15
Oral Insulin-Sensitizing Agents, Insulin-Mimetic Agents, and Amylin
Analog
If diet and exercise are not adequate to bring your blood sugars under
control, the next level of treatment to consider is oral blood sugar–lowering
medication, commonly known as oral hypoglycemic agents (OHAs).
There are three categories of OHAs, those that increase sensitivity
to insulin, those whose action resembles that of insulin, and those
that provoke your pancreas to produce more insulin. The first group
is known as insulin sensitizers (or ISAs, for insulin-sensitizing agents);
the second are the insulin mimetics (or IMAs, for insulin-mimetic agents),
which act like insulin but do not build fat. Finally, there are the
original OHAs, like sulfonylureas.
I only recommend the insulin sensitizers and insulin mimetics, for
reasons that will become plain in short order. (Some drug companies
have combined the old OHAs with insulin sensitizers, a move I strongly
challenge. Tell your doctor you do not want any product containing an
agent that works by causing the pancreas to make more insulin. This
includes the old sulfonylureas and the new, similar drugs called meglitinides.*)
For people who still have sufficient insulin-producing capacity, insulin
sensitizers alone may provide the extra help they need to reach their
blood sugar target. Some insulin-resistant individuals who produce little
or no insulin on their own may find a combination of insulin sensitizers
and insulin mimetics useful in reducing their doses of injected insulin.
*In addition to causing beta cell burnout, sulfonylureas also impair
circulation in the heart and elsewhere by closing ATP-sensitive potassium
channels that relax blood vessels.
There are three ISAs currently on the market, and at this writing I
prescribe all three of them—metformin (Glucophage), rosiglitazone (Avandia),
and pioglitazone (Actos). Another, troglitazone (Rezulin), was taken
off the market by its manufacturer in March 2000 because of the potential
for causing liver damage. Rosiglitazone and pioglitazone have similar
effects upon blood sugar but do not, apparently, have significant adverse
effects upon the liver.
A note: Since brand names vary from country to country, I will use
only the generic names in my discussion of these drugs.
Most of the OHAs on the market are not insulin-sensitizing or -mimetic.
Instead, they provoke the pancreas to produce more insulin. For several
reasons, this is considerably less desirable than taking a medication
that sensitizes you to insulin. First, the pancreas-provoking OHAs can
cause dangerously low blood sugar levels (hypoglycemia) if used improperly
or if meals are skipped or delayed. Furthermore, forcing an already
overworked pancreas to produce yet more insulin
can lead to the burnout of remaining beta cells. These products also
facilitate beta cell destruction by increasing levels of a toxic substance
called amyloid. Finally, it has been repeatedly shown in experiments—
and I have seen it in my own patients—that controlling diabetes through
blood sugar normalization can help restore weakened or damaged beta
cells. It makes absolutely no sense to prescribe or recommend agents
that will cause them renewed damage. In a nutshell, pancreas-provoking
drugs are counterproductive and no longer have any place in the sensible
treatment of diabetes.
As it’s far more productive to talk about good medicine, I will leave
OHAs in the past, where they belong, and from here on out discuss only
insulin sensitizers and insulin mimetics. Then, at the end of the chapter,
I will look at a brand-new treatment tool, a synthetic amylin analog,
that shows possible promise as a means to help stabilize postmeal blood
sugars in type 2 diabetes.
INSULIN-SENSITIZING AGENTS
The great advantage of insulin sensitizers is that they help to reduce
blood sugar by making the body’s tissues more sensitive to insulin,
whether it’s the body’s own or injected. This is a benefit that can’t
be underestimated. Not only is it a boon to those trying to get their
blood sugars under control, but it’s also quite useful to those who
are obese and simultaneously trying to get their weight down. By helping
to reduce the amount of insulin in the bloodstream at any given time,
these drugs can help alleviate the powerful fat-building properties
of insulin.
I have patients who are not diabetic but have come to me for treatment
of their obesity. Insulin sensitizers have been a real plus to the weight-loss
efforts of some because of their ability to curtail insulin resistance.
Their major shortcoming is that they’re rather slow to act—for example,
they will not prevent a blood sugar rise from a meal if taken an hour
before eating, as some of the beta cell–pushing medications will. As
you will learn, however, this can be circumvented.
Some obese diabetic patients come to me who are injecting very large
doses of insulin because their obesity makes them highly insulinresistant.
These high doses of insulin facilitate fat storage, and weight loss
becomes more difficult. Insulin sensitizers make these patients more
sensitive to the insulin they’re injecting. In one case I had a patient
taking 27 units of insulin at bedtime, even though he was on our low-carbohydrate
diet. After he started on metformin, he was able to cut the dose to
about 20 units. This is still a very high dose, but the metformin facilitated
the reduction.
Insulin sensitizers have also been shown to improve a number of measurable
cardiac risk factors, including blood clotting tendency, lipid profile,
lipoprotein(a), serum fibrinogen, blood pressure, C-reactive protein,
and even abnormal thickening of the heart muscle. In addition, metformin
has been found to inhibit the destructive binding of glucose to proteins
throughout the body—independent of its effect upon blood sugar. It has
been shown to reduce absorption of dietary
glucose, and also improves circulation, reduces oxidative stress, reduces
blood vessel leakage—in the eyes and kidneys—and reduces the growth
of fragile new blood vessels in the eyes. Thiazolidinediones such as
rosiglitazone and pioglitazone can slow the progression of diabetic
kidney disease, independent of their effects on blood sugars.
These medications can also down-regulate the genes that cause fat storage.
INSULIN-MIMETIC AGENTS
In addition to the insulin sensitizers, there are some substances sold
in the United States as dietary supplements that are effective for helping
to control blood sugars. Many studies in Germany have demonstrated this
effect from alpha lipoic acid, or ALA. A 2001 study showed it to work
in muscle and fat cells by mobilizing and activating glucose transporters—in
other words, it works like insulin, or is an insulin mimetic. German
studies have also shown that its effectiveness in mimicking the effects
of insulin is greatly enhanced when used with equivalent amounts of
evening primrose oil, another dietary supplement. ALA and evening primrose
oil are no substitute, however, for injected insulin—they are at best
a fraction as potent. Still, their combined effectiveness is significant.
Additionally, ALA is perhaps the most potent antioxidant on the market
and has certain cardiovascular benefits similar to those claimed for
vitamin E, but more notable. Many of the cardiologists who were taking
vitamin E ten years ago are now taking ALA. I’ve been taking it myself
for about four years. When I began, I promptly found that I had to lower
my insulin doses by about one-third. ALA and evening primrose oil do
not appear to mimic one important property
of insulin—they don’t appear to facilitate fat storage. They are both
available without prescription from health food stores and from some
pharmacies. They have the potential to cause hypoglycemia in diabetics
who inject insulin if they don’t adjust their insulin dosages accordingly.
I have never seen them cause hypoglycemia, however, when they are not
used with injected insulin.
Other German studies have shown dramatic improvements in diabetic neuropathy
(nerve damage) when alpha lipoic acid is administered intravenously
in large doses over several weeks. Given its antioxidant and likely
anti-inflammatory properties, this isn’t that surprising. But it falls
under the category of “Don’t Try This at Home.” Alpha lipoic acid, like
high-dose vitamin E and metformin, can impede glycosylation and glycation
of proteins, both of which cause many diabetic complications when blood
sugars are elevated. I prefer a brand of alpha lipoic acid called Alpha
Lipoic Sustain 300. This is manufactured by Jarrow Formulas, phone (800)
726-0886, and is available from Trotta’s Pharmacy, (877) 987-6882, many
health food stores, and over the Internet. This particular brand has
two advantages— it is soluble in both water and lipids (fats), and it
is timed release, so that it lasts many hours. I usually recommend two
300 mg tablets every 8 hours or so, with two 500 mg capsules of evening
primrose oil at the same times. If an insulin-resistant patient is already
taking insulin, I will start her on half this dose once daily and observe
blood glucose profiles and lower insulin dose as I raise alpha lipoic
acid and evening primrose oil. Again, it’s all trial and error.
WHO IS A LIKELY CANDIDATE FOR INSULIN-SENSITIZING OR INSULINMIMETIC
AGENTS?
Generally speaking, these agents are natural choices for a type 2 diabetic
who despite a low-carbohydrate diet cannot get his weight down or his
blood sugars into normal ranges. The blood sugar elevation may be limited
to a particular time of the day, it may be during the night, or it may
entail a slight elevation all day. We base our prescription on the individual’s
blood sugar profiles. If even on our diet, blood sugar exceeds 300 mg/dl
at any time of the day, I’ll immediately prescribe insulin and won’t
even attempt to use these agents, except to eventually reduce doses
of injected insulin. If your blood sugar is higher upon arising than
at bedtime, we’d give you the sustained-release version of metformin
at bedtime. If your blood sugar goes up after a particular meal, we’d
give you an insulin sensitizer about 2 hours before that meal. Since
food enhances the absorption of the thiazolidinediones, we might give
them with the meal. If blood sugars are slightly elevated all day long,
we might use alpha lipoic acid and evening primrose oil on arising,
postlunch, and postdinner.
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