Interesting Study on Insulin Resistance

[MYS]

J Hepatol. 2009 Apr;50(4):712-718.

Insulin resistance predicts response to peginterferon-alpha/ribavirin combination therapy in chronic hepatitis C patients.

Dai CY, Huang JF, Hsieh MY, Hou NJ, Lin ZY, Chen SC, Hsieh MY, Wang LY, Chang WY, Chuang WL, Yu ML.
Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Rd, Kaohsiung 807, Taiwan; Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Occupational and Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

BACKGROUND/AIMS: Insulin resistance (IR) might be associated with hepatitis C virus (HCV) infection. This study aimed to elucidate impact of IR and beta-cell function on the response to peginterferon-alpha (PEG-IFN)/ribavirin combination therapy in chronic hepatitis C (CHC) patients.

METHODS: Three hundred and thirty patients without overt diabetes were treated with combination therapy with (PEG-IFN)/ribavirin for 24 weeks. The IR and beta-cell function were evaluated by homeostasis model assessment of IR (HOMA-IR) and homeostasis model assessment of beta-cell function (HOMA-beta) before treatment.

RESULTS: HCV genotype, pretreatment HCV RNA level and pretreatment HOMA-IR, but not HOMA-beta, were independent factors associated with sustained virologic response (SVR). In 150 patients with genotype 1b infection, pretreatment HCV RNA level, HOMA-IR and age were independent predictors for SVR. The significantly lower SVR rate in high HOMA-IR patients was observed in 76 patients with high HCV RNA levels (400,000IU/mL) who were defined as 'difficult-to-treat' patients. The mean HOMA-IR of 'difficult-to-treat' patients was significantly lower in 42 sustained responders than in 34 non-responders.

CONCLUSIONS: IR was associated with SVR to (PEG-IFN)/ribavirin therapy for CHC, especially among 'difficult-to-treat' patients. These findings suggested clinical application of pretreatment HOMA-IR could enable treatment outcome to be predicted and treatment regimens to be determined.

[geterdone]

Treatment may not be in vain for those who may not know that they are IR or boarder line diabetic and to be tested before starting treatment will give more information for a better outcome rather than finding out that the past 48 weeks was a waste.
jasper

[Trinity4]

Thank you Max

[Trinity4]

Just a matter to time wasn't it.......

[Trinity4]

Correction:  matter OF time

[bandman54]

Wish I had read something about IR before I treated and failed.

Still fighting it.. just got my labs today.
HOMA = 4.48  ... uggghh.

Jacked up the metormin , hopefully that will help.
Took me a long time to become IR and it will probably take awhile to get back to "normal".

My dad was a type II diabetic, so was his mother.
If you have a family history of diabetes , it is worth looking in to.

IR's are 7 years from progressing to type II diabetes if not treated.
Wish they had known about IR (many doctors are still not aware, mine wasn't) when my dad was alive.  He eventually progressed to renal disease and diaylisis (sp?).
they always said the kidney problem caused the diabetes... but I am convinced that the diabetes caused his kidney problems.



bandman

[Trinity4]

It would have been fine if the case in point was just IR awareness but we know it goes a whole lot deeper than that.  
Let sleeping dogs lie

[GreatBird]

My understanding is that diabetes type 1 involves underproducing insulin. Type 2 is with overproduction. Do you know whether the diabetics who cleared were type 1 or type 2?

[Bill1954]

I am a type 2 diabetic that SVRrd. Although I had a slow response during the first treatment, the second time I cleared relatively early, and went on to achieve sustained viral response. I think part of the misunderstanding here is that some members on this board have become obsessed by insulin resistance, and look at it as if it were a panacea to HCV treatment; but it doesn’t *preclude* SVR; it’s only another hurdle to jump on the path. I’m not suggesting it be ignored either; but a balance needs to be found.

Type 1 diabetes typically involves underproduction of insulin from the beta cells in the pancreas. Type 2, on the other hand, can be a combination of factors; underproduction of insulin, coupled with insulin resistance that prevents cells from absorbing or utilizing the insulin that *is* produced. A type 1diabetic typically requires very little exogenous insulin; they can get by with injecting small amounts. I, on the other hand, at times require very large amounts of insulin because my body is unable to ‘accept’ either my own insulin (endogenous), or the insulin we inject (exogenous). It’s common for type 2 diabetics such as myself to require both oral insulin sensitizers (metformin) as well as insulin injections to maintain firm blood sugar control.

Take care—

Bill

[Max60]

My original post asked for clarification. . . which was not given.

What were the viral loads? What were the ages of the successful and unsuccessful participants?  Who do the terms 'difficult to treat' mean precisely in the context of this study?

Is there some reason you can not post the full text?

[jdwithhcv]

Google this and you will get the articles.  

J Hepatol. 2009 Apr;50(4):712-718.

[geterdone]

did you know the first time around that your IR would play a part in your not being successful in treatment? Just curious, thanks!
jasper

[Bill1954]

Actually, both treatments occurred prior to current studies showing any correlation between insulin resistance and SVR; any attempts at challenging IR were in the interest of blood glucose control only.


Bill

[geterdone]

Thanks! I don’t know what could or can be done to ease these obstacles to those who have IR problems or are db1 or 2 and starting to look at treatment but it is better to be aware than not and am sure it will come up again.

jasper

[Deb_c430]

  

Diabetes is a serious disease, so is treating,  Bill as always your words are clear and honest!  maybe a sidebar like  the Occult Hep C? trihep is great about posting new articles,  

[jmjm530]

Max: Is there some reason you can not post the full text?
--------------
Can't speak for the original poster, but I hear you.

A very quick search shows that  full-text is not available for free online as is the case with many studies.

For anyone who would like to read full-text, here's a link to the study and note the "full-text" box to the right.

http://www.ncbi.nlm.nih.gov/pubmed/19231011

That will take you to one or two sites where you can download the full-text for a fee. Alternatively, some of you with professional or university access may be able to get it that way. Also, full-text is generally available for free in some public medical libraries.

When I was treating, I always ordered full-text for any study I was going to base an important treatment decision on. Abstracts often leave as many question unanswered as answered.

-- Jim

[jmjm530]

For further interested, here is a collection of HCV/IR/Diabetes articles from the HIVandHepatitis.com web site:

http://www.hivandhepatitis.com/hep_c/hepc_news_insulin.html

"CoWriter" has also compiled a list along with commentary here:
http://www.medhelp.org/user_journals/index/568322?personal_page_id=450
--------------------------
IR and HCV tx is definitely an evolving subject and hopefully anyone with HCV, and especially about to treat, will first get tested for IR including a fasting serum glucose and serum insulin test. The fasting glucose is commonly a part of a normal HealthScreen but really don't see why a doc would refuse a serum insulin test if requested, mine didn't even though my fasting glucose values were normal.

Beyond that, study up as much as you feel comfortable with, and discuss with your medical team where relevant. Diet and exercise are the first line defense for IR but they may not work in all cases.

With tests in hand (and perhaps some supplied studies) hopefully your medical team can put your IR status in a clinical context and come up with a plan where needed. And again, if you're not seeing a hepatolgoist, I highly recommend you switch over to one if feasible. They tend to be more on top of HCV and related topics and would be best to help pull your HCV strategy together.

-- Jim

[CoWriter]

"I am a type 2 diabetic that SVRrd. Although I had a slow response during the first treatment, the second time I cleared relatively early, and went on to achieve sustained viral response."
--------------------
I am going to take a wild guess and say that perhaps your blood sugar control was better the second time?


"Type 1 diabetes typically involves underproduction of insulin from the beta cells in the pancreas."
--------------

Actually Bill, Type 1 means that you don't produce ANY insulin at all.  


" A type 1diabetic typically requires very little exogenous insulin; they can get by with injecting small amounts."
----------------

Think about it.  They don't produce any insulin at all.


"but it doesn’t *preclude* SVR"
------------------
I disagree with that, however, I do agree that IR is only one of many hurdles.



"some members on this board have become obsessed by insulin resistance"
-------------------

You can't be talking about me.  I didn't just become.  I've been obssessed with it for years...LOL

I find your case incredibly interesting and wish I could see what the difference was between the two times you treated (same with FlGuy) since high levels of insulin make interferon ineffective and that includes injected insulin...and you were on quite a bit of Lantus insulin.

It's fascinating.  I would love it if you share more details.

Co  


Dig Dis Sci. 2009 Jan 16.

Diabetes Mellitus Is Associated with Impaired Response to Antiviral Therapy in Chronic Hepatitis C Infection.

Elgouhari HM, Zein CO, Hanouneh I, Feldstein AE, Zein NN.
Avera Center for Liver Disease, Transplant Institute, Sanford School of Medicine, University of South Dakota, 1001 East 21st Street, Suite 303, Sioux Falls, 57105, South Dakota, USA

Insulin resistance may promote hepatic fibrosis in chronic hepatitis C (HCV) and has emerged as a cofactor in failure to achieve sustained viral response (SVR). Aims (1) To assess the association of diabetes mellitus (DM) in HCV patients to the severity of hepatic fibrosis and to the response to antiviral treatment. (2) To assess the safety of pegylated interferon and ribavirin combination therapy (Peg IFN/RBV) in diabetic HCV patients. Methods HCV diabetics (n = 61) were identified. A 2:1 matching control group was used to identify independent factors of advanced fibrosis and treatment failure. Results Compared to HCV non-diabetics, HCV diabetics were more likely to have steatosis (P < 0.0001) and advanced fibrosis (P = 0.003). Patients' age, Caucasian ethnicity, obesity, and histologic activity index were independently associated with advanced fibrosis (P < 0.05). Only 23% of HCV diabetics achieved SVR compared to 46% of HCV non-diabetics (P = 0.003). DM, genotype 1, high baseline viral load, and African-American ethnicity were independently associated with less SVR (P < 0.05). Significant adverse events were more common in HCV diabetics compared to HCV non-diabetics (P = 0.001). Side effects did not increase in patients receiving PEG IFN/RBV and insulin sensitizers. Conclusion DM was associated with impaired virologic response to PEG IFN/RBV in HCV patients. Adverse events during therapy were more frequent in diabetic compared to non-diabetic HCV patients.

http://www.ncbi.nlm.nih.gov/pubmed/19148751?ordinalpos=19&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

[CoWriter]

I'll share the full text with you as soon as I can secure it without having to pay for it.  Call me Scrooge...LOL

Co

[jmjm530]

Call me Scrooge...LOL
--------------------------------
Do I know you from somewhere? Your name sounds familiar, but what is this thing called "Insulin Resistance", never heard of it :)

[CoWriter]

"Do I know you from somewhere? Your name sounds familiar, but what is this thing called "Insulin Resistance", never heard of it :) "
-----------------
I'm starting to think you like the sound of my voice...LOL.  No problem.  I'll explain it to you again ; )


Here's a great article......yes Sir...full text....

Co
P.S.  To Mark60...let me know if there are questions I can answer for you.


Annals of Hepatology 2009
Insulin Resistance & Steatosis in Chronic Hepatitis C.

Abstract
In chronic hepatitis C, insulin resistance (IR) and type 2 diabetes mellitus (DM) are more prevalent than in healthy controls or in chronic hepatitis B patients.  HCV infection promotes IR mainly through increased TNF-α and cytokine suppressor (SOCS-3) production.  Both events inhibit insulin receptor and IRS-1 (insulin receptor substrate) tyrosine phosphorylation. Hepatic steatosis is also 2.5 fold more frequent in hepatitis C virus (HCV) infected patients as compared to the general population. Metabolic factors play a crucial role in the etiology of hepatic steatosis genotype non-3 related, which are also the genotypes with a greater association to IR. However, genotype 3, and particularly 3a, has a greater direct steatogenic capacity, and consequently, in those patients, the association with metabolic factors is weaker. Instead, in genotype 3, steatosis associates with viral factors like viral load. Those metabolic factors influence not only the natural history of HCV infection, as well as associate to an accelerated hepatic fibrosis progression, to a worse prognosis when hepatic cirrhosis is present, namely an increased risk of hepatocellular carcinoma, and to a lower sustained viral response rate. On the other hand, in patients who achieve viral eradication, IR and hepatic steatosis may regress, and return if viral infection recurs, which once
again indicates an intrinsic steatosis and IR promoter action by HCV.


For the full text (9 pages) see...

http://www.medigraphic.com/pdfs/hepato/ah-2009/ahs091k.pdf

[jmjm530]

Thanks for the full-text.

At the bottom of this post is "Treatment implications" section excerpted from the article.. The advice (see last paragraph) still appears to be weight loss and diet as a first line strategy to improve treatment outcomes. As to IR sensitive agents, it reads " however medication with insulin sensitizer agents in this context still do not have an evidence based fundament"

To be fair this has to be put in the context of perhaps even more recent studies, but as "Willing" pointed out in an older thread, the newer data may not yet be clear cut.

Here, for example, a good case is made for the IR sensitizer agents such as Metformin, which showed improved SVR rates but especially in the subset of "heavier weight women". Again, the question might be asked should these women have at least attempted  a program of diet and exercise instead.
http://www.hivandhepatitis.com/2008icr/aasld/docs/112108_a.html

And here's another recent article where the insulin-sensittizing agent, Pioglitazone (Actos) did Not Improve Response to Re-treatment with Pegylated Interferon plus Ribavirin. http://www.hivandhepatitis.com/hep_c/news/2008/082908_a.html

Also of interest is the difference types of steatotis for genotypes 3 (viral induced) as opposed to 1, 2 and 4 (primarily metabolic reduced), a topic covered more in depth in the body of the study.

From the full-text study:

"Treatment implications

Obesity and steatosis decrease anti-viral treatment response.
40,54,118-122 However, that negative influence seems
to be limited to metabolic steatosis and not to viral one,
since genotype 3 associated steatosis does not seem to
change the response to anti-viral treatment.40 Patients
with BMI higher than 30 kg/m2 have a 4 fold lower
chance of sustained viral response.118 A pilot study
showed that weight loss, even if mild, associates to an
improvement not only in steatosis, but also in fibrosis, in
patients with chronic hepatitis C, after as little as 3
months.123,124
There are 3 mechanisms which may explain why obesity
compromises anti-viral treatment response. First,
obesity may interfere with interferon bio-availability. In
fact, subcutaneous administration of pegylated interferon
in obese patients may decrease its absorption as a consequence
of defective subcutaneous lymph drainage, leading
to lower plasma levels.125
Another proposed mechanism is obesity as a pro-inflammatory
state126 with a negative influence in immune
response to therapy. Several adipokines may have a major
role in that immune deregulation. Leptine is an adipocyte
secreted cytokine that is increased in obesity.
However, in obesity, despite there is hyperleptinemia,
there is also resistance to leptin actions.127 Leptine has a
pro-inflammatory action promoting Th1 immune response,
which is believed to be essential in achieving a
sustained response to interferon. Therefore, leptin resistance
may have a negative influence in anti-viral treatment.
128 Another important cytokine is adiponectin,
which has an anti-inflammatory activity antagonizing
TNF-α,129 being decreased in obesity and HCV infection.
130,131 On the contrary, TNF-α not only has a pro-inflammatory
activity, as directly promotes IR, and inversely
correlates to anti-viral treatment response.132
MV Machado et al. Insulin resistance and steatosis in chronic hepatitis C S71
www.medigraphic.com
Lastly, obesity promotes IR, which is known to associate
to a negative influence in anti-viral treatment response.
133-135 In fact, Romero-Gómez et al. showed 33%
sustained viral response rate in genotype 1 in patients
with IR, as opposed to 66% in patients without IR.136
Also, Poustchi et al. found a 6.5 times lower sustained viral
response in patients with IR.135 The association between
IR and no response to anti-viral treatment may be a
due to a SOCS-3 activation, which not only promotes IR,
but also inhibits STAT-1 (signal transducer and activator
of transcription).137 After α interferon binds to its receptor,
it activates tyrosine kinases that phosphorylate
STAT-1, promoting its migration to the nucleus, where it
regulates several anti-viral genes transcription. SOCS-3
protein inhibits that tyrosine phosphorylation, thus inhibiting
α interferon action.138
We still do not know whether treating IR actually
translates in a better response to α interferon. At the moment,
patients should be advised to change to healthier
life styles that promote less IR, as weight loss and physical
exercise; however medication with insulin sensitizer
agents in this context still do not have an evidence based
fundament,139 although a small retrospective study suggests
that a better glycemic control may improve survival
in these patients.140 However, a pilot study in previously
non responders to standard anti-viral therapy with IR,
showed no benefit of a triple therapy with pioglitazone"

###

[portann]

Jim makes a crucial point. The study itself shows that relying exclusively on Metformin is a second-best tactic. The real strategy requires us to deal head-on with the need for better nutrition and more exercise.

[CoWriter]

You know what I'm concerned about Jim?  Some people are trying to reduce their HOMA with exercise and diet and have done great.  Their weight, total cholesterol, LDH, triglycerides and blood pressure are down...but not the HOMA.  Blood sugar and insulin have remainedc exactly the same as 3 months ago.

And get this....either with or without Metformin (some needed the Metformin because their blood sugar was high).

Co

[portann]

In terms of the posted study, this is the conclusion:

"We still do not know whether treating IR actually
translates in a better response to α interferon. At the moment,
patients should be advised to change to healthier
life styles that promote less IR, as weight loss and physical
exercise; however medication with insulin sensitizer
agents in this context still do not have an evidence based
fundament,139 although a small retrospective study suggests
that a better glycemic control may improve survival
in these patients."

Based on the study provided, the conclusion speaks for itself. Perhaps we need further studies to conclude otherwise. Until then, "we still do not know whether treating IR actually translates in a better response to α interferon".