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
Since ALA and evening primrose oil work as insulin mimetics, it is certainly appropriate to add these to any combination of the other agents.
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.