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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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