Avoiding or reducing obesity is crucial for preventing insulin resistance and diabetes

You fat rat!" Can you imagine James Cagney snarling that line instead of following the script? It might not have been quite so memorable. But there are fat rats in addition to dirty ones. Being rats, of course, they don’t get much respect. That’s a shame, because rats—lab rats—have contributed enormously to human health and well-being. In innumerable laboratories throughout the world, millions of rats have been the subjects of thousands of experiments by scientists seeking knowledge that might benefit the rats’ natural enemy: mankind.

Take Korea, for example. A research team there, in collaboration with colleagues in France and the United States, recently published a study conducted in part on a strain of genetically obese lab rats called OLETF (Otsuka Long-Evans Tokushima Fatty).1 The name may not roll trippingly off the tongue, but these fat rats are useful in investigations of obesity because they’re so much like us humans in most respects (insert your own joke here). What occurs in their fat little bodies is likely to occur in our big ones as well, although there is never a guarantee that this assumption is valid—only human clinical trials can tell the real story.

Lipoic Acid Protects Against Diabetes

With that proviso in mind, let’s see what the Korean team found. The focus of their study was lipoic acid (also called alpha-lipoic acid or thioctic acid), a remarkable compound that has been featured in a number of recent articles in this magazine.* Lipoic acid (which is a short-chain saturated fatty acid containing two sulfur atoms) is called “the antioxidant’s antioxidant” because of its exceptional potency and versatility in that regard. Indeed, it is lipoic acid’s antioxidant action that is thought to be largely responsible for its many health benefits (see the sidebar “The Other Benefits of Lipoic Acid”).


The Other Benefits of Lipoic Acid

  1. Elevation of glutathione levels through chemical interactions in the body’s antioxidant network, of which lipoic acid is the linchpin. This may be lipoic acid’s most valuable role, because glutathione is the body’s most important antioxidant molecule. (Because digestive enzymes destroy glutathione, it cannot be taken as a supplement.)
  2. Prevention and treatment of type 2 (adult-onset) diabetes, for which it has been widely prescribed in Europe for over two decades. It improves glucose metabolism and increases insulin sensitivity in diabetic patients—it seems, in fact, to mimic the actions of insulin. It has been found to be particularly helpful in treating the peripheral neuropathies (functional disorders due to nerve damage in the extremities) commonly associated with diabetes.
  3. Alleviation of burning mouth syndrome, a bizarre but not rare affliction that is believed to be a kind of peripheral neuropathy possibly related to diabetes.
  4. Protection from some of the major diseases of aging—notably cardiovascular disease, cerebrovascular disease, and cataracts—through its inhibition of lipid peroxidation.
  5. Protection against age-related memory loss—a function it performs particularly well because of the ease with which it can cross the blood-brain barrier and gain access to the brain’s cells.
  6. Mitigation of damage caused by AGEs (advanced glycation end products), harmful molecular complexes that are thought to be an important factor in the aging process.
  7. Participation, as a vital coenzyme, in the Krebs cycle, the complex series of chemical reactions responsible for generating energy through cellular respiration in the mitochondria, the cells’ tiny “powerhouses.”
  8. Regulation of the activity of nuclear factor kappa-B, a disease-fighting protein that can turn harmful if it becomes overactive (through oxidative stress, e.g.).
  9. Improvements in certain dysfunctions of the senses of smell and taste.

Because of lipoic acid’s role in our bodies’ energy metabolism and its protective effect against type 2 diabetes, the Korean researchers investigated the possibility that it might help combat obesity (which is by far the most prevalent cause of that form of diabetes). For 14 weeks, they fed the OLETF rats commercial rat chow containing lipoic acid in the amount of 0.5% by weight. [The equivalent amount of lipoic acid for a human who consumed about 1/2 pound (dry weight) of food daily would be about 1 gram—not much more than the 600 mg commonly taken daily as a nutritional supplement.]

Lipoic Acid Cuts the Rat Fat

The results were encouraging: whereas the control rats (which received no lipoic acid) had a weight gain of about 47% during those 14 weeks, the treated rats gained only about 18%; put another way, the treated rats wound up being about 20% lighter than the controls (no, not 29% lighter—the math doesn’t work that way). The weight loss was mostly in visceral fat, as revealed by CT scans of the rats’ bellies. This was accompanied by moderate reductions in their blood sugar and free fatty acid levels and by major reductions in their levels of insulin and leptin. (Leptin is a hormonal neurotransmitter produced by fat cells; it acts on receptors in the brain to regulate body weight and fat deposition.)

Lipoic Acid Is Safe and Effective

Most of the Koreans’ results were obtained not with the fat rats but with a commonly used strain of normal rats called Sprague-Dawley. For 2 weeks, they were given rat chow containing lipoic acid in the amounts of 0% (controls), 0.25%, 0.5%, or 1% by weight. Although it wasn’t mentioned in the paper, these rats must have been young because, despite an unchanging daily food intake, the controls increased their weight by one-third during the 2-week period.

By contrast, the rats on lipoic acid ate less than the controls and lost weight correspondingly—relative to the controls. Actually, at the two lower doses, the rats gained some weight, but not as rapidly as the controls; at the highest dose, however, they lost some weight, winding up about 30% lighter than the controls. The overall effects were dose-dependent.

Through various experiments that we need not go into here, the researchers came to several conclusions regarding these results:

  • The weight losses were not the result of any toxicity or illness caused by lipoic acid (which is regarded as extremely safe, with no known side effects).
  • The weight losses were due not just to reduced energy intake (less food consumed), but also, in part, to increased energy expenditure (more fat burned).
  • Although the effects of lipoic acid on food intake and energy metabolism were similar to those reported for leptin, they were not mediated by leptin or by leptin-receptor signaling in the brain. In other words, leptin and its receptors are not necessary for weight loss caused by lipoic acid.



Got Vitamin D?

Let’s put the spotlight for a moment on one of the vitamins that doesn’t usually get much attention: vitamin D. You probably know that it’s found in milk, that it also comes from sunlight (via ultraviolet radiation-induced chemical reactions in the skin), and that it helps make strong bones and teeth—but that’s about it, right? Well, there’s more to vitamin D than that. Its primary role is to aid in our use of calcium and phosphorus, but it also protects against muscle weakness and may slow the progression of arthritis. When taken with calcium, especially in conjunction with regular exercise, it helps prevent osteoporosis. It is also believed to strengthen the immune system and possibly prevent some cancers.

It may be particularly important for obese people to take supplemental vitamin D, because excess body fat hoards this fat-soluble vitamin, making it less bioavailable for its healthful actions. Because obesity is the principal cause of type 2 diabetes, it’s no surprise that vitamin D deficiency is strongly associated with that disease.

Researchers at UCLA recently investigated the relation between vitamin D and insulin resistance, the precursor condition to diabetes.1 Using a mixed-race group of 126 healthy, glucose-tolerant individuals in their mid-twenties, they found, for starters, that vitamin D was a predictor of BMI (body mass index)—the lower the vitamin D level, the higher the BMI. Similar inverse correlations were found between vitamin D and total and LDL cholesterol levels, and between vitamin D and the risk for metabolic syndrome. (These results are interesting and suggestive, but bear in mind a cardinal rule of scientific evidence: correlation is not causation).

As to the central issue of the study, the researchers found that vitamin D was negatively correlated with insulin resistance; in other words, it was positively correlated (and to a highly significant degree) with insulin sensitivity. At the same time, they found that low levels of vitamin D impaired the function of pancreatic beta cells, the body’s source of insulin. This resulted in a reduced insulin response to glucose in the blood, leading to blood sugar levels that were higher than those in subjects with higher vitamin D levels. These findings are in agreement with evidence from other human studies showing that vitamin D is essential for normal insulin secretion and thus for blood sugar control.

Low levels of vitamin D are prevalent in our society. The elderly are at greater risk for this problem because of inadequate exposure to sunlight, inadequate intake of D-rich foods (mainly fatty fish, eggs, and D-fortified dairy products), and the use of drugs that interfere with the absorption or metabolism of vitamin D. A good source of this vitamin (along with an abundance of other healthful nutrients) is a multivitamin/multimineral/multiantioxidant formulation.

  1. Chiu KC, Chu A, Go VLW, Saad MF. Hypovitaminosis D is associated with insulin resistance and b cell dysfunction. Am J Clin Nutr 2004; 79:820-5.



The hypothalamus is the seat of appetite regulation as well as other involuntary bodily functions.
Lipoic Acid Fools the Hypothalamus

In related experiments with the Sprague-Dawley rats, the Korean researchers injected lipoic acid into their abdominal cavities or directly into their brains—specifically, the third intracerebral ventricle, a cavity located just above the hypothalamus. (Most humans would probably have a problem with this method of weight loss. But wait—think how much they’d lose just in contemplating having to undergo such a procedure. That’s it—scare the pounds off ’em!)

Anyhow, the weight-loss results were similar to those obtained with the fat rats. The researchers concluded that lipoic acid exerts its effect on food intake mainly by suppressing the action of an enzyme called AMPK (AMP-activated protein kinase) in the hypothalamus. Among the many vital functions of this small brain structure, which lies deep in the forebrain, just above the pituitary gland, is the regulation of certain involuntary physical and emotional functions, such as sleep, mood, temperature regulation, heart rate, sex drive, and appetite.

Studies have shown that some groups of hypothalamic neurons can detect changes in local or whole-body energy status (as revealed mainly by glucose levels) and can initiate appropriate physiological and behavioral responses—such as feeling hungry and eating more, or feeling full and eating less. According to the authors, the latter is apparently what happens in response to lipoic acid, as a result of its ability—like that of insulin—to stimulate glucose uptake and metabolism. This fools the hypothalamus into thinking that there’s more glucose in the blood than there really is, so AMPK levels drop, which sends the signal to stop eating.

Lipoic Acid Reduces Food Intake and Increases Energy Expenditure

It turned out, however, that lipoic acid’s weight-loss effect was not solely the result of reduced food intake. The other half of the weight-loss equation is energy expenditure, and there too, lipoic acid produced the desired result, namely, to increase it. Energy expenditure occurs primarily in skeletal muscles, where lipoic acid exerts beneficial metabolic effects through an insulin-dependent mechanism: it increases glucose uptake and fatty acid oxidation by activating (not suppressing) AMPK.

Thus lipoic acid has opposite effects on AMPK in the muscles and the hypothalamus—a curious situation, but not unique, because leptin does the same thing. This suggests that lipoic acid and leptin may share common biochemical signaling pathways for regulating AMPK levels, but other evidence indicates that this is probably not true. Furthermore, leptin is ineffective in treating human obesity, because most obese people are resistant to it (it can’t be taken as a supplement in any case). The authors concluded:

Thus, alpha-lipoic acid may be a promising antiobesity drug for treatment of leptin-resistant human obesity. … [it] has previously unknown antiobesity effects mediated by the suppression of hypothalamic AMPK activity.

Lighten Your Load with Lipoic Acid

Obesity is a major element of the metabolic syndrome and is associated with increased risks for insulin resistance and its awful consequence, type 2 diabetes, as well as for hypertension, heart disease, peripheral vascular disease, diseases of the gallbladder, osteoarthritis, sleep apnea, depression, hernia, gout, and various cancers (especially colon, rectum, and prostate in men, and breast, ovaries, endometrium, and cervix in women). Obese women often experience menstrual irregularities and ovulatory failure, and all obese people are at greater risk of complications when they undergo surgery.

With the exception of gallstone formation, weight loss will reduce all these health risks. And if lipoic acid—on top of all its other health benefits—might help with weight loss, isn’t it worth a try?


  1. Kim M-S, Park J-Y, Namkoong C, et al. Anti-obesity effects of a-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nature Med 2004 Jun 13;1-7 (advance online publication).