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 extra insulin in the bloodstream at any given time, these drugs can help aUeviate the powerful fat-buUding proper ties of insulin.
I have patients who arenot 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 abiUty to cur- taU insulin resistance.
Their major shortcoming is that they're rather slow to act , for example, they wiU not prevent a blood sugar rise from a meal if taken an hour before eating, as some of the beta ceU-pushing medications wiU.
As you wiU learn, however,this can be circumvented.
Some obese diabetic patients come to me who are injecting very large doses ofinsuUnbecausetheir obesity makes them highly insulin- resistant.
These high doses of insulin faciUtate fat storage, and weight loss becomes more difficult.
Insulin sensitizers make these patients more sensitive to the insulin they're injecting.
In a typical 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 faciUtated the reduction.
Insulin sensitizers have also been shown to improve a number of measurable cardiac risk factors, including blood clotting tendency, lipid profile,Upoprotein(a), serum fibrinogen,blood pressure,C-reac tive protein, and even abnormal thickening of the heart muscle.
In ad dition, metformin hasbeen 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, re duces blood vessel leakage , in the eyes and kidneys , and reduces the growth of fragUe new blood vessels in the eyes.
It has also been shown to improve satiety in women near menopause.
Thiazolidine- diones such asrosigUtazone and piogUtazone can slow the progression of diabetic kidney disease, independent of their effects on blood sug ars.
These medications can also down-regulatethe genesthat cause fat storage, and they have been found to delayor prevent the onset of di abetesin some high-risk individuals.
238 Treatment
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 effectfrom R-alphalipoicacid,or ALA.
A 2001 study showed it to work in muscle and fat ceUs 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 oU, another dietary supple ment.
ALA can reduce the body's natural levels of biotin, so it should be taken in a preparation that contains biotin (see footnote below).
ALA and evening primrose oU are no substitute, however, for injected insulin , they are at best a fraction as potent.
Still,their combined ef fectiveness is significant.
AdditionaUy, ALA is perhaps the most potent antioxidant on the market and has certain cardiovascular benefits simUar to those claimed for fish oU.
Many of the cardiologists who were taking vita min E for its antioxidant properties ten yearsago are now taking ALA.
I've been taking it myself for about eight years.
When I began, I promptly found that I had to lower my insuUn doses by about one- third.
R-ALA and evening primrose oU do not appear to mimic one important property of insulin, they don't appear to facUitate fat storage.
They are both avaUable without prescription from some health food stores and from some pharmacies.* They have the po tential to cause hypoglycemia in diabetics who inject insulin if they don't adjust their insulin dosages accordingly.
I havenever 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 Upoic acid is ad-
Although conventionalALA is widely available, R-ALA is more effective. As of this writing, the principal manufacturer in the United States is GlucoreU Inc.,of Orlando, Florida,phone (866) 467-8569, www.insulow.com. Their product In- sulowcontains 100mg R-ALA per capsule, plus 750meg (0.75mg) biotin. Insu- low is also available from RosedalePharmacy.
OralInsulin-Sensitizing Agents, Insulin-Mimetic Agents, and OtherOptions 239
ministered intravenously in large doses over several weeks.
Given its antioxidant and likely anti-inflammatory properties, this isn't that surprising.
But it faUs under the category of "Don't Try This at Home." AlphaUpoic acid,likehigh-dose vitaminE (the form caUed gamma tocopherol) and metformin, can impede glycosylation and glycation of proteins, both of which cause many diabetic compUcations when blood sugars are elevated.
I usuaUy recommend two 100 mg tablets every 8 hours or so, with one 500 mg capsule of evening primrose oU at the same time.
If an insulin-resistant patient is already taking insulin, I wUl start her on half this dose once daUy and observe blood glucose profiles and lower insulin dose as I raise alpha Upoic acid and evening primrose oU.
Again, it's aU trial and error.
WHO IS A LIKELY CANDIDATE FOR INSULIN-SENSITIZING OR INSULIN- MIMETIC AGENTS?
GeneraUy 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 ele vation may be limited to a particular time of the day, it may be dur ing the night, or it may entaU a sUght elevation aU 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 im mediately prescribe insulin and won't even attempt to use these agents, except to eventuaUy 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 a relatively rapid acting insulin sensitizer (rosigUtazone) about 2 hours before that meal.
Since food enhances the absorption of the thiazoUdinediones, we might give it with the meal.
If blood sugars are sUghtiy elevated aU daylong,we might use alphaUpoic acidand evening primrose oU on arising, postiunch, and postdinner.
It should be noted, however, that the ISAs are considerably more effective than IMAs at loweringblood sugars.
240 Treatment
GETTING STARTED: SOME TYPICAL PROTOCOLS
Let'ssayyou're a type 2 diabetic and through weight loss,exercise, and diet, you pretty much have your blood sugars within your target range.
StiU, your blood sugar profiles show a regular elevation in the mornings after a low-carbohydrate breakfast, probably due to the dawn phenomenon.
Of the medications I've described here, the most rapid to start act ing is rosigUtazone, which, although it reaches peak levels in the bloodstream in about an hour, probably achieves its fuU effect after about 2 hours.
Soyou might take a starting dose of 4 mg upon arising and then eat breakfast 1-2 hours later.
If this is only partly effective, the dose can be increased to two 4 mg tablets or one 8 mg tablet (the maximum recommended daUy dose).
If this is somewhat effective, but 2 hours after breakfast your blood sugars are still above target, you might add an extended-release dose of metformin before you go to bed.
This type of metformin achieves its peak blood levels after about 7 hours.
A starting point would be one 500 mg tablet at bedtime.
If this stiU doesn't get your blood sugars into target range, then you could increase the dose graduaUy, perhaps by one more tablet at bed time for a week and so on, until you reach a maximum of 4 tablets a night or you hit your target.
I always recommend the least possible dosage, partly due to the Laws of SmaU Numbers, but also because of the reduction of likelihood for potential side effects.
With met formin, if you buUdup your dosageslowly, it lessensthe possibUity of gastrointestinal discomfort that about one-third of users of the older, more-rapid-acting version experience.
In some cases, blood sugar levels either increase overnight or in crease during the first 2 hours after you arise.
The latter situation is most likely due to the dawn phenomenon.
Either situation may re spond to timed-release versions of metformin (Glucophage XRin the United States) with or without ALA plus evening primrose oU, aU taken at bedtime, using the doses described above.
If need be, piogU tazone may also be added at bedtime.
Tablets of piogUtazone are sold in 15 mg and 45 mg doses.The maximum daUy dose is 45 mg.
Another possibUity that wouldwarrant oral medication would be if your blood sugar levels increasedafter lunch or dinner.
We could pos sibly cover the problem meal with rosigUtazone by taking it 1-2 hours before eating.
OralInsulin-SensitizingAgents, Insulin-Mimetic Agents, andOtherOptions 241
TABLE 15-1 RECOMMENDED ORAL AGENTS FOR BLOOD SUGAR CONTROL
Maximum U.S. brand Available (effective) Agent Type name dosages dally dosage
Metformin InsuUn Glucophage 500,850, 2,500mgf sensitizer and generic 1,000 mg* Metformin InsuUn Glucophage XR 500 mg 2,000mg1 extended sensitizer and generic release
RosigUtazone Insulin Avandia 4,8mg 8mg sensitizer
PiogUtazone InsuUn Actos 15,30,45 mg 45 mg sensitizer
R-alpha Upoic InsuUn Insulow 100 mg 1,800 mg acid (ALA) mimetic with biotin
Evening InsuUn Many 500 mg 3,000 mg primrose oil mimetic recommended (EPO) booster for every 300 mg of ALA
Also availableas a Uquid. f Forreasons not apparent to me,the manufacturer's recommendation for maxi mum daily dosing is lessfor extended-release metformin than for the standard ver sion.
WILL THESE MEDICATIONS CAUSE HYPOGLYCEMIA?
Sulfonylurea and the newer gUtazar OHAs carry the very real possi bUity of causing dangerously low blood sugars, which is one of the reasons I never prescribe them. However, this is only remotely likely with the insulin-sensitizing and insulin-mimetic agents Usted above. Noneof them interferes with the self-regulating system of a pancreas that can stiU make its own insulin. If your blood sugar drops too low,
242 Treatment