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[IPm] Re: Humalog Sensitivity -- Problem, Solutions

Dear Michael:

The explanations that you have been given are very improbable.

Although I am not privy to all of the physico-chemical data regarding
lispro insulin, insulin loss can occur by one of three mechanisms.

The first is by adhesion.  Peptides, like insulin, strongly adhere to
plastics, such as the walls of your infusion lines.  The addition of a
small amount of another protein can protect the insulin by competitively
coating the plastic's surface.  However, I am aware of nothing that would
make it likely that regular insulin (including Velosin, its buffered
version) would adhere in preference to lispro.  Furthermore, the adhesion
is so avid that coating of the plastic is probably essentially complete by
the time that you have finished priming your line.  Thus, adhesion is an
extremely unlikely explanation for the need to change lines early.

The second mechanism is degradation.  Insulin can be degraded by a variety
of peptidases, but it is difficult to imagine how they would be introduced
into your lines, or what effect regular insulin would have to spare lispro.
 Denaturation is another form of degradation.  The most familiar type of
denaturation is cooking with heat.  Beating an egg-white causes ovalbumin
to become denatured at the air-"white" interfaces of myriads of bubbles
(This is the reason that insulin should NEVER be shaken--not the mythical
lethality of an injected bubble!).  Other common causes of denaturation
include ultraviolet light (to which lispro is susceptible), oxidation and
other chemical changes, and freezing.  I am aware of nothing that would
allow regular insulin to protect lispro insulin against denaturation
(except the trivial drop in the solution's freezing point!).

The other mechanism is precipitation, including crystallization.  Guess
what!  The cloudy stuff that everyone occasionally sees in his line is
crystalline insulin.  Note that this has NOTHING to do with the monomers
(single insulin molecules) of lispro, which remain soluble, or with better
"stability" of mixed dimers (pairs of insulin molecules) than of pure
dimers (which are less likely to disassociate into monomers, and are, in
that sense, MORE stable).  Obviously, if insulin precipitates out in your
infusion line, you did not receive some of the insulin that you intended. 
Likewise, precipitant is a reservoir for unpredictable "boluses" of
particles containing large amounts of insulin.  To make matters worse, that
insulin's physico-chemical properties have been converted from immediate-
to delayed-action (It is the particles that make insulins such as NPH,
ultralente, and a variety of now-obsolete insulins long-acting.  Glargine
is a soluable insulin, but it is designed to precipitate at the pH of
tissue fluids, making an ultra-long-acting insulin.).  In addition to the
benefits of a simultaneous site change, changing your infusion line
"cleanses" your pump of an unpredictable reservoir of an NPH-like depot

What does this have to do with mixing lispro and regular insulins?  A
mixture of any two different chemicals has a greater solubility than a pure
solution of either one of them.  In addition, regular self-association
(crystalinization) is disrupted by impurities; regular insulin is an
impurity in a lispro crystal and vice versa.  Hence, a mixture of insulins
with two different conformations will be not only be more soluble, but any
precipitant that does occur will be less likely to form slowly dissolving

I invite your pharmacist contact, Sofia A. Iqbal, R.Ph., to respond to my

I have had limited experience with aspart (Novolog) insulin, and that has
mostly been in users of pumps.  From my experience so far, it appears that
aspart will be more stable in the infusion lines (as promised).  Anyone
using a pump who lives or works in a very hot environment or whose infusion
line is likely to become exposed to ultraviolet light will probably benefit
by changing to aspart, when it becomes generally available in two to three
weeks.  Anyone who must routinely change his infusion lines early should
consider it, rather than unpredictably degrading the pharmakokinetics of
his insulin by mixing lispro and regular.  Aspart insulin is seems likely
to become the new standard for insulin pumps.


M. Shank, M.D., Ph.D.
Diabetes and Metabolism Special1st Care (sm)
715 W. North St.
Lima, OH   45801
email @ redacted

Michael writes:

> Humalog Sensitivity -- Problem, Solutions
> There is substantial anecdotal evidence that something on the order of
> 5-6% of insulin pump users that use Humalog in their pumps experience
> premature infusion site failure, marked by rising blood sugar levels
> and increasing resistance to further administration of Humalog to the
> same site. The solution to this problem for many has been to mix a
> small amount of Velosulin or regular insulin with the Humalog. The
> most common mix is 5 parts Humalog and 1 part Velosulin or regular
> (Velosulin being the most common choice in the US). For current stats
> see:
> http:/www.insulin-pumpers.org/about.shtml#mix
> For some time I have been in communication with Novo Nordisk about
> their new insulin analog, Novolog. Recently I have received a "few"
> reports from first users of Novolog that previously were using an H/V
> mix because of the aforementioned problems indicating that the
> premature site loss problems do not appear to be present when they use
> Novolog in their pumps. This is not very conclusive and not at all
> scientific. There is some science behind this but the problem is still
> under investigation and this the description of the problem I received
> from the researcher. If you would like further information, contact me
> privately and I will provide you with a phone number and/or email as
> you choose. ------------- quote" ...What is going on in the tubing set
> is a very complicated interaction between lispro, the tubing and any
> human insulin you have put in the formulation.  To understand it
> thoroughly, you need to understand a lot about protein chemistry and
> protein-protein interactions.... I don't think (although I can not
> prove it) that the formulation that the human insulin is in makes a
> difference. ....what I can say is that the "site loss" is related to
> lispro chemistry and the presence of lispro monomer in the tubing.  I
> believe that the addition of Velosulin competes for lispro monomer and
> that the lispro-insulin heterodimer is more stable than the
> lispro-lispro dimer." --------------
> Last week I receive a communication from Novo indicating that they
> would make Novolog available under their compassionate use program for
> people with diabetes who are experiencing difficulty  with other
> insulins. The details follow. Hopefully this information will allow
> you to make a few more patient's lives a little more pleasant.
> Respectfully,
> Michael Robinton
> Executive Director
> Insulin Pumpers
> email @ redacted
> Tel: 650 947-3350
> Fax: 650 947-3356
> > Novo Nordisk compassionate use program
> >
> > NovoLog(tm) is expected to be commercially available sometime in
> > September or October.  In the meanwhile the medical department would
> > like to provide NovoLog(tm) as a treatment option in individuals who
> > are experiencing problems with other insulin products or who would
> > clinically benefit from NovoLog(tm).
> >
> > If you would like to obtain NovoLog(tm), I would recommend you send 
> > in the following material for consideration: 
> > 1.	a letter from your
> > treating physician on his/her letterhead stating your name and why
> > they feel that NovoLog(tm) would be of clinical benefit to you in 
> > your treatment. 
> > 2.	A prescription for NovoLog(tm) specifically 
> > stating how many vials you would need for a two month period.
> >
> > Please FAX the materials to my attention at 609-919-7713 and I will
> > have our endocrinologist review them.  We will let you know of the
> > results and the estimated shipping date if you are approved.
> >
> > If you need any additional information, please feel free to call me 
> > at 609-987-5872.
> >
> > Kind regards,
> > Sofia A. Iqbal, R.Ph.
> > Drug Information Scientist
> > 
> > Novo Nordisk Pharmaceuticals, Inc.
> > 100 College Road West
> > Princeton, NJ 08540
> > (609)987-5872
> > email @ redacted
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