15
Oral Insulin-Sensitizing Agents, Insulin-Mimetic Agents, and Amylin
Analog
*A deficit of vitamin B-12 can increase serum levels of the cardiac
risk factor homocysteine. It would therefore be wise for your physician
to check your serum homocysteine every six months while you are using
metformin. †Even though reports of liver toxicity are far fewer than
with some commonly used medications such as niacin and the so-called
statins, it’s a good idea for users of these insulin sensitizers to
have their blood tested for liver enzymes every three to six months.
I usually start people on rosiglitazone to avoid potential competition
for clearance by the liver with other drugs another physician might
prescribe in the future.
USING MULTIPLE AGENTS
Metformin works principally by lowering insulin in the liver. Thiazolidinediones
principally affect muscle and fat, and to a lesser degree the liver.
Thus, if metformin does not fully normalize blood sugars, it makes sense
to add one of the thiazolidinediones—and vice versa. Since rosiglitazone
and pioglitazone work by the same mechanisms, it makes little sense
to use both in the same individual. The FDA suggests that doses of pioglitazone
not exceed 30 mg daily when taken with
metformin.
Since ALA and evening primrose oil work as insulin mimetics, it is
certainly appropriate to add these to any combination of the other agents.
OTHER CONSIDERATIONS
The thiazolidinediones do not have their full blood sugar–lowering
effects on the day they are started. Pioglitazone achieves its full
potency after a few weeks, and rosiglitazone may require up to twelve
weeks. When blood sugars are much higher than the targets that I set,
both metformin and the thiazolidinediones can cause the pancreas to
increase its insulin production in response to glucose. Because of the
lower blood sugars that we see, this effect becomes insignificant.
Vitamin A supplementation has been shown to lower insulin resistance
(as does vitamin E) in doses of about 25,000 IU daily. Since slightly
higher doses of vitamin A are potentially toxic, and doses as low as
5,000 IU can cause calcium loss from bone, I would only consider its
nontoxic precursor, beta carotene, for this purpose.
Studies have shown that magnesium deficiency can cause insulin resistance.
It would therefore be a sensible idea for physicians to test type 2
diabetics for red blood cell magnesium (not serum magnesium) levels.
If the level is low, magnesium supplementation should help. I recommend
a product called slow-mag in small doses that can be increased if the
test remains low after one month. Excessive doses can cause diarrhea.
Similarly, zinc deficiency can cause diminished production of leptin,
a hormone that impedes overeating and weight gain. Such deficiency can
also impair functioning of the thyroid gland. It is thus wise for all
type 2 patients to ask their physicians to test their serum zinc levels
and to prescribe zinc supplementation if warranted.
Compounds of the heavy metal vanadium have been shown to lower insulin
resistance, reduce appetite, and possibly also act as insulinmimetic
agents. They are quite potent in lowering blood sugars, but there’s
a catch. Vanadium compounds work by inhibiting the enzyme tyrosine phosphatase,
which is essential to many vital biochemical processes in the body.
The possibility is quite real that this inhibition can be damaging.
Since clinical trials in humans have not exceeded three weeks in duration,
long-term freedom from adverse effects has yet to be documented. Some
users of vanadium compounds have experienced gastrointestinal irritation.
Although vanadyl sulfate is widely available in health food stores as
a dietary supplement and has been used for years without any reports
of adverse effects in medical journals, I tentatively recommend that
it be avoided until more is known.
SYMLIN: SYNTHETIC HUMAN HORMONE AMYLIN
A new tool for the treatment of diabetes should be available around
the time this book is published, or shortly thereafter. Symlin (pramlintide
acetate), the brand name for Amylin Pharmaceuticals’ synthetic version
of the human hormone amylin, has not yet come to market and I have not
used it, but the literature is quite intriguing, particularly as it
applies to the treatment of type 2 diabetes. You may not have heard
of amylin before, but it plays an important role in the stabilization
of postprandial blood sugars in nondiabetics. Natural amylin is not
water soluble and therefore has not been useful as a medication for
diabetes. This new synthetic amylin analog is water soluble.
One unit (1/100 cc) of the injectable insulin that I use is such a
small volume that many older folks, like me, or others with impaired
vision, cannot measure it without visual aids, such as my bifocals.
Yet this minute amount will lower my blood sugar by 40 mg/dl. Since
the insulin in my vial has been diluted 25 times, 1 unit of the real
stuff, as produced by the pancreas, would lower me 25 x 40 mg/dl, or
1,000 mg/dl. In other words, insulin is powerful stuff.
Blood sugar cannot be controlled by such a powerful substance alone,
so the body makes several less powerful hormones to fine-tune the net
effect. One of these hormones is glucagon, which is much less potent
than insulin but is secreted in larger amounts to prevent blood sugar
from dropping too low in response to secreted insulin. In the nondiabetic,
these hormones—insulin and its helpers—go about this balancing act unseen.
Another of these fine-tuning hormones is amylin. This hormone is produced
in the same beta cells of the pancreas that produce insulin, but it
seems to be more of a regulatory adjunct to glucagon than to insulin.
That is to say that it seems to fine-tune the fine-tuner glucagon.
When food empties from the stomach and enters the intestines, in nondiabetics
the slight distention of the intestines causes them to produce hormones
that stimulate the pancreas to release other hormones.
In effect, they signal the pancreas, “Hey! There’s food on the way,
get some insulin out here before blood sugar goes up!” The beta cells
of the pancreas then release insulin, as well as replenish what’s being
released to keep up with demand. Since insulin is so powerful, the alpha
cells make glucagon to offset insulin and fine-tune blood sugar more
precisely. The same beta cells that make insulin also produce amylin
to reduce the liver’s response to glucagon, thereby achieving even more
precise control.
Amylin also slows the rate at which the stomach empties, causing a
sustained sense of fullness, or satiety, and in turn inhibiting overeating
that might overwhelm the ability of insulin to control blood sugar.
By inhibiting both the Chinese restaurant effect and overeating, amylin
has particular usefulness in the treatment of type 2 diabetes. Because
it indirectly diminishes the need for insulin, it provides the individual
with the opportunity to rest exhausted beta cells and to lose
weight (insulin, you’ll recall, is the main fat-building hormone).
Symlin amylin analog can only be taken by injection. It should be administered
15 minutes before meals. It is provided in a slightly acid preparation
that may cause a burning sensation upon injection. The dosing used for
type 2 diabetics in recent clinical trials required a large injection
(by my standards—1/5 cc, or 20 units on an insulin syringe). This is
three times the volume of the largest single insulin injection my insulin-requiring
patients administer and brings the possibility of discomfort at injection
sites.
I foresee the action of amylin as most beneficial for type 2 diabetics.
It’s been my experience that most type 1s who’ve had the disease for
more than five years or so have some degree of gastroparesis, or delayed
stomach-emptying. I anticipate a reasonable likelihood that type
1 diabetics with gastroparesis would experience more difficulty with
blood sugar control, rather than less, if they were to use this product.
If you are taking insulin and your physician wants you to try Symlin,
he should start the medication at a very low dose and slowly increase
dosing while lowering premeal insulin doses if your blood sugars indicate
that it’s necessary. The slow tapering up of the Symlin dose should
reduce the likelihood of its most common side effect— nausea—and also
the likelihood of hypoglycemia as less injected insulin becomes necessary.
Get Adobe Acrobat Now