Metformin (Glucophage( ®)) is an anti-diabetic biguanide drug which is now available in the United States for the treatment of both Type I diabetes (insulin dependent) as well as Type II (non-insulin-dependent) diabetes. In addition to its dramatic ability to improve the condition of diabetics, ~Metformin is also one of the most promising anti-aging, life extending drugs available. Many physicians (as well as their patients) are often surprised and pleased to find an unexpected “side effect” of Metformin therapy is a profound and often dramatic loss of body fat.

Metformin is chemically very similar to Phenformin, an anti-diabetic drug which was discontinued in the United States by the FDA in 1976. The reason for Phenformin’s removal from the market was because of a number of excess deaths in diabetic patients, caused by lactic acidosis. These deaths were invariably due to the continued use of phenformin by diabetics who had compromised kidney or liver function. No deaths were ever reported in patients who had normal kidney and liver function.

Phenformin’s removal from the market was greatly lamented by most diabetologists at the time, one of whom once told me, “Phenformin did everything! It lowered blood sugar, lowered insulin, reduced blood cholesterol and triglycerides, stimulated immunity, and even resulted in weight loss!” He blamed the excess deaths associated with phenformin’s use on the “stupid docs” who continued to use it in the face of abnormal liver or kidney function. Metformin is similar to phenformin in its beneficial metabolic effects, but it is much safer, in that it has even less propensity to cause lactic acidosis than phenformin.

Age-Related Loss of Insulin Sensitivity

One of the most universal changes with age is a progressive loss of glucose tolerance (Fig. 1). When this loss of glucose tolerance becomes pronounced, it is diagnosed as diabetes. The diagnostic criteria for older people are much less strict than the criteria for younger people. If the same criteria were used for older people as are used for younger people, nearly every senior citizen would be diagnosed as diabetic. The most likely cause of this loss of glucose tolerance with age is a progressive loss of insulin sensitivity – i.e., a loss of sensitivity to insulin by hypothalamic receptors, and a decreased response to glucose and insulin by the peripheral tissues (Fig. 2).

Metformin’s Mechanism of Action

Metformin’s mechanism of action is unlike other anti-diabetic drugs, like the sulfonylureas (e.g., Glyburide, Diabinase, Micronase, etc). The sulfonylureas act by increasing the output of insulin from the pancreas-kind of like putting the pancreas on the dining room table and going over it with a rolling pin, squeezing out whatever insulin remains in the already overworked pancreas. After a period of time, this often results in pancreatic failure, transforming a Type II (non-insulin dependent) diabetic into a Type I (insulin-dependent) diabetic.

Metformin, on the contrary, acts by increasing the sensitivity of the hypothalamus and peripheral tissues (like muscles) to the effects of insulin. In effect, it rejuvenates this response, restoring the effects of glucose and insulin to much younger physiological levels. Insulin-dependent diabetics are often able to dramatically reduce their doses of insulin, and more easily maintain stable levels of blood glucose.

Metformin acts in a much more physiologic manner than either the sulfonylureas, or even exogensously administered (i.e., injected) insulin itself. Consequently, Metformin does not cause hypoglycemia, which may often result from the use of insulin or the sulfonylureas. One potential side effect in long-term users of Metformin, is that it may cause malabsorption of vitamin B12 (Deutsch, et al, 1996). Consequently, I recommend that anyone taking Metformin also supplement their diet liberally with vitamin B12.

Insulin Resistance, Hyperinsulinemia, Obesity and Aging

Loss of sensitivity of the hypothalamus and peripheral tissues to the effects of insulin, results in hyperinsulinemia (elevated blood insulin levels). Hyperinsulinemia results in a number of adverse and age-accelerating effects. Among these effects of hyperinsulinemia are hypercholesterolemia, hypertension, premature atherosclerosis, and obesity. This constellation of symptoms has now been recognized as Syndrome X. Normalizing insulin sensitivity by a low carbohydrate diet, exercise, and Metformin, can dramatically alleviate many of the metabolic changes that accompany aging, including normalizing body weight.

Although I have not found any studies that specifically evaluated the fat-burning and weight-normalizing potential of Metformin, the clinical experience of my patients and reports from other physicians confirms that Metformin should be considered a key component of a weight loss program.

Life Extension Uses of Metformin

Diabetes is believed by many gerontologists to be an example of accelerated or premature aging. Since nearly everyone past middle age suffers from “subclinical” diabetes (i.e., a loss of glucose tolerance with age – [Fig. 2]), I recommend Metformin to all of my life extension patients who are over 40. I believe Metformin has a profound and truly “rejuvenating effect” on glucose and insulin metabolism. Among other benefits, this results in a reduced rate of pro-aging cross-linkages in collagen. In our book, Neuroendocrine Theory Of Aging and Degenerative Disease (Dilman and Dean, 1992), we list the following benefits of Phenformin, which I believe are shared by Metformin:

To this list of benefits, we should also add that it reduces body fat and enhances lean body mass.

Cautions and Contraindications:

Metformin should be used with caution and under the supervision of their physicians by patients with compromised liver or kidney function, or congestive heart failure. Otherwise, it is an extremely safe substance.

Summary:

In view of its record of safety and paucity of adverse side effects, its physiological mode of action, and its broad range of beneficial effects, I strongly encourage all of my patients over the age of 40 to take 500 mg of Metformin two or three times per day. In addition, I also incorporate it as the keystone of a weight loss program-either alone, or in conjunction with other dietary and lifestyle approaches to weight loss.

References:

1. Dean, Ward. Biological Aging Measurement – Clinical Applications. The Center for Bio-Gerontology, Pensacola, Florida, 1988.
2. Deutsch, J.C., Santhosh-Kumar, C.R., Kolhouse, J.F. Efficacy of Metformin in non-insulin-dependent diabetes mellitus. NEJM, 1996, 334, 4: 269. Dilman, Vladimir, and Dean, Ward.
3. Dilman, Vladimir, and Dean, Ward. Neuroendocrine Theory Of Aging, The Center for Bio-Gerontology, Pensacola, Florida, 1992.