By David N. Leff
Does obesity bring on diabetes, or does diabetes cause obesity?
Here's how molecular endocrinologist Mitchell Lazar, director of the University of Pennsylvania's Diabetes Center in Philadelphia, answers this chicken-and-egg-puzzle:
"It's almost certain that obesity brings on diabetes," he told BioWorld Today. "Because, for example, Type I diabetic patients, who have no insulin, get thin, unless they receive treatment for their disease. What happens is that insulin improves diabetes by pushing glucose into the cells of the body - including fat cells.
"But if you get insulin to treat your diabetes," Lazar said, "unless that replacement insulin could be perfectly returned to the patient - which is very difficult with injections - when it pushes glucose into those adipocytes, those cells convert the glucose into lipid. That is, into more fat. So insulin treatment of diabetes leads to weight gain, and weight gain of course can exacerbate diabetes. It becomes a vicious cycle."
Lazar is senior author of a paper in the current issue of Nature, dated Jan. 18, 2001. It is titled: "The hormone resistin links obesity to diabetes."
"We found a previously unrecognized, unknown, fat-cell hormone," he noted, "that we've called resistin, because it promotes resistance to insulin in Type II diabetics. Insulin resistance is the hallmark of Type II diabetes, which is the most prevalent form of the disease. It means that the same dose of insulin doesn't work as well in lowering blood sugar in Type II diabetics as it does in the normal person. And that's called insulin resistance. Type II has nothing to do with Type I, which is only about 5 percent of diabetes.
"The mechanism of insulin resistance is unknown," Lazar said, "But we believe that our resistin hormone is part of the mechanism, that it's somehow antagonizing the effects of insulin, and contributing to this overall reduction of insulin action that is seen in Type II diabetics. How it does that is very important to know, and we're working on it."
Lazar and his co-authors discovered the resistin hormone, he said, "by looking for molecules that were down-regulated by certain new antidiabetic drugs, now on the market, called TZDs - or thiazolidinediones. We looked for genes that were turned off in fat cells by these antidiabetic TZD drugs. We think they work through a nuclear receptor called PPAR-gamma, (peroxisome proliferator activated receptor), which my group and others have been studying for some time."
The Devil Is In The Receptor
"That receptor is best understood," he explained, "for its role in making adipocytes. Mice lacking PPAR-gamma can't make fat. Cells in culture that are forced to make PPAR-gamma, when you give them PPAR-gamma plus one of these TZD drugs, they turn into fat cells - adipocytes. These are cells that look like fibroblast skin cells, but if they are made to express PPAR-gamma, and given one of these TZD drugs, they turn into fat cells."
Once Lazar's group found resistin as a gene on human chromosome 19, he said, "we noted that its nucleotide sequence predicted it to express a secreted protein - that is, a signal sequence - 114 amino acids long in mice. We determined that indeed this resistin protein was secreted by adipocytes, and that in mice it was present in their circulation. What's more, their blood levels were increased in obesity - consistent with the notion that it might be attributed to insulin resistance." He added, "We haven't completely mapped the mouse gene, and I'm hoping that human geneticists and molecular epidemiologists will look at the human chromosome".
In in vivo experiments, Lazar noted, "we tested mice with genetic forms of obesity and diabetes, or mice that were fed a high-fat diet leading to acquired obesity and diabetes. In both those scenarios, resistin levels were elevated. The mice on high-fat food we injected with antibodies against recombinant resistin. Attempting to neutralize their endogenous resistin raised their blood sugar levels - consistent with the idea that their own resistin was contributing to their diabetes. Conversely, when we injected recombinant resistin into normal mice, we noticed impaired glucose tolerance - also supporting the notion that resistin is contributing to insulin resistance."
Looking to future research, Lazar observed, "At the mouse level we need to have models such as knockouts of the resistin gene to determine if its protein has any normal function. We need to develop better assays, both at the murine, and especially the human, levels, where right now our methodologies are not sufficient for studying human resistin serum levels. That's basically because we discovered the mouse hormone first, and studied it longer."
In both cases, he said, "we would like to identify the cellular receptor for the resistin protein. Then we could find small molecules that inhibit that receptor because if our theory is correct, blocking the insulin-resistance action should help diabetic patients." Lazar suggested, "I think we'd want to find an antagonist to the resistin receptor, and our hope would be that such an antagonist drug might improve diabetes Type II therapy." He commented, "We've got a long way to go. We need to find the receptor, and the molecules that block it - but with modern technology that's available. I would optimistically say that within five years it should be do-able."
X Marks The Fat
What about resistin's possible benefit for nondiabetic obese people?
"They frequently have insulin resistance that is compensated by extra secretion of insulin by their pancreas," Lazar said. "Those people with high serum insulin levels have what is called 'Syndrome X,' and that represents a huge percentage of Americans. You don't have to be obese, but it's one of the most common clinical findings.
"Syndrome X," he explained, "is a sort of pre-diabetic state in which the obese person is not technically diabetic, but does have insulin resistance. It's been a little controversial, but now it has become almost universally accepted that this hyperinsulinemia is a real syndrome, and that Syndrome X is associated with hypertension, hyperlipidemia and atherosclerosis - all critical risk factors for heart disease. So it's possible that improving insulin resistance, even in nondiabetic obese patients, would have a cardiovascular benefit." If so, Lazar noted, "that would affect many more Americans than the considerable number known to have diabetes."