By David N. Leff

Resistance is a dirty 10-letter word by which bacteria get smart and turn the tables on antibiotics. Insulin resistance, in which pancreatic islet cells get stupid, is equally alarming.

In diabetes mellitus Type II, the body¿s insulin falls down on its job of controlling glucose metabolism, which in turn manages the body¿s energy balance. In a vain attempt to counter this insulin loss, the body overexpresses more and more insulin, which encounters more resistance. That excess insulin can¿t harness the blood sugar¿s gig of turning food into energy. Over time, Type II diabetics incur life-threatening complications of heart, kidney, eyesight and blood vessels. Blindness and limb amputations are among the outcomes.

Some 15 million to 16 million people in the U.S. acquire Type II diabetes as a consequence of their inheritance pattern and lifestyle. A diagnosis of frank Type II diabetes usually follows years or decades of a predisposition to the disease, marked by low-lying but increasing insulin resistance.

¿There is a genetic background that is necessary for that,¿ observed molecular diabetologist Steven Shoelson, at the Joslin Diabetes Center in Boston. ¿One can manipulate that predisposition environmentally,¿ he pointed out. ¿Increased body weight ¿ obesity ¿ a high-fat diet and sedentary life style all promote insulin resistance; exercise and diet can reverse it.

¿Insulin resistance in a predisposed person may cause Type II diabetes,¿ Shoelson continued. ¿That means the individual is probably predisposed genetically so the pancreatic beta cells have a limited capacity to produce enough insulin to overcome a particular level of resistance. Some people get resistant, and produce enough insulin to overcome it, while others don¿t ¿ and become diabetic.¿

The onset point at which predisposition becomes disposition, Shoelson pointed out, ¿depends on the individual. Some people become diabetic ¿ don¿t have enough reserve in their beta cells even if they¿re not insulin resistant. Others can produce enough insulin to overcome very severe resistance. So each individual has their own set-point.¿

Shoelson is senior author of a paper in today¿s Science, dated Aug. 31, 2001. It¿s titled: ¿Reversal of obesity- and diet-induced insulin resistance with salicylates [as in aspirin] or targeted disruption of Ikkb.¿

Anti-Diabetes High-Dose Aspirin Revival

¿We have identified a distinct inflammatory pathway that impinges on insulin signaling,¿ Shoelson told BioWorld Today, ¿and by inhibiting this pathway we have reversed insulin resistance in rodent models. We know that this is relevant to the human condition,¿ he added, ¿because in times gone by high doses of salicylates have had similar effects in patients with diabetes. High-dose salicylates we use today would inhibit the pathway, particularly the proteins in an inflammatory pathway called IKK-beta.

¿The regular dose of aspirin,¿ Shoelson continued, ¿two 650-milligram pills, has the effect of calming inflammation, lowering fever, reducing pain. The old-time anti-diabetes effects required 5 to 8 grams of aspirin a day ¿ a lot more. This is the dose that¿s been used for many years to treat rheumatic fever and rheumatoid arthritis. Recent evidence reveals that the target of aspirin in both these diseases is a protein called IKK-beta. That¿s been a great clue for us, because we connected IKK-beta with its effect on glucose, and the dosage that seemed similar. It helped us figure out that probably IKK-beta was involved in inhibiting the glucose-lowering effect as well.

¿IKK-beta,¿ Shoelson explained, ¿is an enzyme that¿s activated by several mechanisms. One is through pro-inflammatory cytokines, such as tumor necrosis factor. But IKK-beta is also activated by hyperglycemia ¿ a hallmark of diabetes, and a cause of insulin resistance.¿

Shoelson and his co-authors have tested the therapeutic effects of inhibiting IKK-beta in two in vivo experiments: ¿We did the first set of tests,¿ he recounted, ¿in genetically obese insulin-resistant animals ¿ fatty rats and ob/ob mice. We infused both of them with high doses of aspirin and sodium salicylate for three to four weeks at doses of 120 milligrams per kilogram per day. That roughly equaled 5 to 10 grams of aspirin per day in humans.

¿Before, during and after the treatment, we conducted glucose-tolerance and insulin-tolerance tests to assess the level of insulin resistance in these animals. We also followed other blood chemicals, including free fatty acids, triglycerides and liver functions. In both sets of animals, insulin levels and glucose levels came down, while overall insulin sensitivity ¿ the reverse of resistance ¿ increased dramatically. Free fatty acids in the animals¿ bloodstreams dropped to 20 percent of their original high levels.

¿In the second set of experiments,¿ Shoelson went on, ¿we treated genetically altered rodents that, if we could reduce their levels of IKK-beta, would sensitize them to insulin. When we removed both parental gene alleles, both copies of IKK-beta proved lethal during embryonic development. So we were unable to study those. But the heterozygotes ¿ those with one normal gene ¿ looked to be normal, so we could study them. That gave about a 50 percent reduction in levels of the IKK-beta protein, because we were reducing the gene dose by 50 percent exactly.

¿Those animals were protected against developing insulin resistance. They had slightly lower blood glucose and insulin levels. When we crossed them onto the ob/ob mouse with their heterozygotes for IKK-beta to make them very insulin resistant, it protected them. Also when we fed those animals a high-fat diet, which usually promotes an insulin-resistant state, they were again protected.¿

Drug Therapy Is Goal

Shoelson has launched two Phase I clinical trials, testing high-dose aspirin and an inhibitor of IKK-beta.

¿One site is at Joslin and one at Yale,¿ he noted. ¿We¿re recruiting in each bunch of participants three different groups ¿ Type II diabetic patients, two obese individuals that aren¿t Type II, and normal people. We¿re looking for 10 or so subjects in each cohort. At Yale the trial is moving along quite well; at Joslin it¿s just beginning.

¿We think we have a molecular target for drug therapy,¿ Shoelson volunteered. ¿Aspirin has multiple targets, and therefore multiple side effects ¿ from dizziness, tinnitus, nausea and vomiting to gastrointestinal bleeding. We¿d like to have a selective drug that inhibits only IKK-beta, and therefore would be without many of the side effects. So that¿s the direction we¿re working toward.¿

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