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diabetes FAQ: treatment (part 3 of 5)
Section - Extreme insulin resistance

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Mayer Davidson writes several pages about insulin resistance in his
book _Diabetes Mellitus: Diagnosis and Treatment_. Except for what's in
[brackets], the following information is from pp 126-132 of the third
edition or pp 112-119 in the fourth edition. I'd recommend finding a
copy. Most university libraries will have it, even those without
medical schools. It's about $65; if necessary you can order from the
Rittenhouse Medical Bookstore in Philadelphia at 215-545-6072.

In this context, "insulin resistance" refers to patients requiring more
than the arbitrary amount of 200 units/day. Davidson uses the term
"insulin antagonism" for the phenomenon which is commonly part of type
2 diabetes.

Davidson cites ten major causes of insulin resistance. The first eight
are obvious major medical problems that you would immediately suspect
were related, so I won't bother listing those. Rarely, insulin is
destroyed at the subcutaneous injection site; this form can be treated
with normal amounts of insulin administered intravenously or

The most common form of insulin resistance is immune-mediated. Everyone
taking injected insulin develops IgG antibodies to insulin. In most,
the antibody levels are low. In about 1 in 1000, the levels are much
higher, from 5 to over 1000 times higher than usual. In Davidson's

     The reason for this markedly enhanced response and the
     subsequent decline to normal levels is completely unknown.

The antibodies bind to, and neutralize, the insulin.

At one time it was thought that the antibodies resulted from impurities
in the insulin preparations, and that using highly purified
preparations would avoid the problem. This has proven not to be the
case; purified insulin helps but usually does not resolve the problem,
[though it seems to be worth trying].

Also, switching to a different insulin does not help, as the antibodies
bind to beef, pork and human insulin. They may bind to one more than
the others, but the titers of antibody are so high as to neutralize
virtually all of any of the insulins.

Two treatments which are effective are not generally available in the

First, insulin can be treated with sulfuric acid. The modified molecule
retains some biological activity but has reduced affinity for binding
to the IgG antibodies to insulin. This treatment was tested by a
Canadian laboratory in the late 1960s but is available in the US only
by special petition to the FDA. Novo Nordisk Pharmaceutical can provide
information at 609-987-5800.

Second, fish insulin works in humans but does not bind to the
antibodies. Cod insulin, for example, differs from human insulin in 33
amino acid positions compared with 3 differences for beef insulin. But
nonmammalian insulins are not available in the US at all.

This leaves the two treatments that are actually used on a regular
basis, and a promising new treatment.

Because this condition is rare, there's been little experience treating
it with lispro insulin (Humalog). That experience is promising; it
appears that the structural change in lispro may inhibit the antibody
binding. If this is borne out by further experience, lispro will be the
treatment of choice for extreme insulin resistance.

Glucorticoids such as prednisone decrease the extreme insulin
resistance, possibly by inhibiting the production of IgG antibodies. As
the antibodies have a half life of 3-4 weeks, the response is delayed,
during which time bg control is even more difficult due to the effects
of the glucocorticoids. After several weeks the dosage can be reduced
to maintenance levels or eliminated, but relapse is common. Since
glucocorticoids have other nasty effects in addition to the problems
listed above, there are significant problems with this course of

Davidson's recommendation is based on The Good News: insulin resistance
is self-limited and only lasts a few months to a year. He simply uses
as much insulin as is needed in the meantime. U-500 concentration is
available for this purpose. The antibodies delay the action, so even
though U-500 is regular insulin it acts like a lente or semilente in
resistant patients. For unknown reasons, much less U-500 is needed than
the equivalent amount of U-100, 50% to 75% less. Since the situation is
difficult to manage and is temporary, Davidson advises not trying for
good bg control, but just avoiding ketosis and the overt symptoms of
hyperglycemia (thirst, excess urination, infections).

When insulin sensitivity returns, it can happen quite suddenly.
Davidson starts reducing the high insulin doses when fasting bg is
under 200 mg/dl (11.0 mmol/L). At these times, large amounts of insulin
previously bound to the antibodies may be released, so avoiding
hypoglycemia is a major concern. The return to normal sensitivity will
take at least several weeks due to the half-life of the antibodies, and
insulin requirements may fluctuate a great deal during this time. A
fast response to U-500 insulin (2-4 hours from injection to measurably
lower bg) may indicate the decline of insulin resistance.

[This was the movie. Now go read the book.]

User Contributions:

Raqiba Shihab
Report this comment as inappropriate
May 10, 2012 @ 2:14 pm
Many thanks. My husband has Type 2 diabetes and we were a bit concerned about his blood sugar/glucose levels because he was experiencing symptoms of hyperglyceamia. We used a glucometer which displays the reading mg/dl so in my need to know what the difference
between and mg/dl and mmol/l is, i came across your article and was so pleased to aquire a lot more info regarding blood glucose, how to read and convert it.
Report this comment as inappropriate
Aug 11, 2012 @ 9:09 am
It was really informative and useful for people who don't know conversion. Thanks to you

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Top Document: diabetes FAQ: treatment (part 3 of 5)
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