diabetes FAQ: research (part 5 of 5)
Edward Reid
Posting-Frequency: biweekly
Last-modified: 14 July 2005
Changes: see part 1 of the FAQ for a list of changes to all parts.
------------------------------
Subject: READ THIS FIRST
Copyright 1993-2005 by Edward Reid. Re-use beyond the fair use provisions
of copyright law and convention requires the author's permission.
Advice given in m.h.d is *never* medical advice. That includes this FAQ.
Never substitute advice from the net for a physician's care. Diabetes is a
critical health topic and you should always consult your physician or
personally understand the ramifications before taking any therapeutic action
based on advice found here or elsewhere on the net.
------------------------------
Subject: Table of Contents
INTRODUCTION (found in all parts)
READ THIS FIRST
Table of Contents
GENERAL (found in part 1)
Where's the FAQ?
What's this newsgroup like?
Abuse of the newsgroup
The newsgroup charter
Newsgroup posting guidelines
What is glucose? What does "bG" mean?
What are mmol/L? How do I convert between mmol/L and mg/dl?
What is c-peptide? What do c-peptide levels mean?
What's type 1 and type 2 diabetes?
Is it OK to discuss diabetes insipidus here? What is it?
How about discussing hypoglycemia?
Helping with the diagnosis (DM or hypoglycemia) and waiting
Exercise and insulin
BLOOD GLUCOSE MONITORING (found in part 2)
How accurate is my meter?
Ouch! The cost of blood glucose measurement strips hurts my wallet!
What do meters cost?
Comparing blood glucose meters
How can I download data from my meter?
I've heard of a non-invasive bG meter -- the Dream Beam?
What's HbA1c and what's it mean?
Why is interpreting HbA1c values tricky?
Who determined the HbA1c reaction rates and the consequences?
HbA1c by mail
Why is my morning bg high? What are dawn phenomenon, rebound,
and Somogyi effect?
TREATMENT (found in part 3)
My diabetic father isn't taking care of himself. What can I do?
Managing adolescence, including the adult forms
So-and-so eats sugar! Isn't that poison for diabetics?
Insulin nomenclature
What is Humalog / LysPro / lispro / ultrafast insulin?
Travelling with insulin
Injectors: Syringe and lancet reuse and disposal
Injectors: Pens
Injectors: Jets
Insulin pumps
Type 1 cures -- beta cell implants
Type 1 cures -- pancreas transplants
Type 2 cures -- barely a dream
What's a glycemic index? How can I get a GI table for foods?
Should I take a chromium supplement?
I beat my wife! (and other aspects of hypoglycemia) (not yet written)
Does falling blood glucose feel like hypoglycemia?
Alcohol and diabetes
Necrobiosis lipoidica diabeticorum
Has anybody heard of frozen shoulder (adhesive capsulitis)?
Gastroparesis
Extreme insulin resistance
What is pycnogenol? Where and how is it sold?
What claims do the sales pitches make for pycnogenol?
What's the real published scientific knowledge about pycnogenol?
How reliable is the literature cited by the pycnogenol ads?
What's the bottom line on pycnogenol?
Pycnogenol references
SOURCES (found in part 4)
Online resources: diabetes-related newsgroups
Online resources: diabetes-related mailing lists
Online resources: commercial services
Online resources: FTP
Online resources: World Wide Web
Online resources: other
Where can I mail order XYZ?
How can I contact the American Diabetes Association (ADA) ?
How can I contact the Juvenile Diabetes Foundation (JDF) ?
How can I contact the British Diabetic Association (BDA) ?
How can I contact the Canadian Diabetes Association (CDA) ?
What about diabetes organizations outside North America?
How can I contact the United Network for Organ Sharing (UNOS)?
Could you recommend some good reading?
Could you recommend some good magazines?
RESEARCH (found in part 5)
What is the DCCT? What are the results?
More details about the DCCT
DCCT philosophy: what did it really show?
Is aspartame dangerous?
IN CLOSING (found in all parts)
Who did this?
------------------------------
Subject: What is the DCCT? What are the results?
The Diabetes Control and Complications Trial was a large multi-center
trial involving over 1400 volunteer patients with type 1 diabetes. It
began in 1983, ramped up to full speed by 1989, and ended early in 1993
when the investigators felt the results were clear. The volunteers were
all undergoing "standard" treatment when they were recruited, meaning
one or two injections per day. They were randomly assigned to two
groups. One group continued as before. The other group received
intensive treatment aimed at achieving blood glucose (bG) profiles as
close as possible to normal. The intensive treatment involved multiple
bG checks per day, multiple injections and/or an insulin pump, and
access to and regular consultation with a team of treatment experts.
It is particularly important to note that intensive treatment was
defined as a collaborative effort involving the patient and a skilled
team of health care professionals. It was not defined by particular
techniques, although certain techniques were typically used. The
frequent consultations and availability of a professional team were
critical components of intensive therapy.
The results show that the intensive treatment group did indeed achieve
bG levels closer to normal, and that they experienced far fewer
diabetic complications though also more hypoglycemia. In particular,
patients who maintained HbA1c levels around 7% appear to be much better
off than those whose HbA1c hovers around 9%. (See caveats in the
section on HbA1c.) Though it is not possible to separate the effects of
all the aspects of the intensive treatment, it is reasonable to believe
that lowering average bG may be effective even in isolation from the
other aspects of the intensive treatment. In its position statement,
the ADA says
Patients should aim for the best level of glucose control they can
achieve without placing themselves at undue risk for hypoglycemia or
other hazards associated with tight control.
Though type 2 patients were not included in the study, it is generally
believed that the results showing the benefits of tight control apply
to type 2 patients as well.
The entire position statement was published in most of the ADA's
publications (see "could you recommend some good reading") in the
summer and fall of 1993.
The formal report detailing the results was published in The New England
Journal of Medicine, aka NEJM, of September 30,1993 (v 329 pp 977-986).
The following discussion is based on that article.
Several DCCT subjects participate in m.h.d and are willing to answer
questions related to the personal aspects of DCCT participation.
------------------------------
Subject: More details about the DCCT
The study placed subjects into two cohorts, primary prevention or
secondary intervention, depending on duration of diabetes and existing
complications -- the primary prevention cohort were those with
essentially no complications.
Specifically: all subjects met these criteria:
Insulin dependent as evidenced by deficient C-peptide secretion
Age 13 to 39 years at entry to the study
No hypertension, hypercholesterolemia, severe diabetic complications,
or other severe medical conditions
Meet the criteria for one of the cohorts
and were separated into the two cohorts by these criteria:
Primary Secondary
Prevention Intervention
Cohort Cohort
Duration of IDDM 1-5 yrs 1-15 yrs
Retinopathy none detectable very mild to moderate
nonproliferative
Urinary albumin < 40 mg / 24 hr < 200 mg / 24 hr
Within each cohort, the subjects were randomly assigned to either
conventional therapy or intensive therapy. Thus the study compared
intensive to conventional therapy in two different cohorts. The two
questions the study was mainly designed to answer were
1) Will intensive therapy prevent the development of diabetic
retinopathy in patients with no retinopathy (primary
prevention), and
2) Will intensive therapy affect the progression of early
retinopathy (secondary intervention)?
Conventional therapy included one or two injections per day, daily self
monitoring of blood or urine glucose, education, quarterly
consultations, and intensive therapy during pregnancy. Intensive
therapy included three or more daily injections or an insulin pump, bG
monitoring at least 4x/day, adjustment of insulin dosage for bG level
and food and exercise, monthly personal consultations and more frequent
phone consultations.
To simplify a lot, the DCCT showed the following changes in the
intensive therapy groups compared to the conventional therapy groups.
Note that '-' shows a decrease, '+' shows an increase, in the number of
patients affected. Patients were judged as affected or not based on
binary criteria, so the results only say how many subjects were
affected, not how severely those subjects were affected.
Intensive therapy compared to conventional therapy:
Primary Secondary
Complication Prevention Combined Intervention
------------ ---------- -------- ------------
Retinopathy(*) - 75% - 55%
Nephropathy(*) - 35% - 45%
Neuropathy(*) - 70% - 55%
Hypoglycemia(*) +200%
Weight gain(*) + 33%
Hypercholesterolemia(*) - 35%
(*) This brief table begs many questions about what exactly was
measured and how. For more details, read the paper.
There were no detectable differences on several measures:
Macrovascular disease
Mortality
Changes in neuropsychological function
(a feared result of severe hypoglycemia)
Quality of life (based on a questionnaire)
Some limitations of the study: type 1 only, patients young and with
short duration (under 15 years) of diabetes, and short duration of the
study (5-9 years). Measured only number of subjects affected according
to binary criteria, not by measurement of severity of complications.
Excluded patients who already had severe complications and who thus
might benefit the most. The difference between the groups increased
during the study, but there is no proof that the difference would
continue to increase with time.
It is tempting to extrapolate the results to all diabetic patients --
all types, ages, and durations -- and there is at least some support
for doing so. However, the DCCT by itself does not show results for
type 2 patients, older patients, patients who have had diabetes for
many years, or those who already have severe complications. On the
other hand, a different group of subjects might shows differences in
areas such as mortality and macrovascular disease, where the young DCCT
cohorts simply did not have significantly measurable incidence. The
DCCT subjects are being tracked in a followup study which may shed
light on some of the unanswered questions.
Secondary analysis of the data indicates that retinopathy decreases with
decreasing HbA1c. This measure was not part of the study design and is
more difficult to interpret, but still shows clearly a correlation
between HbA1c and retinopathy.
------------------------------
Subject: DCCT philosophy: what did it really show?
It is often stated that the DCCT proved that tight control or lowered
HbA1c reduces complications. This is not the case. The controlled
variable in the DCCT was intensive vs conventional therapy, and
intensive therapy was defined by several factors including a team of
skilled health care professionals acting in partnership with the
patient. The results show that intensive therapy results in both
lowered HbA1c and fewer complications, but do not show that one causes
the other. The lead authors provide a good summary of this point in a
followup (NEJM 330:642, March 3, 1994):
We want to stress that the most valid interpretation of the trial
is that intensive therapy, with the **goal** of achieving blood
glucose concentrations as close to the nondiabetic range as
possible, delays the onset and slows the progression of long-term
diabetic complications. The secondary analyses support the notion
that lower glycosylated hemoglobin values are associated with a
lower risk of progression of retinopathy, but they do not prove
that hyperglycemia in itself causes retinopathy. [emphasis added]
Many of us believe, and believed before the DCCT, that actually
achieving good control aids our health. The DCCT adds weight to this
case but does not prove the point.
------------------------------
Subject: Is aspartame dangerous?
In short, no, except for phenylketonurics.
Aspartame is one of the most intensively studied food additives ever,
and the overwhelming scientific evidence is that it poses no danger.
The many claims of harm are all either anecdotal and not supported by
adequate observation, or are based on serious lack of understanding of
how to demonstrate facts scientifically. One of the most egregious is
the claim that studies with aspartame in capsules are invalid and that
it's only dangerous in solution. But d'oh -- if you administer
aspartame in solution, the patient will know whether he/she is getting
aspartame or not. This unblinds the experiment. Refer to Reid's Third
Law: Never Underestimate the Power of Suggestion.
An good set of links to web pages on aspartame is at
http://urbanlegends.about.com/library/blasp3.htm. (Unfortunately the
links open framed by about.com's heading, an unfair practice eschewed
by the vast majority of web sites. Ten demerits for about.com.)
The well known low-calorie sweeteners are pretty much all safe:
cyclamates, saccharin, aspartame, acesulfame, sucralose. Yes, even
cyclamates and saccharin -- the studies which resulted in their banning
turned out to be non-reproducible. I don't list stevia because it has
not been adequately studied, but I know of no significant indications
of danger.
If you don't like a given sweetener, try another. If you think you
respond badly in some way to a sweetener, try another. But unless you
have at least a heterozygous gene for phenylketonuria, it's unlikely
that you'll have a verifiable response to aspartame.
------------------------------
Subject: Who did this?
--
Edward Reid <edw...@paleo.org>
Tallahassee FL
--
Art works by Melynda Reid: http://paleo.org
Edward Reid
Posting-Frequency: biweekly
Last-modified: 24 December 2005
------------------------------
Subject: READ THIS FIRST
------------------------------
Subject: Table of Contents
------------------------------
Subject: How accurate is my meter?
bG (blood glucose) meters are not as accurate as the readings you get from
them imply. For example, you might think that 108 means 108 mg/dl, not 107 or
109. But in fact all meters made for home use have at least a 10-15% error
under ideal conditions. Thus you should interpret "108" as "probably between
100 and 120". (Similar considerations apply if you measure in units of
mmol/L.) This is a random error and will not be consistent from one
determination to the next. You cannot expect to get exactly the same reading
from two checks done one after the other, nor from two meters using the same
blood sample.
This is generally considered acceptable because variations in this range will
not make a major difference in treatment decisions. For example, the
difference between 100 and 120 may make no difference in how you treat
yourself, or at most might make a difference of one unit of insulin. With
present technology, more accurate meters would be much more expensive. This
expense is only justified in research work, where such accuracy might detect
small trends which could go undetected with less accurate measurements.
This discussion applies to ideal conditions. The error may be increased by
poor or missing calibration, temperatures outside the intended range,
outdated strips, improper technique, poor timing, insufficient sample size,
contamination, and probably other factors. Contamination is especially
serious since it can happen so easily and is likely to result in an overdose
of insulin. Glucose is found in fruits, juices, sodas, and many other foods.
Even a smidgen can seriously alter a reading.
When comparing meter readings with lab results, also note that plasma readings
are 15% higher than whole blood, and that capillary blood gives different
readings from venous blood.
Visually read strips are slightly less accurate than meters, with an error
rate around 20-25%.
For some meters, strips are available from manufacturers other than the meter
manufacturer. Some m.h.d. readers have compared the strips side-by-side and
found those from one manufacturer to read consistently lower than the strips
from another. The differences are not likely to make a significant difference
in your treatment, but are large enough to be noticeable and possibly
confusing. For this reason it is not a good idea to change strip
manufacturers without comparing the readings from one with the readings from
the other.
I've seen no such direct comparison of meters, but the possibility exists that
some meters might read consistently lower than others. Be careful when
changing meters.
By "error rate" I mean twice the standard deviation from the mean. An error
rate of 15% says that about 95% of the readings will be within 15% of the
actual value.
------------------------------
Subject: Ouch! The cost of blood glucose measurement strips hurts my wallet!
The cost of blood glucose measurement strips is a complex interaction
of R&D costs, manufacturing costs, marketing strategy, insurance
practices, and undoubtedly other factors. You can ask on the net if you
want; you'll get lots of comments but no answers.
There are a few of ways of reducing the cost of blood glucose
monitoring.
One is to seek out the best price for the strips; large stores such as
FEDCO often have good prices, as do some mail order suppliers (see mail
order section).
A second way is to choose a meter with lower cost strips. Your health
care team may be familiar with and prefer a particular meter, but it's
not likely that they considered cost in making their choice. If you
insist that you need a lower cost system, they should be willing to
work with you. All meters now on the market are adequately accurate for
home use.
A third way is to use visually read strips (Chemstrip bG and a couple of
lesser known brands) and cut them in half or even in thirds. Do the
cutting carefully with a pair of strong, *clean* scissors, and get the
strips back into the vial as quickly as possible. Some manufacturers
claim this procedure will cause problems, but those who have used the
technique report that it works well. Visually read strips are slightly
less accurate than meters. However, as of 1998, prices on visually read
strips are relatively high, and you will have to consider whether the
projected savings are worth the time to cut strips and the loss of the
convenience which meters give.
Do *not* cut strips when using them in meters. The results will be
totally incorrect.
Most discussion on m.h.d of the cost of blood glucose measurement strips
has centered on the US. I'm not sure why, though a good guess is that
differences in health care systems and national policies make this
issue more critical to the individual patient in the US. There is no
dearth of non-US participants on m.h.d.
------------------------------
Subject: What do meters cost?
The flip side of expensive blood glucose measurement strips is that
the manufacturers virtually (and sometimes literally) give away the
meters to hook you on their strips. Don't pay full price for a
meter; look for discounts, rebates, and giveaways. For example, as
of this writing I'm looking at a catalog that shows a Glucometer 3
for US$45, with a US$30 manufacturer's rebate *and* a US$30 trade-in
allowance if you already have a competing meter -- which means you
make US$15. There are similar deals on other meters.
But make sure you consider the cost of strips as well as the cost of
meters, and find out which your insurance will pay for. The most
fully featured meters, such as the One Touch II, don't have such
widely advertised deals, though you can probably find ways of
getting them at discount.
If you have insurance that pays for strips but not for the meter,
you should not have to pay anything for the meter. If it's worth the
time to you, call the meter manufacturers' customer service
departments or the mail order outfits (see "Where can I mail order
XYZ?" in part 4, Sources). They will find a way to get you the meter
for free.
As with strips, this discussion of costs applies to the US, and
there has been little discussion of meter costs outside the US on
m.h.d., probably because fewer tradeoffs are available in most
countries.
An Australian correspondent notes a much narrower choice and higher
cost of meters there, but subsidized (pardon, subsidised)
measurement strips.
In Britain, strips are covered by the National Health Service, but
meters may be expensive. However I've also heard of a limited-time
One Touch program providing a full refund for the meter if you
submit the strip wrappers. Likely other companies will compete.
Elsewhere? Please post. It's likely that the situation is continuing
to change rapidly, so if the cost of the meter is painful for you,
investigate other options before paying full price -- wherever you
live.
------------------------------
Subject: Comparing blood glucose meters
Here are three ways of getting a list of the specs for most currently
available meters.
1) Call Hospital Center Pharmacy in Boston, 1-800-824-2401 (US only).
They have a chart which they will gladly send you.
2) The ADA publishes a Buyer's Guide to Diabetes Products once a
year in the Resource Guide, a supplement to the January isue of
Diabetes Forecast. As of January 2000, the latest is the Resource
Guide 2000. The meters section lists meters and features in a table.
The ADA does not recommend one meter over another, but does include
some tips on choosing a meter.
3) The ADA has this same Buyer's Guide information online at
http://diabetes.org/diabetesforecast/2000BuyersGuide/default.asp
This URL will change in future years.
The caveat is that you must be patient. The table is a huge scanned
graphic rather than text. It will take about ten minutes to download
all the graphics on the page on a good 28.8 modem connection, and
possibly much longer.
------------------------------
Subject: How can I download data from my meter?
You can get a cable to hook the One Touch II and Profile meters to a PC
from the meter manufacturer, LifeScan. The cable includes some
electronics, not just a cable, so you probably don't want to make your
own -- but if you do, check out the schematics at either of these
sites:
http://www.sci.fi/~keytech/otcable.html
http://www.geocities.com/SiliconValley/Haven/5371/indexe.html
In the US the cable is free (or nearly so -- some mhd readers report
being quoted a small fee). Elsewhere, LifeScan lets each international
office set its own policy on cable distribution, and some are charging
substantial fees. North American telephone numbers are:
U.S.A. 1-800-227-8862
+1 408 263 9789
Canada 1-800-663-5521
LifeScan provides some software for downloading the data. The more
recent versions provide considerable additional analysis.
A wide variety of other software is available as of 1998. I can't keep
up with it. See Rick Mendosa's companion posting on software.
Most meter makers now offer some software to be used with their meters.
Third party software is more abundant for the One Touch meters because
LifeScan, unlike other makers, publishes the download protocol. You can
ask them to send you a copy of the specs, or download it from
One Touch II: ftp://vic.cc.purdue.edu/pub/lifescan.ot2
One Touch Profile: ftp://vic.cc.purdue.edu/pub/lifescan.pro
Since these are simple tty-oriented protocols, you can download the raw
data from your meter using a basic telecom program such as Kermit or
ZTerm.
I'll mention just one piece of software here. Vic Abell
<abe(AT)purdue.edu> has long provided a simple free DOS program to
download and analyze One Touch II and Profile data. Vic posts update
announcements to misc.health.diabetes and has been known to support his
program via the newsgroup. TOUCH2 interfaces to the RS-232 data port of
the One Touch, downloads the data on command, and provides a variety of
analytical displays. It's available in a couple of compressed forms via
anonymous ftp from vic.cc.purdue.edu in the /pub directory, or using a
web browser,
------------------------------
Subject: I've heard of a non-invasive bG meter -- the Dream Beam?
***The following information is incomplete, as another company has introduced
a non-invasive meter for about $8000. It has been discussed in the
newsgroup. Rumors of other non-invasive (and "non-evasive") meters abound.
I won't be trying to keep this section up to date until the situation
stabilizes. ***
There is at least one development project in hot pursuit of a bG monitor
which operates by shining light through flesh (through the thumbnail in one
case) and analyzing the light that passes through. Glucose doesn't affect
light much differently from many other substances in the body, so this is not
an easy task. Some field trials have been done, but the developers have a way
to go to reach acceptable accuracy. A successful product is far from
guaranteed, and may be several years away if it arrives at all.
One estimate is that such a meter might cost about US$1000. Assuming the
per-check cost is zero, this would pay for itself in 1-2 years for many
patients. Look for the insurance companies to throw up some roadblock to
achieving these savings, at least in the US.
------------------------------
Subject: What's HbA1c and what's it mean?
Hb = hemoglobin, the compound in the red blood cells that transports
oxygen. Hemoglobin occurs in several variants; the one which composes
about 90% of the total is known as hemoglobin A. A1c is a specific
subtype of hemoglobin A. The 1 is actually a subscript to the A, and
the c is a subscript to the 1. "Hemoglobin" is also spelled
"haemoglobin", depending on your geographic allegiance.
Glucose binds slowly to hemoglobin A, forming the A1c subtype. The
reverse reaction, or decomposition, proceeds relatively slowly, so any
buildup persists for roughly 4 weeks. Because of the reverse reaction,
the actual HbA1c level is strongly weighted toward the present. Some of
the HbA1c is also removed when erythrocytes (red blood cells) are
recycled after their normal lifetime of about 90-120 days. These
factors combine so that the HbA1c level represents the average bG level
of approximately the past 4 weeks, strongly weighted toward the most
recent 2 weeks. It is almost entirely insensitive to bG levels more
than 4 weeks previous.
In non-diabetic persons, the formation, decomposition and destruction of
HbA1c reach a steady state with about 3.0% to 6.5% of the hemoglobin
being the A1c subtype. Most diabetic individuals have a higher average
bG level than non-diabetics, resulting in a higher HbA1c level. The
actual HbA1c level can be used as an indicator of the average recent bG
level. This in turn indicates the possible level of glycation damage to
tissues, and thus of diabetic complications, if continued for years.
Interpreting HbA1c values can be tricky for several reasons. See the
following section for more details.
------------------------------
Subject: Why is interpreting HbA1c values tricky?
Interpreting HbA1c values is tricky for several reasons: differing lab
measurements, variation among individuals, and misapprehension of the
relevant timeframe.
First trick: several different lab measurements have been introduced
since 1980, measuring slightly different subtypes with different limits
for normal values and thus different interpretive scales.
A National Glycohemoglobin Standardization Program began in 1996,
sponsored by the American Diabetes Association and others. See
reference 1. This program certifies HbA1c assays which conform to the
method used in the DCCT. However, as of 1998 other versions are still
in use in many places, both in the US and elsewhere. When you get a lab
result, be sure to look at what the lab considers to be the normal
range. Most discussion of HbA1c values in m.h.d appears to be based on
the DCCT, where the normal range is approximately 3.0-6.1%. Caveat
lector. (See part 5, Research, of this FAQ for more information on the
DCCT, the Diabetes Control and Complications Trial.)
Second trick: HbA1c levels appear to vary by up to 1.0% among
individuals with the same average bG. See reference 2.
This is very recent research and its implications are not yet clear. The
actual reaction rates governing the formation of HbA1c may vary among
individuals. Some of the variation may be due to differences in
erythrocyte (red blood cell) survival times -- the rough 90-120 day
range noted earlier -- although other work limits this to a small part
of the total variation (see reference 5). Variations in the HbA1c
formation rate may or may not correlate with the rate of damage to
other tissues.
While we await further research, we can only say that differences of
1.0% from one individual to another may not be meaningful.
Although HbA1c varies among individuals with the same average bG, it is
very stable for any given individual. Thus a change of 1.0% in your own
HbA1c is definitely meaningful.
Third and final trick: most medical professionals have been given
incorrect information about the timeframe which HbA1c represents.
Even textbooks normally state the 90-120 day average, as does the
American Diabetes Association in its Position Statement on Tests of
Glycemia in Diabetes (see reference 1).
The longer estimate is based on the assumption that the conversion of
hemoglobin A to HbA1c is essentially irreversible. This was a
reasonable assumption before the reaction rates were actually measured.
See the following section for information about the research which
measured the reaction rates and simulated the consequences.
See the following section for the references mentioned above.
------------------------------
Subject: Who determined the HbA1c reaction rates and the consequences?
In the early 1980s, Henrik Mortensen and colleagues at Glostrup
University Hospital, in Denmark, measured the reaction rates in vitro.
Their results showed the assumption of irreversibility to be untrue. In
fact the reverse reaction (HbA1c to HbA and glucose) proceeds at about
1/8 the rate of the forward reaction, which is very far from
irreversible. Mortensen et alia also built a biokinetic model based on
the measurements, and validated the model by comparing its predictions
to actual patients. See references 3-5.
Among other things, Mortensen's work shows that after a change in
average bG level, the HbA1c level restabilizes after about 4 weeks.
This has several consequences. Clinically, the most important are
these:
First, the HbA1c is an exponentially weighted average of blood glucose
levels from the preceding 4 weeks, with the most recent 2 weeks being
by far the most important.
Second, measuring HbA1c less often than monthly results in unmonitored
gaps between measurements. To use HbA1c as a continuous monitoring
tool, you need to check it at least once a month.
Third, it is worthwhile checking the HbA1c of newly diagnosed patients
as often as once a week to determine the effectiveness of the newly
imposed treatment.
Reference 1: American Diabetes Association, Tests of Glycemia in
Diabetes, Diabetes Care 23:S80-S82, January 2000 Supplement 1.
This specific issue is no longer available online, but the most recent
version is available at http://diabetes.org/cpr/.
Reference 2: Kilpatrick ES, Maylor PW, Keevil BG: Biological Variation
of Glycated Hemoglobin. Diabetes Care 21:261-264, February 1998.
Abstract available on the web at
http://care.diabetesjournals.org/cgi/content/abstract/21/2/261.
Reference 3: Mortensen HB, Christophersen C: Glucosylation of human
haemoglobin a in red blood cells studied in vitro. Kinetics of the
formation and dissociation of haemoglobin A1c. Clinica Chimica Acta
134:317-326, 15 November 1983.
Reference 4: Mortensen HB, Volund A, Christophersen C: Glucosylation of
human haemoglobin A. Dynamic variation in HbA1c described by a
biokinetic model. Clinica Chimica Acta 136:75-81, 16 January 1984.
Reference 5: Mortensen HB, Volund A: Application of a biokinetic model
for prediction and assessment of glycated haemoglobins in diabetic
patients. Scandinavian Journal of Clinical and Laboratory Investigation
48:595-602, October 1988.
------------------------------
Subject: HbA1c by mail
You may find it cheaper and/or more convenient to have your HbA1c
measurements done by mail -- and you collect the sample by fingerstick.
Diabetes Technologies provides a "Accu-Base A1c (tm) Glycohemoglobin
Testing System". The cost is $19.95 per kit plus S/H (I think it's $3.85
per order), which includes the laboratory analysis. All needed supplies
are provided, including postage to the lab. They normally ask for a
doctor's prescription before sending the kit -- not because it's
required but because they want to make sure to keep the doctors in the
loop. Unhappy doctors are not good for their business.
The procedure is simple: they provide a capillary tube already attached
to a clip. Stick your finger (using a one-use lancet they provide, if
you wish) and touch the end of the tube to the drop until the tube is
full -- a fraction of a second to a few seconds. Drop the tube into a
small vial with fluid in it (pre-filled) and shake for a few seconds.
Fill out a little paperwork. Pack the vial in a Biopack, padding and
package, all provided and even prestamped. Drop it in the mail. You
provide: writing pen, blood, tissue for the excess blood.
The lab analyzes the sample using HPLC (high performance liquid
chromotography). This is the same as the major labs use. In other words,
SmithKline takes an entire vial of blood and uses one drop.
Diabetes Technologies is in Thomasville, GA. Their phone number is
888-872-2443.
Express-Med used to make a kit which I used once, but they no longer
sell it.
Becton-Dickinson (BD) was advertising a HbA1c kit in 1998. However, the
last time I spoke with someone there, they were only distributing it
through health care organizations (such as HMOs) and plans for
individual sales were indefinite.
A personal note: I have used the Diabetes Technologies kit, and a
predecessor supplied by Diabetes Support Systems, since 1996. Without
this service, I probably would have had at most one HbA1c measurement
per year due to the cost and the inconvenience of visiting the lab or
doctor's office -- and I really needed the tests at times. I plan to
continue using the service.
(As of the start of 2003 there are some other options. I need to update
this section.)
------------------------------
Subject: Why is my morning bg high? What are dawn phenomenon, rebound,
and Somogyi effect?
This section is written by Charles Coughran <ccoughran(AT)ucsd.edu>.
There are three main causes of high morning fasting bg. In decreasing order of
probability they are insufficient insulin, dawn phenomenon, and Somogyi
effect (aka rebound). Insufficient or waning insulin is simple. If the
effective duration of intermediate or long acting insulin ends sometime
during the night, the relative level of circulating insulin will be too low,
and your blood sugars will rise.
Dawn phenomenon refers to increased glucose production and insulin resistance
brought on by the release of counterregulatory hormones in the early morning
hours near waking. It happens in normal people as well as in diabetics; in
nondiabetics it shows up as measurably increased insulin secretion around
dawn. Dawn phenomenon is variable in strength both within the population and
over time in individuals. It can show up as either high fasting glucose
levels or an increased insulin requirement to cover breakfast compared to
equivalent meals at other times of day.
Somogyi effect refers to a rebound in bg after nocturnal hypoglycemia which
occurs during sleep with the patient not experiencing any symptoms. The
hypoglycemia triggers the release of counterregulatory hormones. Somogyi
effect appears to be less prevalent than previously thought. While it does
occur, some episodes of hyperglycemia following hypoglycemia are actually
waning insulin levels following an insulin peak with medium acting insulin.
This can be difficult to sort out.
The best way to sort it out is to test every couple of hours from bedtime to
morning.
If your bg rises all, or much of the night, it is a lack of circulating
insulin.
If it is stable all night, but rises sharply sometime before you wake in
the morning, it is dawn phenomenon.
If your bg declines to the point of a hypoglycemic reaction, it is
*possibly* Somogyi effect.
You may have to test on several nights to nail the problem. Once you have
figured out the problem you and your doctor can discuss changes in your
insulin regimen to correct it. The answer depends critically on your
particular circumstances.
Mayer Davidson, in _Diabetes Mellitus: Diagnosis and Treatment_ (p 252 in the
3rd edition) says that Somogyi effect rarely causes fasting hyperglycemia,
and cites studies.