on this button. To return to the previous page, close this browser window or click the 'X' button in the top right corner of the page.

ID# LB6
Location: General Session Room (Moscone West Convention Center)
Time of Presentation: Nov 03 4:15 PM - 4:30 PM
Category: Q05. HCV: Clinical Trials and Therapeutic Developments



Metformin with Peginterferon Alfa-2a and Ribavirin in the Treatment of Naïve Genotype 1 Chronic Hepatitis C Patients with Insulin Resistance (TRIC-1): Final Results of a Randomized and Double-Blinded Trial.
M. Romero-Gomez1; M. Diago2; R. J. Andrade3; J. Calleja4; J. Salmeron5; C. M. Fernández-Rodriguez6; R. Solà7; J. M. Herrerías8; I. Carmona8; J. García-Samaniego9; R. Moreno-Otero10; R. Morillas11; C. Ramírez13; M. De la Mata12; P. Giner14; A. Olveira15; O. Nuñez16; F. Jorquera17; S. Duran19; R. Martin-Vivaldi18
1. UCM Digestive Diseases, Hospital Universitario de Valme, Sevilla, Spain.
2. Hepatology Section, Hospital General de Valencia , Valencia, Spain.
3. Hepatology Unit, Hospital Universitario Virgen de la Victoria, Málaga, Spain.
4. Gastroenterology Unit, Hospital Puerta de Hierro, Madrid, Spain.
5. UC Aparato Digestivo, Hospital San Cecilio, Granada, Spain.
6. Gastroenterology Unit, Hospital Fundación Alcorcón, Madrid, Spain.
7. Hepatology Section, Hospital del Mar, Barcelona, Spain.
8. Gastroenterology Unit, Hospital Virgen Macarena, Sevilla, Spain.
9. Hepatology Unit, Hospital Carlos III, Madrid, Spain.
10. Digestive Unit, Hospital La Princesa, Madrid, Spain.
11. Digestive Unit, Hospital Germans Trias i Pujol, Badalona, Spain.
12. Hepatology Unit, Hospital Reina Sofia, Córdoba, Spain.
13. Medical Departament, Roche Farma, S.A., Madrid, Spain.
14. Pharmacy Unit, Hospital Germans Trias i Pujol, Badalona, Spain.
15. Digestive Unit, Hospital La Paz, Madrid, Spain.
16. Hepatology Section, Hospital Gregorio Marañón, Madrid, Spain.
17. Digestive Unit, Hospital de León, Leon, Spain.
18. Digestive Service, Hospital Virgen de las Nieves, Granada, Spain.
19. Endocrine Unit, Hospital Universitario de Valme, Sevilla, Spain.

Background&Aims: Insulin resistance affects sustained virological response (SVR) in patients with chronic hepatitis C (CHC). We sought to determine if the addition of metformin to the standard of care regimen could improve SVR in naïve patients with genotype 1 CHC and insulin resistance.
Methods: In a prospective, multicenter, randomized, double-blinded, placebo-controlled trial (TRIC-1), 125 consecutive patients with genotype 1 CHC and insulin resistance (HOMA > 2) received either metformin 425 mg t.id during the first month and 850 mg t.i.d. from week 4 to 48 (Arm A; n=59) or placebo (Arm B; n=64) in addition to peginterferon alfa-2a 180 micrograms weekly and ribavirin 1000-1200 mg daily. Treatment was withdrawal in patients without early virological response (EVR) or HCV-RNA positive at week 24. No baseline differences between arms A and B were seen in the following demographic, biochemical and virological data: age (47+/-8 vs. 48+/-8 years); HOMA (4.3+/-2.2 vs. 4.4+/-2.6); Sydney index (0.43+/-0.27 vs. 0.45+/-0.31); baseline viral load (6.33+/-0.73 vs. 6.48+/-0.76 log10 UI/ml); p=ns for all comparisons. Virological response was assessed at week 4, 12, 24 and 72 by intention-to-treat (ITT) analysis.
Results: In the ITT analysis viral clearance was seen in 54.2% vs. 48.4% at week 12, in 74.6% vs. 75% at week 24, and in 52.5% vs. 42.2% at week 72 (SVR rate) in arm A and arm B respectively. In females (n=54), viral clearance was higher in the metformin arm at week 12 (57.7% vs. 39.3%) at week 24 (80.8% vs. 71.4%) and SVR (57.7% vs. 28.6%;p=0.031). In patients receiving metformin (arm A) viral load decreased during the first 12 weeks in a gender-dependent manner (-4.18+/-1.18 vs. -4.02+/-1.68 log10 IU/ml;p=0.044). SVR was 56.3% in women showing a weight higher than 75 Kg. Patients in arm A showed a greater decrease in their HOMA index than those in arm B (-1.6+/-2.14 vs. -0.87+/-2.11; p=0.008). Triple therapy was well tolerated. Gastrointestinal discomfort, mainly mild diarrhea, was more often seen in arm A (34.1% vs. 11.4%; p<0.05).
Conclusions: Triple therapy with metformin, peginterferon and ribavirin was well tolerated, decreased insulin resistance and increased SVR in this difficult-to-treat group of patients. This therapy was especially effective in females in whom metformin raised significantly the SVR rate. It agrees to the improved sensitivity to metformin reported in obese women. Our data suggest that triple therapy should be the standard of care for females with hepatitis C genotype 1 and insulin resistance.

Acknowledgments: Supported by an unrestricted grant from Roche-Farma, S.A.

[comeagain]

On my first tx my weight was 90kg (200lbs) and stayed that way allthrough tx 24weeks.
This tx started up with 89kg after 3 months 80kg current weigt 1month left 78kg.

first tx I was a popcornoholic with a lot of seasalt on also a chocolate and candyholic eated that everyday and relapsed.

This tx time I continued the pocorn habbit first two motnhs but then stopped that candy I only eat once or twice a week.

As I have said here on forum several times before every geno 3 I know of  5-6 persons all got SVR except me and they were all at least 25lbs lighter then me according to their lengt compared with mine.
My gut told me this was important even before I ever heard of IR .

I had had plans to loos weigt before starting this tx but since I had only 10months time and my ex, mother to my children still was txing and I had to take care of children dog and other things I neither had the energi or the time to get in shape.

I´m very glad cowriter is going on about this and even glader cocksparrow is gonna intensify hes engagement if she stops.
My gut is talking even lauder know that this is even more imported then I first thought and more  people can get to SVR and who knows by being forced to change lifestile which is very difficult the older one gets, a curse can be transformed to a blessing.

ca

Ps can´t provide any studys about SVR nr predicted by talking guts.

[meki]

baja - I'm a 3a --- I did the full 24 weeks - But I'm amazed at the doctor --- who didn't even consider extending.. Or at least didn't discuss it with me... I was pretty NIAVE.

But I can tell you this much - I did go SVR... Been over a year and 8 months UND. Roughest 3 years of my life...

Don't want to do it again - that's for sure

But I lost weight POST TX...

Gained weight during TX

Totally off the wall..

I still smoke --- but did quit during TX most of the time couldn't bring the smoke to my mouth -- could hardly move some days


LMAO --- on dipping your fingers in --- I find myself licking the bottom of the can of the roasted peanuts to get that salt. LOL!

Anyhow - yeah --- It's all pretty strange to me.


I do think Weight based Riba is important

[Marcia2202]

It's so good to see you around... always a breeze of fresh air! It's good to see you rockin' it, too.

Hugs, Marcia

[CockSparrow]

Jim - BTW what is your position on using first-line measures like diet, exercise, stop smoking, etc, before taking on another drug like Metaformin?

Completely agree. I would add taking sups such as ALA NAC Taurine Astragalus Stevia and possibly Resveratrol. All of wich have shown some benefit in reducing IR.
However no sup is going to help much if the metabolic pressure is still in place.

Diet is especially important. Any of the Low Carb ones will help, as they seem to turn around poor glucose metabolism.

I would do all of the above before taking Metformin. Whether i succeed in quitting smoking is another thing, and dont try Chantix.
There is one things, and its the IR we get on Tx that we need to deal with, not pre Tx per se. That said you don’t want to go into Tx already Insulin Resistant. So Metformin is probably still part of the solution.

You don’t have to necessarily be over weight to be Insulin Resistant.
Below is some patient data from
Pioglitazone (Actos) in chronic hepatitis C not responding to pegylated interferon-a and ribavirin Journal of Hepatology 49 (2008) 295–298

They messed this study up btw.

Patient #1 was a 46-year-old female who had failed previous treatment of Pegasys and Copegus  four years earlier.
A liver biopsy performed in 2004 showed a Metavir score of A2 F3, with mild steatosis affecting 20% of hepatocytes.

She had a normal body weight with a BMI of 20.8, and was not known for a hypertension or a dyslipidemia.

As concomitant medications, she was receiving duloxetine 60 mg QD and zopiclone 7.5 mg QD.
After 12 weeks of treatment, serum HCV RNA level did not change (from 176,000 IU/ml to 154,000 IU/ml, measured by Cobas TaqMan HCV, Roche Diagnostics, Rotkreuz, Switzerland) and, oddly enough, the HOMA-IR score increased from 2.65 to 11.
Thus, therapy was discontinued. Her body weight remained stable during therapy.

Patient #5 was a 46-year-old male.
A liver biopsy carried out one year before enrolment had shown mild activity and portal fibrosis (Metavir A1 F1), with a mild steatosis affecting 20% of hepatocytes.
The patient had received a 12-week course of combination with Pegasys and Copegus resulting in a -0.95 Log change in his serum HCV RNA level one year prior to enrolment.

His baseline HCV RNA was 2,700,000 IU/ml (genotype 1a), and the HOMA score 2.88.
He had normal body weight (60 kg, waist circumference 87 cm) and normal blood pressure.

As concomitant medications, he was receiving olanzapine 15 mg QD and escitalopram
20 mg QD for a well controlled depression.
The study drugs were well tolerated, but after 12 weeks from start the HOMA-IR had increased to 3.72, while the serum HCV RNA had decreased to 300,000 IU/ml, i.e. -0.85 Log, even less than on the occasion of the first treatment.

Body weight and waist circumference were slightly reduced (58 kg and 85 cm).

CS

[nonABC]

Go get 'em CO!!

"That's right.  The women did much better than the men."  

[CoWriter]

"As I mentioned in the other thread, many liver specialists having been asking patients to lose weight for some time prior to treatment -- so even without specific studies they have been connecting the dots which seems quite logical. BTW what is your position on using first-line measures like diet, exercise, stop smoking, etc, before taking on another drug like Metaformin?"
_____________________________

Really?  Let's see.  Here's what a couple of hepatologists said in response to these questions back in Sept 2005.....

Questions....

"Based on the information about insulin resistance lowering SVR, I would like to know how many of you test for insulin resistance and use insulin sensitizers even though the patient may not be diagnosed as a diabetic yet--just insulin resistant. If so, what are you using, and have you seen any toxic effects from glitazones? (medications that improve insulin resistance).

Since the HCV damages the mitochondria (the power plant of liver cells and location of the interferon response mechanism) by a process of oxidative stress and the same may be true for insulin resistance, are you recommending anti-oxidants and if so, what amounts?

Since aerobic exercise helps produce more mitochondria and a high-protein diet boosts the benefit of exercise, possibly decreasing insulin resistance, are you recommending compensated patients do this and if so, how much protein?"
____________________________


Dr Zobair Younossi said.....

"The issue of metabolic syndrome in patients infected with HCV is quite interesting. It seems that HCV patients with components of metabolic syndrome (diabetes mellitus, central obesity, insulin resistance) can have more advanced liver disease as well as lower response to antiviral therapy. The exact mechanism of this interaction is not well known but could involve insulin resistance (IR), adipokines (adiponectin, leptin), cytokines, and associated oxidative stress.

Despite this interesting data, I DON'T routinely check HCV patients for Insulin Resistance. Although theoretically it makes sense to use medications/strategies to improve IR and oxidative stress, there are currently no convincing data that these treatment strategies (including amount of protein intake) improve outcomes in patients with HCV.

However, for overweight HCV patients, I do recommend gradual weight loss."
_____________


So he didn't test ANY Hep C patients for insulin resistance....didn't recommend any certain diet or supplements.  Just "gradual weight loss".




Dr Marcelo Kugelmas said.....

"I agree with Dr. Younossi's comments; however, if the liver biopsy of a hepatitis C patient shows features of steatohepatitis (fatty liver), I do measure HOMA and try to sensitize the patient to insulin by weight LOSS through diet and exercise, and consider use of metformin."


And Dr K only tested patients for IR and recommended weight loss if they had fatty liver.


Pitiful.

Realistically....how many people will loose weight if they're given no education?

Co
P.S. Notice how neither one mentioned smoking.

[CoWriter]

"I hope they do a better job than this study did. Talk about mess it up."
______

You're totally not helping me.  Let me give you a better one.  It's the same drug, which by the way, was also used in the study that I posted in the other thread.  They used Metformin, Avandia or Actos.




Drug Lowers Conversion To Type 2 Diabetes By 81% In Multicenter Study

June 11, 2008

In a research study of hundreds of patients facing the prospect of developing type 2 diabetes, the oral drug pioglitazone (Actos) reduced the rate of conversion to the disease by 81 percent in the active therapy group compared to those taking a placebo, the study leader, Ralph A. DeFronzo, M.D., reported June 9 during the 68th Scientific Sessions of the American Diabetes Association in San Francisco.

Individuals randomized to take pioglitazone also recovered part of their insulin production and their bodies became more sensitive to insulin, therefore using it more efficiently to control plasma glucose or blood sugar, Dr. DeFronzo, professor and chief of diabetes at The University of Texas Health Science Center at San Antonio, said.

He designed and led the four-year ACTos NOW for the Prevention of Diabetes (ACT NOW) Study that enrolled 602 individuals with impaired glucose tolerance, a prediabetic state, along with 102 healthy controls.

Currently no drug is approved by the U.S. Food and Drug Administration for treatment of prediabetes to prevent progression to diabetes.

The maker of Actos®, Takeda Pharmaceuticals of Japan, funded the study but gave the researchers complete freedom to perform the study and interpret the results, whether positive or negative, Dr. DeFronzo said.

The study was conducted at eight of the foremost centers for diabetes in the U.S. The American Diabetes Association labeled the ACT NOW presentation late breaking and clinically relevant.

Pioglitazone corrects two core defects in type 2 diabetes, insulin resistance and beta cell failure. Beta cells are the cells in the pancreas that secrete insulin.

"The drug is the best insulin sensitizer we have and it also preserves beta cell function," Dr. DeFronzo said. "The clinical response in this study is next to astronomical, not 100 percent but obviously highly significant."

Pioglitazone came to the U.S. market in 2000 and the original mechanism-of-action studies were conducted by the Division of Diabetes in the UT Health Science Center's School of Medicine.

Subjects in the ACT NOW study were treated at the clinical research area of the Texas Diabetes Institute, a comprehensive diabetes treatment and research facility staffed by UT Health Science Center faculty physicians in a University Health System facility on San Antonio's West Side.

About 1 in 10 individuals with impaired glucose tolerance shows signs of diabetic retinopathy (damage to blood vessels in the retina that may affect vision), and 5 percent to 10 percent of prediabetic individuals are estimated to have peripheral neuropathy (blood vessel damage in extremities). A drug to treat impaired glucose tolerance and prevent further decline is therefore of great importance.

"Prediabetes, I believe, is really diabetes," Dr. DeFronzo said.

In the ACT NOW study, 10 subjects with impaired glucose tolerance developed diabetes while taking pioglitazone. That compared to 45 subjects with impaired glucose tolerance who developed diabetes after receiving a placebo. Patients were randomly assigned to receive either active drug or a placebo.

Forty-two percent of individuals in the pioglitazone arm of the study returned to normal glucose tolerance at the study's end versus 28 percent of those in the placebo arm.

Pioglitazone was safe and well tolerated during the study. Weight gain and edema were more frequent in the treatment group.

http://www.medicalnewstoday.com/articles/110717.php

[CoWriter]

"I am curious have any studies been done if IR is a leading factor for Non Response to interferon treatment"  
___________

It is now the MOST important host factor......



"Thus, insulin resistance emerges as THE MOST IMPORTANT host factor in the prediction of response in non-diabetic patients treated with the best available option -peginterferon plus ribavirin. Interestingly, insulin resistance has been found a common denominator to the majority of features associated with difficult-to-treat patients. Patients with cirrhosis, obesity, HIV coinfection and Afro-American showed all insulin resistance."

http://scielo.isciii.es/scielo.php?pid= ... ci_arttext



"of all the Non Responders How many are Insulin Resistant? From what I am reading seems Many?"

We don't know exactly.  Most of the doctors do NOT test people with Hep C for insulin resistance.  Even though we've known for years that insulin resistance lowers SVR.  According to some of the studies, up to two thirds of Hep C patients have IR.



" Why after all these years of the Interferon treatment  is this only now coming to light??"

(I've been asking that for years).

Because even though they knew that IR lowered SVR, they hadn't done any studies (until recently) using medications to lower the insulin resistance.



"Diabetics with Chronic HCV  is that different than insulin resistant?  Or are Diabetic conditions the same as Pre Diabetic"


First comes PRE-DIABETES (a fasting blood sugar above 100)....When you start becoming insensitive to insulin, your blood sugar starts to go up.  A study showed that a blood sugar above 100 lowers SVR.

Then the insulin resistance gets worse.....and for a long time your pancreas works fast and makes extra insulin, so it's able to keep your blood sugar in the normal range even though you're insulin resistant..  

But eventually, you become more insensitive to insulin and the pancreas can no longer keep working so fast.....slows down....sugar goes above 126....and you're now considered a diabetic.

So that means that you have to be insulin resistant before you can become a diabetic.  All diabetics type 2 are insulin resistant.



"and do people with Diabetes on tx do they SVR "

I believe CS and I created a monster...LOL

Great question.

Years ago, I used to work with both diabetics and people with Hep C.  And I noticed that many diabetics didn't clear.  If their blood sugar was kept under very strict control they did better.  But the problem is that treatment can also make the diabetes worse.  

Don't stop asking.....

Co

[CoWriter]

Go get 'em CO!!

"That's right.  The women did much better than the men."  

____________________

High five sista!

Co

[jmjm530]

JM: .."many liver specialists having been asking patients to lose weight for some time prior to treatment -- so even without specific studies they have been connecting the dots..."
_____________________________

Really?  Let's see.  Here's what a couple of hepatologists said in response to these questions back in Sept 2005.....
-----------------------
Yes, "really" MS sarcastic one these days.  

Please read again my statement, and your response. BOTH doctors you quote (from 2005) suggest weight loss.

I was talking about "connecting the dots" and again, specifically to weight loss recommedations.  The first doctor connected the dots by recommending gradual weight loss for overweight patients. Hmmm (sacrasm unecessarily added) Hmmmm (why not over do it) isn't that exactly what I said? Hmmmm

Second doctor you noted ALSO suggests weight loss and you speculate on whether or not he would recommend weight loss in overweight patients without fatty liver. He agrees with the first doctor so just because he might go for weight loss and metaformin with fatty liver biopsy does not mean he "only" does it in those cases.

---------
CO:
Realistically....how many people will loose weight if they're given no education?
--------------
Not sure what you mean by this. All I am saying is that weight loss has been suggested by good liver specialists for some time now, and that -- along with lifestyle changes such as exercise, stopping smoking, etc, -- rightly should be the first line attack for IR. This is not to criticize using drugs like Metaformin if first line measures do not work. And yes, a number of people here have lost signficant weight prior to treatment because their doctors told them to. "Gauf" is one example. When someone has something as serious as Hep C can be, and their doc tells them that losing weight will help SVR, that can be a real motivation.

[CoWriter]

The insulin resistance caused by Hep C is actually hepatic hyperglycemia.  It's not the same as the simple antagonism of PPAR gamma of adipose tissue associated with Type 2 diabetes.  

In some people, Hep C causes the liver to disgorge huge amounts of glucagon.  This kind of sugar infusion would overwhelm most people's ability to produce enough insulin to control it.

You can be insulin resistant without being overweight.  

[CoWriter]

That's right.

Co


Association among cigarette smoking, metabolic syndrome, and its individual components: the metabolic syndrome study in Taiwan.

Chen CC, Li TC, Chang PC, Liu CS, Lin WY, Wu MT, Li CI, Lai MM, Lin CC.
Division of Endocrinology and Metabolism, Department of Medicine, China Medical University Hospital, Taichung 404, Taiwan.

Insulin resistance is a common feature of metabolic syndrome. Smokers are at great risk of developing insulin resistance. Theoretically, smoking status should be associated with metabolic syndrome. This study aimed to explore the association among cigarette smoking, metabolic syndrome, and its individual components. Information of participants regarding previous and current diseases, family history of disease, smoking habits, alcohol consumption, betel nut chewing, and physical activity status were gathered from self-reported nutrition and lifestyle questionnaires. The fasting plasma glucose, triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, blood pressure, and anthropometric indices in each patient were measured. Data of 1146 male subjects were analyzed. Individuals who currently smoked had a higher prevalence of metabolic syndrome than those who had never smoked and those who had quit smoking. The adjusted odds ratios of current smoking amount showed a statistically significant dose-dependent association with metabolic syndrome, high triglyceride level, and low HDL-C level. Current smokers who smoke > or =20 pack-years have a significantly increased risk of developing metabolic syndrome, high triglyceride level, and low HDL-C level. The higher risk of development of metabolic syndrome, high triglyceride level, and low HDL-C level was insignificant in former smokers. In conclusion, this community-based study supports the view that smoking is associated with metabolic syndrome and its individual components. Smoking cessation is beneficial to metabolic syndrome and its individual components.

http://www.ncbi.nlm.nih.gov/pubmed/18328358?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

[jmjm530]

CO: You can be insulin resistant without being overweight.
--------------
That's correct, and you can also have fatty liver without being overweight -- but that was not my point. The fact that you can have fatty liver without being overweight does not mean that IF you're overweight, one should necessarily dispense with first line treatment, i.e. weight loss and lifestyle changes. And as far as I know, this prinicple holds true whether the IR is caused by Hep C or not. That's why good liver specialists have (and still are) recommed weight loss and lifestyle changes to their overweight patients.

And to be clear, as the sub-text of some of these posts may suggest to some -- I am not against treating IR whatever means is deemed appropriate, not do I have any pic with the current studies, not do have any illusions that the medical profession as a whole has been on top of this situation.

Quite the contrary. The medical profession as a whole has been behind the curve on both IR as well as many other issues, and that's one of the reasons why a place like this is such a valuable resource. It's also why I, and others, always urge people to seek out the best possible liver specialist they can reasonably find, because top line liver specialists tend to be ahead of the curve, not behind it.

So please, let's not turn this into an argument, because I'm not sure what we're arguing here, unless you don't believe that recommending weight loss and lifestyle changes to an overweight patient with IR is not a reasonable first approach.

-- Jim

[CockSparrow]

Say one thing about CoWriter, She is passionate.

As for losing weight, I doubt anyone would diagree in princple.
But as the South Beach Diet indicates being overweight can be caused by IR.
From memory doesnt Agatston state that being overweight is a direct result of a high carb diet. Leptin is also getting the blame in similar diets ie rosedale. All gets a bit circular i know. Being over weight leads to IR. IR leads to weight gain.

In otherwords I guess Co is saying if you resolve IR then the weight loss will look after itself as it did in Meki's case. Which is also what Agatston is saying.

No simple answers really
CS

PS Meki, I'll try and answer you Posts Questions Tonite. My Tonite that is.

[CockSparrow]

Just to make it clear i believe that we should try and resolve IR before we start Tx.
Using whatever means we can.
I dont like the way some of these studies similstart Insulin sensitising drugs with the first shot of IFN. Seeing as IFN can induce IR yet at the same time also resolve it.

CS

[CoWriter]

"As for losing weight, I doubt anyone would diagree in princple.
But as the South Beach Diet indicates being overweight can be caused by IR.
From memory doesnt Agatston state that being overweight is a direct result of a high carb diet. Leptin is also getting the blame in similar diets ie rosedale. All gets a bit circular i know. Being over weight leads to IR. IR leads to weight gain."


Thank YOU!

Of course I'm not saying lifestyle changes aren't important.  I'm just saying they're not enough.  

Co

[jmjm530]

From memory, Agaston states that a low-carb diet like South Beach can bring IR and metabolic syndrome under control, therefore diet should be a first-line treatment.

CO, But they can "be enough" in some cases and that's why they should be (and are recommended) as a first-line treatment IR in many cases. If your personal opinion is that people aren't motivated enough to do the hard work, that's another story. And I'm still not clear on your position -- would you ask your IR patients to try and lose weight and make lifestyle changes before administering a drug like Metaformin -- do you even give them a choice -- or do you just skip that step and put them right on Metaformin?

[mikesimon]

I think CO would advise obese patients to try and lose weight. Perhaps I am being presumptuous but my impression is that she believes that Metformin can also be a significant aid in reducing IR in patients who don't achieve the goal through weight loss alone and for those patients who are IR and don't have a weight problem. If that is her position I agree with her and if it isn't I still agree with the position.
Mike

[jmjm530]

If that is her position, then I also agree with her.

But unless I'm reading things wrong, that has been MY position, not hers,  but maybe I'm reading things wrong.

But once again, my opinion is that in the majority of cases you try weight loss and lifestyle changes first, then try something like Metformin if that doesn't work. And yes, where IR presents itself and there isn't a weight problem, it's not just a matter of losing weight.

-- Jim

[bajawoman]

Thank you for a very interesting read which has very much to do with me and many others that are pre tx in considering what they will be speaking to their Doctors about
I for one would not have known I was IR if it was not for CO  thank you a million times
Knowing more about each individual as an individual instead of lumping all together for the same SOC is surely an advantage for SVR but taking it one step further with more studies can also prevent some sx that are miserable for people always I hear every one is different but yet they are not treated differently before tx all have the same tests going in most concerned with Viral Load and Genotype but very little else is looked at
in relation to an indivduals symptoms that brought them to the doctor in the first place
one could have many other factors besides HCV that need to be addressed before Tx I would assume if this was SOC then maybe the patient would not have to have so many uncomfortable sx in tx just a thought
Genetics would play a very important role
Lifestyle right up there with Genetics
Other conditions such as IR  Fibromyalgia Lupus Arthritis and any other pre exsiting disorders which with todays population and current lifestyle of todays population
I would think Males and Females would also have different issues as well
All very interesting to say the least  Since these conditions are not considered in most cases and there is a rush to tx  It would seem in trials they would make is SOC
The main objective not to sell drugs but the ultimate goal of SOC
The smoking issue little to be found but since I smoke and am Insulin resistant there are many studies done on it I just typed in Insulin Resistance and Smoking and sure enough no one should smoke as they should not drink Alcohol prior to tx  
Nor should any one be obese however the weight issue and smoking are two difficult issues for most people to control which is why I feel there is a real good need for pre treatment thorough dx and then tx  just a thought
CS  why did you say not to use Champix for quitting smoking I have used the patch the gum have not had any luck with the gum but have had luck with the patch in the past however with all the worry over this situation I am dieting good diet and starting with excercising 3 times a week and will increase  Smoking is one thing very difficult for me
to stop at this time so anxed up about this HCV I find my self smoking more need an aid to quit diet has come easy the excercise not so easy but doing it  
I searched the Champix drug Varenicilina  and it seems ok what was your take on it CS?
Still need a Fibroscan I am betting there is one here in Mexico so will look here if I do not hear back about one in LA  all the best and I will keep asking questions
thanks again super thread
Baja

[CoWriter]

"think CO would advise obese patients to try and lose weight."

You know me well. :)  Besides teaching them about IR, I put them in my nutrition class.  

"Perhaps I am being presumptuous but my impression is that she believes that Metformin can also be a significant aid in reducing IR in patients who don't achieve the goal through weight loss alone"

And it may also aid weight loss.

Using insulin sensitizers worked for co-infected patients and non-responders.  Give me your honest opinion.  Do you think weight loss/diet would give them a 71% EVR?

It isn't that I believe that people are lazy or not determined to loose weight.....it's that some of them just can't.  

People are willing to double dose and face whatever risk for a chance at less than 71%.  Now there's a new option.....and I'm really excited.

Co

[CoWriter]

"Knowing more about each individual as an individual instead of lumping all together"

You said it best.

Co

[meki]

So you guys think that because my liver started healing itself - it stopped producing SUGAR.. SUGAR..  Sugar.

And the sugar is melting offa my hipsters?

Hmmm..


LMAO!

That's kinda funny.

[CoWriter]

"I searched the Champix drug Varenicilina  and it seems ok what was your take on it CS?"

There have been several cases of elevated liver enzymes caused by it.

Co  

[CockSparrow]

It didnt work so i didnt finish the pack, but it did give me a sweet tooth.
So yeh i'd say it raised enzymes

CS

[mikesimon]

I haven't read enough to know the particulars but if the study is as you describe then - No, I do not think that an EVR of 71% would be likely through diet/weight loss alone.
I have been diabetic since my transplant in 2000. I am a control freak with my glucose - my HBA1c from 5 months ago was a flat 4. Anyway, I was an EVR when I was dosed correctly with Peg/Riba and I did achieve SVR - I treated for 73 weeks to get there but I did get there. I was not overweight and I believe that if I hadn't controlled my glucose as tightly as I did it is possible and maybe likely that I wouldn't  have reached SVR. And I tend to believe that for many who are IR weight loss alone might not be enough. Drugs very well might be the key. Perhaps for those people who are able to lose enough weight and achieve a corresponding insulin response diet is enough. I think we both agree that significant weight loss does confer a significant benefit in those patients who are overweight or obese. But from the little I know I too am excited about Metformin. I just don't know enough to be really confident at this point. But it looks good from here - very good!
Mike

[desrt]

A couple points:

1) Getting rid of the virus didn't automatically fix my steatosis or IR. Ultrasound at 1 year and 4 years post-tx showed NAFLD. Diagnosed with diabetes 5 years post-tx. After carrying a geno 3 virus for almost 30 years, damge done, even though 2001 bx showed only mild fibrosis.

2) Metformin worked where diet and exercise didn't.

6'2"
225 lb. pre-tx
220 lb. EOT
230 lb. post-tx

All the low carb / no carb diet and exercise for 5 years post-tx was only able to budge my weight +or- 5lb. Lost 40 lb in 6 months taking Metformin and my glucose is the best it's been in years.

[bajawoman]

That is great news for you Did you have a special diet?  Have you stopped teh Metformin and can you keep the weight off? thanks for posting
Baja

[desrt]

My understanding is that the longer I stay on an insulin sensitizer the more good years I'll get out of my pancreas. I went on a fairly strict 'chef salad' diet when first dx with diabetes, but since I've dropped under 190 I've been adding more fats and carbs back into my diet.

[CockSparrow]

Is there anything actually incorrect with what Co has posted.
Cause if there is i have also got it wrong.

What is your point with this, or are you just trying to stir up trouble
Why are you a member here.
Your 4 posts so far have been breathtaking in their Brevity and pontlessness.

CS

[Dee1956]

Just found this thread and it was so interesting I had to add my experience which is purely anecdotal and is not part of a study.:)
I have diabetes, while on the last tx in 2008 I was so sick I did not watch my sugar but the weekly draws showed it was fine so I continued on and relapsed.
This time pretx I am seriously watching my sugar, taking Metformin, while logically I know it doesn't mean much however my viral load has gone from over 6M to 350K since starting in April and my ALT and AST are both at 21.  Something is happening.
I pray this enough to get me to SVR when I start tx, thanks for this post
Dee